EA041548B1 - METHOD FOR TREATMENT OF LOCAL LATE STAGE SOLID TUMORS OR METASTATIC SOLID TUMORS - Google Patents

Description

This application claims advantage and priority over U.S. Provisional Applications 62/448869, filed January 20, 2017, and 62/458447, filed February 13, 2017, the disclosures of both of which are incorporated herein by reference in their entirety.

Technical field

This invention relates to the combination of cabozantinib and atezolizumab for the treatment of local advanced solid tumors or metastatic solid tumors.

State of the art

Multitargeted tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICTIs) are two systemic therapies that have played an important role in recent advances in cancer treatment over the past few years. Both classes of therapies have demonstrated broad clinical effects, leading to new approved treatment options for a variety of tumor types, including renal cell carcinoma (RCC), urothelial carcinoma (UC), melanoma, non-small cell lung cancer (NSCLC), and others. The success of these types of therapies as standalone agents with different mechanisms of action has naturally led to interest in evaluating combinations of TKIs with ICTIOs in search of additional, possibly synergistic, anticancer clinical effects.

Atezolizumab (TECENTRIQ®) (Genentech Oncology, a subsidiary of Roche)

Atezolizumab is a humanized immunoglobulin (Ig) G1 monoclonal antibody that targets programmed death receptor 1 (PD-L1) ligand and inhibits the interaction between PD-L1 and its receptors, programmed death receptor 1 (PD-1) and B7-1 ( also known as CD80), both of which function as inhibitory receptors expressed on T lymphocytes. It is approved in the United States and the European Union for the treatment of patients with localized advanced or metastatic UC after prior platinum-containing chemotherapy, or those deemed unsuitable for cisplatin treatment (Rosenberg et al. 2016, Loriot et al. 2016). Atezolizumab is also approved for patients with local advanced or metastatic NSCLC after prior chemotherapy (Fehrenbacher et al. 2016; Tecentriq US Prescribing Information; EMA SmPC). Patients with epidermal growth factor receptor (EGFR)-activating mutations or tumors positive for anaplastic lymphoma kinase (ALK) mutations should also receive targeted therapy prior to atezolizumab. Additionally, atezolizumab has demonstrated clinical activity in untreated and chemotherapy-treated advanced PD-L1 positive NSCLC (Peters et al. 2017) and in advanced RCC as a single agent (McDermott et al. 2016), and in combination with an antibody targeted vascular endothelial growth factor (VEGF), bevacizumab (Sznol et al. 2015). In addition, atezolizumab is currently being evaluated in combination with enzalutamide for metastatic castration-recurrent prostate cancer (CRPC; NCT 03016312). Enzalutamide resistance in CRPC has been associated with increased expression of PD-L1 (Bishop et al. 2015), and early clinical evidence suggests that ICTI therapy may provide clinical benefit for CRPC patients after progression with enzalutamide (Graff et al. 2016) .

Despite these achievements, there is still room for improvement. There is also still a need to develop new systemic therapies for late stage local or metastatic solid tumors.

The essence of the invention

These and other needs are satisfied by the present invention, which relates to a method of treating local advanced solid tumors or metastatic solid tumors, comprising administering to a patient in need of such treatment, a compound of formula I

Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein

R ¹ is halogen;

R ² is halogen and

Q is CH or N;

in combination with atezolizumab, where local advanced solid tumors or metastatic solid tumors are castration recurrent prostate cancer (CRPC).

In a preferred embodiment of the invention, the compound of formula I is compounds 1:

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Compound 1 or a pharmaceutically acceptable salt thereof.

In another embodiment of the invention, compound 1 is administered as a salt of L-malic acid, or as a salt of D-malic acid, preferably atezolizumab is administered intravenously (IV), in particular, compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab are administered simultaneously or sequentially.

In another embodiment of the invention according to the method up to and including 1200 mg of atezolizumab is administered to the patient once every three weeks in combination with 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40 , 35, 30, 25, 20, 15, 10 or 5 mg of Compound 1, or a pharmaceutically acceptable salt thereof, once a day on an empty stomach, in particular up to and including 1200 mg of atezolizumab, is administered to the patient once every three weeks in combination with 60 , 40 or 20 mg of Compound 1, or a pharmaceutically acceptable salt thereof, once daily on an empty stomach.

In another embodiment of the invention according to the method up to and including 1100 mg of atezolizumab is administered to the patient once every three weeks in combination with 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10 or 5 mg of compound 1, or a pharmaceutically acceptable salt thereof, once daily on an empty stomach, in particular up to and including 1100 mg of atezolizumab, is administered to the patient once every three weeks in combination with 60 , 40 or 20 mg of Compound 1, or a pharmaceutically acceptable salt thereof, once daily on an empty stomach.

In another embodiment of the invention according to the method up to and including 1000 mg of atezolizumab is administered to the patient once every three weeks in combination with 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40 , 35, 30, 25, 20, 15, 10 or 5 mg of compound 1, or a pharmaceutically acceptable salt thereof, once daily on an empty stomach, in particular up to and including 1000 mg of atezolizumab, is administered to the patient once every three weeks in combination with 60, 40 or 20 mg of Compound 1, or a pharmaceutically acceptable salt thereof, once daily on an empty stomach.

In a further embodiment of the invention according to the method up to and including 900 mg of atezolizumab is administered to the patient once every three weeks in combination with 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10 or 5 mg of compound 1, or a pharmaceutically acceptable salt thereof, once a day on an empty stomach, in particular up to and including 900 mg of atezolizumab, is administered to the patient once every three weeks in combination with 60 , 40 or 20 mg of compound 1 or its pharmaceutically acceptable salt, once a day on an empty stomach.

In a preferred embodiment of the invention, compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab are administered simultaneously or sequentially, in particular, atezolizumab is administered intravenously by infusion over 60 or 30 minutes.

When implementing the methods according to the invention in patients treated with this combination, stabilization of the disease is observed.

Definitions

ACT g adrenocorticotropic hormone DAT anti-androgen therapy PE by-effect

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payoi side effect of particular interest AIDS acquired immunodeficiency syndrome ALK anaplastic lymphoma kinase AP alkaline phosphatase ALT alanine aminotransferase AKN absolute neutrophil count ACT aspartate aminotransferase AUC area under the plasma drug concentration versus time curve cd blood pressure With cop skeletal bone scintigraphy AMC blood urea nitrogen C#D# (for example, Cycle # Day # GBT thoracic/abdominal/pelvic areas UAC general clinical blood test SFP Code of Federal Regulations CI confidence interval CNS central nervous system BY full answer COG Group Evaluation Committee IRK individual registration card CRRP castration-recurrent prostate cancer kt CT scan otkpo General terminology of side effect criteria PONV Cancer Therapy Evaluation Program CYP cytochrome P450 ddMVAC doses of methotrexate, vinblastine, doxorubicin, and ppp drug-induced liver injury odt dose-limiting toxicity Pro response duration tgv deep vein thrombosis ke ethics committee ECG electrocardiogram vkog Eastern United Group of Oncologists EGFR epidermal growth factor receptor IKB Safety Executive Committee FACS fluorescent cell sorting FDA the Food and Drug Administration and FSH follicle-stimulating hormone FXa Ha factor PPKKI Rules for conducting quality clinical With KF glomerular filtration rate

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lcd gastrointestinal NLP good laboratory practice GnRH gonadotropin-releasing hormone MPS genitourinary system HBsAg hepatitis B surface antigen HCV hepatitis C virus HCV Ab antibody to hepatitis C virus HIV AIDS virus OP relative risk FIS informed consent form MKU International Conference on Unification ICTIO immune checkpoint inhibitor Ig immunoglobulin IHC immunohistochemical IMDC International Database Consortium for MHK International normalized coefficient ISPE immunity-related side effect KIE Research Ethics Committee HPK independent radiological commission NKU independent supervisory institution eSPE immunity-associated serious side effect DRANK originally prescribed treatment i/v intravenously ldg lactate dehydrogenase BPFP biochemical indicator of liver function LG luteinizing hormone NMG low molecular weight heparins KSMP myeloid-derived suppressor cell MSTRO Medical glossary of terms for regulatory GCGC major histocompatibility complex them myocardial infarction MMR mismatch repair MRI Magnetic resonance imaging men microsatellite instability MSKCC Memorial Sloan Cancer Center- MTC medullary thyroid cancer mpd maximum tolerated dose np not applicable HBOC National Universal Cancer Network research National Cancer Institute But Not Evaluated NS not reported nepp non-steroidal anti-inflammatory drug NSCLC non-small cell lung cancer

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onch osteonecrosis of the jaw CHOO objective response rate ov overall survival pz progressive disease PD-1 receptor 1 programmed death PD-L1 receptor ligand 1 programmed death GDP progression-free survival FC pharmacokinetics POR orally PES palmoplantar erythrodysesthesia ipp proton pump inhibitor 40 partial response PSA prostate specific antigen PV prothrombin time chtv partial thromboplastin time r/day once a day r/h/day once a day QTcF corrected QT interval calculated using the formula PAC renal cell carcinoma COOSO (1.1) Criteria for assessing the response of solid tumors (version SLDF reversible posterior leukoencephalopathy syndrome NIB safety background RTK receptor tyrosine kinases PPA serious side effect Psta statistical analysis plan 03 stable disease MO International system sdop the sum of the diameters of the lesions SNP single nucleotide polymorphism Court sum of diameters TK triiodothyronine T4 thyroxine About AM tumor-associated macrophage TBS technetium bone scan PIA transient ischemic attack NTC tyrosine kinase inhibitor omv point in time response Treg regulatory T-lymphocyte TSH thyroid-stimulating hormone UK urothelial carcinoma VPN upper limit of normal OBCM urine protein-to-creatinine ratio ZHVU ventricular assist device VEGF vascular endothelial growth factor VEGFR vascular endothelial growth factor receptor i#d# Week # Day # WBC leukocytes

Detailed Description of the Invention

As stated above, the present invention relates to a method of treating a locally advanced or metastatic solid tumor comprising administering a compound of formula I or compound 1 or a pharmaceutically acceptable salt thereof in combination with atezolizumab.

Compound 1 is known by its chemical name N-(4-{[6,7-bis(methyloxy)quinolin-4yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide and by the name cabozantinib . COMETRIQ™ (cabozantinib S-malate oral capsules) was approved on November 29, 2012 by the US Food and Drug Administration (FDA) for the treatment of patients with advanced metastatic medullary thyroid cancer (MTC). CABOMETYX™ (cabozantinib S-malate oral tablets) was approved on April 25, 2016 by the US Food and Drug Administration (FDA) for the treatment of advanced renal cell carcinoma (RCC) in patients who have previously received anti-angiogenic therapy. . Cabozantinib is formulated as the L-malic acid salt N-(4-{[6,7bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropan-1,1-dicarboxamide. WO 2005/030140, the entire content of which is incorporated herein by reference, discloses compound 1 and describes a method for its preparation, and also discloses the therapeutic activity of this compound with respect to inhibition, regulation and/or modulation of kinase signal transduction (analysis results, table. 4, entry 289). In November 2012, cabozantinib was approved by US regulators for the treatment of advanced metastatic medullary thyroid cancer.

- 5 041548 gland. WO 2005/030140 describes the synthesis of cabozantinib (Example 48) and also discloses the therapeutic activity of this molecule in terms of inhibition, regulation and/or modulation of kinase signal transduction (analysis results, Table 4, entry 289). Example 48 begins with paragraph [0353] in WO 2005/030140. Compound 1 information is provided by the FDA at http://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=208692 (last updated 19 December 2016) and is included in this document by reference in its entirety.

Atezolizumab is known under the name TECENTRIQ® (Genentech Oncology, a subsidiary of the Roche Group). On May 18, 2016, atezolizumab received U.S. Food and Drug Administration (FDA) formal approval for the treatment of advanced localized or metastatic urothelial carcinoma in patients who have: disease progression during or after platinum-containing chemotherapy, and disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. On October 18, 2016, atezolizumab received official approval from the US Food and Drug Administration (FDA) for the treatment of metastatic non-small cell lung cancer in patients with metastatic non-small cell lung cancer (NSCLC) who experience disease progression during or after platinum-containing chemotherapy .

Information on atezolizumab is provided by the FDA at http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm525 780.html (last updated December 19, 2016) and incorporated herein by reference in its entirety.

In these and other embodiments, the compound of formula I or compound 1, or a pharmaceutically acceptable salt thereof, is administered as a pharmaceutical composition, the pharmaceutical composition further comprising a pharmaceutically acceptable carrier, excipient or diluent. In a specific embodiment, the compound of formula I is compound 1, or a pharmaceutically acceptable salt thereof.

The compound of formula I or compound 1, or a pharmaceutically acceptable salt thereof, as described herein, includes both the listed compounds and individual isomers and mixtures of isomers. In each case, the compound of formula I includes pharmaceutically acceptable salts, hydrates and/or solvates of the mentioned compounds and any of their individual isomers or mixtures of their isomers.

In other embodiments, the compound of formula I or compound 1 may be (L)-malic acid salt (also referred to as S-malic acid salt) or (D)-malic acid salt (also referred to as R-malic acid salt). The malic acid salt of the compound of formula I and compound 1 is disclosed in PCT/US 2010/021194 and US Patent Application No. 61/325095, the entire content of each of which is incorporated herein by reference.

In other embodiments, the compound of formula I may be a salt of malic acid.

In other embodiments, the implementation of the compound of formula I may be a salt of (D)malic acid.

In other embodiments, the compound of formula I may be a salt of (L)malic acid.

In other embodiments, Compound 1 may be a salt of malic acid.

In other embodiments, Compound 1 may be a (D)-malic acid salt.

In other embodiments, Compound 1 may be a C)-malic acid salt.

In another embodiment, the malic acid salt is in the form of (L)-malic acid salt and/or (D)-malic acid salt crystalline form N-1 of Compound 1 as disclosed in US Patent Application No. 61/325095. See also WO 2008/083319 for properties of crystalline enantiomers, including N-2 crystalline forms of the C)-malic acid salt (also referred to as S-malic acid salt) or (D)-malic acid salt (also referred to as R-malic acid salt) and/ or crystalline N-1 forms of the C)-malic acid salt (also referred to as S-malic acid salt) or (D)-malic acid salt (also referred to as R-malic acid salt) of Compound 1. Methods for preparing and characterizing such forms are fully described in PCT/US 10/21194, which is incorporated herein by reference in its entirety.

In one embodiment, the compound of formula I or compound 1, or a pharmaceutically acceptable salt thereof, is administered simultaneously (at the same time) or sequentially (one after the other) with atezolizumab. In a further embodiment, Compound 1 or a pharmaceutically acceptable salt thereof is administered once daily and atezolizumab is administered once every three weeks (p3n). In an additional embodiment, the compound of formula I or compound 1, or a pharmaceutically acceptable salt thereof, is administered on an empty stomach (ie without food) for about 2 hours before and 1 hour after administration. The compound of formula I, or compound 1, or a pharmaceutically acceptable salt thereof, is preferably administered with a glass of water (about 8 oz or 240 ml).

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In another embodiment, the compound of formula I or compound 1, or a pharmaceutically acceptable salt thereof, is administered orally once a day as a tablet or capsule.

In another embodiment, atezolizumab is administered intravenously (IV) once every three weeks (for 3 weeks) as an infusion.

In another embodiment, the compound of formula I or compound 1, or a pharmaceutically acceptable salt thereof, is administered orally as its free base or malic acid salt, in the form of a capsule or tablet.

The amounts of a compound of formula I or compound 1 or a pharmaceutically acceptable salt thereof will vary. In one embodiment, a compound of formula I, or compound 1, or a pharmaceutically acceptable salt thereof, is administered as a single 60 mg tablet. In another embodiment, the amount of a compound of formula I or compound 1, or a pharmaceutically acceptable salt thereof, is administered as a single 40 mg tablet. In another embodiment, the amount of a compound of formula I or compound 1, or a pharmaceutically acceptable salt thereof, is administered as a single 20 mg tablet. In each of these embodiments, the amount of atezolizumab administered is 1200 mg, which is administered intravenously (IV) as an infusion.

In these and other embodiments, the compound of formula I or compound 1, or a pharmaceutically acceptable salt thereof, is administered orally once a day as its free base or as its malic acid salt, in the form of a capsule or tablet. In a further embodiment, Compound 1 is administered as (L)-malic acid salt (also referred to as S-malic acid salt) or (D)-malic acid salt (also referred to as R-malic acid salt). In a further embodiment, up to and including 100 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 95 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 90 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 85 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 80 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 75 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 70 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 65 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 60 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 55 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 50 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 45 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 40 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 35 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 30 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 25 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 20 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 15 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered;

up to and including 10 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered;

or up to and including 5 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered;

In these and other embodiments, up to and including 1200 mg of atezolizumab once every three weeks (p3n) is administered in combination with compound 1, which is administered orally once a day on an empty stomach, as its free base or as its malate salt )-malic acid (also called S-malic acid salt) or (D)-malic acid salt (also called R-malic acid salt)) in the form of a capsule or tablet.

In a further embodiment, up to and including 100 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 95 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 90 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 85 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 80 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 75 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 70 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 65 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 60 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 55 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 50 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 45 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 40 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 35 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered;

- 7 041548 administered up to and including 30 mg of compound 1 or its pharmaceutically acceptable salt; up to and including 25 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 20 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 15 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 10 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered;

or up to and including 5 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered;

In these and other embodiments, up to and including 1100 mg of atezolizumab once every three weeks (p3n) is administered in combination with compound 1, which is administered orally once a day on an empty stomach, as its free base or as its malate salt (salt ( b)-malic acid (also called S-malic acid salt) or (D)-malic acid salt (also called R-malic acid salt)) in the form of a capsule or tablet.

In a further embodiment, up to and including 100 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 95 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 90 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 85 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 80 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 75 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 70 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 65 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 60 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 55 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 50 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 45 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 40 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 35 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 30 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 25 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 20 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 15 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered;

up to and including 10 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered;

or up to and including 5 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered.

In these and other embodiments, up to and including 1000 mg of atezolizumab once every three weeks (p3n) is administered in combination with compound 1, which is administered orally once a day on an empty stomach, as its free base or as its malate salt )-malic acid (also called S-malic acid salt) or (D)-malic acid salt (also called R-malic acid salt)) in capsule or tablet form:

up to and including 100 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 95 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 90 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 85 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 80 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 75 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 70 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 65 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 60 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 55 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 50 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 45 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 40 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 35 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 30 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 25 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 20 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 15 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered;

up to and including 10 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered, or up to and including 5 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered;

In these and other embodiments, up to and including 900 mg of atezolizumab once every three weeks (p3n) is administered in combination with compound 1, which is administered orally once a day.

- 8 041548 fasting day, as its free base or as its malate salt ((L)-malic acid salt (also called S-malic acid salt) or (D)-malic acid salt (also called R-malic acid salt) ) in the form of a capsule or tablet:

up to and including 100 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 95 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 90 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 85 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 80 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 75 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 70 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 65 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 60 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 55 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 50 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 45 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 40 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 35 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 30 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 25 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 20 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered; up to and including 15 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered;

up to and including 10 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered, or up to and including 5 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered;

In other embodiments, 1500 mg or 1400 mg or 1300 mg or 1200 mg or 1100 mg or 1000 mg or 900 mg or 800 mg or 700 mg or 600 mg of atezolizumab is administered once every three weeks ( p3h) in combination with Compound 1 or a pharmaceutically acceptable salt thereof, as a tablet or capsule containing 60, 40, or 20 mg of Compound 1 administered orally once a day on an empty stomach, as its free base or as malate salt ((L)-malic acid salt (also called S-malic acid salt) or (D)-malic acid salt (also called R-malic acid salt)).

In other embodiments, 1300 mg of atezolizumab is administered once every three weeks (p3n), in combination with Compound 1 or a pharmaceutically acceptable salt thereof, as a tablet or capsule formulation containing 60, 40, or 20 mg of Compound 1 administered orally alone once daily on an empty stomach, as its free base or as its malate salt ((L)-malic acid salt (also called S-malic acid salt) or (D)-malic acid salt (also called R-malic acid salt)) .

In other embodiments, 1200 mg of atezolizumab is administered once every three weeks (p3n) in combination with compound 1 as a tablet or capsule containing 60, 40, or 20 mg of compound 1, which is administered orally once a day on an empty stomach, as its free base or as its malate salt ((L)-malic acid salt (also called S-malic acid salt) or (D)-malic acid salt (also called R-malic acid salt)).

In other embodiments, 1100 mg of atezolizumab is administered once every three weeks (p3n), in combination with Compound 1 or a pharmaceutically acceptable salt thereof, as a tablet or capsule formulation containing 60, 40, or 20 mg of Compound 1 administered orally alone once daily on an empty stomach, as its free base or as its malate salt ((L)-malic acid salt (also called S-malic acid salt) or (D)-malic acid salt (also called R-malic acid salt)) .

In another embodiment, treatment comprises administering atezolizumab 1300 mg or 1200 mg or 1100 mg once every three weeks intravenously as an intravenous (IV) infusion in combination with cabozantinib (S)-malate, which is administered orally, once daily on an empty stomach as a tablet containing cabozantinib (S)-malate, microcrystalline cellulose, lactose anhydrous, hydroxypropyl cellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, and a film coating containing hypromellose, titanium dioxide, triacetin, and iron oxide yellow.

In a further embodiment, cabozantinib (S)-malate is administered as a tablet formulation containing approximately

30-32 wt% cabozantinib, (S)-malic acid salt;

38-40 wt.% microcrystalline cellulose;

18-22 wt.% lactose;

2-4 wt.% hydroxypropylcellulose;

4-8 wt.% croscarmellose sodium;

0.2-0.6 wt.% colloidal silicon dioxide;

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0.5-1 wt.% magnesium stearate; and additionally containing a film coating material containing hypromellose, titanium dioxide, triacetin and yellow iron oxide.

In a further embodiment, cabozantinib (S)-malate is administered as a tablet formulation containing approximately (% w/w):

31-32 wt% cabozantinib, (S)-malic acid salt;

39-40 wt.% microcrystalline cellulose;

19-20 wt.% lactose;

2.5-3.5 wt% hydroxypropyl cellulose;

5.5-6.5 wt% croscarmellose sodium;

0.25-0.35 wt.% colloidal silicon dioxide;

0.7-0.8 wt.% magnesium stearate; and additionally containing:

3.9-4.1 wt.% of the film coating material containing hypromellose, titanium dioxide, triacetin and yellow iron oxide.

In a further embodiment, cabozantinib (S)-malate is administered as a tablet formulation containing 20, 40, or 60 mg of cabozantinib, orally once daily on an empty stomach.

In a further embodiment, cabozantinib (S)-malate is administered as a tablet formulation selected from the group consisting of ____________________________

Ingredient Theoretical amount (mg/single dose) Tablet 2 0 mg Tablet 40 mg Tablet 60 mg Cabozantinib (S)-malate 25, 34 50, 69 76.03 Microcrystalline cellulose PH-102 31.08 62.16 93.24 Lactose anhydrous, 60M 15, 54 31.07 46, 61 Hydroxypropylcellulose, EXF 2,400 4,800 7,200 Croscarmellose sodium 4,800 9,600 14.40 colloidal silicon dioxide 0.2400 0.4800 0.7200 Magnesium stearate (non-bovine) 0.6000 1,200 1,800 Opadry® yellow (03K92254) 3,200 6,400 9,600 Total tablet weight 83.20 166.4 249.6

In a further embodiment, cabozantinib (8)-malate is administered orally once a day.

In a further embodiment, the amount of cabozantinib (S)-malate administered orally once a day is 60 mg.

In a further embodiment, the amount of cabozantinib (S)-malate administered orally once a day is 40 mg.

In a further embodiment, the amount of cabozantinib (S)-malate administered orally once a day is 20 mg.

In a further embodiment, cabozantinib (R)-malate is administered orally once a day.

In a further embodiment, the amount of cabozantinib (R)-malate administered orally once a day is 60 mg.

In a further embodiment, the amount of cabozantinib (R)-malate administered orally once a day is 40 mg.

In a further embodiment, the amount of cabozantinib (R)-malate administered orally once a day is 20 mg.

In another embodiment, Compound 1 is administered orally as its free base or as its malate salt ((L)-malic acid salt (also referred to as S-malic acid salt) or (D)-malic acid salt (also referred to as R-malic acid salt). acid)) once a day as a tablet, as suggested in the following table.

- 10 041548

Ingredient (% w/w) Compound 1 25.0-33.3 Microcrystalline cellulose in sufficient quantity Hydroxypropylcellulose 3 Poloxamer 0-3 Croscarmellose sodium 6.0 colloidal silicon dioxide 0.5 magnesium stearate 0.5-1.0 Total 100

In another embodiment, Compound 1 is administered orally as its free base or as its malate salt ((L)-malic acid salt (also referred to as S-malic acid salt) or (D)-malic acid salt (also referred to as R- malic acid)) once a day as a tablet as suggested in the following table.

Ingredient Theoretical amount (mg/single dose) Compound 1 100.0 Microcrystalline cellulose RN-102 155.4 Lactose anhydrous 60M 77.7 Hydroxypropylcellulose, EXF 12.0 Croscarmellose sodium 24 colloidal silicon dioxide 1.2 Magnesium stearate (non-bovine) thirty Opadray yellow 16.0 Total 416

In another embodiment, Compound 1 is administered orally as its free base or as its malate salt ((L)-malic acid salt (also referred to as S-malic acid salt) or (D)-malic acid salt (also referred to as R- malic acid) ) once a day as a tablet as suggested in the following table.

Ingredient Function % wt./mass. The drug substance cabozantinib Active (25% drug load as free base) Microcrystalline cellulose ingredient 31.7 (Avicel RN-102) Filler 38.9 Lactose, anhydrous (60M) Filler 19.4 Hydroxypropylcellulose (EXF) Binder thirty Croscarmellose sodium (Ac-Di-Sol) Baking powder Means, 6.0 colloidal silicon dioxide conducive slip Lubricating 0.3 magnesium stearate means 0.75

Film coating based on Opadry yellow, which includes:

Film

HPMC 2910/hypromellose, 6 cP 4.00 coating Titanium dioxide

Triacetin

iron oxide yellow

In some embodiments, atezolizumab is administered by intravenous (IV) infusion comprising 1200 mg of a fully humanized IgG1 isotype monoclonal antibody. Dosage of atezolizumab used as part of a combination treatment with a compound of formula I or compound 1, or a pharmaceutically acceptable salt thereof, e.g. as a malic acid salt, e.g. (L)-malic acid salt (also called S-malic acid salt), or (D)-malic acid salt (also called R-malic acid salt) is 1200 mg/20 ml (60 mg/ml) as a single dose vial which can be diluted with -0.9% diluent

- 11 041548 sodium chloride for injection only, with gentle mixing by gentle inversion, and administered to a patient in need of it within 60 or 30 minutes.

Any of the tablet formulations provided above may be adjusted according to the dosage of Compound 1 or its pharmaceutically acceptable salt as desired. Thus, the amount of each of the formulation ingredients can be proportionally adjusted to produce a tablet formulation containing varying amounts of Compound 1 or a pharmaceutically acceptable salt thereof, as provided in the preceding paragraphs. In another embodiment, the formulations may contain 20, 40, 60 or 80 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

Embodiments

The invention is further defined by the following non-limiting embodiments.

Embodiment 1. A method of treating locally advanced or metastatic solid tumors comprising administering to a patient in need of such treatment a compound of formula I

or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein

R ¹ is halogen;

R ² is halogen and

Q is CH or N;

in combination with atezolizumab.

Embodiment 2. The method of Embodiment 1 wherein the compound of Formula I is Compound 1 or a pharmaceutically acceptable salt thereof.

Compound 1

Embodiment 3 The method of Embodiment 2 wherein Compound 1 is administered as L-malic acid salt.

Embodiment 4 The method of Embodiment 2 wherein Compound 1 is administered as S-malic acid salt.

Embodiment 5. The method of Embodiment 2-4 wherein atezolizumab is administered intravenously (IV).

Embodiment 6. The method of Embodiments 1 to 5 wherein the late stage local or metastatic solid tumors are UC, RCC, CRPC, and advanced NSCLC.

Embodiment 7. The method of Embodiments 2-6 wherein Compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab are administered simultaneously or sequentially.

Embodiment 8. The method of Embodiment 6 wherein up to and including 1200 mg of atezolizumab is administered to the patient every three weeks in combination with 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50 , 45, 40, 35, 30, 25, 20, 15, 10, or 5 mg, or Compound 1, or a pharmaceutically acceptable salt thereof, once a day on an empty stomach.

Embodiment 9. The method of Embodiment 8 wherein up to and including 1200 mg of atezolizumab is administered to the patient once every three weeks in combination with 60, 40 or 20 mg of Compound 1, or a pharmaceutically acceptable salt thereof, once daily on an empty stomach.

Embodiment 10. The method of Embodiment 6 wherein up to and including 1100 mg of atezolizumab is administered to the patient once every three weeks in combination with 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50 , 45, 40, 35, 30, 25, 20, 15, 10 or 5 mg of Compound 1, or a pharmaceutically acceptable salt thereof, once daily on an empty stomach.

- 12 041548

Embodiment 11. The method of Embodiment 10 wherein up to and including 1100 mg of atezolizumab is administered to the patient once every three weeks in combination with 60, 40 or 20 mg of Compound 1, or a pharmaceutically acceptable salt thereof, once daily on an empty stomach.

Embodiment 12. The method of Embodiment 6 wherein up to and including 1000 mg of atezolizumab is administered to the patient once every three weeks in combination with 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50 , 45, 40, 35, 30, 25, 20, 15, 10 or 5 mg of Compound 1, or a pharmaceutically acceptable salt thereof, once daily on an empty stomach.

Embodiment 13. The method of Embodiment 12 wherein up to and including 1000 mg of atezolizumab is administered to the patient once every three weeks in combination with 60, 40 or 20 mg of Compound 1, or a pharmaceutically acceptable salt thereof, once daily on an empty stomach.

Embodiment 14. The method of Embodiment 6 wherein up to and including 900 mg of atezolizumab is administered to the patient once every three weeks in combination with 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50 , 45, 40, 35, 30, 25, 20, 15, 10 or 5 mg of Compound 1, or a pharmaceutically acceptable salt thereof, once daily on an empty stomach.

Embodiment 15. The method of Embodiment 14 wherein up to and including 900 mg of atezolizumab is administered to the patient once every three weeks in combination with 60, 40 or 20 mg of Compound 1, or a pharmaceutically acceptable salt thereof, once daily on an empty stomach.

Embodiment 16. The method of Embodiments 8-15 wherein Compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab are administered simultaneously or sequentially.

Embodiment 17. The method of Embodiments 7-16 wherein atezolizumab is administered intravenously by infusion over 60 or 30 minutes.

Embodiment 18. The method of Embodiments 1-17 wherein patients treated with the combination experience a complete serologic response.

Embodiment 19. The method of Embodiments 1-17 wherein a serological partial response is observed in patients treated with the combination.

Embodiment 20. The method of Embodiments 1-17 wherein the patients treated with the combination have a stable disease course.

Compound preparation 1.

Preparation of 1-(4-fluorophenylcarbamoyl)cyclopropanecarboxylic acid (Compound A-1)

The starting 1,1-cyclopropanedicarboxylic acid was treated with thionyl chloride (1.05 equivalents) in about 8 volumes of isopropyl acetate at 25°C for 5 hours. The resulting mixture was then treated with a solution of 4-fluoroaniline (1.1 equivalents) and triethylamine (1.1 equivalents ) in isopropyl acetate (2 volumes) for 1 hour. The product slurry was quenched with 5N NaOH solution (5 vols) and the aqueous phase was discarded. The organic phase was extracted with 0.5N NaOH (10 vols) and the main extract was washed with heptane (5 vols) and then acidified with 30% HCl to give a suspension. Compound A-1 was isolated by filtration.

Compound A-1 was prepared on a 1.00 kg scale using 1,1-cyclopropanedicarboxylic acid as a limiting reagent to give 1.32 kg of compound A-1 (isolated yield 77%; mass balance 84%) with a purity of 99.92% (HPLC) and 100.3% analysis.

Preparation of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropan-1,1-dicarboxamide (compound 1) and its salt ( L)-malic acid

A synthetic route that can be used to prepare N-(4-{[6,7bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropan-1,1-dicarboxamide and its salt of (L)-malic acid is shown in Scheme 1.

- 13 041548

Scheme 1

Another synthetic route that can be used to prepare N-(4-{[6,7bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide and its (L)-malic acid salt is depicted in Scheme 2.

Scheme 2

Obtaining 4-chloro-6,7-dimethoxyquinoline

The reactor was sequentially loaded with 6,7-dimethoxyquinolin-4-ol (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to about 60° C. and phosphorus oxychloride (POCl ₃ , 130.6 kg) was added. After adding POCl ₃ the temperature of the reaction mixture was raised to about 77°C. The reaction was considered complete (about 13 hours) when less than 3% of starting material remained, as measured by high performance liquid chromatography (HPLC) included in the analysis. The reaction mixture was cooled to about 2-7°C and then quenched in a cold solution of dichloromethane (DCM, 482.8 kg), 26% NH4OH (251.3 kg) and water (900 L). The resulting mixture was heated to about 20-25° C. and the phases were separated. The organic phase was filtered through a pad of AW Hyflo Super-Cel NF (Celite; 5.4 kg) and the filter cake washed with DCM (118.9 kg). The combined organic phase was washed with brine (282.9 kg) and mixed with water (120 L). The phases were separated and the organic phase was concentrated by vacuum distillation to remove the solvent (approximate residual volume 95 L). DCM (686.5 kg) was loaded into the reactor containing the organic phase and concentrated by vacuum distillation to remove the solvent (approximate residual volume 90 L). Methyl tert-butyl ether (MTBE, 226.0 kg) was then charged and the temperature of the mixture was brought to -20 to -25° C. and held for 2.5 hours to give a solid precipitate which was then filtered off and washed with n -heptane (92.0 kg) and dried on a filter at about 25°C under nitrogen to give the title compound (35.6 kg).

Preparation of 4-(6,7-dimethoxyquinolin-4-yloxy)phenylamine

4-aminophenol (24.4 kg) dissolved in N,N-dimethylacetamide (DMA, 184.3 kg) was charged to a reactor containing 4-chloro-6,7-dimethoxyquinoline (35.3 kg), tert-butoxide sodium (21.4 kg) and DMA (167.2 kg) at 20-25°C. This mixture was then heated to 100-105°C for about 13 hours. After the reaction

- 14 041548 was considered complete, as determined by HPLC analysis included in the analysis (less than 2% of starting material remained), the contents of the reactor were cooled to 15-20 ° C and water (pre-cooled to 2-7 ° C, 587 l) was loaded at a speed maintaining the temperature from 15 to 30°C. The resulting solid was filtered off, washed with a mixture of water (47 L) and DMA (89.1 kg) and finally washed with water (214 L). The filter cake was then dried at about 25° C. on the filter to give crude 4-(6,7-dimethoxyquinolin-4-yloxy)-phenylamine (moisture 59.4 kg, dryness 41.6 kg based on LOD). The crude 4-(6,7-dimethoxyquinolin-4yloxy)phenylamine was refluxed (about 75° C.) in a mixture of tetrahydrofuran (THF, 211.4 kg) and DMA (108.8 kg) for about 1 hour, and then cooled to 0-5°C and held for about 1 hour, after which the solid was filtered off, washed with THF (147.6 kg) and dried on the filter under vacuum at about 25°C to obtain 4-(6,7-dimethoxyquinoline -4-yloxy)-phenylamine (34.0 kg).

Alternative preparation of 4-(6,7-dimethoxyquinolin-4-yloxy)phenylamine

4-chloro-6,7-dimethoxyquinoline (34.8 kg) and 4-aminophenol (30.8 kg), and sodium tert-pentoxide (1.8 equivalents) 88.7 kg, 35 wt% in THF) were loaded to the reactor, then N,N-dimethylacetamide (DMA, 293.3 kg) was added. This mixture was then heated to 105-115° C. for about 9 hours. After the reaction was considered complete, as determined by HPLC analysis included in the process (less than 2% of the starting material remained), the contents of the reactor were cooled at 15- 25°C and added water (315 kg) for 2 h, maintaining the temperature at 20-30°C. Then the reaction mixture was stirred for another 1 h at 20-25°C. The crude product was collected by filtration and washed with a mixture of 88 kg of water and 82.1 kg of DMA, then 175 kg of water. The product was dried on the filter-drier for 53 hours LOD showed less than 1 wt./wt.%.

In an alternative method, used 1.6 equivalents of sodium tert-pentoxide and raised the reaction temperature to 110-120°C. In addition, the cooling temperature was raised to 35-40°C, and the initial temperature of adding water was adjusted to 35-40°C with an allowable exotherm of up to 45°C.

Preparation of 1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl chloride

Oxalyl chloride (12.6 kg) was added to a solution of 1-(4-fluorophenylcarbamoyl)-cyclopropanecarboxylic acid (22.8 kg) in a mixture of THF (96.1 kg) and N,N-dimethylformamide (DMF; 0.23 kg) at such a rate that the temperature of the mixture does not exceed 25°C. The resulting solution was used in the next step without further processing.

Alternative preparation of 1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl chloride

The reactor was charged with 1-(4-fluorophenylcarbamoyl)-cyclopropanecarboxylic acid (35 kg), 344 g of DMF and 175 kg of THF. The reaction mixture was brought to 12-17°C, and then 19.9 kg of oxalyl chloride was added to the reaction mixture over 1 hour. The reaction mixture was allowed to stir at 12-17°C for 3-8 hours. The resulting solution was used in the next step without additional processing.

Preparation of cyclopropan-1,1-dicarboxylic acid [4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]amide (4-fluorophenyl)amide

The solution from the previous step containing 1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl chloride was added to a mixture of 4-(6,7-dimethoxyquinolin-4-yloxy)phenylamine compound (23.5 kg) and potassium carbonate (31.9 kg) in THF (245.7 kg) and water (116 l) at such a rate that the temperature of the mixture does not exceed 30°C. Upon completion of the reaction (about 20 min), water (653 L) was added. The mixture was stirred at 20-25° C. for about 10 hours, causing the product to precipitate. The product was isolated by filtration, washed with a previously prepared solution of THF (68.6 kg) and water (256 kg), and dried first on a filter under nitrogen at about 25°C and then at about 45°C under vacuum to give the title compound (41.0 kg, 38.1 kg, calculated based on LOD).

Alternative preparation of cyclopropane-1,1-dicarboxylic acid [4-(6,7dimethoxyquinolin-4-yloxy)phenyl]amide (4-fluorophenyl)amide

The reactor was charged with 4-(6,7-dimethoxyquinolin-4-yloxy)-phenylamine (35.7 kg, 1 eq.) followed by 412.9 kg of THF. A solution of K ₂ CO ₃ (48.3 kg) in water (169 kg) was added to the reaction mixture. The acid chloride solution described above in the alternative method for preparing 1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl chloride was transferred to a reactor containing 4-(6,7-dimethoxyquinolin4-yloxy)phenylamine, maintaining the temperature between 20-30°C for a minimum of 2 hours. The reaction mixture was stirred at 20-25° C. for a minimum of 3 hours. Then the temperature of the reaction mixture was brought to 30-25° C. and the mixture was stirred. Stirring was stopped and the phases of the mixture were allowed to separate. The lower aqueous phase was removed and discarded. Water (804 kg) was added to the remaining upper organic phase. The reaction mixture was allowed to stir at 15-25°C for a minimum of 16 hours.

The product has fallen out. The product was filtered and washed with a mixture of water (179 kg) and THF (157.9 kg) in two portions. The crude product was dried under vacuum for at least 2 hours. The dried product was then dissolved in THF (285.1 kg). The resulting suspension was transferred to the reaction

- 15 041548 vessel and stirred until the suspension turned into a clear (dissolved) solution, which required heating to 30-35°C for about 30 minutes. Water (456 kg) was then added to the solution, as well as SDAG-1 ethanol (20 kg, ethanol denatured with methanol for 2 h). The mixture was stirred at 15-25° C. for at least 16 hours. The product was filtered off and washed with a mixture of water (143 kg and 126.7 kg) and THF (143 kg) in two portions. The product was dried at a maximum temperature of 40°C.

In an alternative method, the reaction temperature during the formation of the acid chloride was brought to 1015°C. The recrystallization temperature was changed from 15-25°C to 45-50°C for 1 hour and then cooled to 15-25°C for 2 hours.

Preparation of cyclopropan-1,1-dicarboxylic acid [4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]amide(4-fluorophenyl)amide, cabozantinib salt of (G)-malic acid

[4-(6,7-Dimethoxyquinolin-4-yloxy)phenyl]amide-(4-fluorophenyl)amide cyclopropane-1,1-dicarboxylic acid (13.3 kg), L-malic acid (4.96 kg), methyl ethyl ketone (MEK; 188.6 kg) and water (37.3 kg) were charged into the reactor and the mixture was heated to reflux (about 74° C.) for about 2 hours. The reactor temperature was lowered to 50-55° C. and filtered the contents of the reactor. These successive steps described above were repeated two more times, starting from the same amounts of cyclopropane-1,1-dicarboxylic acid [4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]amide-(4fluorophenyl)amide (13, 3 kg), L-malic acid (4.96 kg), MEK (198.6 kg) and water (37.2 kg). The combined filtrate was azeotropically dried at atmospheric pressure using MEK (1133.2 kg) (residual volume approx. 711 L; KF < 0.5% w/w) at approximately 74°C. The temperature of the reactor contents was lowered to 20-25°C and held for about 4 hours to give a solid precipitate which was filtered off, washed with MEK (448 kg) and dried under vacuum at 50°C to give the title compound (45.5 kg ).

Alternative preparation of cyclopropane-1,1-dicarboxylic acid [4-(6,7-dimethoxyquinolin-4yloxy)phenyl]amide (4-fluorophenyl)amide, (b)-malic acid salts [4-(6,7-dimethoxyquinoline-4 -yloxy)phenyl]amide(4-fluorophenyl)amide cyclopropane-1,1-dicarboxylic acid (47.9 kg), L-malic acid (17.2 kg), methyl ethyl ketone (658.2 kg) and water (129. 1 kg) was loaded into the reactor and the mixture was heated to 50-55°C for about 1-3 hours, and then to 55 to 60°C for an additional 4-5 hours. The mixture was purified by filtration through a 1 μm cartridge. The reactor temperature was brought to 20-25°C and distilled under vacuum with a vacuum pressure of 150-200 mmHg. with a maximum jacket temperature of 55°C up to a volume of 558-731 liters.

Vacuum distillation was carried out two more times with a load of 380 and 380.2 kg of methyl ethyl ketone, respectively. After the third distillation, the batch volume was adjusted to 18 vol./mass. Cyclopropane-1,1-dicarboxylic acid [4-(6,7-dimethoxyquinolin-4yloxy)phenyl]amide-(4-fluorophenyl)amide, loading methyl ethyl ketone (159.9 kg) to give a total volume of 880 L. Additional vacuum distillation was carried out by adding methyl ethyl ketone (245.7 kg). The reaction mixture was left with moderate stirring at 20-25° C. for at least 24 hours. The product was filtered off and washed with methyl ethyl ketone (415.1 kg) in three portions. The product was dried under vacuum with the jacket temperature set to 45°C.

In an alternative method, the order of addition was reversed so that a solution of L-malic acid (17.7 kg) dissolved in water (129.9 kg) was added to [4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]amide cyclopropane-1,1-dicarboxylic acid (4-fluorophenyl)amide (48.7 kg) in methyl ethyl ketone (673.3 kg).

Cabozantinib (XL184) is a highly potent inhibitor of multiple receptor tyrosine kinases (RTKs) known to play an important role in tumor cell proliferation and/or tumor neovascularization, including MET, vascular endothelial growth factor receptor (VEGFR), AXL, and RET. Increased expression of MET and AXL has been implicated in the development of resistance to VEGFR inhibitors in preclinical models of several cancers (Shojaei et al. 2010, Zhou et al. 2015, Sennino et al. 2012, Ciamporcero et al. 2015). In addition, cabozantinib targets are involved in promoting tumor immune suppression, including TYRO3, MER, and AXL (tumor-associated macrophage kinase (TAM) family). Cabozantinib capsules (140 mg) are approved for the treatment of advanced metastatic medullary thyroid cancer (MTC) in the US and the European Union (Elisei et al. 2013; CometriqTM US PI and EMA SmPC).

Cabozantinib tablets (60 mg) are approved in the United States and the European Union for the treatment of advanced RCC after prior anti-angiogenic/VEGFR-targeted therapy (Choueiri et al. 2016, CabometyxTM US PI and EMA SmPC). Cabozantinib is also listed as a recommended therapy in patients with untreated moderate to low risk RCC (NCCN 2017) and is currently being considered by US and European Union regulators based on statistically improved progression-free survival (PFS) compared to sunitinib (Choueiri et al. al [J Clin Oncol] 2017, Choueiri et al [Ann Oncol] 2017).

Cabozantinib (60 mg) also demonstrated clinical activity in a phase 2 study in subjects with recurrent or difficult-to-treat metastatic UC (Apolo et al. [J Clin Oncol] 2016) and in a phase 3 study in subjects with CRPC after prior docetaxel and antiandrogen (against the receptor ) therapy (Smith et al. 2016). Although the primary measured parameter

- 16 041548 overall survival (OS) was not achieved in the phase 3 CRPC study, treatment with cabozantinib resulted in a significant improvement in PFS compared with prednisone and other clinically beneficial effects and biomarker changes, such as improved bone scan response (BSR) and markers of bone remodeling, reduced incidence of skeletal related disease, and reduced circulating tumor cells. Encouraging clinical activity of cabozantinib has also been observed in the early phases of several clinical trials in advanced NSCLC (Drilon et al. 2016, Neal et al. 2016, Hellerstedt et al. 2012, Wakelee et al. 2017; Schoffski et al. 2017). The objective response rate (ORR) in heavily pretreated non-selected NSCLC was approximately 10% and 28% in RET-rearranged NSCLC. Median PFS and median OS were comparable to standard chemotherapy in this patient population (Alimta [pemetrexed] US PI, Taxotere [docetaxel] US PI).

Preclinical studies (Kwilas et al. 2014, Song et al. 2015, Lu et al. 2017) and clinical observations of circulating immunosuppressive cells and immune effector cells (Apolo et al. 2014) suggest that cabozantinib promotes the formation of an immunopermissive environment by inhibiting immunomodulatory targets on immune cells. This may provide an opportunity for synergistic effects from combined treatment with ICTIO. In an ongoing Phase 1 study into genitourinary (GU) malignancies, cabozantinib was evaluated in combination with ICTI nivolumab, an anti-PD-1 monoclonal antibody. The dose escalation phase was completed and no dose-limiting toxicity (ODT) was reported.

The recommended dose for phase 2 (R2PD) was defined as 40 mg per day (r/day) for cabozantinib in combination with 3 mg/kg nivolumab (intravenous (IV), every two weeks (r2n)). At the end of data collection, 400 was 39% among the various types of MPS tumors. Among subjects with CM, 44%400 were reported, and among the nine reported CRPC, 67% achieved a stable disease state and one subject had a partial response (Nadal et al 2017). The combination of cabozantinib with ICTI may also provide a strategy to overcome resistance to ICTI therapy. This conclusion is based on a recent observation in a clinical trial where retreatment with ICTI in combination with VEGFR-TKI sitravatinib, which has a cabozantinib-like target profile, resulted in the abolition of existing ICTI resistance in patients with NSCLC (Leal et al. 2017) . These results suggest that the combination of ICTO with cabozantinib may confer a tumor microenvironment that promotes resensitization to ICTI therapy after prior progression to ICTI.

The dose escalation phase of the current study (XL184-021) has been initiated and is ongoing in subjects with advanced UC or RCC. In Group 1, no ODTs were identified during the dose escalation phase for the combination of 40 mg cabozantinib r/day and 1200 mg atezolizumab r3n. Group 2 is currently being evaluated with a combination of 60 mg cabozantinib r/day and 1200 mg atezolizumab r3n. Once the recommended dose of cabozantinib has been established for combination therapy with the standard dose of atezolizumab, the expansion stage in the tumor-specific groups of UC, RCC, CRPC, and NSCLC will be recorded to further evaluate the safety and efficacy of this combination in these tumor-related symptoms.

Example 1 Summary of an experimental clinical trial investigating the combination of cabozantinib (XL184) with atezolizumab in subjects with locally advanced or metastatic solid tumors such as UC, RCC, CRPC, and advanced NSCLC

Rationale

Multitarget tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICTIs) are two systemic therapies that have played an important role in recent advances in cancer treatment over the past few years. Both classes of therapies have demonstrated broad clinical effects, leading to new approved treatment options for a variety of tumor types, including renal cell carcinoma (RCC), urothelial carcinoma (UC), melanoma, non-small cell lung cancer (NSCLC), and others. The success of these types of therapies as standalone agents with different mechanisms of action has naturally led to interest in evaluating combinations of TKIs with ICTIOs in search of additional, possibly synergistic, anticancer clinical effects.

Atezolizumab is a humanized immunoglobulin (Ig) G1 monoclonal antibody that targets programmed death receptor 1 (PD-L1) ligand and inhibits the interaction between PD-L1 and its receptors, programmed death receptor 1 (PD-1) and B7-1 (also known as CD80), both of which function as inhibitory receptors expressed on T lymphocytes. It is approved in the United States and the European Union for the treatment of patients with locally advanced or metastatic UC after previous platinum-containing chemotherapy, or those considered unsuitable for cisplatin treatment (Rosenberg et al. 2016, Loriot et al. 2016). Atezolizumab is also approved for patients with localized advanced fold

- 17 041548 development or metastatic NSCLC after prior chemotherapy (Fehrenbacher et al. 2016; Tecentriq US Prescribing Information; EMA SmPC). Patients with epidermal growth factor receptor (EGFR)-activating mutations or tumors positive for anaplastic lymphoma kinase (ALK) mutations should also receive targeted therapy prior to atezolizumab. Additionally, atezolizumab has demonstrated clinical activity in untreated and chemotherapy-treated advanced PD-L1 positive NSCLC (Peters et al 2017) and in advanced RCC as a single agent (McDermott et al. 2016), and in combination with an antibody targeted vascular endothelial growth factor (VEGF), bevacizumab (Sznol et al. 2015). In addition, atezolizumab is currently being evaluated in combination with enzalutamide for metastatic castration-recurrent prostate cancer (CRPC; NCT 03016312). Enzalutamide resistance in CRPC has been associated with increased expression of PD-L1 (Bishop et al. 2015), and early clinical evidence suggests that ICTI therapy may provide clinical benefit for patients with CRPC after progression with enzalutamide (Graff et al. 2016) .

Cabozantinib (XL184) is a highly potent inhibitor of multiple receptor tyrosine kinases (RTKs) known to play an important role in tumor cell proliferation and/or tumor neovascularization, including MET, vascular endothelial growth factor receptor (VEGFR), AXL, and RET. Increased expression of MET and AXL has been implicated in the development of resistance to VEGFR inhibitors in preclinical models of several cancers (Shojaei et al. 2010, Zhou et al. 2015, Sennino et al. 2012, Ciamporcero et al. 2015). In addition, cabozantinib targets are involved in promoting tumor immune suppression, including TYRO3, MER, and AXL (tumor-associated macrophage kinase (TAM) family). Cabozantinib capsules (140 mg) are approved for the treatment of advanced metastatic medullary thyroid cancer (MTC) in the US and the European Union (Elisei et al. 2013; CometriqTM US PI and EMA SmPC).

Cabozantinib tablets (60 mg) are approved in the United States and the European Union for the treatment of advanced RCC after prior anti-angiogenic/VEGFR-targeted therapy (Choueiri et al. 2016, CabometyxTM US PI and EMA SmPC). Cabozantinib is also listed as a recommended therapy in patients with untreated moderate to low risk RCC (NCCN 2017) and is currently being considered by US and European Union regulators based on statistically improved progression-free survival (PFS) compared to sunitinib (Choueiri et al. al [J Clin Oncol] 2017, Choueiri et al [Ann Oncol] 2017).

Cabozantinib (60 mg) also demonstrated clinical activity in a phase 2 study in subjects with recurrent or difficult-to-treat metastatic UC (Apolo et al. [J Clin Oncol] 2016) and in a phase 3 study in subjects with CRPC after prior docetaxel and antiandrogen (against the receptor ) therapy (Smith et al. 2016). Although the primary measurable overall survival (OS) parameter was not achieved in the phase 3 CRPC trial, treatment with cabozantinib resulted in a significant improvement in GDP compared to prednisone and other clinically beneficial effects and biomarker changes, such as improved response on skeletal bone scans ( BSR) and markers of bone remodeling, reduced incidence of skeletal related diseases, and reduced circulating tumor cells. Encouraging clinical activity of cabozantinib has also been observed in the early phases of several clinical trials in advanced NSCLC (Drilon et al. 2016, Neal et al. 2016, Hellerstedt et al. 2012, Wakelee et al. 2017; Schoffski et al. 2017). The objective response rate (ORR) in heavily pretreated non-selected NSCLC was approximately 10% and 28% in RET-rearranged NSCLC. Median PFS and median OS were comparable to standard chemotherapy in this patient population (Alimta [pemetrexed] US PI, Taxotere [docetaxel] US PI).

Preclinical studies (Kwilas et al. 2014, Song et al. 2015, Lu et al. 2017) and clinical observations of circulating immunosuppressive cells and immune effector cells (Apolo et al. 2014) suggest that cabozantinib promotes the formation of an immunopermissive environment by inhibiting immunomodulatory targets on immune cells. This may provide an opportunity for synergistic effects from combined treatment with ICTIO. In an ongoing Phase 1 study into genitourinary (GU) malignancies, cabozantinib was evaluated in combination with ICTI nivolumab, an anti-PD-1 monoclonal antibody. The dose escalation phase was completed and no dose-limiting toxicity (ODT) was reported.

The recommended dose for phase 2 (R2PD) was defined as 40 mg per day (r/day) for cabozantinib in combination with 3 mg/kg nivolumab (intravenous (IV), every two weeks (r2n)). At the end of the data collection, ORR was 39% among various types of MPS tumors. Among subjects with CM, 44% of PRRs were reported, and among nine reported CRPCs, 67% achieved a stable state of disease, and one subject had a partial response (Nadal et al. 2017). The combination of cabozantinib with ICTI may also provide a strategy to overcome resistance to ICTI therapy. This conclusion is based on a recent observation in a clinical study where retreatment with ICTIO in combination with VEGFR-TKI sitravatinib, which has

- 18 041548 A target profile similar to cabozantinib led to the abolition of existing resistance to ICTO in patients with NSCLC (Leal et al. 2017). These results suggest that the combination of ICTO with cabozantinib may confer a tumor microenvironment that promotes resensitization to ICTI therapy after prior progression to ICTI.

The dose escalation phase of the current study (XL184-021) has been initiated and is ongoing in subjects with advanced UC or RCC. In Group 1, no ODTs were identified during the dose escalation phase for the combination of 40 mg cabozantinib r/day and 1200 mg atezolizumab r3n. Group 2 is currently being evaluated with a combination of 60 mg cabozantinib r/day and 1200 mg atezolizumab r3n. Once the recommended dose of cabozantinib has been established for combination therapy with the standard dose of atezolizumab, the expansion stage in the tumor-specific groups of UC, RCC, CRPC, and NSCLC will be recorded to further evaluate the safety and efficacy of this combination in these tumor-related symptoms.

Goals

Dose escalation step:

The primary objective is to: Determine the maximum tolerated dose (MTD) and/or recommended dose and schedule for the subsequent phase of expansion of daily oral dosing of cabozantinib in subjects with solid tumors when taken in combination with atezolizumab.

The secondary objective is to: To evaluate the plasma pharmacokinetics (PK) of daily oral cabozantinib in patients with solid tumors when used in combination with atezolizumab.

Assess the safety of combination therapy by evaluating the incidence and severity of non-serious adverse events (AEs) and serious adverse events (SAEs), including immune-related adverse events (IAEs) and adverse events of special interest (SAEs).

The research objective is to: Correlate assays of immune cells, tumor cells, and blood biomarkers with clinical outcome

Expansion stage:

The main objective and measured parameter are as follows:

Assess preliminary efficacy by evaluating the OER as assessed by the Investigator in the Response Evaluation Criteria for Solid Tumors (Version 1.1) (COER 1.1)

The secondary goal is:

Assess the safety of combination therapy by assessing the incidence and severity of non-serious PE and PET, including ISPE and PEOI.

Research objectives and measured parameters:

ORR as assessed by the investigator according to the modified QOOSR for immune response.

Duration of response (TR) as assessed by the investigator according to CCAS 1.1

Progression-free survival as assessed by the investigator according to COOS 1.1

Overall survival

Correlation of immune cell, tumor cell and blood biomarker assays with clinical outcome

Changes in tumor infiltration and/or histology or other molecular changes identified by an optional tumor biopsy.

Additionally, to evaluate the plasma pharmacokinetics (PK) of daily oral cabozantinib in patients with solid tumors when used in combination with atezolizumab.

For CRPC only: changes in prostate-specific antigen (PSA) and evaluation of mismatch repair (MMR) and microsatellite instability (MSI) status

Clinical Study Plan

This is a Phase 1b, multicenter, open-label study to evaluate the safety, tolerability, preliminary efficacy, and PK of cabozantinib given in combination with atezolizumab in patients with UC, RCC, CRPC, and advanced NSCLC.

This study consists of two stages:

Dose escalation phase: to determine dosing schedule and MTD and/or recommended dose of cabozantinib during the escalation phase when used in combination with the standard atezolizumab dosing regimen (1200 mg infusion, once every 3 weeks). Three levels of daily dose of cabozantinib tablet will be considered for evaluation: 20, 40 and 60 mg. Subjects will be added to boost groups of 3-6 subjects using a 3 plus 3 schedule and dosing will begin at the 40 mg dose level of cabozantinib. Subjects with advanced UC or RCC will qualify for dose escalation groups, and groups may contain a combination of subjects with these tumor types. At this stage, the decision to open a new cohort will be made by the Group Evaluation Committee (GRC) if all subjects in the current cohort have taken atezolizumab for at least 21 days after the first dose (defined as the OCT evaluation period). All available safety and PK data will be considered when deciding whether to increase or decrease the dose in the next cohort or when expanding

- 19 041548 of the current group. The MTD of cabozantinib will be defined as the highest dose level evaluated at which no more than 1 in 6 patients experience OTD. The recommended dose and schedule for the expansion phase will be determined by the COG based on the OCT and other relevant safety information.

Relative dose level Cabozantinib Atezolizumab 2 60 mg orally once a day 1200 mg IV rZn 1 40 mg orally once a day 1200 mg IV rZn -1 20 mg orally once a day 1200 mg IV rZn

in / in - intravenously; r3n - once every three weeks

Dose limiting toxicity will be determined by the COG considering all available data and defined as any of the following occurring during the evaluation period of the CCT.

Any associated AE that, in the opinion of the COG, is of potential clinical importance, such that a further increase in the dose of cabozantinib may place subjects at unacceptable risk.

Any associated AE > Grade 3 that is unexpected in severity and/or duration compared to the known safety profiles of cabozantinib and atezolizumab when used as separate agents, and that cannot be managed by dose modification (reduction or interruption) and adequate maintenance therapy and requires long-term discontinuation of cabozantinib and/or atezolizumab.

Failure to take > 75% of the total scheduled dose of cabozantinib during the ODT evaluation period due to treatment-related PE resulting in dose reduction and/or interruption.

Subjects in the dose escalation phase will receive study treatment on one of two dosing schedules: the standard dosing schedule or the cabozatinib introductory dosing schedule. The dose escalation step will be started using the standard dosing schedule. An introductory dosing schedule for cabozantinib may be used at the request of the COG if, after evaluating the standard dosing schedule, the recommended dose of the expansion stage has not been determined.

Standard Dosing Schedule: Initial dose escalation groups will follow a combined schedule according to the Standard Dosing Schedule with the first infusion of atezolizumab administered on the same day as the first dose of cabozantinib (in Cycle 1 Day 1 [C1D1]).

Cabozantinib Introductory Dosing Schedule: If an analysis of the safety data for all enrolled subjects on the standard dosing schedule does not provide a recommended dose for the expansion phase, the COG may decide to enroll additional groups treated according to the cabozantinib introductory dosing schedule. Subjects in these groups will receive the first infusion of atezolizumab in C2D1 21 days after the first dose of cabozantinib agent alone (same possible dose levels as described above). Subjects will only be assessed for the presence of OTD within the 21-day period after receiving the first infusion of atezolizumab (ODT assessment period). These cohorts will be enrolled according to the 3+3 strategy described above, but the COG may enroll subjects in one or more dose levels to ensure that a sufficient number of subjects reach the RCT evaluation period while still receiving the cohort's assigned dose (i.e. e., experienced no dose reduction on the cabozantinib introductory dosing schedule). Administration of the first dose of atezolizumab should not occur while treatment with cabozantinib is interrupted; initiation of cycle 2 should be delayed until cabozantinib treatment is resumed, well tolerated, and the investigator has determined that atezolizumab can be administered safely. Subjects who discontinue cabozantinib treatment during Cycle 1 as per the introductory cabozantinib dosing schedule will not be eligible to receive atezolizumab during the study. The purpose of this dosing schedule is to help the COG evaluate whether subjects could improve tolerability of the combination of cabozantinib and atezolizumab if they were first given the opportunity to optimize their tolerance to cabozantinib alone during a three-week run-in period. Therefore, the COG will take into account the safety data from all dose escalation groups when determining the recommended dose and scheduling of the expansion stage.

Expansion Stage: Once the COG determines the recommended dose and schedule for cabozantinib in combination with the standard dose of atezolizumab, the study will enter the Expansion Stage. Eight expansion groups will be enrolled at this stage for patients with UC, RCC, CRPC, and advanced NSCLC to provide additional safety, PK, and pharmacodynamic data at the recommended dose and schedule. Only one dose level and dosing schedule will be evaluated during the expansion phase (standard dosing schedule or cabozantinib introductory dosing schedule).

The following is an abbreviated description of 1-8 expansion groups:

- 20 041548

Group Type of tumor (Histology) Abbreviated suitability description Initial group size (P) Possible additional enrollment (p) 1 PCC (transparent cell) No prior systemic anticancer therapy thirty - 2 UK (transitional cell) Prior platinum-containing chemotherapy was prescribed thirty - 3 UK (transitional cell) Unsuitable for treatment with cisplatin, but not previously treated with systemic cancer therapy thirty - 4 UK (transitional cell) Suitable for treatment with cisplatin, but not yet thirty -

systemic anti-cancer therapy 5 UK (transitional cell) Appointed pre-treatment with an immune checkpoint inhibitor thirty 50 6 CRPC (adeno) Pre-treatment with enzalutamide and/or abiraterone thirty - 7 NSCLC (non-squamous) Appointed pre-treatment with an immune checkpoint inhibitor thirty 50 8 NSCLC (non-squamous) Not appointed pre-treatment with an immune checkpoint inhibitor thirty - Total registered 240 340

All expansion groups will initially include 30 entities. Due to the high unmet need for patients who have progressed on prior ICTI therapy, the Study Review Committee may, after reviewing the data for expansion groups 5 and 7, allow additional enrollment in every 50 subjects to further evaluate the clinical activity and safety of cabozantinib in combination with atezolizumab after progression to IKTIO. All subjects enrolled in an expansion group will follow the same evaluation schedule and dosing instructions. For more information on subject eligibility for this study, please refer to the inclusion and exclusion criteria. The rationale for enrollment in each expansion group is given in section 1.3.1.

Treatment periods for both stages:

The course of treatment for each subject will consist of the following periods:

Pretreatment Period: Potential subjects will be screened for eligibility criteria. Qualification screening evaluations must be conducted within 28 days prior to the first dose of investigational treatment, unless otherwise specified.

Treatment Period: Eligible subjects will receive open combination treatment. Cabozantinib (20, 40, or 60 mg depending on study stage and dose escalation group) will be given orally once a day. The date of the first dose of cabozantinib will be defined as C1D1. Atezolizumab (1200 mg infusion) will be administered once every three weeks (-2 days) on Day 1 of each cycle, starting with C1D1 for the standard dosing schedule or C2D1 for the cabozantinib induction dosing schedule.

Permitted modifications to the investigational medicinal product include:

- 21 041548 dose reduction (from 60 to 40 mg per day, from 40 to 20 mg per day, or from 20 mg per day to 20 mg once every other day (r / h / s)) or interruptions in cabozantinib and dose delay for atezolizumab.

Subjects will receive study treatment for as long as they continue to receive clinical benefit, in the opinion of the investigator, or until unacceptable toxicity or the need for subsequent systemic anticancer treatment occurs. Treatment may continue after progression is detected by x-ray as long as the investigator believes that the subject is still receiving clinical benefit from investigational treatment and that the potential benefit of continuing investigational treatment outweighs the potential risk. Upon notification of the sponsor, subjects may be allowed to discontinue one component of the investigational treatment but continue to receive the other.

Post-Treatment Period: A final safety assessment will be conducted post-treatment at a follow-up visit 30 (+14) days after the date of the decision to discontinue treatment. If the subject experiences PET, PEOI, or Grade 3 or 4 PE on or during this visit, they will continue to be monitored until the PE resolves, PE improves to Grade 2 or less, or the investigator will determine that the side effect has become stable or irreversible.

Maintenance Phase: When enough data has been collected to adequately evaluate all measured study parameters, and after local notification of the sponsor, subjects remaining on study treatment will enter the maintenance phase. During the maintenance phase, subjects will continue to receive study treatment until the protocol's withdrawal criteria are met. Upon notification of the sponsor, subjects may be allowed to discontinue one component of the investigational treatment but continue to receive the other.

During the maintenance phase, subjects should undergo periodic safety evaluations (including local laboratory analyzes) and tumor evaluations; the nature and frequency of such assessments should be consistent with the standard of care, if permitted by local regulations. To continue gathering important safety information on subjects still participating in the study, POC reporting; AEs (including PEOIs), whether serious or not, and whether they lead to dose modification or discontinuation of treatment; ESPE and other reported adverse events (mistakes in pregnancy and medication with residuals) should be continued in accordance with protocol requirements specific to the maintenance phase.

Post-treatment assessments (including follow-up visits after treatment discontinuation) are not required for subjects who discontinue treatment in a maintenance phase study (such subjects must adhere to the standard of care).

Only data collected prior to the start of the maintenance phase will be included in the clinical study report.

Completion of the study by country or field: Once sufficient data have been collected to adequately assess all measured study parameters, and upon notification of the center by the sponsor, the study will be considered completed in the field and in countries where there are no more active subjects.

Number of subjects

From 9 to 36 subjects can be treated during the dose escalation step. In the dose group expansion phase, about 240 to 340 subjects will be treated in eight different tumor groups: All expansion groups will initially enroll about 30 subjects each. Enrollment in groups 5 and 7 may be further expanded by an additional 50 subjects to approximately 80 subjects each, subject to the decision of the Study Review Committee confirming that there was clinically significant activity warranting further evaluation of the safety and efficacy of combination therapy in these groups.

Target population

To be eligible for participation in the study, a subject must meet all of the inclusion criteria and none of the exclusion criteria. Sponsor will not grant exceptions to these eligibility criteria:

Inclusion Criteria

1. Cytologically or histologically and radiologically confirmed solid tumor, inoperable, late-stage local, metastatic or recurrent:

Dose escalation step:

Subjects with UC (including renal pelvis, ureter, bladder, urethra) after prior platinum-based therapy, or

Subjects with RCC (histology - clear cells, opaque cells) with or without expansion stage in prior systemic cancer therapy:

Expansion Group 1: Subjects with RCC with clear cell histology (including those with a mixed sarcomatoid component) and no previous systemic anti-cancer therapy.

Expansion Group 2: CM subjects with transitional cell histology (including renal pelvis

- 22 041548 ku, ureter, bladder, urethra), whose progression is confirmed radiographically on or after platinum-containing chemotherapy, including subjects who received previous neoadjuvant or adjuvant platinum-containing therapy with disease recurrence < 12 months from the end of the last therapy.

Expansion group 3: CM subjects with transitional cell histology (including renal pelvis, ureter, bladder, urethra) who are ineligible for cisplatin-based chemotherapy and have not previously received systemic cancer therapy for unresectable local advanced or metastatic disease .

Eligibility for cisplatin-based chemotherapy is determined by one of the following criteria:

Impaired renal function (glomerular filtration rate [GFR] > 30 ml/min/1.73 m ² and < 60 ml/min/1.73 m ² , hearing loss > 25 dB at two adjacent frequencies, or peripheral neuropathy > 2nd degree in the Common Terminology Criteria for Adverse Effects (GCSE) v4.

Prior neoadjuvant or adjuvant platinum-based chemotherapy is allowed if disease recurrence occurs > 12 months after the end of the last therapy.

Expansion Group 4: CM subjects with transitional cell histology (including renal pelvis, ureter, bladder, urethra) who are eligible for cisplatin-based chemotherapy and have not previously received systemic anticancer therapy for unresectable local advanced or metastatic disease .

Prior neoadjuvant or adjuvant platinum-based chemotherapy is allowed if disease recurrence occurs > 12 months after the end of the last therapy.

Expansion Group 5: Subjects with CM with transitional cell histology (including renal pelvis, ureter, bladder, urethra) whose progression is confirmed radiologically with or after prior administration of one immune checkpoint inhibitor (anti-PD-1 or anti- PD-L1) as the most recent therapy for the treatment of unresectable local advanced or metastatic disease.

Up to 2 lines of prior systemic cancer therapy for treatment of localized advanced stage or metastatic UC are allowed, including prior treatment with an anti-CTLA-4 agent.

Excluded are subjects who have previously received combination therapy with an immune checkpoint inhibitor (anti-PD-1 or anti-PD-L1) VEGFR-targeted TKI.

Expansion Group 6: Subjects with metastatic CRPC (prostate adenocarcinoma without neuroendocrine differentiation or small cell features) who have radiological evidence of soft tissue progression on or after taking enzalutamide and/or abiraterone acetate for the treatment of metastatic disease (Note: PSA progression or progression in the bones do not allow to determine suitability).

Prior chemotherapy is not allowed, except for docetaxel given in combination with anti-androgen therapy (AAT) for the treatment of advanced castration-sensitive disease prior to treatment with enzalutamide and/or abiraterone acetate.

Prior treatment with radium Ra 223 dichloride is not allowed.

The subject must have a castration testosterone level (< 50 ng/dL [< 2 nM]) after bilateral orchiectomy or ongoing anti-androgen therapy using a gonadotropin-releasing hormone (GnRH) analog that was started more than 4 weeks prior to the first dose study treatment, and should continue throughout the study.

Expansion group 7: Subjects with non-squamous stage IV NSCLC whose progression is confirmed radiographically with or after previous use of a single immune response checkpoint inhibitor (anti-PD-1 or anti-PD-L1) as the most recent therapy for the treatment of metastatic disease .

Up to 2 lines of prior systemic anti-cancer therapy for the treatment of metastatic NSCLC is allowed, including prior treatment with an anti-CTHA-4 agent.

Excluded are subjects who have previously received combination therapy with an immune checkpoint inhibitor (anti-PD-1 or anti-PD-1) with a VEGFR-targeted TKI and have been diagnosed with an EGFR mutation, ALK translocation, ROS1 rearrangement, or mutation. BRAF V600E.

Expansion group 8: Subjects with non-squamous stage IV NSCLC who have not previously received immune checkpoint inhibitor (anti-PD-1 or anti-PD-L1) therapy.

One line of previous systemic anticancer therapy for the treatment of metastatic NSCLC is allowed.

Subjects diagnosed with an EGFR mutation, an ALK translocation, a ROS1 rearrangement, or a BRAF V600E mutation are excluded.

2. Measurable manifestations of the disease according to CCAS 1.1, as determined by the investigator

- 23 041548 Lem. A measurable manifestation of the disease should be outside the radiation field if previous radiation therapy has been performed.

3. Tumor tissue material available (archival or recent tumor biopsy)

4. Recovery to baseline or < HRMS v4 grade 1 from toxicity associated with any prior treatment, unless AEs are clinically non-significant and/or stable on maintenance therapy.

5. Age eighteen or older on the date of consent.

6. General condition 0 or 1 according to the Eastern Cooperative Oncology Group (ECOG).

7. Adequate organ and bone marrow function based on compliance with all of the following laboratory criteria within 14 days prior to the first dose of study treatment:

Absolute neutrophil count (ANC) > 1500/mm ³ (> 1.5 billion/L) without granulocyte colony-stimulating factor support within 2 weeks prior to laboratory screening of collected samples.

The number of leukocytes> 2500 / mm ³ (> 2.5 billion / l).

Platelets > 100,000/mm ³ (> 100 billion/L) without blood transfusion within 2 weeks prior to laboratory screening of collected samples.

Hemoglobin > 9 g/dL (> 90 g/L) without blood transfusion within 2 weeks prior to laboratory screening of collected samples.

Alanine aminotransferase (ALT), aspartate aminotransferase (ACT), and alkaline phosphatase (AP) < 3 times upper limit of normal (ULN). ALP < 5x ULN with documented bone metastases.

Total bilirubin > 1.5 times ULN (for subjects with Gilbert's disease > 3 times ULN).

Serum creatinine > 2.0 times ULN or estimated creatinine clearance < 30 ml/min (< 0.5 ml/s) using the Cockcroft-Gault equation (see Table 5-2 for the Cockcroft-Gault formula).

Urinary protein/creatinine ratio (MPKR) < 1 mg/mg (< 113.2 mg/mmol) for subjects with RCC, CRPC, or NSCLC; and < 2 mg/mg (< 226.4 mg/mmol) creatinine for subjects with CM.

8. Able to understand and comply with protocol requirements and must sign an informed consent document.

9. Sexually active fertile subjects and their partners must agree to use medically accepted methods of contraception (eg, barrier methods, including the male condom, female condom, or diaphragm with spermicidal gel) during the study and for 5 months after the last dose of treatment in within the framework of the study.

10. Female subjects must not be pregnant at screening. Women of childbearing potential are defined as premenopausal women who are able to become pregnant (i.e., women who have had any signs of menstruation in the last 12 months, excluding those who have had a previous hysterectomy). However, women who have been amenorrheic for 12 months or more are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogen, low body weight, ovarian suppression, or other causes.

Exclusion Criteria

Prior treatment with cabozantinib or ICTO, including anti-CTLA-4, anti-PD-1, anti-PD-L1, anti-PD-L2, anti-OX-40, anti-CD137 therapy, except expansion groups 5 and 7, in which prior anti-PD-1 or anti-PD-L1 therapy is required for eligibility (see Inclusion Criteria 1g and 1i, respectively, for details).

Receiving any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 2 weeks prior to the first dose of investigational treatment.

For CRPC subjects: receiving flutamide or nilutamide within 4 weeks or bicalutamide within 6 weeks prior to the first dose of study treatment.

4. Receipt of any type of antitumor antibody (including investigational antibody) or systemic chemotherapy within 4 weeks prior to the first dose of investigational treatment, except expansion groups 5 and 7, for which receipt of an antibody targeting PD-1, PD-L1, or CTLA- 4 resolved within 4 weeks prior to the first dose of study treatment.

5. Radiation therapy to treat bone metastases within 2 weeks, any other radiation therapy within 4 weeks prior to the first dose of study treatment. Subjects with clinically significant non-resolving complications from prior radiation therapy are ineligible.

6. Known brain metastases or cranial epidural disease, unless they are adequately treated with radiation therapy and/or surgery (including radiosurgery) and are stable for at least 4 weeks prior to the first dose of investigational treatment. Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of the first dose of study treatment.

7. Concomitant anticoagulation therapy with oral anticoagulants (eg, var

- 24 041548 farin, direct inhibitors of thrombin and factor Xa) or platelet inhibitors (eg clopidogrel).

Permitted anticoagulants are as follows:

Low-dose aspirin for cardioprotection (according to locally applicable guidelines) and low-dose low molecular weight heparins (LMWHs).

Anticoagulation with therapeutic doses of LMWH in subjects without known brain metastases who are taking an unchanged dose of LMWH for at least 6 weeks prior to the first dose of study treatment and who have not had clinically significant bleeding complications due to anticoagulation therapy or tumor.

8. Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 2 weeks prior to the first dose of investigational treatment. Inhaled and topical corticosteroids and mineralocorticoids are allowed.

9. Administer a live, attenuated vaccine within 30 days prior to the first dose of study treatment.

10. The subject has an uncontrolled, significant intercurrent or recent illness, including but not limited to the following pathologies:

a) Cardiovascular diseases:

New York Heart Association grade 3 or 4 congestive heart failure, unstable angina, severe arrhythmias.

Uncontrolled high blood pressure, defined as constant blood pressure (BP) > 150 mm. Hg systolic or > 100 mmHg diastolic despite optimal antihypertensive treatment.

Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI), or other ischemic or thromboembolic event (eg, deep vein thrombosis [DVT], pulmonary embolism) within 6 months prior to the first dose.

Subjects diagnosed with DVT within 6 months are eligible if they are stable, asymptomatic and have taken LMWH for at least 6 weeks prior to the first dose.

b) Gastrointestinal disorders (GID), including those associated with a high risk of perforation or fistula formation:

Tumors affecting the gastrointestinal tract, active peptic ulcer, inflammatory bowel disease, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreas or bile ducts, or pylorus obstruction.

Abdominal fistula, gastrointestinal perforation, intestinal obstruction, or intra-abdominal abscess within 6 months prior to first dose.

Note: Complete cure of an intra-abdominal abscess must be confirmed prior to the first dose.

Clinically significant hematuria, hematemesis, or hemoptysis > 0.5 teaspoon (2.5 ml) of red blood, or other significant bleeding (eg, pulmonary hemorrhage) within 12 weeks prior to the first dose.

Cavitating lung disease or known manifestation of endobronchial disease.

Lesions affecting large pulmonary blood vessels.

Other clinically significant disorders such as:

i) Having an active or history of autoimmune disease or immunodeficiency, including but not limited to: myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener's granulomatosis, Sjogren's syndrome, Guillain-Barré syndrome, or multiple sclerosis (for a more detailed list of autoimmune diseases and immunodeficiencies, see Appendix D).

Subjects with the following pathologies may participate in the study:

History of autoimmune hypothyroidism and thyroid hormone replacement therapy.

Controlled type 1 diabetes mellitus and intake regimen.

Asthma requiring intermittent use of bronchodilators.

Eczema, psoriasis, lichen simplex chronicus or vitiligo with dermatological manifestations only if the following are observed:

Rash covers < 10% of body surface area.

The disease is well controlled at baseline and requires only low-potency topical corticosteroids.

Absence of acute exacerbations of the underlying pathology requiring psoralen plus ultraviolet A, methotrexate, retinoids, biological agents, oral calcineurin inhibitors, or high potency or oral corticosteroids within the previous 12 months.

Active infection requiring systemic treatment, human immunodeficiency virus infection

- 25 041548 ka (HIV) or disease associated with acquired immunodeficiency syndrome (AIDS), or acute or chronic infection with hepatitis B or C, or a positive test for tuberculosis.

History of idiopathic pulmonary fibrosis, pneumosclerosis (eg, bronchiolitis obliterans), drug-induced pneumonia, idiopathic pneumonia, or evidence of active pneumonia on chest examination using computed tomography (CT). A history of radiation pneumonia in the radiation area (fibrosis) is allowed.

Serious non-healing wounds/ulcers/bone fractures.

Malabsorption syndrome.

Uncompensated/symptomatic hypothyroidism.

Moderate to severe liver failure (Child-Pugh classification B or C).

The need for hemodialysis or peritoneal dialysis.

History of whole organ or allogeneic stem cell transplantation.

Major surgery (eg, gastrointestinal surgery, removal or biopsy of brain metastases) within 8 weeks prior to the first dose of study treatment, except prior nephrectomy within 6 weeks prior to the first dose. Complete wound healing from major surgery should occur 3 weeks before the first dose, and from minor surgery (eg, simple excision, tooth extraction) at least 10 days before the first dose. Subjects with clinically significant non-resolving complications from prior surgery are not eligible.

Friederick corrected QT interval (QTcF) > 500 ms per electrocardiogram (ECG) within 28 days prior to the first dose of study treatment (see Section 5.6.4 for Friederick formula).

Note: If a single ECG shows a QTcF with an absolute value > 500 ms, within 30 minutes of the initial ECG, two additional ECGs should be performed approximately 3 minutes apart and the average of these three consecutive QTcF results will be used to determine eligibility.

Pregnant or lactating women.

Inability to swallow tablets.

Previously identified allergy or hypersensitivity to the components of the formulation used in the study treatment.

Diagnosis of other malignancy within 2 years prior to the first dose of investigational treatment, except for shallow skin cancer or low-grade localized tumors that are considered cured and not treated with systemic therapy. Incidentally diagnosed prostate cancer is allowed in subjects with CM if it is graded as stage < T2N0M0, Gleason score < 6, and PSA is undetectable.

Estimated duration of subject participation

It is anticipated that subjects with previously treated UA, CRPC, advanced NSCLC may receive study treatment for a median of 6 months, and that subjects with previously untreated UA, RCC, advanced NSCLC may receive study treatment. an average of 9 months. However, subjects will be observed until death, withdrawal of consent, or a sponsor's decision to stop collecting this data.

Estimated study period

It is anticipated that it will take 6 months to enroll subjects and determine the recommended dose and dose escalation phase schedule. It is estimated that it will take 16 months to register eight groups at the expansion stage.

Investigated dose regimen/route of administration/frequency

Cabozantinib will be provided as 60 mg and 20 mg tablets (expressed as the free base). During the dose escalation phase, cabozantinib will be administered orally daily at doses of 20, 40, or 60 mg.

Atezolizumab will be given at the standard dose of 1200 mg as an IV infusion once every 3 weeks (p3n). An initial atezolizumab infusion will be given over 60 (± 15) minutes without premedication to test for possible infusion-related reactions. Subsequent IV infusions may be given over 30 (± 10) minutes if the initial infusion is tolerable. Premedication of an infusion reaction is permitted after the initial infusion. Do not bolus or IV atezolizumab.

Initial dose escalation groups will receive a combined regimen on a standard dosing schedule with the first infusion of atezolizumab administered on the same day as the first dose of cabozantinib. If deemed necessary, the COG may decide to include additional groups in the dose escalation phase according to the cabozantinib introductory dosing schedule with the first infusion of atezolizumab given on day 2 of cycle 1 (C2D1), 21 days after the first dose of cabozantinib as the only agent. All in the expansion stage

- 26 041548 Subjects will receive cabozantinib at the recommended dose and schedule as established by the COG.

Safety assessments

Safety assessments will include assessments of PE (including ESPE and PEOP), vital signs, ECG, laboratory tests, and concomitant medications. The severity of adverse events, severity, treatment relevance within the study, and association with immune effects (i.e., ECPE) will be assessed by the investigator. Severity will be determined according to NCI OTKPO version 4.

Tumor assessments

Tumor response will be assessed using COOS 1.1 (Appendix F). Additional exploratory efficacy evaluation will include the use of a modified KOOS for immune response (Appendix G). Subjects will be assessed using magnetic resonance imaging (MRI) or computed tomography from the date of the first dose of investigational treatment until radiographically confirmed late stage disease progression in accordance with CCAS 1.1, as determined by the investigator, or until the date of the decision to permanently discontinue investigational treatment . Radiographic assessments of tumors will continue according to the schedule defined by the protocol, regardless of whether treatment is reduced, interrupted, delayed or discontinued.

Thoracic/abdominal/pelvic (THP): CT HBT, or CT of the chest and MRI of the abdomen/pelvis will be performed in all subjects at screening and every 6 weeks (± 5 days) after the start of study treatment for the first 12 months of the study. At the end of the 12 months of the study, these evaluations will be conducted every 12 weeks (± 7 days).

Brain: MRI (or CT) of the brain will be performed at screening for all subjects with RCC and NSCLC, and for subjects with CRPC or UC who have a history or clinical symptoms of brain metastasis. After initiation of investigational treatment, MRI (or CT) brain scans are required only for subjects with known brain metastases or clinical signs or symptoms suggestive of new central nervous system (CNS) metastases. Assessments will be held every 12 weeks (± 7 days). MRI is the preferred way to image the brain. If brain CT is performed instead of MRI, inconclusive results should be confirmed by MRI. Subjects without documented brain metastases at the time of screening evaluation are not required to undergo brain imaging after C1D1 unless clinically indicated. To qualify for study participation, brain metastasis must be stable and at least 4 weeks prior to the first dose.

Bone Scan: Technetium Bone Scan (TBS) will be performed at screening for all subjects with CRPC and for subjects with RCC, UC, or NSCLC who have a history or clinical symptoms (eg, bone pain) of bone metastases. After initiation of investigational treatment, bone scans are required only for subjects with documented bone lesions or if clinically marked by signs and symptoms suggestive of new bone metastases. Evaluations after the first dose will be performed according to normal clinical practice (approximately every 12 weeks for the first 12 months and every 24 weeks thereafter). Lesions identified on bone scans should not be recorded as targets, non-targets, or new lesions. Bone scan should be used to guide confirmatory imaging with CT/MRI if needed (these CT/MRI results will be used to evaluate CCSD v1.1), and bone scan results alone should not be used to determine progression in this study.

Subsequent assessments of overall survival

Subjects will be contacted approximately every 12 weeks after the post-treatment follow-up visit to assess survival status and document receipt of subsequent anti-cancer therapy until consent to participation in survival follow-up is withdrawn or until the sponsor determines that sufficient data have been collected about efficiency to study.

Pharmacokinetic studies

Dose escalation step:

For subjects on a standard dosing schedule, blood samples for PK analysis will be obtained on the day of the first dose of study treatment (C1D1; prior to administration of study drug [cabozantinib and atezolizumab], approximately 5 minutes after completion of atezolizumab infusion, and 2, 4, and 6-8 hours after administration of cabozantinib) and before the start of study treatment doses at C1D10, C2D1, and C3D1. For subjects on an introductory cabozantinib dosing schedule, blood samples for PK analysis will be obtained on the day of the first dose (C1D1; samples taken prior to study administration [cabozantinib and atezolizumab], and 2, 4, and 6-8 hours after cabozantinib administration), and also before the study

- 27 041548 treatment in C2D1, C2D10 and C3D1.

Expansion stage:

For subjects on a standard dosing schedule, blood samples for PK analysis will be obtained on the day of the first dose of study treatment (C1D1; prior to study treatment administration [cabozantinib and atezolizumab], approximately 5 minutes after completion of atezolizumab infusion, and 2 hours after the first cabozantinib doses) and prior to initiation of study treatment doses at C2D1 and C3D1. For subjects on an introductory cabozantinib dosing schedule, blood samples for PK analysis will be obtained on the day of the first dose (C1D1; samples taken prior to study administration [cabozantinib and atezolizumab], and 2 hours after the first dose of cabozantinib), as well as prior to study treatment at C2D1 and C3D1.

At both stages, samples will be analyzed for cabozantinib concentration; atezolizumab concentrations can be measured if necessary. PK sampling may be stopped early or the frequency of sampling may be changed at the discretion of the sponsor.

Biomarker assessments

Peripheral blood and tumor tissue will be collected and can be evaluated using exploratory biomarker assays. Peripheral blood samples will be obtained according to the evaluation schedule. Tumor tissue (archived) will be obtained prior to the first dose of study treatment, and may optionally be biopsied with fresh tumor tissue. Exploratory analyzes may include the following: MET, AXL, and PD-L1 in tumor samples to identify associations with clinical outcomes.

Immune cell infiltration and tumor characterization (i.e., mutation load assessment) in tumor and blood samples to identify association with clinical outcome

Circulating immune cells in peripheral blood (i.e., lymphocyte subset analysis by flow cytometry)

Blood biomarkers (i.e., cytokines/chemokines, VEGF)

For CRPC only: Changes in PSA and evaluation of MMR and MSI status

Collection of samples for biomarker analysis may be stopped early or the frequency of sampling may be changed at the discretion of the sponsor.

For NSCLC subjects, free tumor mutation analysis reports should be provided at screening.

Statistical methods

Dose escalation step:

The number of subjects in each dose escalation group was selected based on the well-designed design of the Phase 1 dose escalation study. Subjects are enrolled in groups on a 3 plus 3 basis, with each group initially consisting of 3 subjects and potentially expanding to 6 subjects depending on the number of patients observed. CCT. It is expected that 9 to 36 subjects will be enrolled at this stage, depending on the number of dose escalation groups and the subjects needed to establish the MTD or recommended dose and schedule for the expansion stage.

The summaries will focus on PE and tumor response by group. A timeline will also be prepared to describe enrollment and expansion of dose escalation groups, subject replacement, observed CCTs, COG decisions, and final rationale for the recommended dose and expansion stage schedule.

Expansion stage:

Objective Response Rate: The purpose of the expansion stage is to evaluate the ORR, defined as the proportion of subjects with a confirmed complete response (CR) or partial response (PR) according to CCAS 1.1, as determined by the investigator. ESR will be assessed independently in each of the expansion groups.

The main purpose of evaluating ORR is to assess whether the actual response rate with a given combination regimen is better than expected with monotherapy. Thus, two-sided Blyfe-Steel-Casell 80% and 60% confidence intervals (CI) will be constructed for ORR, providing 90% and 80% one-sided confidence intervals, respectively, when interpreting the lower bound. The sample size of 30 subjects for expansion groups was chosen to ensure that the lower bound of the two-tailed 80% CI did not exceed 12 percentage points from the point estimate. An example of 80% and 60% 2-tailed CIs with one-tailed interpretations of the lower bound is shown in the table below for the range of potential values for the observed ORR.

- 28 041548

Blyfe-Steel-Casell Confidence Intervals Example for OERs for Expansion Groups of 30 Subjects with One-Sided Interpretations of the Lower Bound

Observed responses (Total N=30) Observed MRO 80% 2-way CI 60% 2-way CI NDP VRT True MRR ^a (90% certainty) NDP VRT True MRR ^a (80% confidence) 17 0.57 0.44 0.69 > 44% 0.47 0.66 > 47% 15 0.50 0.38 0.62 > 38% 0.41 0.59 > 41% 12 0.40 0.28 0.53 > 28% 0.31 0.47 > 31% eleven 0.37 0.25 0.50 > 25% 0.28 0.44 > 28% 10 0.33 0.23 0.46 > 23% 0.25 0.41 > 25% 9 0.30 0.19 0.42 > 19% 0.24 0.38 > 24% 8 0.27 0.16 0.38 > 16% 0.19 0.34 > 19% 7 0.23 0.15 0.34 > 15% 0.16 0.31 > 16% 6 0.20 0.11 0.31 > 11% 0.13 0.28 > 13% 5 0.17 0.09 0.28 > 9% 0.12 0.24 > 12% 4 0.13 0.06 0.25 > 6% 0.08 0.19 > 8%

CI, confidence interval; LDP, lower confidence limit; ORR, objective response rate; UCL, upper confidence limit, and Per each one-sided interpretation of the lower bound.

The planned enrollment of 30 subjects in expansion groups 5 and 7 will be divided between 15 subjects with ICTIO-refractory disease (PT as the best response to prior ICTTI therapy) and 15 subjects with ICTIO-resistant disease (PO, OR, stable disease [SZ] as the best response to previous ICTIO therapy). The sample size of 15 subjects was chosen to ensure that the lower bound of the 2-tailed 80% CI did not exceed 19 percentage points from the point estimate. An example of 80% and 60% 2-tailed CIs with one-tailed interpretations of the lower bound is shown in the table below for the range of potential values for the observed ORR. If subjects who are difficult to treat with ICTI and/or are resistant to ICTI achieve a clinically significant ORR, as determined by the Study Review Committee, approximately 50 subjects can be added to group 5 and/or 7 (i.e., up to 80 subjects per each group) to further explore the safety and clinical benefit of the combination with these treatment options, having a highly unmet need and a novel mechanism of action for resensitization to ICTI therapy. Study Review Committee decisions regarding the clinical significance of the achieved OER in expansion groups 5 and 7 will be based on a lower bound of 80% CI for the entire cohort of 30 subjects, or 15 subjects with ICTIO-refractory disease and 15 subjects with ICTIO-resistant disease, as appropriate. As a guideline, the Study Review Committee may use a target observed ORR of 20-25% for expansion group 5, and 15-20% for expansion group 7. In general, this generally corresponds to an 80% confidence in the true ORR of > 11% for n=15 or >13% for n=30. The expansion of group 5 and/or 7 to 50 additional subjects may be limited to either ICTIO-refractory or ICTIO-resistant subjects, or may include subjects from both groups depending on the observed ORR.

Blyfe-Steel-Casell Confidence Intervals Example for OER for Expansion Groups of 15 Subjects with One-Sided Interpretations of the Lower Bound

Observed responses (Total N=15) Observed MRO 80% 2-way CI 60% 2-way CI NDP VRT True MRR ^a (90% certainty) NDP VRT True MRR ^a (80% confidence) 9 0.60 0.42 0.77 > 43% 0.46 0.70 > 46% 7 0.47 0.28 0.64 > 28% 0.33 0.61 > 33% 6 0.40 0.23 0.57 > 23% 0.30 0.54 > 30% 5 0.33 0.20 0.51 > 20% 0.23 0.46 > 23% 4 0.27 0.12 0.44 > 12% 0.16 0.39 > 16% 3 0.20 0.10 0.36 > 10% 0.11 0.33 > 11% 2 0.13 0.06 0.28 > 6% 0.08 0.23 > 8% 1 0.07 0.01 0.23 > 1% 0.03 0.16 > 3%

CI, confidence interval; LDP, lower confidence limit; FER, objective frequency

- 29 041548 response; UCL, upper confidence limit, and Per each one-sided interpretation of the lower bound.

PFS and OS: Median WSP and OS will be estimated using Kaplan-Meier methods.

PrO: Median PoA values will be assessed using Kaplan-Meier analysis and will be limited to patients who have experienced a confirmed objective response.

Safety: Data for PE, ESPE, PEOI and PE will be tabulated into groups according to organ system class and preferred general morbidity term; worst reported severity; and links to treatment within the study. Individual laboratory test results will be aggregated by treatment group to assess worse after

Example 2 Phase Ib Trial of Cabozantinib with Atezolizumab for the Treatment of Locally Advanced or Metastatic Solid Tumors

1. Background and rationale

1.1 Background

Immunotherapies with multitargeted tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICTIs) are two systemic modalities that have played an important role in recent advances in cancer treatment over the past few years. Both classes of therapies have demonstrated broad clinical effects, leading to new approved treatment options for a variety of tumor types, including renal cell carcinoma (RCC), urothelial carcinoma (UC), melanoma, non-small cell lung cancer (NSCLC), and others. The success of these types of therapies as standalone agents with different mechanisms of action has naturally led to interest in evaluating combinations of TKIs with ICTIOs in search of additional, possibly synergistic, anticancer clinical effects.

1.1.1 Atezolizumab

Atezolizumab is a humanized immunoglobulin (Ig) G1 monoclonal antibody that potently and selectively inhibits programmed death receptor 1 (PD-L1) ligand binding on tumor cells and tumor-infiltrating immune cells in the tumor microenvironment (McDermott et al. 2016). Through this interaction, atezolizumab interrupts the negative regulatory effects of PD-L1 on T cell proliferation and function that result from PD-L1 binding to programmed death receptor 1 (PD-1) and B7.1 (CD80) expressed on T cells. and other immune cells. The result is an increase in the susceptibility of tumor cells to a T-lymphocyte-mediated immune response, an effect that has been demonstrated in clinical practice for several types of tumors.

Atezolizumab is approved in the United States and the European Union for the treatment of patients with locally advanced or metastatic UC after prior platinum-containing chemotherapy, or those deemed unsuitable for cisplatin treatment (Rosenberg et al. 2016, Loriot et al. 2016). Atezolizumab is also approved for patients with advanced localized or metastatic NSCLC after prior chemotherapy (Fehrenbacher et al. 2016; Tecentriq US Prescribing Information and EMA SmPC). Patients with epidermal growth factor receptor (EGFR)-activating mutations or tumors positive for anaplastic lymphoma kinase (ALK) mutations should also receive targeted therapy prior to atezolizumab. In these tumor indications, atezolizumab either has a prolonged overall survival (OB) or elicits persistent disease responses. Notably, like other ICTIs, the effect of atezolizumab on progression-free survival (PFS) was modest, suggesting the possibility of delayed antitumor immune effects contributing to the observed survival advantage (Fehrenbacher et al. 2016). Like other ICTIs, treatment with atezolizumab is generally well tolerated but may be associated with immune-related adverse events (IAEs) including pneumonia, hepatitis, colitis, endocrinopathies including hypophysitis, ocular toxicity, myocarditis, and pancreatitis (Michot et al . 2016).

1.1.1.1. Clinical experience with urothelial cancer

Regulatory approval for atezolizumab in locally advanced or metastatic UC was obtained based on the results of a Phase 2, multicenter, open-label study using an objective response rate (ORR) versus Criteria for Response Evaluation in Solid Tumors (Version 1.1) (COER 1.1) by an Independent Regulatory Institution (IGI). ) as the primary measurable variable, and based on the results of a Phase 3 randomized, multicenter trial comparing atezolizumab with standard of care chemotherapy in subjects previously treated with platinum-based chemotherapy.

In the second arm of the Phase 2 study, which enrolled subjects with CM who had previously received platinum-based chemotherapy, the overall ORR according to the GCR was 14.8% (95% confidence interval [CI]: 11.1, 19.3), for subjects with 5% PD-L1 expression - 26.0% [95% CI: 17.7, 35.7], and for subjects with < 5% PD-L1 expression - 9.5% [95% CI: 5 .9, 14.3] (Rosenberg et al. 2016; TE

- 30 041548

CENTRIQ® US Prescription Information). The median PFS for the entire population was 2.1 months (95% CI: 2.1, 2.1); PFS analysis in subgroups gave similar results regardless of the level of PD-L1 expression. The median OS for the entire population was 7.9 months (95% CI: 6.6, 9.3); however, survival was longer in subjects with 5% PD-L1 expression, with a median OS of 11.9 months [95% CI: 9.0, not estimated {NR}] (Loriot et al. 2016). Atezolizumab was well tolerated in this study population; The most common adverse events (AEs), in descending order of frequency, were fatigue, decreased appetite, nausea, urinary tract infection, pyrexia, and constipation. Side effects led to treatment discontinuation in 3.2% of subjects. Pneumonia and elevated levels of aspartate aminotransferase (ACT) were the most common EIEs (2% each). During treatment, anti-drug antibodies were detected in 41.5% of subjects at one or more time points post-dose. However, the presence of such antibodies did not appear to have a clinically significant effect on pharmacokinetics (PK), safety or efficacy.

In a Phase 3 study, which also included subjects with UC after previous platinum-based chemotherapy, the results of atezolizumab were broadly consistent with those of the Phase 2 study. expression of PD-L123.0% [95% CI: 16, 32]. The duration of response (TR) in the general population for the atezolizumab arm was 21.7 months compared to 7.4 months for the chemotherapy arm. Although the primary measurable OS in this study was not achieved in PD-L1-positive (expression level 5%), the numerical improvement in OS in the general population (HR=0.85; 95% CI 0.73, 0.99) confirms the clinical benefit of atezolizumab in this patient population compared to standard of care chemotherapy. In addition, the safety profile of atezolizumab in this study was more favorable than for chemotherapy (Powles et al 2017).

In arm 1 of the Phase 2 study, which included untreated subjects with CL unsuitable for cisplatin treatment, the overall ORR was 23% (95% CI: 16, 31), for subjects with >5% PD-L1 expression -28% (95% CI: 14, 47) and for subjects with <5% PD-L1-21% (Bellmunt et al. 2016). The median OS for all subjects, regardless of PD-L1 expression level, was 15.9 months (95% CI: 10.4, NR). Experienced safety data for untreated CM subjects were similar to those for subjects who had previously received platinum-based therapy.

A Phase 3, multicenter, randomized trial evaluating atezolizumab as a single agent or in combination with platinum-based chemotherapy in untreated, advanced CM subjects (eligible for cisplatin and non-eligible for cisplatin) is ongoing and the results of this study are not yet available. (NCT02 8 07 63 6).

1.1.1.2. Clinical experience with renal cell carcinoma

The safety, tolerability, and tentative clinical activity of atezolizumab as a single agent in advanced RCC subjects with clear or opaque cell histology was demonstrated in a Phase 1 study (McDermott et al. 2016). Approximately 10% of the subjects in this study had not received prior systemic treatment with RCC. The ORR for PKK in clear cells ranged from 9 to 18% depending on the PD-L1 expression status. Overall median PFS and median OS for clear cell RCC subjects were 5.6 months (95% CI: 3.9, 8.2) and 28.9 months (95% CI: 20.0, NE), respectively . One subject with RCC with opaque cells responded according to the immuno-dependent criteria for response to immunotherapy. Treatment-related grade 3 effects were reported in 17% of subjects, but no treatment-related grade 4 or 5 PE was observed.

Atezolizumab also demonstrated promising clinical activity in combination with bevacizumab, an antibody targeting vascular endothelial growth factor (VEGF), in a Phase 2 randomized trial in untreated metastatic RCCs (Atkins et al 2017). The RR regardless of PD-L1 expression level was 32% and in PD-L1 positive subjects (>1% PD-L1 expression) was 46%. The median PFS regardless of PD-L1 expression level was 11.7 months (95% CI: 8.4-17.3), and in PD-L1-positive subjects it was 14.7 months (95% CI: 8.2 -25.1). The safety profile of this combination therapy was consistent with the safety profiles of the individual drug components.

A Phase 3, multicenter, randomized trial comparing atezolizumab plus bevacizumab with sunitinib as first-line treatment for progressive RCC is ongoing (NCT01984242). A sensational positive result was recently announced for a co-primary PFS measure. The combination of atezolizumab with bevacizumab demonstrated a statistically significant improvement in investigator-assessed PFS compared with sunitinib in patients expressing PD-L1 (Roche data on file).

1.1.1.3 Clinical experience with non-small cell lung cancer

The regulatory approval of atezolizumab for NSCL prior to platinum was obtained based on the results of a multicenter, randomized Phase 1 trial of atezolizumab.

- 31 041548 compared to docetaxel (Rittmeyer et al. 2017). Subjects received atezolizumab (1200 mg) or docetaxel (75 mg/m ² ) every 3 weeks. The co-primary parameters measured were OS in the PNL population (analysis of data from all subjects without any exclusion) and PD-L1 positive population (21% PD-L1 expression). Overall survival was significantly improved with atezolizumab compared with docetaxel in the PNL population (median OS: 13.8 vs. 9.6 months; relative risk [RR] = 0.73, p=0.0003) and in PD -L1 positive population (median OS: 15.7 vs. 10.3 months RR=0.74, p=0.0102). The ORR was similar across treatment groups (14% for atezolizumab versus 13% for docetaxel) in the PCNL population; however, the median PQ was longer with atezolizumab (16.3 months vs. 6.2 months). Fewer subjects discontinued treatment due to PE in the atezolizumab group (8%) compared to the docetaxel group (19%). The most common AEs of any grade for subjects on atezolizumab were fatigue (14%), nausea (9%), anorexia (9%), and asthenia (8%). Immune-related AEs reported for atezolizumab included pneumonia (four subjects, all grade 3), hepatitis (two subjects, both grade 4), and colitis (two subjects, both grade 2). Fewer subjects had treatment-related grade 3 or 4 PE with atezolizumab (15%) than with docetaxel (43%).

Promising clinical activity of atezolizumab as a first-line therapy for advanced NSCLC has been demonstrated in a Phase 2 multicentre study (Peters et al 2017). Enrollment was based on the expression of PD-L1 (25%) on tumor cells or immune cells. In untreated NSCLC patients with 250% PD-L1 expression on tumor cells, or 210% on immune cells (PD-L1 high group), 400 (31%) in NSC was comparable to standard care chemotherapy with these treatment options. The median OS (26.9 months) in the high PD-L1 group was longer compared to standard-of-care chemotherapy with these treatment options. The median duration of response in the high PD-L1 group was approximately 10 months, and the median PFS was 5.4 months. Subgroup analysis confirmed the hypothesis that the results of radiologically measured PFS and ORR were dependent on PD-L1 expression; however, the observed OS advantage is believed to be independent of PD-L1 expression. Treatment-related grade 3 or 4 PE with atezolizumab monotherapy occurred in 9% of subjects. Treatment grade 5 was not observed. Adverse events leading to treatment discontinuation occurred in 7% of subjects and included grade 3 or 4 pneumonia (1%), and pneumonia of any grade (1%).

The ongoing Phase 3 multicenter randomized trials in subjects with advanced NSCLC not receiving chemotherapy are evaluating atezolizumab versus chemotherapy (non-squamous NSCLC: NCT02409342, squamous NSCLC: NCT02409355), atezolizumab plus chemotherapy versus chemotherapy (not squamous NSCLC: NCT02367781; squamous NSCLC: NCT02367794) or atezolizumab in combination with chemotherapy and bevacizumab versus chemotherapy and bevacizumab (non-squamous NSCLC: NCT02366143). Positive results have recently been announced for the atezolizumab/chemotherapy/bevacizumab combination. Combination chemotherapy with atezolizumab/bevacizumab demonstrated an improvement in the co-primary measured parameter PFS compared with chemotherapy/bevacizumab in subjects with non-squamous NSCLC (median PFS 8.3 vs. 6.8 months; RR 0.617 (95% CI: 0.517, 0.737; P < 0.0001. PFS benefit was also observed in subjects with EGFR and ALK genetic alterations, PD-L1-negative tumors, and liver metastases. At the time of PFS analysis, co-primary OD data were not available (Reck et al. 2017 ).

1.1.1.4 Clinical experience with castration-recurrent prostate cancer

Patients with prostate cancer who progress on antiandrogen therapy (castration-recurrent prostate cancer, CRPC) have a poor prognosis. At this stage of the disease, standard treatment options include antiandrogen therapy (eg, enzalutamide, abiraterone), chemotherapy (eg, docetaxel, cabazitaxel), and radionuclides (eg, radium 223). Evidence is emerging that certain types of immunotherapy may provide clinical benefit to patients with advanced prostate cancer. For example, Sipuleucel T, a cancer vaccine, has been approved for minimally symptomatic metastatic CRPC (Kantoff et al. 2010). Recently, immune checkpoint inhibitors (ICTIs) have been evaluated as potential new treatments for patients with CRPC. For example, the PD1 inhibitor pembrolizumab has shown encouraging preliminary clinical activity in patients with CRPC after progression on the antiandrogen blocker enzalutamide, with prostate-specific antigen (PSA) normalization, radiological responses, and cessation of cancer pain (Graff et al. 2016). A possible explanation for the observed clinical activity is based on the observation of increased PD-L1 expression upon exposure to enzalutamide (Bishop et al. 2015). These data suggest that the likelihood of response to immunotherapy in CRPC may be improved after progression on therapy with enzalutamide. In addition, targeting immunosuppressive

- 32 041548 a variety of cells found both in the tumor and in the peripheral blood may be important for enhancing antitumor immune responses in patients with prostate cancer (Miller et al. 2010; Idorn et al. 2014).

A Phase 3, multicenter, randomized trial of the combination of atezolizumab with enzalutamide is ongoing after failed androgen synthesis inhibitor therapy in CRPC; the results of this study are not yet available (NCT03016312).

1.2 Cabozantinib

Cabozantinib (XL184) is a highly potent inhibitor of multiple receptor tyrosine kinases (RTKs) known to play an important role in tumor cell proliferation and/or tumor neovascularization, including MET, vascular endothelial growth factor receptor (VEGFR), AXL, and RET. Increased expression of MET and AXL has been implicated in the development of resistance to VEGFR inhibitors in preclinical models of several cancers (Shojaei et al. 2010, Zhou et al. 2016, Sennino et al. 2012, Ciamporcero et al. 2015). In addition, cabozantinib targets are involved in promoting tumor immune suppression, including TYRO3, MER, and AXL (tumor-associated macrophage kinase (TAM) family). Cabozantinib has demonstrated broad preclinical and clinical activity in several tumor types, including RCC, UC, CRPC, and NSCLC. In the US and the European Union, cabozantinib 140 mg capsules are approved for the treatment of advanced metastatic medullary thyroid cancer (Elisei et al. 2013; CometriqTM US PI and EMA SmPC) and cabozantinib tablets (60 mg) are approved for patients with advanced RCC after previous anti-angiogenic/VEGFR-targeted therapy (Choueiri et al. 2015, Choueiri et al. 2016, CabometyxTM US PI and EMA SmPC). Cabozantinib is also listed as a recommended therapy for patients with moderate to low risk untreated RCC (NCCN 2017), and is currently being considered by US and European Union regulators based on a statistically improved PFS compared with sunitinib (Choueiri et al. [J Clin Oncol] 2017, Choueiri et al [Ann Oncol] 2017).

A summary of the pharmacology, toxicology, PK, and clinical data for cabozantinib is provided in the sponsor's (or designee's) Investigator's Brochure, which must be reviewed prior to initiation of the study.

1.2.1 Non-clinical toxicology

The preclinical toxicology of cabozantinib has been characterized in single and repeated dose studies in several species. Details can be found in the investigator's brochure.

1.2.2. Clinical experience with renal cell carcinoma

The approval of the use of cabozantinib by early-treated RCCs was based on the results of a Phase 3, multicentre, randomized, controlled trial comparing open-label administration of cabozantinib (60 mg, tablets) with everolimus in 658 subjects (330 cabozantinib, 328 everolimus) with advanced disease who had earlier received therapy with at least one VEGFR-TKI (Choueiri et al. 2015, Choueiri et al. 2016, Cabometyx US PI and EMA SmPC). Cabozantinib demonstrated statistically significant improvements in the primary measurable variable (PFS) and both secondary measurable parameters (ORR, OS) compared with standard treatment in the control group (everolimus). In the primary PFS analysis performed with the first 375 randomized subjects (primary measure of the initial treatment population), the RR for each independent radiological panel (IRC) adjusted for stratification factors was 0.58 (95% CI: 0.45, 0, 74; stratified log-rank <0.0001), and Kaplan-Meier estimates for median PFS duration were 7.4 months in the cabozantinib group compared to 3.8 months in the everolimus group. In the primary analysis of ORRs for each NRC conducted in the originally prescribed treatment (PNL) population during the primary analysis of PFS, the ORRs for cabozantinib and everolimus groups were 17% (95% CI: 13, 22) and 3% (95% CI: 2 , 6), respectively (unstratified p<0.0001). In a subsequent unscheduled 0B interim analysis with a predetermined cut-off date providing a minimum follow-up of 13 months after last subject randomization, a statistically significant prolongation of OB was demonstrated for subjects in the cabozantinib arm compared with the everolimus arm: stratification-adjusted RR was 0 .66 (95% CI: 0.53, 0.83; stratified log-rank p-value 0.0003). Kaplan-Meier estimates for mean OS were 21.4 months in the cabozantinib group and 16.5 months in the everolimus group. The results of extensive subgroup analyzes of PFS, OS, and ORR showed a consistent benefit of treatment with cabozantinib compared with everolimus. The observed clinical activity of cabozantinib was applicable to subjects in all risk categories according to the Memorial Sloan-Kettering Cancer Center (MSKCC) criteria and was independent of previous treatments and tumor burden. Based on the known safety profile for cabozantinib, the most commonly reported adverse events for subjects treated with cabozantinib in a descending frequency study were diarrhea, fatigue, nausea, anorexia, palmoplantar erythrodysesthesia (PPE), hypertension, vomiting, weight loss, and constipation. (Cabometyx US Prescribing Information

- 33 041548tion). Side effects were generally managed with dose modifications (reductions and interruptions) with a dose reduction from 60 to 40 mg occurring in 60% of subjects and an additional dose reduction from 40 to 20 mg occurring in 20% of subjects. Treatment discontinuations due to PE were similar between the two treatment groups (10% of cases in each group), and the most common AEs leading to treatment discontinuation in the cabozantinib group were decreased appetite and fatigue.

In addition, study results were positive in a Phase 2 randomized trial of cabozantinib (60 mg) with 157 subjects (79 cabozantinib, 78 sunitinib) with previously untreated RCC conducted in collaboration with the US National Cancer Institute (NCI) Therapeutic Evaluation Program cancer (STER; Choueiri et al. [J Clin Oncol] 2017). The trial was consistent with its primary measurable endpoint, demonstrating a statistically significant and clinically significant improvement in PFS for cabozantinib compared with sunitinib in previously untreated patients with advanced intermediate-to-low-risk RCC according to the Consortium of the International Metastatic RCC Database Consortium criteria. The median per-investigator PFS for the cabozantinib arm was 8.2 months (95% CI 6.2, 8.8) compared with 5.6 months (95% CI 3.4, 8.1) for the sunitinib arm. Cabozantinib reduced the rate of disease progression or death by 34% compared with sunitinib (adjusted RR, 0.66, 95% CI 0.46 to 0.95; Choueiri et al. [J Clin Oncol] 2017). Median PFS for each ARC for cabozantinib was 8.6 months (95% CI 6.8, 14.0) compared with 5.3 months (95% CI 3.0, 8.2) for sunitinib (Choueiri et al. al [Ann Oncol] 2017). Median OS was 26.6 months in the cabozantinib group and 21.2 months in the sunitinib group (OOP 0.79, 95% CI 0.53, 1.2; two-tailed p = 0.27). Adverse effects greater than grade 3, regardless of causation, were found in 68% of subjects taking cabozantinib and 65% of subjects taking sunitinib; these effects included diarrhea (cabozantinib 10%, sunitinib 11%), fatigue (6%, 17%), hypertension (28%, 21%), PPE (8%, 4%), and hematologic side effects (2%, 21%). In both study arms, 16 subjects (20% cabozantinib, 21% sunitinib) discontinued treatment due to PE. The safety data in the cabozantinib group were consistent with those obtained in previous studies in subjects with progressive RCC.

1.2.3. Clinical experience with urothelial carcinoma

Cabozantinib (60 mg) was evaluated as a single agent in an open Phase 2 study in subjects with relapsed or refractory metastatic UC (NCT01688999, Apolo et al. [J Clin Oncol] 2016). A total of 67 eligible subjects with diagnoses of advanced metastatic carcinoma of the bladder, urethra, ureter, or renal pelvis were included in three groups. The largest group (Group 1) included 50 subjects with metastatic UC. In group 1, the primary measured ORR for the 42 evaluable subjects was 19.1% with 7 ORRs and 1 complete response (CR) for cabozantinib as the sole agent. Median PFS and median OS for these subjects were 3.7 months (95% CI: 3.1, 6.5) and 8.0 months (95% CI: 5.2, 10.3), respectively. Among all groups (n=67), the most common (>5% of cases) grade 3 PE associated with cabozantinib treatment was fatigue (9%), hypertension (7%), and hypophosphatemia (6%). Cabozantinib-associated grade 4 PE with hypomagnesaemia (3%) and increased lipase (1%) have been reported.

In an ongoing Phase 1 clinical trial in subjects with refractory metastatic UC and other genitourinary tumors (MPS), cabozantinib was evaluated in combination with nivolumab, a monoclonal antibody to PD-1 (designated as dual therapy), and in combination with nivolumab and ipilimumab, a monoclonal antibody targeting CTL4-A (designated as triple therapy) (Apolo et al. 2016, Nadal et al. 2017). Double and triple combinations were well tolerated and no dose-limiting toxicity (ODT) was reported (Apolo et al. 2016). The recommended Phase 2 dose for the dual combination was 40 mg cabozantinib daily (r/d) with nivolumab 3 mg/kg i.v. every other week (r2w), and for the triple combination 40 mg cabozantinib r/d with nivolumab 3 mg/day. kg IV r2n and ipilimumab 1 mg/kg iv every three weeks (r3n; maximum 4 doses). At cut-off, 42 subjects remained for both double and triple combinations for safety and response analyses. The ORR for all subjects with largely pretreated MPS tumors was 33% (Nadal et al. 2017). Among subjects with metastatic UC, 38% of ORRs were reported, and 15% achieved CR. In addition, subjects with rare types of UC, such as ureteral adenocarcinoma and bladder squamous cell carcinoma, responded to this combination therapy. After follow-up with a median up to 16 months, the median PQ was not reached for approximately 70% of ongoing responses; median OS was 20 months among reported cases of MPS. Treatment-related grade 3 and 4 AEs among all different dose levels studied for the dual combination (n=24 subjects) were: fatigue (12%), hypertension (8%), diarrhea (4% ), nausea or vomiting (4%), abdominal pain (4%), thromboembolic events (4%), and kidney infection (4%). The most frequent treatment-related grade 3 and 4 AEs among all different dose levels studied for the triple combination (n=18 subjects) were

- 34 041548 were: fatigue (11%), hypertension (17%), diarrhea (5%), anorexia (5%), inflammation of the oral mucosa or sore throat (5%), thromboembolic complications (5%) . Grade 3 and 4 immune-related AEs for the double combination group included one case of aseptic meningitis, and the triple combination group included one case of colitis and hepatitis. Grade 3 and 4 laboratory abnormalities reported for 2 subjects in the dual therapy group at all dose levels studied were: decreased neutrophil count (n=6), hypophosphatemia (n=5), increased lipase ( n=4), decreased platelet count (n=2), hyponatremia (n=2) and proteinuria (n=2). Grade 3 and 4 laboratory abnormalities reported for 2 subjects in the triple therapy group at all dose levels studied were: hypophosphatemia (n=4), increased lipase (n=4), decreased lymphocyte count ( n=3), hyponatremia (n=2) hypocalcemia (n=2), increased alanine aminotransferase (ALT) (n=2, both grade 3), increased ACT (n=1, grade 3), and increase in amylase level (n=1). PE grade 5 was not observed. This study currently enrolls additional subjects with MPS cancer in expansion groups.

1.2.4 Clinical experience with castration-recurrent prostate cancer

Following promising preliminary results for subjects with CRPC treated with cabozantinib in a Phase 2 study (Smith et al. 2013, Smith et al. 2014, Basch et al. 2015), a randomized, double-blind, drug-controlled comparison Phase 3 study was conducted. , with heavily pretreated subjects with advanced CRPC with bone metastases. Subjects were randomized to receive either cabozantinib or prednisone and OS was the primary parameter measured. The pre-scheduled primary OS analysis was based on PCNL analysis of all randomized subjects and showed no statistically significant improvement for subjects in the cabozantinib group compared with the prednisone group (RR = 0.90 [95% CI: 0.76, 1.06; stratified log-rank p-value 0.213]); Kaplan-Meier estimates for mean OS were 11.0 months in the cabozantinib group and 9.8 months in the prednisone group (Smith et al 2016). Although the study did not reach the primary measurand, encouraging activity was still demonstrated for the secondary and exploratory measurables. The secondary efficacy measure was the proportion of subjects with a bone scan response (BRR; defined as >30% reduction in total lesion area on bone scan from baseline without disease progression to soft tissue) for each NRC by week 12. The analysis demonstrated a statistically significant improvement in OSVR in the cabozantinib group compared with the prednisone group (42% vs. 3%; Cochran-Mantel-Haenszel stratified [CMH] p-value < 0.001). The mean duration of OSCC was 5.8 compared to 1.8 months. The median per-investigator PFS (exploratory measurable variable) was 5.6 months in the cabozantinib group and 2.8 months in the prednisone group (RR = 0.48 [95% CI: 0.40, 0.57; stratified log-rank p-value). < 0.0001]). Cabozantinib treatment was also associated with improvements in bone-related biomarkers and skeletal side effects.

Additional encouraging preliminary results in subjects with CRPC have been observed in the ongoing Phase 1 study, with the combination of cabozantinib and ICTI nivolumab (+/ipilimumab). One of nine registered subjects with metastatic CRPC (11%) experienced LR, and 67% had disease stabilization as the best response. (Nadal et al. 2017). These results indicate the need for further evaluation of the combination of cabozantinib with ICTI for CRPC.

1.2.5 Clinical experience with non-small cell lung cancer

Cabozantinib has been evaluated as a single agent or in combination in several early stage clinical trials in patients with advanced NSCLC.

In a Phase 2, open-label, randomized study, 125 subjects with NSCLC without EGFR genetic alterations received cabozantinib, erlotinib, or both agents in combination as second or third line treatment (Neal et al. 2016). Compared with erlotinib alone, primary measured PFS was significantly improved in subjects treated with cabozantinib as the sole agent (4.3 versus 1.8 months; RR=0.39, p=0.0003) and combination with erlotinib ( 4.7 m for 1.8 months; RR=0.37, p=0.0003). The estimated median OS for subjects treated with cabozantinib was 9.2 months (95% CI 5.1,15.0), for cabozantinib with erlotinib it was 13.3 months (95% CI 7.6, NR), and for erlotinib alone, 5.1 months (95% CI 3.3-9.3). The ORR for subjects treated with cabozantinib alone was 11%, while for the combination of cabozantinib with erlotinib it was 3% and with erlotinib alone it was 3%. Notably, progression as best response was reported for 66% of subjects treated with erlotinib alone, compared with 2324% for subjects treated with cabozantinib alone or in combination with erlotinib. The most common grade 3 or 4 AEs for cabozantinib as the sole agent were hypertension (25%), fatigue (15%), oral mucositis (10%), diarrhea

- 35 041548 (8%) and thromboembolic complications (8%). One death due to respiratory failure assessed as possibly related to study drug occurred in the cabozantinib group, and one death due to pneumonia assessed as related to either study drug or the combination occurred in the erlotinib plus cabozantinib group.

In a phase 2 randomized trial with discontinuation, 60 subjects with advanced NSCLC were enrolled and received cabozantinib as monotherapy (Schoffski et al 2017). The ORR was 10%, and 48.3% of subjects had disease stabilization as the best response. The median PFS in this study was 4.0 months.

In a Phase 2, single-arm, open-label study, 26 subjects with advanced RET-reorganized NSCLC received cabozantinib as the sole agent of therapy (Drilon et al 2016). The study reached its primary measurable parameter, with an overall response rate of 28% (95% CI 12, 49). The median duration of treatment was 4.7 months. Median PFS was 5.5 months (95% CI 3.8 to 8.4). Median OS was 9.9 months (95% CI 8.1 not achieved). The most common treatment-related grade 3 AEs were lipase elevation (15%), ALT elevation (8%), ACT elevation (8%), platelet count decline (8%), and hypophosphatemia (8%). ). No treatment-related deaths were reported.

1.2.6 Immunological effects

Cabozantinib is a potent inhibitor of multiple RTKs known to play an important role in tumor cell proliferation and/or tumor neovascularization, including MET, VEGFR, and RET. In addition, cabozantinib targets are involved in promoting tumor immunosuppression, including TYRO3, MER, and AXL (TAM family kinases). Preclinical and preliminary clinical evaluations have shown that treatment with cabozantinib affects tumor cells and the tumor microenvironment in ways that potentially make them more susceptible to immune-mediated attack. In vitro and in vivo experiments using a mouse colon carcinoma cell line (MC38-CEA) have shown that cabozantinib treatment alters immune modulation and immune subset formation (Kwilas et al. 2014). In particular, treatment of tumor cells with cabozantinib in vitro resulted in increased expression of major histocompatibility complex (MHC) class 1 antigen by tumor cells and greater sensitivity of tumor cells to T-lymphocyte-mediated killing. In a mouse MC3 tumor model, 8-CEA treatment with cabozantinib resulted in an increase in peripheral CD8+ T lymphocytes, a decrease in regulatory T lymphocytes ( _Tregs ) and myeloid suppressor cells (MDSC), and a decrease in _Treg suppressor activity. In addition, synergistic effects, including increased CD8+ T lymphocyte infiltration and reduced MDSC and TAM infiltration, were observed in a mouse tumor model when a poxyvirus-based cancer vaccine was administered with cabozantinib.

In clinical settings, a decrease in immunosuppressive Treg lymphocytes following treatment with cabozantinib was observed in a Phase 2 study in subjects with progressive refractory UC, as discussed in section 1.2.3 (Apolo et al. 2014). In a Phase 2 study of metastatic triple-negative breast cancer, subjects treated with cabozantinib experienced a persistent increase in the proportion of circulating CD3+ T lymphocytes and a persistent decrease in the number of CD14+ monocytes, possibly reflecting activation of systemic antitumor immunity (Tolaney et al. 2016).

Together, the preclinical and clinical observations presented above indicate that cabozantinib promotes an immunopermissive environment that may allow for synergistic effects from combination treatment with PD-1 checkpoint inhibitors.

1.3 Rationale

1.3.1 Rationale for the study and study design

Rationale for the therapeutic combination:

Through strong inhibition of RTKs, including MET, VEGFR, and RET, cabozantinib has demonstrated clinical activity as a single agent in multiple tumor types, including UC, RCC, CRPC, and advanced NSCLC. In addition, cabozantinib targets are involved in stimulating tumor immune suppression, including TYRO3, MER, AXL (TAM family kinases). Preclinical studies (Kwilas et al. 2014, Song et al 2015, Lu et al. 2017) and clinical observations of circulating immunosuppressive cells and immune effector cells (Apolo et al. [J Clin Oncol] 2014) suggest that cabozantinib promotes immune permissive environment, which may create the possibility for synergistic effects from combined ICTI treatment that may be independent of tumor PD-L1 expression. Atezolizumab, a potent PD-L1 inhibitor that has also shown clinical activity in multiple tumor types including UC, RCC, and NSCLC, is an appropriate combination therapy for this evaluation.

Rationale for the dose escalation step:

During the dose escalation phase of the study, the appropriate cabozantinib dose and dosing schedule for the combination of cabozantinib with standard dose atezolizumab will be established for the subject.

- 36 041548 projects with progressive UC or RCC. This will be achieved by implementing the traditional 3+3 dose escalation study design, evaluating three possible cabozantinib dose levels and two possible treatment regimens.

The dose escalation step was initiated according to the standard dosing schedule. Three subjects were included in Level 1 dose arm 1 (cabozantinib 40 mg daily with atezolizumab 1200 mg IV, 3 times daily). During follow-up COG group 1, there were no dose-dependent toxic effects (ODT), ESPEs, PETIs, or PEs for the first three subjects; all three subjects completed the OCT evaluation period, and Cycle 4 safety follow-up was available for the first enrolled subject. The following cabozantinib-related AEs were reported in Arm 1 (one for each subject): each 1st stage); hypertension (3rd stage). The following laboratory abnormalities have been reported associated with cabozantinib (each for one subject unless otherwise noted): ACT elevation, lipase elevation, hyponatremia, hypoalbuminemia, serum creatinine elevation, proteinuria, alkaline phosphatase (AP) elevation (two subjects) , decrease in the absolute level of neutrophils (each 1st degree); hypophosphatemia (2nd degree). No grade 4 or grade 5 PE was observed. Enrollment continues into Group 2 at dose level 2 (cabozantinib 60 mg daily with atezolizumab 1200 mg IV three times daily) and into Group 1 with an additional 3 subjects at dose level 1.

Rationale for evaluating selected tumor types:

During the expansion phase, eight tumor-specific groups for UC, RCC, CRPC, and NSCLC will be enrolled for combination treatment to further evaluate safety and efficacy in these tumors at the recommended dose and schedule. The rationale for the planned expansion group is based on the available clinical activity of one agent and the safety of both drugs in these solid tumors. Cabozantinib activity as a single agent has been demonstrated in untreated and previously treated RCC (Choueiri et al. 2015; Choueiri et al. 2016; Choueiri et al. [J Clin Oncol] 2017), previously treated UA (Apolo et al. [J Clin Oncol] 2016), previously treated with CRPC (Smith et al 2013, Smith et al 2014, Basch et al. 2015, Smith et al. 2016), and NSCLC (Neal et al. 2016, Drilon et al. 2016 , Schoffski et al. 2017). Atezolizumab has demonstrated clinical activity as a single agent for previously treated with platinum and untreated cisplatin-ineligible UC (Rosenberg et al. 2016; Loriot et al. 2016), for previously treated RCCs (Bellmunt et al 2016; McDermott et al. 2016 ), as well as in chemotherapy-treated and non-chemo-treated NSCLC (Peters et al. 2017; Rittmeyer et al. 2017; Fehrenbacher et al. 2016, Reck et al. 2017). In addition, atezolizumab has demonstrated stimulatory clinical activity in combination with an antibody targeting VEGF in untreated RCC (Atkins et al. 2017).

In addition to the study of cabozantinib in combination with atezolizumab in subjects who were already receiving standard cancer therapy, expansion groups 1, 3, and 4 will include subjects who were not receiving treatment. This is supported by the observed activity of both cabozantinib and atezolizumab as the sole agent in these tumor indications and the evolving treatment setting in which ICTO therapy is being explored in untreated and previously treated cancer patients. Rationale for Group 1 Expansion:

Expansion group 1 will evaluate subjects with untreated advanced RCC. Current treatment guidelines for patients with advanced RCC include VEGFR-targeted drugs as initial systemic anticancer therapy (Escudier et al 2016; Sutent [sunitinib] SmPC; Votrient [pazopanib] SmPC). Cabozantinib was approved for RCC after prior VEGFR-targeted therapy (Choueiri et al. 2015; Choueiri et al. 2016; Cabometyx [cabozantinib] SmPC). Recently, cabozantinib has demonstrated improved clinical outcomes compared with sunitinib in untreated patients with clear cell RCC at medium or low risk according to the criteria.

International Metastatic RCC Database Consortium (IMDC) (Choueiri et al. [J Clin Oncol] 2017; Choueiri et al. [Ann Oncol] 2017). Based on these results, cabozantinib was included in the list of recommended therapy for untreated moderate-to-low-risk RCC (NCCN 2017). In addition, the PD-1 inhibitor nivolumab has been approved as a single agent after prior therapy (Opdivo [nivolumab] SmPC), and more recently, the combination of nivolumab and ipilimumab (a CTLA-4 antagonist) has demonstrated improved OS compared to sunitinib in untreated RCC patients. with moderate to poor prognosis (Escudier et al. 2017; NCT 02231749). Atezolizumab has also demonstrated pre-clinical activity, alone or in combination with the VEGF-targeting agent bevacizumab, in subjects with advanced RCC (McDermott et al. 2016; Atkins et al. 2017). In addition, several studies of Phase 3 ICTI in combination with agents targeting CTLA-4 or in combination with VEGF(R)-targeted therapy are ongoing (NCT 02231749; NCT 02684006; NCT 02811861; NCT 02853331; NCT 02420821; NCT 03141177) . These clinical observations provide hope for the clinical activity of the combination of cabozantinib and atezolizumab in subjects with advanced RCC.

Rationale for expansion groups 2, 3, 5, and 7: As discussed above, both cabozantinib and ate

- 37 041548 zolizumab has demonstrated clinical activity as single agents in subjects with previously treated UC, RCC, and advanced NSCLC. Evaluation of the combination of two agents in such patient populations may serve to identify synergistic effects that provide greater clinical benefit to patients. In groups 5 (UK) and 7 (NSCLC) with patients previously progressing on ICTI therapy, the combination of cabozantinib with atezolizumab is used as a resensitization strategy to ICTI therapy in order to prolong PrO and survival of patients with cancer. ICTOs are standard treatments for UC and advanced NSCLC in first-line as well as second-line settings (Davarpanah et al. 2017, Hanna et al. 2017). Depending on the treatment setting, tumor type, and PD-L1 expression level, 20 to 45% of patients initially respond to ICTIO therapy as a single agent. Despite this clinical benefit, a large number of patients become resistant to ICTIO therapy and show disease progression. In addition, a subset of patients are unresponsive and a priori refractory to ICTIO therapy (progressive disease [PD] as the best response). There is a highly unmet need to overcome resistance to ICTI therapy. In a recent study in patients with NSCLC, resistance to previous ICTI therapy can be reversed with VEGFR-TKI (sitravatinib), which has a similar target profile to cabozantinib in combination with nivolumab (Leal et al. 2017). These observations support the validity of evaluating the combination of cabozantinib and atezolizumab for subjects who progressed on or after prior ICTI therapy in groups 5 and 7.

Group 4 Expansion Rationale:

In the expansion group, 4 subjects with early untreated CM not eligible for cisplatin will be evaluated. Current treatment guidelines for patients with UC include cisplatin-based chemotherapy (Milowsky et al 2017; Witjes et al 2017). However, cisplatin-based therapy is associated with significant toxicity and is therefore only applicable to eligible patients (Eastern Joint Oncology Group [OCOG] 0-1, renal function with GFR > 65 ml/min, absence of hearing impairment and peripheral neuropathy [both below 2 th grade according to the Common Terminology Criteria for Adverse Effects (CSAE) v4]). In addition, most patients with invasive UC are over 65 years of age. Treatment of elderly patients with cisplatin-based chemotherapy is challenging due to the presence of comorbidities. In patients who can receive first-line cisplatin-based chemotherapy, the median survival is approximately 15 months, the median PFS is approximately 8 months, and the ORR is approximately 50% (von der Maase et al. 2000, von der Maase et al. 2005) . Despite the availability of cisplatin-based combination chemotherapy, the 5-year survival rate is currently only about 15% and is less than 10% for patients with visceral disease (Sternberg et al. 2006; von der Maase et al. 2005). This indicates that more effective first-line therapies are needed to treat UC. Recently, ICTI therapies targeting the PD-1 or PD-L1 signaling pathway of immune cells and tumor cells have demonstrated clinical efficacy, safety, and tolerability in patients with UC who have not been previously treated with platinum and cisplatin (Tecentriq [atezolizumab] SmPC; Keytruda [pembrolizumab]] SmPC). In addition, ICTIs are currently being evaluated as single agents, or as combinations in untreated patients eligible for cisplatin, in several Phase 3 studies (NCT 02807636, NCT 02853305, NCT 02516241, NCT 03036098). Additionally, in a Phase 1 study of cabozantinib in combination with the PD-1 inhibitor nivolumab, positive clinical activity was noted in subjects with MPS tumors (Nadal et al. 2017). These clinical observations represent the potential for clinical activity of combination therapy of cabozantinib with atezolizumab in expansion group 4.

Group 6 Expansion Rationale:

Expansion group 6 will include subjects with CRPC who have previously received enzalutamide and/or abiraterone acetate and have experienced soft tissue progression of the disease as shown by radiography. Overexpression of PD-L1 after exposure to enzalutamide has been associated with an immunological antitumor response to ICTI therapy (Graff et al. 2016, Bishop et al. 2015). In addition, targeting immunosuppressive cells has been proposed as a treatment strategy to further enhance the antitumor immune response in patients with prostate cancer. For example, MET inhibition has been shown to prevent neutrophil recruitment to tumors and lymph nodes, and this activity enhances T-lymphocyte antitumor immunity (Glodde et al. 2017). Preclinical studies in mice lacking PTEN/p53 treated with cabozantinib showed rapid clearance of invasive prostate cancer by a neutrophil-mediated antitumor innate immune response (Patnaik et al. 2017). In addition, high levels of circulating CMMPs, which are involved in tumor evasion from immunity (Gabrilovich and Nagaraj 2009), are associated with PSA levels and metastasis (VukPavlovic et al. 2010, Brusa et al. 2013, Hossain et al. 2015, Idorn et al. . 2014). In addition, high levels of immunosuppressive peripheral blood regulatory T lymphocytes (Treg) have been identified in patients with prostate cancer and may interfere with the antitumor response (Miller et al.

- 38 041548 al. 2010). Combination therapy with cabozantinib and ICTI has been shown to be potentially applicable in a preclinical model of CRPC, with the combination inducing a sustained response at both the primary and metastatic sites by reducing the immunosuppressive activity of CSMP in the tumor microenvironment (Lu et al. 2017). The pooled preclinical data support the combination of cabozantinib with atezolizumab as a therapeutic strategy for CRPC.

Group 8 Expansion Rationale:

Expansion group 8 will include subjects with advanced stage IV non-squamous NSCLC without tumor genetic alteration (EGFR, ALK, ROS1, BRAF V600E) who have not received prior ICTI therapy. Current treatment guidelines for this subset of patients with NSCLC include pembrolizumab as the sole agent as first-line therapy in patients with high PD-L1 expression (>50% tumor fraction) (Reck et al. 2016, Hanna et al. . 2017). Cabozantinib has demonstrated activity as a single agent in unselected previously treated subjects with NSCLC, with results comparable to standard-of-care second-line chemotherapy (Neal et al. 2016; Schoffski et al. 2017). Encouraging activity of cabozantinib as a single agent has also been demonstrated in untreated and treated subjects with RET-rearranged NSCLC (Drilon et al. 2016). Atezolizumab has been approved for the treatment of NSCLC in prior chemotherapy based on improved OS compared to docetaxel (Rittmeyer et al. 2017). Clinically relevant activity of atezolizumab as a single agent has also been demonstrated in selected untreated subjects with NSCLC. For example, OS in patients treated with atezolizumab compared favorably with historical combination chemotherapy (23.5 months with atezolizumab versus 1012 months with platinum-based chemotherapy). The objective response rate in untreated and treated subjects with NSCLC depended on PD-L1 status (Peters et al. 2017). Preliminary results in patients with MPS cancer suggest that the combination of cabozantinib with ICTI may develop synergistic effects with greater clinical benefit (Nadal et al. ESMO 2017). These clinical observations are promising for the clinical benefit of cabozantinib plus atezolizumab combination therapy in an expansion group of 8 patients with NSCLC. Recently, the combination of atezolizumab/chemotherapy/bevacizumab demonstrated a statistically significant improvement in the primary measured parameter of PFS compared with chemotherapy/bevacizumab. At the time of the PFS analysis, data for the co-primary measured parameter OS were not complete (Reck et al. 2017).

1.3.2 Rationale for dose selection and treatment schedule

Based on prescribing information in the US, atezolizumab will be given as a standard dosing regimen of 1200 mg IV infusion over 60 minutes (± 15 minutes) every 3 weeks (-2 days) on Day 1 of each 21-day cycle .

During the dose escalation phase, cabozantinib will be administered orally at doses of 20, 40, or 60 mg in the escalation groups. Sixty (60) mg is the approved single-drug tablet dose level for the treatment of advanced RCC and the dose used to evaluate cabozantinib as a single agent in a Phase 2 study in subjects with relapsed or refractory metastatic UC. The dose escalation step was initiated at the dose level of 40 mg cabozantinib in arm 1. This dose is consistent with the average daily dose of 41 mg/day received by subjects in the METEOR Phase 3 study for RCC and was also the recommended dose determined for cabozantinib for clinical evaluation in combination with nivolumab, another PD-1/PD-L1 pathway inhibitor antibody (Apolo et al [Ann Oncol] 2016). No CTD was identified in group 1, and enrollment is ongoing in group 2 for a dose of cabozantinib 60 mg and expansion of group 1 with three additional subjects.

Initial cohorts use a standard dosing regimen where cabozantinib and atezolizumab are started on Day 1 of Cycle 1. After evaluating the initial escalation cohorts on the standard dosing schedule, the Group Evaluation Committee (GEC) may decide to enroll additional cohorts of subjects in the dose escalation phase who will receive their first atezolizumab infusion 21 days after the first dose of cabozantinib (cabozantinib introductory dosing schedule). The purpose of launching this schedule is to help the COG evaluate whether subjects would be better able to tolerate the combination of cabozantinib and atezolizumab if they were first given the opportunity to optimize their tolerance to cabozantinib alone. Cabozantinib dose levels for these groups will be determined by the COG, but will not exceed 60 mg per day.

Once all subjects enrolled in the dose escalation phase have completed the OCT evaluation period, the COG will recommend a cabozantinib dose and schedule for the escalation phase based on all available safety data. Subjects who enroll in the dose group expansion phase will receive this daily dose of cabozantinib as well as 1200 mg intravenous atezolizumab infusions every 3 weeks.

1.4 Assessing the overall risk-benefit

The study will evaluate the safety, tolerability and pre-activity of

- 39 041548 bosantinib in combination with atezolizumab for neoplastic symptoms, where both drugs as separate agents have either received regulatory approval or demonstrated stimulatory clinical activity in early clinical trials (see Sections 1.1.1 and 1.2). In addition, the scientific rationale for treatment with the combination of cabozantinib with ICTI has been established in both preclinical and clinical settings (Kwilas et al. 2014, Apolo et al. 2014, Tolaney et al. 2016). In addition, the safety and preliminary clinical activity of cabozantinib in combination with the PD-1 inhibitor nivolumab has been demonstrated in non-ICTI patients in a Phase 1 study in subjects with MPS cancer, including metastatic UC and RCC (Nadal et al. [Ann Oncol] 2017). In addition, a recent study demonstrated that nivolumab in combination with TKIs with a target profile similar to cabozantinib (an inhibitory target that regulates the immune system) was able to provide clinical benefit for cancer patients who progressed on ICTI therapy (Leal et al . 2017). The latter suggests that combining ICTI treatment with cabozantinib may provide a tumor microenvironment that promotes resensitization to ICTI treatment after progression, potentially filling an important unmet need as most cancer patients develop resistance and some patients are a priori refractory to ICTI therapy.

The safety profiles of both cabozantinib and atezolizumab are well documented based on numerous clinical evaluations. However, it is not known whether the combination of cabozantinib with atezolizumab has the same acceptable safety profile as seen with them as single agents. During the initial 3+3 standard dose escalation phase, the safe dose and dosing regimen of cabozantinib that can be given in combination with the standard dose of atezolizumab in this study population will be determined by the COG (Section 12.1). The recommended dose for Phase 2 will be evaluated in all eight tumor groups in the expansion stage. Throughout the study, all registered subjects will need to perform regular safety assessment visits to ensure adequate monitoring and reporting of PE. The Study Review Committee will review the safety and efficacy data during the expansion phase and decide on further expansion of groups 5 and 7 after the first 30 subjects have been enrolled (Sections 9.1.2 and 12.2). In addition to the COG, the Sponsor's Safety Executive Committee (SEC; Section 12.3) will review all safety data for subjects in this study. At the date of the COG review of the first three subjects included in Group 1, the dose escalation phase for Group 1 (40 mg cabozantinib plus 1200 mg atezolizumab) of the standard dosing schedule had been completed with a favorable safety profile. Enrollment in group 2 (cabozantinib 60 mg dose) and expansion of group 1 with additional subjects is ongoing.

To minimize safety risks for participating subjects, this protocol has population-specific acceptance criteria and includes allowance for dose reduction (cabozantinib) and treatment delay (cabozantinib, atezolizumab). Periodic clinical evaluations (physical examination, vital signs, and electrocardiographic evaluations) and clinical laboratory analyzes will monitor for toxicity associated with cabozantinib and atezolizumab. Subjects will also be closely monitored for AEs potentially associated with VEGFR inhibition by cabozantinib, including: gastrointestinal (GI) perforation, fistula formation, wound enlargement, major bleeding, proteinuria, hypertension, thromboembolic complications, osteonecrosis, and reversible posterior leukoencephalopathy ( PRLS), as well as immune-related side effects associated with atezolizumab (pneumonitis, hepatitis, colitis, endocrinopathies, skin disorders, ocular events, neurological toxicity, pancreatitis, and infections).

Based on the activity of cabozantinib and atezolizumab as separate agents and the demonstrated tolerability of cabozantinib in combination with another ICTI (nivolumab), the potential benefit of using cabozantinib in combination with atezolizumab appears to outweigh the potential risks in subjects with UC, RCC, CRPC, and NSCLC late stages of development.

Research objectives

Dose escalation step:

The main goal is to:

To determine the maximum tolerated dose (MTD) and/or recommended dose, and schedule for the subsequent step of increasing the daily oral dose of cabozantinib in subjects with solid tumors when taken in combination with atezolizumab.

The secondary goal is:

To evaluate the plasma PK of daily oral cabozantinib in subjects with solid tumors when used in combination with atezolizumab.

Assess the safety of combination therapy by assessing the incidence and severity of non-serious AEs and serious adverse events (SAEs), including ESAEs and PEOIs.

The research goal is to:

Correlation of analyzes of immune cells, tumor cells and blood biomarkers with clinical

- 40 041548 out

Expansion stage:

The main objective and measured parameter are as follows:

Evaluate preliminary effectiveness by evaluating the OER, assessed according to COOS 1.1

The secondary goal is:

Assess the safety of combination therapy by assessing the incidence and severity of non-serious PE and PET, including ISPE and PEOI.

Research objectives and measured parameters:

ORR as assessed by the investigator according to the modified QOOSR for immune response.

SbA assessed by the researcher in accordance with COOS 1.1

PFS assessed by the investigator according to CCAS 1.1

Overall survival

Correlation of analyzes of immune cells, tumor cells and blood biomarkers with clinical outcome.

Changes in tumor infiltration and/or histology, or other molecular changes identified by an optional tumor biopsy.

Additionally, evaluate plasma PK in daily oral cabozantinib in subjects with solid tumors when used in combination with atezolizumab.

For CRPC only: PSA changes and assessment of mismatch repair (MMR) and microsatellite instability (MSI) status.

Clinical Study Plan

3.1 Overview

This is a multicenter, open-label Phase 1b study to evaluate the safety, tolerability, preliminary efficacy, and PK of cabozantinib given in combination with atezolizumab in subjects with CM, RCC, CRPC, and advanced NSCLC. This study consists of two stages: a dose escalation stage and an expansion stage.

3.2 Research centers

The dose escalation phase of this study will be conducted at up to five clinical centers in the United States. For the expansion phase, additional centers will be added in the US and Europe (about 50 centers in total).

3.3 Data anonymization and randomization

This is an open-label study with assignment to a treatment arm based on the current recorded dose level in the escalation stage and tumor type, and prior anti-cancer therapy in the escalation stage. There will be no data anonymization or randomization in this study.

3.4 Period before treatment

Potential subjects will be screened for eligibility criteria. Qualification screening evaluations must be conducted within 28 days prior to the first dose of study treatment, unless otherwise specified (certain laboratory values should be obtained closer to the first dose; see evaluation tables for details [dose escalation stage, Appendix A; expansion stage, Appendix B) ]).

3.5 Treatment period

Subjects will receive study treatment for as long as they continue to experience clinical benefit in the investigator's judgment or until unacceptable toxicity occurs, the need for subsequent systemic anticancer treatment, or until any other reason for discontinuing treatment occurs. will be specified in the protocol (Section 3.8). Treatment may continue after progression is detected by x-ray as long as the investigator believes that the subject is still receiving clinical benefit from investigational treatment and that the potential benefit of continuing investigational treatment outweighs the potential risk. Clinical judgment should be used to allow treatment without progression according to radiography. Subjects with a clinically significant worsening of symptoms during progression on x-ray may not be eligible for further treatment. The possibility of a delayed antitumor immune response should be considered: mixed responses with decreasing and increasing tumor sizes at the same imaging time point or the appearance of new lesions before reaching a response according to radiology have been reported for ICTI. Discontinuation of one component of the study treatment combination while continuing the other may be permitted with notice to the sponsor.

All enrolled subjects will receive the best possible supportive care during study treatment. This rules out systemic non-protocol cancer therapy, which requires discontinuation of study treatment. Permitted modifications to the PE investigational medicinal product will include a dose reduction (from 60 to 40 mg per day, with

- 41 041548 up to 20 mg daily or from 20 mg daily to 20 mg every other day (r/h/s)), or interruption of cabozantinib and delaying the dose of atezolizumab.

3.5.1 Dose escalation step

The main purpose of the escalation stage is to determine the MTD and/or recommended dose of the escalation stage and dosing schedule for cabozantinib when used in combination with the standard atezolizumab dosing schedule (1200 mg infusion, once every 3 weeks).

Three daily tablet dose levels of cabozantinib will be considered for evaluation: 20, 40, and 60 mg. Atezolizumab will be given as a 1200 mg infusion once every 3 weeks (Table 3-1).

The OCT assessment period is defined as 21 days after the first dose of atezolizumab. Subjects will be added to boost groups of 3-6 subjects using a 3 plus 3 schedule and dosing will begin at the 40 mg dose level of cabozantinib. Subjects with advanced CM or RCC will meet the criteria for these groups, and groups may contain a combination of subjects with these types of tumors. At this stage, the COG will make a decision to open a new cohort when all subjects in the current cohort have completed the CCT evaluation period. Cohort enrollment decisions will largely depend on subject RCT reports during the RCT evaluation period, but all available safety and PK data will be taken into account when deciding whether to increase or decrease the dose in the next cohort, or expand the current cohort. Rules for making a decision to increase / decrease the dose, based on the ODT, are given in table. 3-2 and definitions of the CCT are provided in Section 3.5.1.4. Subject withdrawn from the study due to failure to receive the first dose of atezolizumab or at least 75% of the mandatory doses of cabozantinib during the OCT evaluation period for non-safety reasons (eg, withdrawal of consent, non-compliance, disease progression, or AEs assessed by as not related to the study treatment) may be substituted.

Table 3-1. Dose Combinations to Evaluate Efficacy at the Dose Escalation Stage

Relative dose level cabozantib Atezolizumab 2 60 mg orally once a day 1200 mg IV rZn 1 40 mg orally once a 1200 mg IV rZn day -1 20 mg orally once a day 1200 mg IV rZn

in / in - intravenously; r3n - once every three weeks

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Table 3-2: Decision Rules for the Dose Escalation Stage Number of Subjects per Group with

CCT in the current group Dose escalation decision rules 0 of 3 Enroll three subjects to the next higher dose level. If the current dose level does not meet the protocol-defined maximum dose of cabozantinib (60 mg), the COG may decide to concurrently enroll an additional three subjects at the current dose level. If the current cohort was treated according to the protocol specifying the maximum dose of cabozantinib (60 mg), enroll three more subjects at that dose level. 0 of 6 Carry out additional enrollment at the current dose level. 1 of 3 Enroll three more subjects to the next higher dose level. 1 of 6 Enroll three subjects to the next higher dose level until the evaluation of that dose level is complete. If the current cohort was treated with a protocol that specifies the maximum dose level of cabozantinib (60 mg), then enroll further into the dose escalation step. > 2 out of 3 or 6 Enroll three additional subjects at the next lower dose level, as long as the subjects are being treated at that level. If the current group was treated at the lowest dose level cabozantinib (20 mg) as defined by the protocol, continue enrollment in the dose escalation phase.

COG, Group Evaluation Committee; ODT, dose-limiting toxicity.

The MTD for cabozantinib will be defined as the highest dose level assessed at which no more than 1 in 6 subjects experience OTD. Because dose levels of cabozantinib above 60 mg will not be evaluated, the MTD for cabozantinib may not be achieved. The recommended dose for the expansion stage will be determined by the COG based on the RCTs observed during the RTR evaluation period and other relevant safety information.

Subjects in the dose escalation phase may continue to receive study treatment after the completion of the OCT evaluation period. The COG will evaluate the safety and PK data collected during and after the OCT evaluation period to make informed decisions about enrollment, dose escalation/decrement and MTD, or recommended dose and scheduling.

3.5.1.1 Dosing schedules

Subjects in the dose escalation phase will receive study treatment on one of two dosing schedules: the standard dosing schedule or the cabozatinib dosing schedule. The initial dose escalation step will follow the standard dosing schedule. Additional dose escalation groups may be used after the cabozantinib introductory dosing schedule at the request of the COG if a recommended dose of the escalation stage has not been determined after evaluating the standard dosing schedule. The same cabozantinib dose levels will apply to the cabozantinib introductory dosing schedule as to the standard dosing schedule (Table 3-1).

3.5.1.2 Standard dosing schedule

The initial dose escalation groups will follow a combined schedule according to the Standard Dosing Schedule with the first infusion of atezolizumab administered on the same day as the first dose of cabozantinib (at C1D1).

3.5.1.3 Cabozantinib introductory dosing schedule

If an analysis of the safety data for all registered subjects who followed the standard dosing schedule does not result in a recommended dose for the expansion phase, the COG may decide to include additional groups of subjects in the dose escalation phase who received

- 43 041548 treatment according to the cabozantinib introductory dosing schedule. Subjects in these cohorts will begin treatment with cabozantinib at C1D1 and receive their first infusion of atezolizumab 21 days later in cycle 2 day 1 (C2D1). Subjects will only be assessed for the presence of OTD within the 21-day period after receiving the first infusion of atezolizumab (ODT assessment period). These cohorts will be enrolled according to the 3+3 strategy described above, but the COG may enroll subjects in one or more dose levels to ensure that a sufficient number of subjects reach the RCT evaluation period while still receiving the cohort's assigned dose (i.e. e., experienced no dose reduction on the cabozantinib introductory dosing schedule). Administration of the first dose of atezolizumab should not occur while treatment with cabozantinib is interrupted; initiation of cycle 2 should be delayed until cabozantinib treatment is resumed, well tolerated, and the investigator has determined that atezolizumab can be administered safely. Subjects who discontinue cabozantinib treatment during Cycle 1 as per the introductory cabozantinib dosing schedule will not be eligible to receive atezolizumab during the study.

The purpose of this dosing schedule is to help the COG evaluate whether subjects could improve tolerability of the combination of cabozantinib and atezolizumab if they were first given the opportunity to optimize their tolerance to cabozantinib alone during a three-week run-in period. The COG will consider safety data from all dose escalation groups when determining the recommended dose and schedule for the expansion phase.

3.5.1.4 Dose-limiting toxicities

Dose limiting toxicities will be determined by the COG considering all available data for the group and defined as any of the following occurring during the evaluation period of the HCT:

1. Any associated AE that, in the opinion of the COG, is of potential clinical significance, such that a further increase in the dose of cabozantinib may place subjects at unacceptable risk.

2. Any grade 3 associated AE that is unexpected in severity and/or duration compared to the known safety profiles of cabozantinib and atezolizumab when used as single agents, and that cannot be managed by dose modification (reduction or interruption), and adequate maintenance therapy and requires long-term discontinuation of cabozantinib and/or atezolizumab.

3. Failure to take 75% of the scheduled dose of cabozantinib during the OCT evaluation period due to treatment-related PE

Examples of PEs that would not be considered as CCTs:

Temporary infusion-related AEs that can be controlled with medical treatment (eg, flu-like symptoms, fever)

AEs associated with exacerbation of tumor symptoms (i.e., localized pain, irritation at tumor sites)

Any Grade 3 PE (regardless of study treatment association) that the COG determines is unlikely to compromise the subject's safety and is tolerated to < Grade 1 or controlled by adequate supportive care, including short delays or dose reduction. These may include side effects expected to occur with single agent therapy using cabozantinib or atezolizumab (i.e., hypertension, skin toxicity, headache, nausea, fatigue, vomiting, diarrhea).

Isolated laboratory values that are outside the normal range and are unlikely to be related to study treatment and have no clinical correlates.

3.5.2 Expansion stage

Once the COG determines the recommended dose and schedule for cabozantinib in combination with atezolizumab, the study will move into the expansion phase. Eight expansion groups will be enrolled at this stage for subjects with CM, RCC, CRPC, and advanced NSCLC to obtain additional safety, PK, and pharmacodynamic data at the recommended dose and schedule. An abbreviated description of expansion groups 1-8 is given in table. 3-3.

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Table 3-3. Summary of Expansion Groups

Group Type of tumor (histology) Abbreviated suitability description Initial group size (P) Possible additional enrollment (n) 1 PAC (transparent cell) No prior systemic anticancer therapy thirty - 2 UK (transitional cell) Prior platinum-containing chemotherapy was prescribed thirty - 3 UK (transitional cell) Unsuitable for treatment with cisplatin, but not previously treated with systemic cancer therapy thirty - 4 UK (transitional cell) Suitable for treatment with cisplatin, but not previously prescribed systemic anticancer therapy thirty - 5 UK (transitional Appointed thirty 50

cell) pre-treatment with an immune checkpoint inhibitor 6 CRPC (adeno) Appointed preliminary enzalutamide and/or abiraterone therapy thirty - 7 NSCLC (non-squamous) Appointed pre-treatment with an immune checkpoint inhibitor thirty 50 8 NSCLC (non-squamous) Not appointed pre-treatment with an immune checkpoint inhibitor thirty -

Total registered 240 340

All expansion groups will initially include 30 entities. Due to the high unmet need in patients who have progressed on prior ICTIO therapy, the Study Review Committee (Section 12.2) may, after reviewing the data for expansion groups 5 and 7, allow additional enrollment in every 50 subjects to further evaluate the clinical activity and safety of cabozantinib in combination with atezolizumab after progression to ICTI (Section 9.1.2). All subjects enrolled in an expansion group will follow the same evaluation schedule and dosing instructions. For more information on subject eligibility for this study, please refer to the inclusion and exclusion criteria (Section 4.2 and 4.3). The rationale for enrollment in each expansion group is given in section 1.3.1.

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Only one dose level and dosing schedule will be evaluated during the expansion phase: the standard dosing schedule (Section 3.5.1.2) or the cabozantinib introductory dosing schedule (Section

3.5.1.3). Subjects who discontinued cabozantinib treatment during Cycle 1 will not be eligible to receive atezolizumab during the study if the cabozantinib introductory dosing schedule is the COG's chosen dosing schedule for the expansion stage.

3.6 Post-treatment period and follow-up

A final safety assessment will be performed post-treatment at a follow-up visit 30 (+14) days after the date of the decision to discontinue treatment. If the subject experiences PET, PEOI, or Grade 3 or 4 PE on or during this visit, they will continue to be monitored until the PE resolves, PE improves to Grade 2 or less, or the investigator will determine that the side effect has become stable or irreversible. During the post-treatment period, the survival of each subject will be monitored. The Investigator (or their designee) will contact the subject at least as often as every 12 weeks (± 7 days) after the post-treatment follow-up visit, until the subject's follow-up period expires or the sponsor decides stop collecting this data for the study.

3.7 Maintenance phase

When enough data has been collected to adequately assess all of the study's measurable parameters, and upon notification of the sponsor, subjects remaining on study treatment will enter the maintenance phase. During the maintenance phase, subjects will continue to receive study treatment until the protocol's withdrawal criteria are met. Upon notification of the sponsor, subjects may be allowed to withdraw one component of the investigational treatment but continue to receive the other. After completion of the maintenance phase, the trial will be considered completed in centers and countries where there are no more active subjects.

During the maintenance phase, subjects should undergo periodic safety evaluations (including local laboratory analyzes) and tumor evaluations; the nature and frequency of such assessments should be consistent with the standard of care, if permitted by local regulations. It is the investigator's responsibility to ensure that visits to subjects are frequent enough and that adequate assessments are made to ensure the safety of the subject. To continue gathering important safety information on subjects still participating in the study, POC reporting; AEs (including PEOIs), whether serious or not, and whether they lead to dose modification or discontinuation of treatment; ISPE; and other reported side effects (mistakes in pregnancy and medication with residual effects) should be continued in accordance with protocol requirements specific to the maintenance phase (Section 5.4).

Post-treatment assessments (including follow-up visits after treatment discontinuation) are not required for subjects who discontinue treatment in a maintenance phase study (such subjects must adhere to the standard of care). Additional information is available in Appendix C.

3.8 Termination of treatment and early withdrawals

Subjects may discontinue study treatment and evaluations, or withdraw their consent to participate in the study at any time without restriction. When subjects withdraw consent, all investigational treatments will be stopped. The investigator may terminate a subject early from an investigational treatment or study if, in his or her clinical judgement, it is in the subject's best interests or if the subject is unable to comply with the protocol. The investigator will also remove the subject from the investigational treatment or from the study at the request of the sponsor or if the sponsor decides to terminate the study.

In addition, any of the following conditions require the subject to be excluded from the study treatment:

The subject no longer experiences clinical benefit as determined by the investigator (eg, a clinical worsening associated with disease progression that is unlikely to change with continued investigational treatment and/or maintenance treatment).

The investigator believes that unacceptable side effects may be associated with the study combination treatment. However, discontinuation of one component of a combined investigational treatment while continuing the other may be permitted with sponsor notification in an attempt to manage such side effects in subjects experiencing clinical benefit.

The investigator believes that it is not in the subject's interest to continue participating in the study.

Participation in another clinical trial using an investigational agent, research medical device, or other intervention.

The need for treatment with non-protocol systemic anticancer therapy.

The need to interrupt any investigational drug for more than 12 weeks due to treatment-related PE, unless approved by the sponsor.

Refusal of sexually active fertile subjects (excluding sterilized subjects) to use medically accepted methods of contraception.

Female subjects who become pregnant.

Subject's request to discontinue investigational treatment (with or without concomitant withdrawal of informed consent).

Significant non-adherence to the protocol schedule as judged by the investigator or sponsor.

The sponsor must be notified of all treatment discontinuations in the study of subjects and early withdrawal from the study as soon as possible. The reason for termination or denial will be documented.

For subjects who discontinue investigational treatment, every effort must be made to follow protocol-defined follow-up procedures, including end-of-treatment assessments, survival follow-up, and subsequent anti-cancer treatment, until consent to participation in the study is also withdrawn.

If the subject does not return for the visits specified in the protocol, efforts must be made to determine the cause. If the subject cannot be reached by telephone, at a minimum, a registered letter (or their legal guardian) should be sent to the subject requesting that they contact the clinic.

If a subject is withdrawn from investigational treatment due to an AE (including PEOI) considered to be related to investigational treatment, and the effect continues 30 days after the last dose of study treatment, the effect should be monitored until the effect disappears, or the investigator determines that the effect has become stable or irreversible.

If a subject withdraws consent to participate in a study, no additional study procedures or evaluations will be performed and no additional data will be collected from the study on that subject other than determining survival status for subjects enrolled in the expansion phase. This information may be obtained from publicly available documents, such as government vital statistics or obituaries, in accordance with local law.

3.9 Replacing subjects

Only subjects who sign informed consent and receive any investigational treatment will be considered registered.

During the dose escalation phase, if an enrolled subject does not receive the first dose of atezolizumab or at least 75% of the mandatory doses of cabozantinib during the OCT evaluation period for non-safety reasons (e.g., withdrawal of consent, non-adherence, disease progression, or PE assessed by as not related to study treatment), he or she will be replaced (i.e., an additional subject will be added to the cohort). In addition, subjects on the cabozantinib introductory dosing schedule who, for any reason (including safety), discontinue treatment prior to receiving the first dose of atezolizumab will be replaced. Subjects who are receiving atezolizumab but are unable to complete the OCT evaluation period due to study treatment-related PE will not be replaced. Subjects that are replaced with new ones will not be taken into account in dose escalation decisions, but will be used for safety and other evaluations whenever possible.

Subjects registered for the expansion stage will not be replaced.

Study population

4.1 Target population

Subjects with RCC and advanced CM will be enrolled in this study. Specific populations with these types of tumors will differ slightly between the dose escalation stage and the expansion stage based on prior treatment. The eligibility criteria for this study were carefully considered to ensure the safety of the study subjects and to ensure the integrity of the study results. It is critical that subjects fully meet all of the inclusion criteria and none of the exclusion criteria. The Sponsor will not make exceptions based on study eligibility criteria.

4.2 Inclusion criteria

A subject must meet all of the following criteria to be eligible to participate in the study:

1. Cytologically or histologically and radiologically confirmed solid tumor that is unresectable, late-stage local, metastatic, or recurrent:

Dose escalation step:

Subjects with UC (including renal pelvis, ureter, bladder, urethra) after prior platinum-based therapy or

Subjects with RCC (histology - clear cells, opaque cells) with or without previous systemic anti-cancer therapy

Expansion stage:

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Expansion Group 1: Subjects with RCC with clear cell histology (including those with a mixed sarcomatoid component) and no previous systemic anti-cancer therapy.

Expansion Group 2: Subjects with CM with transitional cell histology (including renal pelvis, ureter, bladder, urethra) whose progression is confirmed radiologically on or after platinum-containing chemotherapy, including subjects who have received previous neoadjuvant or adjuvant platinum-containing therapy with disease recurrence < 12 months from end of last therapy.

Expansion group 3: CM subjects with transitional cell histology (including renal pelvis, ureter, bladder, urethra) who are ineligible for cisplatin-based chemotherapy and have not previously received systemic cancer therapy for unresectable local advanced or metastatic disease .

Eligibility for cisplatin-based chemotherapy is determined by one of the following criteria:

Renal impairment (glomerular filtration rate [GFR] > 30 ml/min/1.73 ^m2 and <60 ml/min/1.73 ^m2 , hearing loss >25 dB at two adjacent frequencies, or peripheral neuropathy >2- th degree according to OTKPO v4.

Prior neoadjuvant or adjuvant platinum-based chemotherapy is allowed if disease recurrence occurs > 12 months after the end of the last therapy.

Expansion Group 4: CM subjects with transitional cell histology (including renal pelvis, ureter, bladder, urethra) who are eligible for cisplatin-based chemotherapy and have not previously received systemic anticancer therapy for unresectable local advanced or metastatic disease .

Prior neoadjuvant or adjuvant platinum-based chemotherapy is allowed if disease recurrence occurs > 12 months after the end of the last therapy.

Expansion Group 5: Subjects with CM with transitional cell histology (including renal pelvis, ureter, bladder, urethra) whose progression is confirmed radiologically with or after prior administration of one immune checkpoint inhibitor (anti-PD-1 or anti- PD-L1) as the most recent therapy for the treatment of unresectable local advanced or metastatic disease.

Up to 2 lines of prior systemic cancer therapy for treatment of localized advanced stage or metastatic UC are allowed, including prior treatment with an anti-CTLA-4 agent.

Excluded are subjects who have previously received combination therapy with an immune checkpoint inhibitor (anti-PD-1 or anti-PD-L1) VEGFR-targeted TKI.

Expansion Group 6: Subjects with metastatic CRPC (adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features) who have radiographic evidence of soft tissue progression on or after taking enzalutamide and/or abiraterone acetate for the treatment of metastatic disease.

(Note: PSA progression or bone progression does not determine fitness).

Prior chemotherapy is not allowed, except for docetaxel given in combination with anti-androgen therapy (AAT) for the treatment of advanced castration-sensitive disease prior to treatment with enzalutamide and/or abiraterone acetate.

Prior treatment with radium Ra 223 dichloride is not allowed.

Subject must have a castration testosterone level (< 50 ng/dL [< 2 nM]) after bilateral orchiectomy or ongoing antiandrogen therapy using a gonadotropin-releasing hormone (GnRH) analog that was initiated more than 4 weeks prior to the first dose of study treatment and should continue throughout the study.

Expansion Group 7: Subjects with non-squamous stage IV NSCLC whose progression is confirmed radiologically with or after prior administration of an immune response checkpoint inhibitor (anti-PD-1 or anti-PD-L1) as the most recent therapy for the treatment of metastatic disease.

Up to 2 lines of prior systemic cancer therapy for the treatment of metastatic NSCLC is allowed, including prior treatment with an anti-CTLA-4 agent.

Excluded are subjects who have previously received combination therapy with an immune checkpoint inhibitor (anti-PD-1 or anti-PD-1) with a VEGFR-targeted TKI and have been diagnosed with an EGFR mutation, ALK translocation, ROS1 rearrangement, or mutation. BRAF V600E.

Expansion group 8: Subjects with non-squamous stage IV NSCLC who have not previously received immune checkpoint inhibitor (anti-PD-1 or anti-PD-L1) therapy.

One line of prior systemic cancer therapy is allowed for the treatment of metastatic NSCLC.

Excluded subjects diagnosed with EGFR mutation, ALK translocation, rearrangement

ROS1 or BRAF V600E mutation.

2. Measurable disease manifestations in accordance with CCAS 1.1, as determined by the investigator. A measurable manifestation of the disease should be outside the radiation field if previous radiation therapy has been performed.

3. Tumor tissue material available (archival or recent tumor biopsy)

4. Recovery to baseline or < HRMS v4 grade 1 from toxicity associated with any prior treatment, unless AEs are clinically non-significant and/or stable on maintenance therapy.

5. Age eighteen or older on the date of consent.

6. General condition 0 or 1 according to VKOG.

7. Adequate organ and bone marrow function based on compliance with all of the following laboratory parameters within 14 days prior to the first dose of study treatment:

Absolute neutrophil count (ANC) > 1500/mm ³ (> 1.5 billion/L) without granulocyte colony-stimulating factor support for 2 weeks prior to laboratory screening of collected samples.

The number of leukocytes> 2500 / mm ³ (> 2.5 billion / l).

Platelets > 100,000/mm ³ (> 100 billion/L) without blood transfusion within 2 weeks prior to laboratory screening of collected samples.

Hemoglobin > 9 g/dL (> 90 g/L) without blood transfusion within 2 weeks prior to laboratory screening of collected samples.

ALT, ACT, and ALP < 3 x upper limit of normal (ULN). ALP < 5 x ULN with documented bone metastases.

Total bilirubin < 1.5 x ULN (for subjects with Gilbert's syndrome < 3 x ULN).

Serum creatinine < 2.0 times ULN or estimated creatinine clearance of 30 ml/min (0.5 ml/s) using the Cockcroft-Gault equation (see Table 5-2 for the Cockcroft-Gault formula).

Urinary protein/creatinine ratio (MPKR) < 1 mg/mg (< 113.2 mg/mmol) for subjects with RCC, CRPC, or NSCLC and < 2 mg/mg (< 226.4 mg/mmol) creatinine for subjects with UK.

8. Able to understand and comply with protocol requirements and must sign an informed consent document.

9. Sexually active fertile subjects and their partners must agree to use medically accepted methods of contraception (eg, barrier methods, including the male condom, female condom, or diaphragm with spermicidal gel) during the study and for 5 months after the last dose of treatment in within the framework of the study.

10. Female subjects must not be pregnant at screening. Women of childbearing potential are defined as premenopausal women who are able to become pregnant (i.e., women who have had any signs of menstruation in the last 12 months, excluding those who have had a previous hysterectomy). However, women who have been amenorrheic for 12 months or more are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogen, low body weight, ovarian suppression, or other causes.

4.3 Exclusion criterion

A subject who meets any of the following criteria is not eligible to participate in the study:

1. Previous treatment with cabozantinib or ICTO, including anti-CTLA-4, anti-PD-1, anti-PD-L1, anti-PD-L2, anti-OX-40, anti-CD137 therapy, excluding expansion groups 5 and 7, in which pre-treatment with anti-PD-1 or anti-PD-L1 is necessary for eligibility (see Inclusion Criteria 1g and 1i respectively for details).

2. Receiving any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 2 weeks prior to the first dose of investigational treatment.

3. For CRPC subjects: receiving flutamide or nilutamide within 4 weeks or bicalutamide within 6 weeks prior to the first dose of study treatment.

4. Receipt of any type of antitumor antibody (including investigational antibody) or systemic chemotherapy within 4 weeks prior to the first dose of investigational treatment, except expansion groups 5 and 7, for which receipt of antibody targeted to PD-1, PD-L1, or CTLA- 4 resolved within 4 weeks prior to the first dose of study treatment.

5. Radiation therapy to treat bone metastases within 2 weeks, any other radiation therapy within 4 weeks prior to the first dose of study treatment. Subjects with clinically significant non-resolving complications from prior radiation therapy are ineligible.

6. Known brain metastases or cranial epidural disease, unless they are adequately treated with radiotherapy and/or surgery (including ra-

- 49 041548 diosurgery) and are stable for at least 4 weeks prior to the first dose of study treatment.

Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of the first dose of study treatment.

7. Concomitant anticoagulation therapy with oral anticoagulants (eg, warfarin, direct thrombin and factor Xa inhibitors) or platelet inhibitors (eg, clopidogrel).

Permitted anticoagulants are as follows: Low dose aspirin for cardioprotection (according to locally applicable guidelines) and low dose low molecular weight heparins (LMWHs).

Anticoagulation with therapeutic doses of LMWH in subjects without known brain metastases who are taking an unchanged dose of LMWH for at least 6 weeks prior to the first dose of study treatment and who have not had clinically significant bleeding complications due to anticoagulation therapy or tumor.

8. Diagnosed with immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 2 weeks prior to the first treatment dose in the study. Inhaled and topical corticosteroids and mineralocorticoids are allowed.

9. Administering a live attenuated vaccine within 30 days prior to the first dose of study treatment.

10. The subject has an uncontrolled, significant intercurrent or recent illness, including but not limited to the following pathologies:

a) Cardiovascular diseases:

New York Heart Association grade 3 or 4 congestive heart failure, unstable angina, severe arrhythmias.

Uncontrolled high blood pressure, defined as constant blood pressure (BP) > 150 mm. Hg systolic or > 100 mmHg diastolic despite optimal antihypertensive treatment.

Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI), or other ischemic or thromboembolic event (eg, deep vein thrombosis [DVT], pulmonary embolism) within 6 months prior to the first dose. Subjects diagnosed with DVT within 6 months are eligible if they are stable, asymptomatic and have taken LMWH for at least 6 weeks prior to the first dose.

b) Gastrointestinal disorders (GID), including those associated with a high risk of perforation or fistula formation:

Tumors affecting the gastrointestinal tract, active peptic ulcer, inflammatory bowel disease, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreas or bile ducts, or pylorus obstruction.

Abdominal fistula, gastrointestinal perforation, intestinal obstruction, or intra-abdominal abscess within 6 months prior to first dose.

Note: Complete cure of an intra-abdominal abscess must be confirmed prior to the first dose.

c) Clinically significant hematuria, hematemesis, or hemoptysis > 0.5 teaspoon (2.5 ml) of red blood, or other significant bleeding (eg, pulmonary hemorrhage) within 12 weeks prior to the first dose.

Cavitating lung disease or known manifestation of endobronchial disease.

Lesions affecting large pulmonary blood vessels.

Other clinically significant disorders such as:

i) Having an active or history of autoimmune disease or immunodeficiency, including but not limited to: myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, or multiple sclerosis (for a more detailed list of autoimmune diseases and immunodeficiencies, see Appendix D). Subjects with the following pathologies may participate in the study:

History of autoimmune hypothyroidism and thyroid hormone replacement therapy.

Controlled type 1 diabetes and insulin intake.

Asthma requiring intermittent use of bronchodilators.

Eczema, psoriasis, lichen simplex chronicus or vitiligo with dermatological manifestations only if the following are observed:

Rash covers < 10% of body surface area.

The disease is well controlled at baseline and requires only low-potency topical corticosteroids.

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Absence of acute exacerbations of the underlying pathology requiring psoralen plus ultraviolet A, methotrexate, retinoids, biological agents, oral calcineurin inhibitors, or high potency or oral corticosteroids within the previous 12 months.

Active infection requiring systemic treatment, infection with human immunodeficiency virus (HIV) or disease associated with acquired immunodeficiency syndrome (AIDS), or acute or chronic infection with hepatitis B or C, or a positive test for tuberculosis.

History of idiopathic pulmonary fibrosis, pneumosclerosis (eg, bronchiolitis obliterans), drug-induced pneumonia, idiopathic pneumonia, or evidence of active pneumonia on chest examination using computed tomography (CT). A history of radiation pneumonia in the radiation area (fibrosis) is allowed.

Serious non-healing wounds/ulcers/bone fractures.

Malabsorption syndrome.

Uncompensated/symptomatic hypothyroidism.

Moderate to severe liver failure (Child-Pugh classification B or C).

The need for hemodialysis or peritoneal dialysis.

History of whole organ or allogeneic stem cell transplantation.

11. Major surgery (eg, gastrointestinal surgery, removal or biopsy of brain metastases) within 8 weeks prior to the first dose of study treatment, excluding prior nephrectomy within 6 weeks prior to the first dose. Complete wound healing from major surgery should occur 3 weeks before the first dose, and from minor surgery (eg, simple excision, tooth extraction) at least 10 days before the first dose. Subjects with clinically significant non-resolving complications from prior surgery are not eligible.

12. Corrected QT interval calculated using Friederick's formula (QTcF) > 500 ms per electrocardiogram (ECG) within 28 days prior to the first dose of study treatment (see Section 5.6.4 for Friederick's formula).

Note: If a single ECG shows a QTcF with an absolute value > 500 ms, within 30 minutes of the initial ECG, two additional ECGs should be performed approximately 3 minutes apart and the average of these three consecutive QTcF results will be used to determine eligibility.

13. Pregnant or lactating women.

14. Inability to swallow pills.

15. Previously identified allergy or hypersensitivity to the components of the finished form used in the study treatment.

16. Diagnosis of other malignancy within 2 years prior to the first dose of investigational treatment, except for shallow skin cancer or low-grade localized tumors that are considered cured and not treated with systemic therapy. Incidentally diagnosed prostate cancer is allowed in subjects with CM if it is graded as stage < T2N0M0, Gleason score < 6, and PSA is undetectable.

Evaluations and Study Procedures Evaluation schedules for the study are presented in Appendix A for the dose escalation stage and Appendix B for the expansion stage.

Most assessments and study procedures (including administration according to treatment) will be performed in cycles. Cycle 1 Day 1 (C1D1) is defined as the date of the first dose of any investigational treatment. The overall cycle is typically a 21-day period starting on the date of the atezolizumab infusion and ending on the day before the next atezolizumab infusion. However, under some circumstances, the dose of atezolizumab may not be administered during the cycle:

If an introductory dosing schedule of cabozantinib is used, the period during which cabozantinib is administered prior to the first dose of atezolizumab will be defined as Cycle 1.

If atezolizumab treatment is discontinued but cabozantinib treatment is allowed to continue with sponsor notification, each subsequent 21-day period beginning on the date of the decision to discontinue atezolizumab will be defined as a cycle. If the decision to stop atezolizumab is made less than 21 days after the last infusion, then the next cycle will begin on the 22nd day after the last infusion.

Cycles may last longer than 21 days if atezolizumab administration is delayed. During atezolizumab dose deferral, subjects should return to the center for scheduled safety visits every three weeks after the last dose of atezolizumab. In addition, the study site should arrange for unscheduled weekly visits (or more frequently if clinically necessary) to monitor the subject's safety and suitability for retreatment with the investigational treatment.

Evaluative imaging (CT, magnetic resonance imaging (MRI), bone tomograms) should be performed at intervals specified in the protocol, based on the first dose of the study

- 51 041548 treatment (defined as Week 1, Day 1 [H1D1]); at all subsequent points in time, the same nomenclature will apply to these estimates and will not be changed as a result of modifications or deletions of treatment administration. Evaluation imaging frequencies are given in Appendix A for the dose escalation stage and in Appendix B for the expansion stage.

Unless otherwise noted, in the absence of toxicity, all scheduled visits will occur within the time periods for the visit schedule specified in the protocol. If a subject experiences toxicity, investigational treatment may be modified or delayed as described in Section 6.5. If a subject is unable to complete a study evaluation within a specified period of time due to a reason beyond their control (e.g., center closure, personal emergency, bad weather, vacation), the evaluation should be conducted as close as possible to the required schedule. Laboratory kits for serum chemistry, hematology and urinalysis are defined in Section 5.6.5.

5.1 Period before treatment

Informed consent must be obtained prior to any clinical screening procedure that is conducted solely for the purpose of determining study eligibility; however, evaluations performed as part of routine care before informed consent is obtained may be used as screening evaluations if permitted by the Research Ethics Committee (REC)/Ethics Committee (EC) policy of the research site. Informed consent may be obtained more than 28 days prior to the first dose of study treatment. With informed consent, subjects will be assigned a subject identification number; Subject ID numbers should not be reassigned if a subject is determined to be unsuitable, and subjects should retain their original ID number if re-screening is required, or if the study site or investigator changes for the subject.

To determine subject eligibility as outlined in Section 4, subjects will undergo the necessary screening evaluations as outlined in Appendix A (dose escalation stage) and Appendix B (expansion stage) and as described in Section 5.6. Qualifying screening evaluations should be performed within 28 days prior to the first dose of study treatment, unless otherwise specified (certain laboratory values should be obtained closer to the first dose of study treatment). Laboratory-based eligibility criteria will be derived from the results of the central laboratory (excluding serological pregnancy test and daily urine protein; see Section 5.6.5). Tests from local laboratories may be obtained and used if the results are required by the investigator in a short time to confirm eligibility. Local laboratory results used to validate suitability must be submitted to the local laboratory management vendor. Study eligibility is based on whether the subject meets all study inclusion criteria and none of the screening exclusion criteria.

5.2 Treatment period

While a subject is receiving study treatment, the subject's clinical condition should be assessed by the attending physician at each clinic visit to confirm that the subject is fit to continue study treatment and to make timely decisions regarding interruption or resumption of study treatment. Results of clinical laboratory tests on specimens obtained during clinic visits and evaluation of tumors during imaging visits should be reviewed by the attending physician. Also refer to Section 5.6.5 regarding handling of specimens for laboratory testing.

Subjects will receive study treatment for as long as they continue to experience clinical benefit in the investigator's judgment or until unacceptable toxicity occurs, the need for subsequent systemic anticancer treatment, or until any other reason for discontinuing treatment occurs. will be specified in the protocol (Section 3.8). Study treatment may continue after radiological confirmation of progression in accordance with CCAS 1.1 if subjects meet all of the following criteria:

Evidence of clinical benefit, as determined by the investigator after review of all available data

Absence of symptoms and signs indicative of unambiguous disease progression (eg, laboratory findings such as clinically significant hypercalcemia in subjects with RCC that cannot be controlled by optimizing maintenance therapy)

Absence of deterioration in the general condition according to VCOH, which may be associated with the progression of the disease

Absence of tumor progression in critical anatomical sites (eg, leptomeningeal disease) that is not treatable with protocol-allowed medical interventions.

The researcher should take into account the possibility of a delayed antitumor immune response with the possibility of regression and increase in tumor lesions at the same time.

- 52 041548 imaging time (mixed response) or appearance of new lesions before radiological response is achieved.

Clinical safety assessment visits will be conducted at least every 3 weeks (± 3 days) from the start of treatment, regardless of any delays or interruptions in dosing. Definitive assessment will be performed at the post-treatment follow-up visit unless PE is determined not to resolve (see Section 5.3).

If study treatment is interrupted or delayed due to PE, investigators should conduct additional safety assessments weekly (or more frequently if clinically necessary).

Radiographic evaluation of tumors will be performed as described in Section 5.6.8. The schedule of assessments must be followed regardless of whether treatment is reduced, interrupted, delayed or discontinued.

5.2.1 Dose escalation step

During the dose escalation phase, groups will be determined by the initial dose level of cabozantinib and the schedule for the first atezolizumab infusion (either at C1D1 with the first dose of cabozantinib or at C2D1, 21 days after the first dose of cabozantinib; see Section 3.5.1). Eligible subjects will be enrolled in an open group, regardless of tumor type. Subjects in the dose escalation phase will be treated and evaluated in accordance with the evaluation schedule in Appendix A.

5.2.2 Expansion stage

Subjects in the expansion stage will be assigned to a treatment group based on tumor type and history of cancer, as described in Section 3.5.2. Subjects in the expansion phase will be treated with a starting dose level of cabozantinib, as determined by COG, in combination with atezolizumab. Study treatment will be administered according to the COG recommended dosing schedule; during the expansion phase, only one dose level and dosing schedule will be evaluated. Expansion group subjects will be evaluated in accordance with the evaluation schedule in Appendix B.

5.3 Period after treatment

Subjects who discontinue study treatment are returned to the center 30 days (+ 14 days) after the study treatment termination decision date for a post-treatment follow-up visit. Safety assessments will be performed during the post-treatment follow-up visit. Refer to Appendix A (dose escalation stage) or Appendix B (expansion stage) for a description of all evaluations for the post-treatment follow-up visit.

Adverse effects (including EPIs and PEOs) should be documented and/or dealt with as described in Section 8.4.

Subjects' OB will be monitored as described in Section 5.6.10. The conclusion of the conclusion on non-protocol anticancer therapy will be made during the observation of survival. If contact with the subject for follow-up is lost, the subject records should document multiple attempts to contact the research subject or their authorized representative.

Radiographic assessments of tumors may need to be collected prior to radiological confirmation of progression, as described in Section 5.6.8.

Such post-treatment evaluations (including follow-up visits after treatment discontinuation) are not required for subjects who discontinue treatment in the maintenance phase of the study (such subjects must adhere to the standard of care).

5.4 Maintenance phase

When sufficient data have been collected to adequately evaluate all measured study parameters, and after local notification of the sponsor, subjects continuing treatment in the study will enter the maintenance phase of the study. After the start of the Maintenance Phase, the sponsor reviews the safety and efficacy profile of the medicinal product in this study in order to be sufficiently prepared for regulatory procedures. After completion of the maintenance phase, the study will be considered completed in centers and countries where there are no more active subjects.

During the maintenance phase, subjects will continue to receive study treatment until the protocol's withdrawal criteria are met (Section 3.8). Subjects should undergo periodic safety assessments (including local laboratory tests) and tumor assessments (Appendix C). The nature and frequency of these assessments should be in accordance with the standard of care, if permitted by local regulations. It is the investigator's responsibility to ensure that visits to subjects are frequent enough and that adequate assessments are made to ensure the safety of the subject.

In order to continue collecting important safety information for subjects still included in the study, reporting of PETs, PEOs, and other reported adverse events (mistakes in pregnancy and medication with residual effects) should continue in accordance with the protocol (Section 8).

In addition, the following PEs (including PEs), whether serious or not, should be reported using the same process as for reporting PEs, as described in the protocol in Section 8.2 (although there are no reporting deadlines for PEs). apply to non-serious cases reported in these categories):

Adverse events (including ESAEs), serious or not, leading to interruption of study treatment

Adverse effects (including EPIs), whether serious or not, leading to a change in dose (i.e., causing interruption, delay, or reduction in investigational treatment). Accounting for the study drug should continue as described in Section 6.4.

Only data collected prior to the start of the maintenance phase will be included in the clinical study report.

5.5 Unscheduled visits or assessments

If the investigator determines that the subject should be monitored more frequently or with additional laboratory evaluations than specified in the schedule established by the protocol, unscheduled visits or evaluations are permitted. Laboratory studies will be carried out by the central laboratory; however, if the results are needed immediately (for example, to control PE), they can be performed by the local laboratory, and the results will be sent to the management vendor for processing of the local laboratory data. Where possible, a sample will also be taken for analysis at a central laboratory. During a dose interruption due to PE (i.e., the time between the last dose and restarting the drug), the study site should arrange for unscheduled weekly visits (or more frequently if clinically necessary) to monitor safety and suitability subject for re-treatment with the study treatment.

5.6 Procedure details

5.6.1 Demographics, clinical and cancer history

Demographics at screening will include informed consent age, medical and cancer history, surgical history, radiation therapy history, and systemic cancer treatment history, including agent names and dates of administration.

Refer to Appendix A for a schedule of such evaluations for the dose escalation stage and Appendix B for the expansion stage.

5.6.2 Clinical examination

Clinical examinations at screening will include height, weight, general condition and assessment of the following systems: skin, head, eyes, ears, nose, throat, respiratory system, cardiovascular system, gastrointestinal system, neurological condition, blood and lymphatic system , and the musculoskeletal system. A symptom-based clinical evaluation will be performed at C1D1 prior to the first dose of study treatment and at subsequent safety visits. Any current/intercurrent pathology(s) prior to the first dose will be recorded in primary documents and in individual registration cards (IRCs).

General status on the Karnofsky score will be assessed during the screening of subjects with RCC to determine the predictive risk score according to the MSKCC prognostic criteria (Motzer et al 2004). At screening and at follow-up visits, all subjects will be assessed for the overall condition of HCHD. A table for both indicators of general condition is included in Appendix E for reference.

Refer to Appendix A for the schedule of clinical examinations and assessments of general condition for the dose escalation stage, and Appendix B for the expansion stage.

5.6.3 Basic physiological parameters

Vital signs, including a 5-minute sitting BP measurement, pulse, respiratory rate, and temperature, will be assessed at screening, during all scheduled safety visits, and during all non-scheduled visits, if possible. On atezolizumab infusion days, vital signs should be assessed within 60 minutes prior to infusion, and further assessment of vital signs should be performed during and after the infusion as clinically indicated.

Refer to Appendix A for a schedule of such evaluations for the dose escalation stage and Appendix B for the expansion stage.

5.6.4 Electrocardiogram evaluations

At screening and during the study, single ECG evaluations will be performed on standard 12-lead ECG equipment in accordance with established practice to determine the corrected QT interval calculated using the Friederick formula (QTcF). To qualify, a QTcF < 500 ms per ECG within 14 days prior to the first dose of study treatment is required. If one ECG shows a QTcF with an absolute value > 500 ms, within 30 min after

- 54 041548 the initial ECG two additional ECGs should be taken approximately 3 minutes apart and the average of these three consecutive QTcF results will be used to determine suitability (see Section 6.5.2.1.16).

ECGs will be taken at the times specified in Appendix A (dose escalation stage) and Appendix B (expansion stage).

ECG abnormalities that result in a change in the subject's management (e.g., dose reduction or interruption, discontinuation of treatment; need for additional treatment or observation) or cause clinical signs and symptoms are considered clinically significant for the purposes of this study and will be considered a PE. If the values meet the criteria for defining them as serious, they should be reported as POCs (Section 8.2).

Friederik's formula is shown below for calculating QTcF.

QT=measured QT interval in milliseconds; RR=measured interval from R to R (which can be obtained from heart rate as 60/heart rate)

5.6.5 Laboratory studies

The laboratory tests that will be performed for this study are listed in Table 1. 5-1. The schedule of laboratory studies is given in Appendix A for the dose increase stage and in Appendix B for the expansion stage. Laboratory tests to determine suitability must be performed within 14 days prior to the first dose of investigational treatment, unless otherwise noted.

Hematology, serum chemistry, coagulation, MBMP including components, and thyroid function tests should be performed by the central laboratory on specimens collected at scheduled safety visits and non-scheduled visits when possible. All results from the central laboratory will be shared with the researcher. Local laboratory tests for these panels can be obtained and used if the results are required by the investigator in a short time frame. All results obtained at the local laboratory must be forwarded to the study management vendor at the local laboratory if they are performed in lieu of evaluation of the central laboratory at any scheduled or unscheduled visit.

Routine (dipstick) urinalysis, microscopic examination of urine, and serum and urine pregnancy tests are performed by the local laboratory. The results or status of these tests will be recorded in the CRF and will not be made available to the study management vendor at the local laboratory.

If performed to determine eligibility or at any scheduled or unscheduled visit, 24-hour urine protein tests must be performed by the local laboratory and laboratory results must be forwarded to the study management vendor at the local laboratory.

Samples for serum chemistry, hematology, and urinalysis should be collected and results reviewed within 72 hours prior to any administration of atezolizumab in the study.

Throughout the study, fasting glucose levels should be monitored (there should be no food intake for at least 8 hours, water intake is allowed).

A serological pregnancy test should be repeated prior to dosing in C1D1, unless a pregnancy test was performed at the time of screening within 7 days prior to administration in C1D1. Urine pregnancy tests will be performed to detect pregnancy after baseline.

The screening will test for hepatitis B surface antigen and hepatitis C antibody (in HCV RNA reflex testing if the antibody test is positive).

For CRPC subjects, baseline testosterone and PSA levels will be assessed at screening. After screening, PSA levels will be assessed as described in Section 5.6.8.3 and according to the assessment schedule for the expansion stage (Appendix B).

- 55 041548

Table 5-1. Clinical laboratory tests

Central laboratory If performed by a local laboratory instead of evaluation by a central laboratory, submit results to the study management vendor at the local laboratory Hematology Leukocytes (WBC) fractional counting (ACN, basophils, eosinophils, lymphocytes, monocytes) hematocrit platelet count red blood cell count hemoglobin Coagulation Serum biochemical analysis albumin total alkaline phosphatase (AP) amylase alanine aminotransferase (ALT) aspartate aminotransferase (ACT) blood urea nitrogen (BUN) blood calcium concentration corrected for albumin bicarbonate Biochemical analysis of urine Protein (single a portion of urine; fully quantitative) Creatinine (single urine sample; fully quantitative) Urine protein/creatinine ratio (MPK; single sample urine) prothrombin time (PT)/International Normalized Ratio (INR) Partial Thromboplastin Time (PTT) thyroid function thyroid stimulating hormone (TSH) Free thyroxine (T4; required at screening; after screening only if TSH is outside normal range) chloride creatinine γ-glutamyl transpeptidase (GGT) glucose (fasting) lactate dehydrogenase (LDH) lipase magnesium phosphorus potassium sodium total bilirubin (conjugated and unconjugated if total bilirubin is elevated) total protein hepatitis B surface antigen (HBsAg; screening) antibody to hepatitis C virus ( Ab HCV; control HCV RNA test if antibodies are positive [screening]) Other tests (for CRRP entities in group 6) Testosterone (serum, baseline only) Prostate specific antigen (PSA) local laboratory Submit clear 24-hour urine protein test results to the test management vendor at the local laboratory Analysis of urine (test strip or common industry analysis) pH specific gravity ketones Microscopic examination of urine Perform at investigator's discretion based on results or clinical indications Urinalysis 24-hour urine protein: Blood test for pregnancy (before the first dose) 13-human gonadotropin (13-HCG) Analysis of urine and blood for protein glucose nitrite urobilin leukocyte esterase blood perform at the discretion of the investigator based on the increase in MBM by conventional tests pregnancy (after the first doses investigational treatment) 13-human gonadotropin (13-HCG)

- 56 041548

Table 5-2. Estimation of creatinine clearance according to Cockcroft and Gault

Serum creatinine in standard units (mg/dL)

Men: (140 - age) x weight (kg) / (serum creatinine x 72)

Women: [(140 - age) x weight (kg) / (serum creatinine x 72)] x 0.85

Serum creatinine in SI units (µmol/l)

Men: [(140 - age) x weight (kg)/(serum creatinine)] χ 1.23

Women: [(140 - age) x weight (kg)/(serum creatinine)] χ 1.04

Abnormalities in any clinical laboratory analysis (including those not required by the protocol) that result in a change in the subject's management (e.g., interrupted dosing, delay or reduction, discontinuation of treatment; need for additional treatment or observation) are considered clinically significant for purposes of of this study and will be reported as PE. If the laboratory values are part of an effect that meets the criteria for a serious effect, the effect (and associated laboratory values) must be reported as a POC (see Section 8.2).

5.6.6 Pharmacokinetic analyzes

Unless otherwise approved by the sponsor, blood samples for PK will be obtained from all registered subjects as described in Section 5.6.6.1, as well as Appendix A for the dose escalation phase and Appendix B for the expansion phase.

5.6.6.1 Blood samples for pharmacokinetics

Samples will be collected to assess the PK of cabozantinib. Plasma concentrations of cabozantinib will be measured and the results will be used to confirm exposure to cabozantinib, to identify possible drug interactions between cabozantinib and atezolizumab, and to further characterize the PK of cabozantinib and/or possible relevant cabozantinib degradation products in these populations. PK analysis can also be performed for atezolizumab if deemed appropriate. PK sampling may be stopped early or the frequency of sampling may be changed at the discretion of the sponsor.

Dose escalation step:

For subjects on a standard dosing schedule, blood samples for PK analysis will be obtained on the day of the first dose of study treatment (C1D1; prior to administration of study drug [cabozantinib and atezolizumab], approximately 5 minutes after completion of atezolizumab infusion, and 2, 4, and 6-8 hours after administration of cabozantinib) and before the start of study treatment doses at C1D10, C2D1, and C3D1. For subjects on an introductory cabozantinib dosing schedule, blood samples for PK analysis will be obtained on the day of the first dose (C1D1; samples taken before study administration [cabozantinib and atezolizumab] and 2, 4, and 6-8 hours after cabozantinib administration), and prior to study treatment at C2D1, C2D10 and C3D1.

Expansion stage:

For subjects on a standard dosing schedule, blood samples for PK analysis will be obtained on the day of the first dose of study treatment (C1D1; prior to study treatment [cabozantinib and atezolizumab], approximately 5 min after completion of atezolizumab infusion, and 2 hours after first dose cabozantinib) and prior to initiation of study treatment doses at C2D1 and C3D1. For subjects on an introductory cabozantinib dosing schedule, blood samples for PK analysis will be obtained on the day of the first dose (C1D1; samples taken prior to study administration [cabozantinib and atezolizumab] and 2 hours after the first dose of cabozantinib) and prior to study treatment at C2D1 and C3D1.

For more details, see Appendix A for a schedule of such evaluations for the dose escalation stage, and Appendix B for the expansion stage.

5.6.7 Biomarker assays

Blood and tissue samples will be obtained from consenting individuals for analysis of common and/or study biomarkers. Refer to Appendix A for a schedule of such evaluations for the dose escalation stage and Appendix B for the expansion stage.

Required and non-required blood samples will be used to study plasma, serum, and cell biomarkers. Archival and optional samples of fresh tumor tissue will be used to evaluate changes in biomarker expression and genetic/genomic changes. The assays will help identify biomarkers that predict response to an investigational drug and may help to better understand tumor development, the tumor microenvironment, and the effect on peripheral immune activity for research purposes.

Tests may include, but are not limited to: DNA and/or RNA sequencing from tissue and/or blood (plasma) to look for genetic/genomic changes (e.g., mutations, copy number variations, mutation load), immunohistochemical (IHC) assessment of bio levels

- 57 041548 markers in tissue (eg MET, AXL, PD-L1) and immune cell profiling by flow cytometer cell sorting assay (FACS). In these studies, both traditional and new technologies or techniques can be used. The aim is to find an association between changes in these predictive biomarkers and clinical outcome following treatment with cabozantinib and atezolizumab. Determination of PD-L1 levels is for scientific/research purposes in this study and will not be shared with investigators as these results do not influence therapeutic decisions. Immune cell profiling by FACS can be performed at selected centers.

In addition, genotyping of single nucleotide polymorphisms (SNPs) can be performed to find an association between changes in a subject's genotype and the safety/tolerance, PK, and/or pharmacodynamics of cabozantinib and atezolizumab.

Biomarker samples can also be used to develop an investigational drug-related diagnostic assay and to discover biomarkers that may be valuable surrogates (targets) for clinical response as well as for understanding underlying disease mechanisms.

For NSCLC subjects, free tumor mutation analysis reports should be provided at screening.

5.6.8 Tumor evaluation

5.6.8.1 Routine tumor evaluation

Determination of the study parameters to be measured ORR, PrO and PFS will be based on the investigator's assessment of the tumor according to COOS 1.1 (Appendix F). Additional exploratory evaluation of the effectiveness of the immune response will include the use of a modified QOOSE (Appendix G). An independent review of tumor scores may be requested at the discretion of the study sponsor; this may include transferring all radiographic images of the study (eg, CT/MRI, technetium bone scan) to an independent key radiology laboratory.

Radiographic assessments of tumors will include the following:

1. Thoracic/abdominal/pelvic (THP): CT HBT, or CT of the chest and MRI of the abdomen/pelvis will be performed in all subjects at screening and every 6 weeks (± 5 days) after starting study treatment for the first 12 months of research. At the end of the 12 months of the study, these evaluations will be conducted every 12 weeks (± 7 days).

2. Brain: MRI (or CT) of the brain will be performed at screening for all subjects with RCC and NSCLC, and for subjects with CRPC or UC who have a history or clinical symptoms of brain metastasis. After initiation of investigational treatment, MRI (or CT) brain scans are required only for subjects with documented, treated brain metastases or clinical signs or symptoms suggestive of new central nervous system (CNS) metastases. Evaluations after the first dose of study treatment will be performed every 12 weeks (± 7 days). MRI is the preferred way to image the brain. If brain CT is performed instead of MRI, inconclusive results should be confirmed by MRI. Subjects without documented brain metastases at the time of screening evaluation are not required to undergo brain imaging after the start of investigational treatment, unless clinically indicated. In order to qualify for study participation, brain metastasis must have been treated and stable for at least 4 weeks prior to the first dose of study treatment.

3. Bone Scan: Technetium Bone Scan (TBS) will be performed at screening for all subjects with CRPC and for subjects with RCC, UC, or NSCLC who have a history or clinical symptoms (eg, bone pain) of bone metastases. After initiation of investigational treatment, bone scans are required only for subjects with documented bone lesions or if clinically marked by signs and symptoms suggestive of new bone metastases. Evaluations after the first dose will be performed according to normal clinical practice (approximately every 12 weeks for the first 12 months and every 24 weeks thereafter). Lesions identified on bone scans should not be recorded as targets, non-targets, or new lesions. Bone scan should be used to guide confirmatory imaging with CT/MRI if needed (these CT/MRI results will be used to evaluate CCSD v1.1), and bone scan results alone should not be used to determine progression in this study.

Investigators are encouraged, if there is any doubt or uncertainty about radiographically confirmed progression, to continue treatment if the subject tolerates it tolerably, repeat radiographic imaging of the tumor at the next scheduled time, and defer conclusion of progression until results indicative of radiographically confirmed progression will not be unambiguous. Radiographically confirmed progression as determined by the investigator is not grounds for discontinuation of tumor evaluation or investigational treatment (see Section 3.8).

Termination of X-ray imaging:

For subjects who discontinue investigational treatment prior to radiological confirmation of disease progression in accordance with CCAS 1.1, if possible, regular scheduled imaging evaluations should be continued until radiological confirmation of progression according to COOS 1.1 or initiation of the next anticancer therapy.

For subjects who interrupt tumor evaluation during radiological confirmation of progression according to CCAS 1.1, additional imaging of the tumor is not required.

Bone scan evaluations will end on the day of the last CT/MRI scan. If the bone scan schedule does not match the last CT/MRI scan, no additional bone scan is required after the last CT/MRI scan.

Refer to Appendix A for a schedule of such evaluations for the dose escalation stage and Appendix B for the expansion stage.

5.6.8.2 Confirmation of tumor response and tumor progression

For subjects with an overall response of OR or CR according to CCAS 1.1 at a given time point, changes in tumor measurements should be confirmed by reassessments performed at least 4 weeks after the response criteria were first met.

In order to detect a potential delayed immune-mediated tumor response, subjects with an overall response rate as per CCAM 1.1 who continue study treatment due to evidence of clinical benefit as assessed by the investigator should have tumor measurements confirmed > 4 weeks after compliance with the primary criterion of the PR. Continuation of investigational treatment after confirmatory tumor imaging is at the discretion of the investigator. For subjects who continue treatment after confirmatory tumor imaging, scheduled imaging will continue regularly.

5.6.8.3 Estimating PSA

For subjects with CRPC (expansion group 6), PSA specimens should be collected at screening, on Day 1 of every third cycle during the first 6 months of the study, and then on Day 1 of every fifth cycle until whichever comes first, the next systemic cancer therapy or permanent loss of radiological follow-up (including hospice admission). The samples will be analyzed by the central laboratory.

PSA estimates should not be used to make study treatment decisions.

5.6.9 Subject's Daily Medication Diary

Subjects in the dose escalation phase will be provided with a daily medication diary with instructions for recording their out-of-clinic cabozantinib intake during the OCT evaluation period.

For subjects on the standard dosing schedule, the diary will be initially provided at C1D1 and will be collected at the start of Cycle 2. For subjects on the introductory dosing schedule of cabozantinib, the diary will be initially provided at C2D1 and it will be collected at the start of Cycle 3.

The daily intake diary is not a CRF. The diary will serve as background documentation and will be retained with the subject's other clinical background documents. Research site personnel should carefully review the subject's diary to ensure it is complete and accurate before transferring its contents to the subject's CRF.

5.6.10 Overall survival

Following cessation of study treatment, each subject will continue to be monitored for survival and subsequent anti-cancer therapy. The Investigator (or their designee) will contact the subject at least as often as every 12 weeks (± 7 days) after the post-treatment follow-up visit, until the subject's follow-up period expires or the sponsor decides to stop collecting this data for the study.

At each contact, the investigator (or his designee) will determine if the subject is alive and collect information about the non-protocol cancer treatment received by the subject. If the subject dies, the investigator will record the date and cause of death as accurately as possible. Study centers should make every effort to determine the date of death (or the last date he was still alive at the time data collection was stopped). This may include, but is not necessarily limited to, telephone contacts, communication during study visits, registered letters, local obituary reviews, and public death records (if permitted by local laws and regulations).

Refer to Appendix A for a schedule of such evaluations for the dose escalation stage and Appendix B for the expansion stage.

Such assessments are not required for subjects who discontinue treatment in the maintenance phase of the study (such subjects must adhere to the standard of care).

6. Therapies

6.1 Composition, finished form and storage

At study sites, all investigational medicinal agents will be stored as described in the appropriate country label (if applicable) or pharmaceutical manual and inventoried in accordance with established state and federal regulations.

6.1.1 Investigational Treatment: Cabozantinib

The sponsor will provide each investigator with sufficient supplies of cabozantinib, which will be supplied as 60 and 20 mg yellow film-coated tablets. The 60 mg tablets are oval and the 20 mg tablets are round. Doses of 40 mg will contain two 20 mg tablets. The components of the tablets are listed in table. 6-1.

Table 6-1. Components and composition of cabozantinib tablets

Ingredient Function % The drug substance cabozantinib (25% of the drug load in the form of Active Ingredient 31, 68 Microcrystalline cellulose Filler 38.85 Lactose, anhydrous (60M) Filler 19, 42 Hydroxypropylcellulose (EXF) Binder 3.00 Croscarmellose sodium (Ac-Di-Sol®) Baking powder 6.00 colloidal silicon dioxide A tool to help 0.30 magnesium stearate Lubricant 0.75 Film coating based on Opadry® yellow, which includes: HPMC 2910/Hypromellose 6 cP Dioxide Film coating 4.00

and mass fraction, expressed as a percentage; HPMC, hydroxypropyl methylcellulose

For more information on storage and handling of cabozantinib, see Pharmaceutical Guidelines.

6.1.2 Combination treatment: Atezolizumab

Atezolizumab is an Fc-engineered humanized monoclonal antibody (non-glycosylated kappa immunoglobulin IgG1) produced in Chinese hamster ovary cells with an estimated molecular weight of 145 kDa.

The sponsor will provide each investigator with an adequate supply of atezolizumab, which will be supplied as a colorless to slightly yellowish 1200 mg/20 ml (60 mg/ml) solution in single dose vials. Atezolizumab solution contains the following inactive ingredients: glacial acetic acid, L-histidine, sucrose, and polysorbate 20. For more information and instructions on how to prepare atezolizumab for infusion, see the package insert (or label) and the Pharmaceutical Formulary. The solution used as diluent (0.9% NaCl) should be supplied by research centers if available and allowed by local regulations.

6.2 Treatment schedule

Cabozantinib will be administered orally at prescribed daily doses of 20, 40, or 60 mg. Atezolizumab will be administered at a standard dose of 1200 mg as an intravenous infusion once every 3 weeks. Subjects on the dose escalation stage of the standard dosing schedule will follow a combined schedule with the first infusion of atezolizumab administered on the same day as the first dose of cabozantinib. In accordance with the cabozantinib introductory dosing schedule (if COG is used), the first infusion of atezolizumab will be administered at C2D1, 21 days after the first dose of cabozantinib as a single agent. During the expansion phase, all subjects will receive cabozantinib at the recommended dose and schedule as established by the COG. Additional instructions for drug administration are provided in Sections 6.2.1 and 6.2.2.

Subjects will receive treatment with cabozantinib and atezolizumab as part of the study for as long as they continue to experience clinical benefit, as judged by the investigator, or until unacceptable toxicity occurs, the need for subsequent systemic anticancer treatment, or until any - or other reasons for stopping treatment will not be indicated in the protocol (Section 3.8). Discontinuation of one component of the study treatment combination while continuing the other may be permitted with notice to the sponsor.

For guidance on dose changes, interruptions, delays, or discontinuation due to PE, see Section 6.5.1.

6.2.1 Clinical introduction

Cabozantinib:

The first dose of cabozantinib will be administered at the clinic. If both investigational drug agents are administered in C1D1, atezolizumab should be administered first. The subject will be without food (excluding water) for at least 2 h prior to receiving cabozantinib. After the end of 2 hours without food, the subject will receive an oral dose of cabozantinib with a minimum of 8 oz (240 ml) of water at the clinic, and then the subject will be without food for 1 hour while being monitored for potential AEs. For cabozantinib dosing on subsequent days, see Section 6.2.2.

Atezolizumab:

Subjects on the standard dosing schedule will receive the first dose of atezolizumab on the day of the first dose of cabozantinib (C1D1). Subjects on the introductory dosing schedule of cabozantinib (if used) will receive the first dose of atezolizumab at C2D1 21 days after the first dose of cabozantinib.

Atezolizumab doses will always be administered intravenously in the clinic by infusion on Day 1 of each 21-day cycle (-2 days). Cycles may last longer than 3 weeks if atezolizumab treatment is delayed due to toxicity or other reasons.

Atezolizumab infusion (1200 mg fixed dose) will be prepared according to local instructions for use or pharmaceutical formulary. IV atezolizumab should only be administered in a clinical setting where staff are experienced in managing infusion-related reactions and have access to emergency services. The first intravenous (IV) infusion of atezolizumab will be given over 60 minutes (± 15 minutes) without medical preparation for possible infusion-related reactions. Subsequent IV infusions may be given over 30 minutes (± 10 minutes) if the first infusion is tolerated. Premedication of an infusion reaction is permitted after the initial infusion. Do not bolus or IV atezolizumab. Dose delays will be tolerated due to toxicity suspected to be associated with atezolizumab administration. Atezolizumab infusion requirements and recommendations are given in Table 1. 6-2.

Table 6-2. Infusion requirements and administration guidelines for atezolizumab

First infusion Subsequent infusions edicamentous preparation is not allowed. vital signs (blood pressure, pulse, respiratory rate, and temperature) should be recorded within 60 minutes prior to infusion. Gezolizumab should be given as an infusion over 60 (± 15) minutes. If clinically appropriate, vital signs should be recorded during the infusion at 15, 30, 45, and 60 minutes (± 5 minutes for all time points) during the infusion and 30 (± 10) minutes after the infusion. /objects must be informed of the possibility of delayed post-infusion symptoms and are instructed to contact their doctor, If the subject has experienced an infusion-related reaction to any previous infusion, medication may be administered with antihistamines, antipyretics, and/or analgesics for subsequent doses at the discretion of the investigator. Vital signs should be recorded within 60 minutes prior to infusion. Gezolizumab should be administered by infusion over 30 (± 10) minutes if the previous infusion was tolerated without an infusion-related reaction, or 60 (± 15) minutes if the subject had an infusion-related reaction with the previous infusion. if the subject had an infusion-related reaction with a previous infusion, or if if they show these symptoms. clinically appropriate, vital signs should be recorded at the time of infusion and 30 (± 5) minutes after infusion.

Following IV administration of the first dose of atezolizumab in the clinic, the subject will wait at least 1 hour before receiving cabozantinib. If the subject develops a transfusion reaction, oral administration of cabozantinib will be delayed or interrupted until the subject has recovered and the investigator considers it safe to administer cabozantinib. To control reactions associated with

- 61 041548 by infusion, refer to Appendix H.

If the first dose of atezolizumab cannot be given for any reason, the following should occur:

At the standard dosing schedule, oral treatment with cabozantinib should not be started.

During the introductory dosing schedule of cabozantinib, cabozantinib should be interrupted (if not already) and consideration should be given to discontinuing study treatment. Continuation of treatment with cabozantinib as the sole agent may be permitted with notice to the sponsor.

6.2.2 Out-of-hospital administration of cabozantinib

The subject must take cabozantinib off-site at approximately the same time each day, preferably at bedtime, and must comply with the fasting requirements described in this section.

Subjects should not take food (except water) for at least 2 hours after eating before taking the dose. After 2 hours without food and at bedtime, subjects should take cabozantinib with a full glass of water (minimum 8 oz or 240 ml) without additional food within one hour of dosing. If the subject's schedule requires cabozantinib to be taken throughout the day, the subject should be instructed to follow the same fasting recommendations.

Cabozantinib tablets should not be crushed or chewed. Grapefruits or oranges (and their products) should be avoided during treatment with cabozantinib.

Subjects should be instructed not to take emetic doses and to follow the planned dosing schedule. Subjects should not make up missed doses if more than 12 hours have passed since the subject normally takes cabozantinib. In the case of missed doses, subjects should not take 2 doses to make up for the one missed.

Subjects enrolled in the dose escalation phase are expected to complete a cabozantinib diary during the OCT Evaluation Period (Section 5.6.8.3).

Any unused study treatment must be returned to the study site for record keeping and drug disposal.

6.3 Compliance

The subject's compliance with outpatient study treatment will be assessed by the center using drug dispensing and return records, dose reduction/discontinuation progress notes, subject interview, and subject's daily intake diary (ODT evaluation period for dose escalation group only, Section 5.6. 8.3). These data will not be directly written to the CFM; rather, the CRF will record the intervals of constant dose and the reasons for changing the dose level (eg, a new entry is made every time the dose level is changed, including periods when the dose was not taken and the reason for changing the dose level).

6.4 Study treatment reporting

The investigator or designee will maintain accurate prescription records for all types of investigational treatment, including the date the prescriptions were received. In addition, accurate records will be kept regarding when and how much the investigational drug is distributed to and used by each subject in the study. The reasons for the deviation from the expected dosing regimen should also be recorded. Upon completion of the study, to comply with regulatory requirements regarding drug accountability, all unused study drug agents will be reconciled and destroyed in accordance with applicable state, federal, and local regulations.

6.5 Security considerations

6.5.1 Control of PE with dose reductions and/or dose interruptions

Subjects will be monitored for PE from the time of signing the informed consent within 30 days (90 days for IET) after the date of the decision to permanently discontinue all types of investigational treatment. Subjects will be instructed to immediately notify their physician of any PE that occurs. An assessment of the causal relationship of PE should include, at a minimum, concomitant factors such as disease and concomitant medications. The severity of the side effect is assessed by the investigator in accordance with the OTKPO v.4.0.

When making decisions regarding dose modification (reduction and/or interruption) in relation to treatment-related side effects, the following should be taken into account:

Cabozantinib and atezolizumab have class-specific safety profiles based on their mechanism of action, but may also cause AEs that overlap. To control AEs that can be clearly attributed to cabozantinib or atezolizumab, independent dose modification for either agent is allowed. Examples of PE associated with VEGFR TKI caused by cabozantinib are hypertension and hand and foot syndrome. Pneumonia and endocrinopathies are examples of atezolizumab-induced ESPEs. For AEs without clear attribution to any study drug, toxicity control should include dose modifications of both agents.

- 62 041548 at the discretion of the investigator. Diarrhea and elevated transaminase levels are examples of overlapping AEs.

As a general approach, all AEs should be treated with supportive care, including both pharmacological and non-pharmacological treatment, in accordance with agreed guidelines for monitoring at the earliest sign of toxicity considered treatment-related within the study.

Study treatment may be continued for mild PE if appropriate supportive care has been initiated to improve symptoms. If this is not effective and toxicity becomes unacceptable, consideration should be given to changing the dose of investigational treatment to prevent worsening toxicity. Moderate to severe AEs usually require dose modification, including dose reduction and/or discontinuation.

Dose interruptions of cabozantinib or atezolizumab for PE may occur at any time and at the discretion of the investigator. If one or both medicinal agents of investigational treatment are interrupted for more than 12 weeks, the sponsor should be contacted to discuss continuation of treatment.

Cabozantinib:

The assigned dose of cabozantinib for group 1 during the dose escalation phase is 40 mg daily. The assigned dose of cabozantinib for the expansion phase will be determined during the dose escalation phase. The maximum protocol-allowed dose for cabozantinib is 60 mg per day.

Three dose reduction levels of cabozantinib are allowed (40 mg daily, 20 mg daily, and 20 mg r/h/s) (see Tables 6-3).

For subjects in the dose escalation phase, dose reduction or discontinuation of cabozantinib during the ODT evaluation period may result in an ODT (see Section 3.5.1.4).

Cabozantinib dose adjustment criteria for treatment-related PE are summarized in Table 1. 6-4.

Restoration of the dose level and re-dose after interruptions and / or dose reductions:

If the subject recovers from his or her toxicity according to the OTC v.4.0 to < Grade 1 or baseline (or below), and the PE was not related to cabozantinib, then cabozantinib may be restarted without dose adjustment.

If the subject recovers from his or her toxicity to < Grade 1 or baseline (or below) and the PE is thought to be possibly due to cabozantinib, then cabozantinib may be restarted at a reduced dose (see Table 6-3).

For subjects receiving a dose of 20 mg r/h/s, it may be restarted at the same dose if considered safe at the discretion of the investigator. Subjects unable to tolerate a dose of 20 mg r/h/s should discontinue cabozantinib.

A return to the previous dose may be allowed during the expansion phase at the investigator's discretion for PEs that are resolved or cured to Grade 1 (or baseline) and are considered tolerable and easily managed with optimized supportive care. Dose escalation is not allowed during dose escalation or after dose reduction of cabozantinib, for grade 4 PE affecting major organs (eg, CNS, heart, liver, kidneys).

Guidelines for the management of specific AEs of cabozantinib such as gastrointestinal disturbances, non-gastrointestinal fistula formation, hemorrhage, thromboembolic complications, hypertension, stomatitis and mucositis, skin diseases, osteonecrosis, proteinuria, nervous system disorders, hepatocellular toxicity, infections and invasions, systemic circulatory disorders, fatigue, weight loss, QTc prolongation, electrolyte imbalance, endocrine disorders, and respiratory disorders are presented in Section 6.5.2.1.

Table 6-3. Dose reduction of cabozantinib (oral dosing)

Initially prescribed dose First level of DOSE reduction Second level of dose reduction Third level of dose reduction 60 mg per day (r / day) 40 mg per day (r / day) 20 mg per day (r / day) 20 mg per day (r/h/day) 40 mg per day (r / day) 20 mg per day (r / day) 20 mg via day (r/h/day) Is not allowed dose reduction 20 mg per day (r / day) 2 0 mg via day No dose reduction

Although a dose level of 20 mg once every other day (r/h/s) is tolerated as a result of dose reduction, this dose level will not be evaluated as the intended starting dose at any stage of this study. Cabozantinib will be discontinued if the 20 mg dose of cabozantinib once every other day (minimum dose) is not tolerated.

Table 6-4. Dose Modifications for Cabozantinib-Associated AEs

Degree according to OTKPO v.4.0 Recommended Control Guides ³ PE 1st degree Add supportive care as indicated. Continue cabozantinib at current dose level if PE is controlled Grade 2 PE that is tolerable and controlled Grade 2 PE that is not tolerated and cannot be adequately controlled Continue introduction cabozantinib with current dose level for maintenance therapy. Dose should be reduced cabozantinib or interrupt introduction. Note: Recommended that dosing interruptions be as short as possible. and portable. PE grade 3 (except for clinically insignificant laboratory abnormalities) Cabozantinib administration should be discontinued if toxicity cannot be easily managed with dose reduction of cabozantinib and optimal medical management. Note: It is recommended that dosing interruptions be as short as possible. PE grade 4 (except for clinically insignificant laboratory abnormalities) Cabozantinib should be discontinued immediately. In general, administration of cabozantinib should generally be terminate if the following criteria are not met: The subject receives a distinct clinical benefit as determined by the investigator and agreed with the sponsor. Toxicity can be control with dose reduction of cabozantinib after return to grade 1 (or baseline) values) and optimal medical assistance Contact sponsor to discuss continuation of treatment after elimination of side effects.

PE, side effect.

Note: Criteria for dose modification of cabozantinib for specific clinical conditions are provided in Section 6.5.2.1.

^a Dose adjustment of investigational treatment is necessary only if toxicity was considered to be treatment-related or was not clearly related to study treatment.

Atezolizumab:

The prescribed dose of atezolizumab is 1200 mg IV every 3 weeks. The infusion will be given once every three weeks (-2 days) on Day 1 of each cycle, unless subjects on the introductory cabozantinib dosing schedule (if applicable) will not receive their first dose of atezolizumab until T2D1.

Dose interruption of atezolizumab is allowed (see Tables 6-5), but dose reduction is not allowed.

Dose change criteria for ISPE and recommendations for reinstating the dose of atezolizumab are given in Table 1. 6-6.

If corticosteroids are provided for the treatment of ISPE, they should be tapered to δ 10 mg/day po prednisone or equivalent over ε1 months before atezolizumab can be restarted.

Guidance for monitoring infusion reactions and ESAEs for atezolizumab (i.e. pneumonia, hepatitis, diarrhea/colitis, myocarditis, endocrinopathies including hypophysitis and infection) are provided in Section 6.5.2.2.

Tab. Figure 6-5: Atezolizumab Dose Interruptions

Assigned Dose Interruption of 1200 mg atezolizumab IV r3n Anytime to control inadmissible r3n EEIs, once every 3 weeks; ISPE immune-related side effects

Table 6-6: Dose Modifications for Atezolizumab-Associated EPEs

Degree according to OTKPO v.4.0 Recommended control

Myocarditis 2nd degree Pneumonia 2nd degree ACT or ALT > 3 and ± 5 x TLN or total bilirubin > 1.5 and ± 3 * TLN Cirrhea or colitis grade 2 or 3 Symptomatic adrenal insufficiency, hypothyroidism or hyperthyroidism; hypophysitis of the 2nd or 3rd degree; or grade 3 or 4 hyperglycemia Grade 2 ocular inflammatory toxicity Grade 2 or 3 pancreatitis, or grade 3 or 4 amylase or lipase elevation (>2.0 x ULN) Grade 3 or 4 infections Grade 2 infusion-related reactions Grade 3 rash Atezolizumab Treatment Delay Treatment may be restarted for subjects after recovery to grade 0-1.

Uncontrolled grade 3 or 4 myocarditis and/or myocarditis of the 2nd degree, with atezolizumab suspension Grade 3 or 4 pneumonia ACT or ALT > 5 x TLN or total bilirubin > 3 x TLN 4th degree ciarrhea or colitis Hypophysitis grade 4 and/or recurrent hypophysitis Myasthenic syndrome/myasthenia gravis, Guillain-Barre or meningoencephalitis (all degrees) Grade 3 or 4 ocular toxicity, Grade 4 or any recurrent pancreatitis associated with infusion grade 3 or 4 reaction, grade 4 rash Stop atezolizumab permanently

ALT, alanine aminotransferase; ACT, aspartate aminotransferase; ISPE, immune-related side effects; HPN, upper limit of normal.

Note: For additional information on atezolizumab dose modification criteria and recommendations for the treatment of ISPE and infusion reactions, see Section 6.5.2.2.

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6.5.2 Warnings, precautions, guidelines for controlling side effects

Subjects will be monitored for PE from the time of signing the informed consent within 30 days (90 days for PET) after the date of the decision to permanently discontinue treatment. Subjects will be instructed to immediately notify their physician of any PE that occurs. An assessment of the causal relationship of PE should include, at a minimum, concomitant factors such as disease and concomitant medications. The severity of the side effect is assessed by the investigator in accordance with the OTKPO v.4.0.

Treatment of severe or intolerable side effects may require temporary dose reduction and/or discontinuation of cabozantinib and/or delay of atezolizumab administration.

6.5.2.1 Cabozantinib

The most common AEs experienced by the 20% of subjects treated with cabozantinib in descending order of frequency were: diarrhea, fatigue, nausea, anorexia, vomiting, weight loss, PPE, constipation, hypertension, dysgeusia, dysphonia, and asthenia. For a full description of the safety profile of cabozantinib, see the Cabozantinib Investigator Brochure.

Other medically important but less common PEs include arterial thrombotic PEs (eg, PIA and MI) and venous thrombotic PEs (eg, DVT and pulmonary embolism), severe hemorrhagic events, proteinuria, wound healing complications, GI perforation , abscesses, including intra-abdominal and hip abscess, the formation of GI and non-GI fistulas, osteonecrosis and RPLS.

Side effects associated with laboratory abnormalities encountered? The 5% of subjects treated with cabozantinib, in descending order of frequency, were: anemia, elevated AST, elevated ALT, hypothyroidism, hypokalemia, hypomagnesemia, thrombocytopenia, hypocalcemia, hypophosphatemia, elevated lactate dehydrogenase (LDH), elevated lipase, neutropenia, hyponatremia , elevated alkaline phosphatase, leukopenia and hyperglycemia.

Side effects may occur during the first few weeks of treatment with cabozantinib, as cabozantinib is expected to reach steady state approximately 2 weeks after the first dose. Effects that usually have an early onset include hypocalcemia, hypokalemia, thrombocytopenia, hypertension, PPE, abdominal pain, mucosal inflammation, constipation, diarrhea, and vomiting. Side effects should be treated with supportive care at the earliest sign of toxicity. Dose reduction and treatment interruption should be considered. Dose reduction is recommended for effects that, if persistent, may become severe or intolerable (Table 6-3).

Cabozantinib should be discontinued in the following AEs: visceral perforation or fistula formation, severe hemorrhage, serious arterial thromboembolic events, nephrotic syndrome, hypertensive crisis, persistent uncontrolled hypertension despite optimal medical treatment, and RPLS.

6.5.2.1.1 Gastrointestinal disorders

Gastrointestinal perforation, GI fistula, and intra-abdominal and pelvic abscess: After initiation of cabozantinib treatment, subjects should be monitored for early signs of gastrointestinal perforation such as abdominal pain, nausea, vomiting, constipation, and fever, especially if known risk factors for gastrointestinal perforation or fistula (Turnage and Badgwell 2016). Stop cabozantinib administration and initiate appropriate treatment for subjects diagnosed with gastrointestinal perforation or fistula.

Diarrhea: Subjects should be instructed to notify their physician immediately at the first sign of poorly formed or loose stools or increased frequency of bowel movements. Recommendations for the evaluation and treatment of diarrhea are given in Table. 6-7. Administration of antidiarrheal/motility suppressing agents is recommended at the first sign of diarrhea as initial treatment. Some subjects may require concurrent treatment with more than one antidiarrheal agent. When antidiarrheal therapy fails to reduce diarrhea to acceptable levels, cabozantinib should be temporarily interrupted or the dose reduced. When diarrhea is controlled, retreatment with cabozantinib may be acceptable at the discretion of the investigator. In addition, general supportive measures should be taken, such as continuous oral isotonic hydration, correction of fluid and electrolyte imbalances, frequent small meals, and avoidance of lactose-containing, high-fat, and high-alcohol meals.

Recurrent or prolonged diarrhea may be associated with anal or perianal skin erosions, which increase the risk of anal abscesses, fistulas, or proctitis. There should be an emphasis on good personal hygiene. Regular perianal examinations should be performed whenever diarrhea occurs during treatment with cabozantinib. Perianal infections should be treated according to local guidelines.

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Table 6-7. Treatment of diarrhea associated with cabozantinib

Status Treatment Portable 1st-2nd degree (duration < 48 h) Continue investigational treatment and consider dose reduction Start antidiarrheal treatment (eg, loperamide 4 mg, then 2 mg after each episode of diarrhea [maximum: 16 mg loperamide per day]) Power modifications (for example, small lactose-free meals, bananas and rice) Consumption of isotonic fluids (1-1.5 L/day) Reassessment after 24 hours: Return from diarrhea to baseline intestinal conditions: gradually add solid foods, and stop or reduce antidiarrheal treatment after 12- hour period without diarrhea Diarrhea does not go away Continue/resume antidiarrheal treatment Intolerable 2nd degree 2nd degree > 48 h, or > 3rd degree Interrupt treatment within research Ask subject to visit clinic Rule out infection (eg. sample chair for culture) Administer antibiotics as needed (for example, if fever or grade 3-4 neutropenia persists > 24 h) Fluid administration (1-1.5 L/day orally or IV, as appropriate) to hydrate or correct abnormalities electrolytic balance For grade 3-4 or lower grade complicated diarrhea, hospitalization and IV hydration should be considered. Reassessment after 24 hours Return from diarrhea to baseline bowel status or grade < 1: consider resuming investigational treatment at a reduced dose Diarrhea persists: Start and/or continue antidiarrheal treatment (eg, loperamide 4 mg, then 2 mg after each episode of diarrhea [maximum: 16 mg loperamide per day]). Consider starting second-line antidiarrheal treatment or referral to a gastroenterologist

Nausea and vomiting: Antiemetics are recommended as clinically acceptable for the treatment or prevention of nausea and vomiting along with supportive care. Dehydration and electrolyte imbalances may be associated with vomiting, and fluid and electrolyte imbalances need to be monitored and corrected. Antiemetics should be evaluated for potential drug interactions (see Section 7.3 for more details).

6.5.2.1.2 Outside gastrointestinal fistula

Complications after radiotherapy, especially in the thoracic cavity, including the mediastinum, have been identified as a possible predisposing risk factor for non-GI fistula formation in subjects treated with VEGF pathway inhibitors.

Stop cabozantinib administration and initiate appropriate treatment for subjects diagnosed with non-GI fistula.

6.5.2.1.3 Bleeding

Bleeding side effects have been reported with cabozantinib. Subjects during the study should be checked for bleeding by serial complete blood counts and physical examination. The risk of hemorrhage in cabozantinib-treated subjects with brain metastases has not been carefully analyzed. Subjects enrolled with treated and stable brain metastases should be monitored with a high index of suspicion if symptoms occur that could be due to CNS hemorrhage.

Cabozantinib should be discontinued for subjects with severe and life-threatening bleeding or recent hemoptysis (>2.5 mL of red blood).

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6.5.2.1.4 Thromboembolic complications

Thromboembolic side effects are common in cancer subjects due to procoagulant changes caused by cancer or anti-cancer therapy. DVT and pulmonary embolism have been observed in clinical studies with cabozantinib, including fatal cases. For subjects who develop pulmonary embolism and/or DVT, study treatment should be interrupted until anticoagulation therapy is initiated. Treatment with cabozantinib may be reinitiated for subjects with pulmonary embolism or DVT if it is determined that the side effect is simple, and that the subject is clinically benefiting from treatment with cabozantinib, and that anticoagulation does not put them at significant risk that outweighs the benefit of restarting treatment. at the discretion of the investigator and in accordance with individual protocols. Low molecular weight heparins are the preferred treatment for thrombotic cases; oral anticoagulants (eg, warfarin or other coumarin-related agents, direct thrombin inhibitors or direct FXa inhibitors, or antiplatelet agents, or chronic use of aspirin above low dose levels for cardioprotection according to locally established guidelines) are not allowed.

Arterial thrombotic side effects (eg, PIA, MI) have been observed in studies with cabozantinib. Further treatment with cabozantinib should be discontinued for subjects who develop acute myocardial infarction, cerebral infarction, or any other clinically significant arterial thromboembolic complication.

6.5.2.1.5 Hypertension

In table. Tables 6-8 provide recommendations for the treatment of hypertension thought to be associated with cabozantinib. Blood pressure should be monitored in the same position from visit to visit, either sitting or lying down in a relaxed environment. Decisions to reduce or interrupt the dose of investigational treatment should be based on BP indications taken by the healthcare professional and should be confirmed by a repeat measurement no less than 5 minutes after the first measurement.

Cabozantinib should be discontinued in subjects with a hypertensive crisis.

Table 6-8. Treatment of hypertension associated with cabozantinib

Criteria for dose modification Treatment/Dose Modification cabozantinib Subjects NOT receiving optimized antihypertensive therapy > 150 mmHg Art. (systolic) ^a and < 160 mm Hg. Art. OR > 100 mmHg Art. (diastolic) and < 110 mm Hg. Art. Optimize Your Treatment antihypertensive agents, adding new or additional antihypertensive agents and/or increasing the dose existing funds. Reduce Healing cabozantinib for one dose level if optimal antihypertensive therapy (usually 3 drugs) causes systolic BP < 150 mm Hg. Art. or diastolic < 100 mmHg. Art. If subject develops symptoms, interrupt cabozantinib treatment > 160 mmHg Art. (systolic) OR > 110 mmHg Art. (diastolic) Decrease cabozantinib dose by one dose level ¹³ or interrupt cabozantinib treatment at investigator's discretion Add new or additional antihypertensive drugs and/or increase dose

- 68 041548 existing medications and carefully observe the subject for hypotension. If optimized antihypertensive therapy (usually including 3 drugs) does not cause a systolic blood pressure <150 mm Hg. East or diastolic < 100 mmHg. treatment with cabozantinib should be further reduced in dose or interrupted Cabozantinib treatment should be interrupted at dose if upper limits of systolic BP (> 160 mm Hg) are stable and not adequately controlled, or if systolic BP > 180 mm Hg. Art., or diastolic blood pressure> 110 mm Hg. Hg or if the subject is symptomatic Resume cabozantinib treatment at the most tolerated dose and re-dose only if BP falls and is maintained at < 150 mm Hg. Art. systolic and < 100 mm Hg. Art. diastolic

Hypertensive crisis: stop cabozantinib treatment KD, blood pressure; MI, myocardial infarction.

a The Investigator may decide to start or adjust antihypertensive treatment at a lower threshold than systolic BP > 150 or diastolic BP > 100 based on their clinical judgment and individual subject judgment.

^b Acceptable dose levels are determined by individual protocols.

^c A hypertensive crisis is defined as an uncontrolled increase in blood pressure with clinical evidence of progressive or impending end organ damage (eg, myocardial infarction/ischemia, intracranial hemorrhage, cerebral ischemia, pulmonary edema, encephalopathy, kidney damage).

6.5.2.1.6 Stomatitis and mucositis

Preventive measures may include a comprehensive oral examination to identify and treat any potential risk of complications prior to starting investigational treatment. Appropriate correction of local factors should be carried out as directed, such as modification of unsuitable dentures and proper care of gingivitis. During treatment with cabozantinib, good oral hygiene and standard local procedures such as non-traumatic and non-irritating cleansing and mouth rinses (eg, weak saline and baking soda) should be observed. Lips should be moisturized with lip balm. Lipstick, lip gloss and petroleum jelly should be avoided.

Topical treatment should be started at the onset of symptoms. Obtain a bacterial/viral culture if an oral infection is suspected and treat the infection as clinically indicated.

6.5.2.1.7 Skin and subcutaneous tissue disorders

Wound healing and surgery: Cabozantinib has the potential to cause wound healing complications and wound dissection, which can occur even after the wound is considered healed. Therefore, surgical and traumatic wounds should not only be completely healed prior to initiation of cabozantinib treatment, but should also be monitored for wound dehiscence, wound infection, and other signs of impaired wound healing when the subject is treated with cabozantinib. If dilatation occurs, cabozantinib treatment should not be restarted until complete healing.

Treatment with cabozantinib should be discontinued at least 28 days prior to scheduled surgery. The decision to resume treatment with cabozantinib after surgery should be based on clinical judgment of adequate wound healing.

Hand-foot erythrodysesthesia (PPE; also known as hand-foot syndrome), skin rash (including wheals, rash erythematous, rash macular, skin detachment, dermatitis, acne, and rash papular), pruritus, dry skin, erythema have been reported for cabozantinib treatment. , pigmentary changes and alopecia. All subjects in the study should be advised to take preventive measures, including use of emollients, removal of calluses, avoidance of vasodilation of hands and feet with hot water, protection of pressure-sensitive areas of the hands and feet, and use of cotton gloves and socks. to prevent injury and keep hands and soles dry.

Early manifestations include tingling, numbness, mild hyperkeratosis, and symmetrical red and swollen areas on the palms and soles. The sides of the fingers or the periungual areas may also be affected. Appropriate measures are necessary to prevent worsening of skin symptoms such as blistering, scaling, ulceration or necrosis of the affected areas. Analgesics may be needed to control pain.

Aggressive treatment of symptoms is recommended, including early referral to a dermatologist. Recommendations for treatment in response to PPE are given in Table 1. 6-9.

Table 6-9. Treatment of palmoplantar erythrodysesthesia (PPE) associated with cabozantinib

Degree according to OTKPO v.4.0 Action to be taken 1st degree Treatment with cabozantinib may be continued at the current dose if PPE is clinically non-significant and tolerable. Otherwise, the dose of cabozantinib should be reduced to the next lower dose level. ^a Give 20% urea cream twice daily AND clobetasol 0.05% cream once daily. Reassess at least weekly; if PPE worsens at any time or does not improve after 2 weeks, go to guideline procedure for the 2nd degree. 2nd degree Treatment with cabozantinib may be continued if PPE is tolerated. The dose of cabozantinib should be reduced or discontinued if the PPE is intolerable. Continue 20% urea cream twice daily AND high potency steroid cream (eg, clobetasol 0.05%) once daily and add analgesics (eg, NSAIDs/gamma-aminobutyric acid agonists) to control pain, if any necessary. Reassess at least weekly; if PPE worsens or interferes with self-care, go to grade 3 procedure guide. 3rd degree Interrupt treatment with cabozantinib until severity decreases to Grade 1 or Grade 0. Continue treating the skin reaction with a high potency steroid cream (eg, clobetasol 0.05%) twice daily AND analgesics. Resume study drug at a reduced dose if LPE returns to grade < 1. Discontinue study treatment of subject if LPE does not improve within 6 weeks.

TSEC, Common Terminology of Criteria for Adverse Effects; NSAID, non-steroidal anti-inflammatory drug; PPE, palmoplantar erythrodysesthesia.

a) Acceptable dose levels are determined by individual protocols.

6.5.2.1.8 Osteonecrosis

Osteonecrosis has been reported in subjects treated with cabozantinib. Additional risk factors include the use of bisphosphonates and denosumab, chemotherapy and antiangiogenic drugs, corticosteroid use, local radiation therapy, and dental or orofacial surgical procedures.

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Osteonecrosis of the jaw (ONJ) may present with jaw pain, osteomyelitis, osteitis, bone erosion, dental or periodontal infection, toothache, gingival ulceration, or gingival erosion.

Persistent pain or slow healing of the mouth or jaw after dental surgery can also be manifestations of osteonecrosis.

Advise subjects on oral hygiene practices and promptly report symptoms to investigator. Caution should be exercised for subjects receiving bisphosphonates.

Invasive dental procedures should be avoided. In cases where dental procedures are unavoidable, treatment with cabozantinib should be interrupted at least 4 weeks before the procedure and resumed after the wound has completely healed. Bone healing can often take a long time.

6.5.2.1.9 Proteinuria

Proteinuria has been reported with cabozantinib treatment. Proteinuria should be monitored by measuring MBMP. In table. Tables 6-10 provide recommendations for the treatment of proteinuria associated with cabozantinib.

Treatment with cabozantinib should be discontinued in subjects with nephrotic syndrome (proteinuria > 3.5 g/day in combination with low blood protein, high cholesterol, high triglycerides, and edema).

Table 6-10. Treatment of proteinuria associated with cabozantinib

Severity of proteinuria Treatment of proteinuria (TPCM) < 1 mg/mg (< 113.1 mg/mmol) No change in treatment cabozantinib or observation For PKK, CRRP, NSCLC: > 1 and < 3.5 mg/mg (> 113.1 and < 395.9 mg/mmol) For UK: > 2 and < 3.5 mg/mg (> 226.2 and < 395.9 mg/mmol) □ Consider confirmation with 24-hour protein assessment within 7 days □ No change in cabozantinib treatment is required if MBMP < 2 mg/mg or urine protein < 2 g/24 g on a 24-hour urine collection. □ Reduce dose or discontinue treatment with cabozantinib if MBMP > 2 mg/mg on repeat TPMT or urinary protein > 2 g/24 hours on 24 hour urine collection. Continue treatment with cabozantinib at a reduced dose if MBMP falls to < 2 mg/mg. Consider discontinuing cabozantinib treatment if MBM remains > 2 mg/mg despite dose reduction until MBM falls to < 2 mg/mg. Restart treatment with cabozantinib at a reduced dose after dose interruption, unless otherwise approved by the sponsor. If MBM > 2 mg/mg, repeat MVK monitoring for 7 days and once a week. If MBMP is < 2 mg/mg on 2 consecutive assays, monitoring MBMP may return to the protocol-defined time. (The second test is confirmatory and can be done within 1 week after the first test.) > 3.5 mg/mg (> 395.9 mg/mmol) Interrupt cabozantinib treatment during follow-up for 7 days of MBMP and/or 24-hour urine protein. If > 3.5 mg/mg on repeat

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monitoring MBMP, continue to interrupt cabozantinib treatment and check MBMP every 7 days. If MBMP decreases to < 2 mg/mg, restart cabozantinib at a reduced dose and monitor MBMP until it remains < 2 mg/mg on two consecutive measurements. If observed MBMP is found to be stable (<20% change) over 1 month, continue monitoring MBMP as per protocol or clinically indicated. nephrotic syndrome □ Stop treatment with cabozantinib

RCC, renal cell carcinoma; UC, urothelial carcinoma; MBMP, urinary protein creatinine ratio.

6.5.2.1.10 Disorders of the nervous system

Cabozantinib appears to pose a minimal risk of adverse neurological effects based on preclinical good laboratory practice (GLP) toxicological studies. Dysphonia, dysgeusia, headache, dizziness, confusion, seizures, depression, memory impairment, hypoesthesia, peripheral neuropathy, insomnia, ataxia, and encephalopathy have been observed in clinical studies with cabozantinib. The development of any new or progressive, unexplained neurological symptoms should be evaluated for underlying causes.

SLDF has been reported. RPLS should be considered in any subject who has seizures, headache, visual disturbances, confusion, or altered mental function. Treatment with cabozantinib should be discontinued in subjects with RPLS.

6.5.2.1.11 Hepatocellular toxicity

Aminotransferases (ALT and ACT) and bilirubin were monitored during treatment with cabozantinib. It is recommended that subjects with elevations in ALT, ACT, and/or bilirubin have more frequent laboratory monitoring of these parameters. If possible, hepatotoxic drugs should be discontinued for subjects with elevated ALT, AST, or bilirubin values, and other causes (eg, cancer-related) should be evaluated.

Table 6-11. Treatment of hepatotoxicity associated with cabozantinib

Severity according to ALT, ACT, total bilirubin according to cabozantinib TKPO Treatment/Dose changes Complications 1st degree Dose adjustment is usually not required. Consider the possibility discontinuation related hepatotoxic drugs and add maintenance therapy according to indications. 2nd degree Interrupt the introduction cabozantinib if lasts longer than 1 week Restart infusion cabozantinib after laboratory abnormalities return to at least degree < 1st GVSD or baseline. Grade > 3 Interrupt cabozantinib and consider more frequent monitoring of ALT, ACT, and bilirubin.

Restart cabozantinib at a reduced dose after laboratory abnormalities return to at least grade < 1st HRMS or baseline.

Stop administration if laboratory abnormalities cannot be corrected despite

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ALT, alanine aminotransferase; ACT, aspartate aminotransferase; QECS, General Terminology of Criteria for Adverse Effects

The following conditions warrant discontinuation of cabozantinib unless these laboratory abnormalities have returned to grade 1 or baseline after discontinuation and the sponsor has approved reintroduction of cabozantinib:

Drug-related ALT or ACT > 8 x ULN.

Drug-related ALT or ACT > 3 x ULN in combination with total bilirubin > 2 x ULN with no other reasonable explanation, consistent with drug-induced liver damage.

An increase in aminotransferases in the presence of liver metastases may not require a dose change if there is no progressive change in aminotransferases (less than two times) and if there is no progressive increase in serum bilirubin concentration or clotting factors.

6.5.2.1.12 Infections and infestations

Infections are commonly seen in subjects with cancer. Predisposing risk factors include reduced immune status (eg, after myelosuppressive cancer therapy, splenectomy), destructive growth of the underlying malignancy, including infiltration into the bone marrow with suppression of normal hematopoiesis, and the presence of intravenous devices.

Infections and abscesses should be treated with appropriate local care and systemic therapy. Cabozantinib should be discontinued until sufficient healing has occurred.

6.5.2.1.13 Disorders of the circulatory and lymphatic system

Hematologic toxicity (i.e., neutropenia and thrombocytopenia) and associated complications have been observed following cabozantinib administration and can be managed with dose interruption and/or dose reduction. Subjects with hematological toxicity may require additional or more frequent laboratory testing in accordance with local guidelines.

Dose reduction or dose interruption for haematological toxicity is not mandatory, but may be used as clinically indicated. Supportive care for thrombocytopenia or anemia, such as transfusion, may be provided according to local guidelines. The use of colony-stimulating growth factors should be considered. Febrile neutropenia or evidence of infection associated with neutropenia should be assessed immediately and treated appropriately and promptly in accordance with established local guidelines.

6.5.2.1.14 Fatigue

Common causes of fatigue such as anemia, impaired performance, emotional disturbances (depression and/or anxiety), poor diet, dehydration, sleep disturbance, and hypothyroidism should be ruled out and treated according to standard medical care.

Pharmacological treatment should be considered after exclusion of specific diseases, unless prohibited.

6.5.2.1.15 Weight loss

Anorexia and weight loss should be treated according to local standards of care, including supportive nutrition. Pharmacological therapy should be considered to improve appetite when not prohibited by a specific protocol.

6.5.2.1.16 Corrected QT interval

The effect of orally administered cabozantinib 140 mg daily on the QTc interval was evaluated in a placebo-controlled study in subjects with medullary thyroid cancer (MTC). A mean QTcF increase of 10-15 ms was observed 4 weeks after the start of cabozantinib treatment. The concentration-QTc relationship could not be definitively established. Changes in the morphology of the heart waveform or new rhythms were not observed. None of the cabozantinib-treated subjects in this study had a QTcF > 500 ms. A review of a larger safety database (approximately 5,000 subjects exposed to cabozantinib in clinical trials and in post-marketing use) confirmed the absence of safety concerns associated with QT prolongation. There were no cases of bidirectional tachycardia (torsades de pointes).

Concomitant treatment with strong inhibitors of cytochrome P450 (CYP) 3A4, which may increase cabozantinib plasma concentrations, should be avoided.

If at any time during the study there is an increase in QTcF to an absolute value > 500 ms, two additional ECGs should be performed at intervals of at least 3 minutes within 30 minutes after the first ECG.

If the average QTcF value for three ECGs is > 500 ms, the following steps should be taken:

interrupt treatment with cabozantinib;

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hospitalize symptomatic subjects (eg, palpitations, dizziness, syncope, orthostatic hypotension, significant ventricular arrhythmia on ECG) for thorough cardiac evaluation and treatment;

Consider consultation with cardiologists for asymptomatic subjects for evaluation and follow-up

Check electrolyte balance, especially magnesium, potassium and calcium; correct deviations from the norm according to clinical indications

Check concomitant medications for medications that may have contributed to QT prolongation and discontinue these medications if possible (http://www.qtdruqs.orq)

Repeat the ECG thrice an hour until the mean QTcF is < 500 ms or otherwise determined in consultation with a cardiologist or appropriate specialist.

Subjects with QTc prolongation and symptoms should be monitored closely until QTc elevation and symptoms are corrected. Cabozantinib treatment may be restarted at a reduced dose level if all of the following conditions are met:

Determined that symptoms are not related to QT prolongation

QTcF value > 500 ms not confirmed

Cabozantinib treatment was interrupted at least 1 week after QTcF returned to < 500 ms.

QT interval prolongation can be unambiguously associated with an event other than cabozantinib administration and is treatable/reversible

Sponsor considered all available information and agreed to continue investigational treatment

After restarting study treatment, the ECG should be repeated weekly for 2 weeks, then every 2 weeks for 1 month, then according to protocol-defined time points.

Treatment with cabozantinib should be permanently discontinued if any of the following apply:

Cardiac evaluation confirms that symptoms are due to QT prolongation;

Recurrence of QTcF prolongation after restarting study treatment at a reduced dose.

6.5.2.1.17 Electrolytic imbalance

Serum electrolyte disturbances, including hyponatremia, hypokalemia, hypomagnesemia, and hypophosphatemia, have been reported during cabozantinib treatment, and serum electrolyte levels should be monitored frequently during cabozantinib treatment. Clinically significant electrolyte disturbances should be treated in accordance with dose modification guidelines as indicated in Table 1. 6-4, or as clinically indicated. Standard clinical practice guidelines should be used to treat electrolyte disorders and may include oral or intravenous rehydration.

6.5.2.1.18 Endocrine disorders

An increase in thyroid-stimulating hormone (TSH) levels has been observed with cabozantinib treatment. Currently available data are insufficient to determine the mechanism of the change in thyroid function and its clinical relevance. Treatment of thyroid dysfunction (eg, symptomatic hypothyroidism) should follow accepted clinical guidelines.

6.5.2.2 Atezolizumab

The most common AEs reported in >20% of subjects treated with atezolizumab include fatigue, decreased appetite, nausea, urinary tract infection, pyrexia, and constipation (Tecentriq USPI).

Subjects treated with atezolizumab may also develop infusion reactions, as well as EPEs such as myocarditis, pneumonia, hepatitis, colitis, endocrinopathies (hypophysitis, thyroid disease, adrenal insufficiency, type 1 diabetes), skin disorders, ocular disorders, neurological toxicity (myasthenic) syndrome/myasthenia gravis, Guillain-Barré syndrome or meningoencephalitis), pancreatitis and embryofetal toxicity. Guidance on the treatment of atezolizumab-associated PE is provided in Sections 6.5.2.2.1 to 6.5.2.2.11.

Systemic immune activation is a rare pathology characterized by an excessive immune response. Given the mechanism of action of atezolizumab, systemic immune activation is considered a potential risk when used in combination with other immunomodulatory agents. Systemic immune activation should be included in the differential diagnosis for subjects who, in the absence of an alternative etiology, develop a sepsis-like syndrome after administration of atezolizumab, and the initial assessment should include the following:

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Complete blood count (OAK) with peripheral blood smear;

Prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen and D-dimer;

Ferritin;

triglycerides;

ACT, ALT and total bilirubin;

LDH;

Complete neurological and abdominal examination (assessment for hepatosplenomegaly).

If systemic immune activation is still suspected after the initial evaluation, contact the sponsor for further guidance.

For detailed information on warnings and precautions, possible PE and guidelines for the treatment of PE, and use in special patient populations, see the local atezolizumab prescribing information and the atezolizumab Investigator Brochure.

6.5.2.2.1 Infusion reaction

In studies of atezolizumab, infusion-related reactions reported occurred within 24 hours of atezolizumab administration and were usually mild to moderate in severity, but severe infusion-related reactions have also occurred. Symptoms associated with atezolizumab infusion may include chills, fever, headache, rash, severe arthralgia, bronchospasm, hypotension, or hypertension.

Prophylactic drugs are permitted after the initial infusion of atezolizumab. The presence of mild or moderate infusion reactions may require the infusion to be interrupted or the infusion rate to be reduced. More severe infusion reactions or recurrent infusion reactions despite prophylactic treatment may require permanent discontinuation of atezolizumab. Supportive care should be given at the earliest sign of an infusion reaction, in accordance with accepted treatment guidelines. Refer to Appendix H for detailed treatment guidance and HBCR classification of infusion-related reactions.

6.5.2.2.2 Immune-related pulmonary side effects

An association has been found between dyspnea, cough, fatigue, hypoxia, pneumonia, and pulmonary infiltrates, and atezolizumab administration. Subjects should be assessed for pulmonary signs and symptoms throughout the study, and a chest CT scan performed at each tumor evaluation.

All pulmonary side effects should be carefully evaluated for other common etiologies such as pneumonia or other infections, lymphangic carcinomatosis, pulmonary embolism, heart failure, chronic obstructive pulmonary disease, or pulmonary hypertension. Recommendations for the treatment of pulmonary side effects are given in table. 6-12.

Table 6-12. Guidelines for the treatment of immune-related pulmonary side effects, including pneumonia

Side effect severity Treatment 1st degree Continue atezolizumab and watch carefully Reassess at serial imaging Consider referral to pulmonologist For recurrent pneumonia, treat as a grade 3 or 4 side effect 2nd degree Stop atezolizumab See a pulmonologist and doctor

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infectious disease specialist and consider bronchoscopy or BAL Start treatment with 1-2 mg/kg/day po prednisone or equivalent. Resume atezolizumab if side effect returns to grade 1 or better within 12 weeks ^{a b} Permanently discontinue atezolizumab treatment and contact sponsor if side effect does not resolve to grade 1 or better within 12 weeks _ALS Recurrent side effects treat as grade 3 or 4 Is it the 4th degree Permanently discontinue atezolizumab and contact sponsor ⁰ Bronchoscopy or BAL recommended. Start treatment with 1-2 mg/kg/day of oral prednisone or equivalent. If the side effect does not improve within 48 hours of starting corticosteroids, consider adding an immunosuppressive agent If the side effect does not resolve to grade 1 or greater, use taper corticosteroids over > 1 month

BAL, bronchoscopic alveolar lavage; IVIG, intravenous immunoglobulin.

^a If corticosteroid treatment has been started, the dose should be tapered over > 1 month to < 10 mg/day oral prednisone or equivalent before atezolizumab treatment can be restarted.

^b Atezolizumab may be discontinued for more than 12 weeks to allow corticosteroids to be reduced to <10 mg/day of oral prednisone or equivalent. The acceptable length of the extension period should be agreed between the investigator and the sponsor.

^c Restarting atezolizumab may be considered in subjects who benefit from and have fully recovered from an immune-related side effect. Subjects may only be re-offered atezolizumab after approval has been documented by both the investigator (or appropriate designee) and the sponsor.

6.5.2.2.3 Immune-related hepatic side effects

Immune-related hepatitis has been associated with the administration of atezolizumab. Eligible subjects should have adequate liver function as measured by measurements of total bilirubin and hepatic transaminases, and liver function will be monitored throughout the study. Guidelines for the treatment of hepatic side effects are given in table. 6-13.

For subjects presenting with right upper quadrant pain and/or unexplained nausea or vomiting, liver function tests (LFTs) should be performed immediately and rechecked before the next dose of study drug is administered.

For subjects with increased BPFP, concomitant drug therapy, viral hepatitis, and toxic or neoplastic causes should be considered and appropriate action taken, as appropriate.

Table 6-13. Guidelines for the treatment of hepatic side effects

Side effect severity Treatment 1st degree Continue atezolizumab Monitor BPFP until values return to normal 2nd degree All side effects: Monitor BPFP more frequently until return to baseline Side effects > 5 days in duration: Stop atezolizumab Start treatment with 102 mg/kg/day of oral prednisone or equivalent. Resume atezolizumab treatment if side effect returns to grade 1 or better within 12 weeks ^a,b

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Stop treatment with atezolizumab permanently and contact sponsor if side effect is not resolved to grade 1 or greater within 12 _weeks 3rd or 4th degree Permanently discontinue atezolizumab and contact sponsor ⁰ Consider referring the subject to a gastroenterologist (GE) for evaluation and liver biopsy to determine the etiology of liver injury. Start treatment with 1-2 mg/kg/day of oral prednisone or equivalent. If the side effect does not improve within 48 hours of starting corticosteroids, consider adding an immunosuppressive agent. If the side effect returns to Grade 1 or greater, use taper corticosteroids for ε 1 month.

LCD, gastrointestinal; BPFP, biochemical indicators of liver function.

^a If corticosteroid treatment has been initiated, the dose should be tapered over > 1 month to < 10 mg/day oral prednisone or equivalent before atezolizumab treatment can be restarted.

^b Atezolizumab may be discontinued for more than 12 weeks to allow corticosteroids to be reduced to <10 mg/day of oral prednisone or equivalent. The acceptable length of the extension period should be agreed between the investigator and the sponsor.

^c Restarting atezolizumab may be considered in subjects who benefit from and have fully recovered from an immune-related side effect. Subjects may only be re-offered atezolizumab after approval has been documented by both the investigator (or appropriate designee) and the sponsor.

6.5.2.2.4 Immune-related colitis or diarrhea

Immune-related colitis has been associated with the administration of atezolizumab. Guidelines for the treatment of diarrhea or colitis are given in Table. 6-14.

All cases of diarrhea or colitis should be carefully evaluated for other more common etiologies. For side effects of significant duration or severity, or associated with signs of systemic inflammation or acute phase reactants (eg, elevated reactive protein, platelet count, or leukemoid reaction): perform sigmoidoscopy (or colonoscopy if needed) with colon biopsy, from three up to five samples for standard preparation of paraffin preparations to test for inflammation and lymphocytic infiltrates to confirm the diagnosis of colitis.

Table 6-14. Treatment guidelines for immune-associated diarrhea or colitis

severity side effect Treatment 1st degree Continue atezolizumab Initiate symptomatic treatment Endoscopy recommended if symptoms persist for > 7 days Observe closely 2nd degree Stop atezolizumab Initiate symptomatic treatment Referral of subject to gastroenterologist recommended For recurrent side effects or side effects that last > 5 days, start treatment with 1-2 mg/kg/day po prednisone or equivalent Resume atezolizumab if side effect returns to 1st grade or better within 12 weeks ^{a b} Permanently discontinue atezolizumab treatment and contact sponsor if side effect is not resolved to grade 1 or greater within 12 weeks _aLS

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3rd degree Withdraw atezolizumab Refer subject to gastroenterologist for biopsy evaluation and confirmation Start treatment with 1–2 mg/kg/day IV methylprednisolone or equivalent, and switch to 1–2 mg/kg/day PO prednisone or equivalent if improved Resume atezolizumab, if side effect recurs to Grade 1 or better within 12 weeks ^a,b Permanently discontinue atezolizumab treatment and contact sponsor if side effect is not resolved to grade 1 or better within 12 weeks _aLc 4th degree Permanently discontinue atezolizumab and contact sponsor ⁰ Refer the subject to a gastroenterologist for biopsy evaluation and confirmation. Start treatment with 1-2 mg/kg/day IV methylprednisolone or equivalent, and move to 1-2 mg/kg/day oral prednisone or equivalent if improved If the side effect does not improve within 48 hours of starting corticosteroids, consider adding an immunosuppressive agent If side effect recurs to grade 1 or greater, administer tapering corticosteroids for > 1 month.

LCD, gastrointestinal; IV, IV ^a If corticosteroid treatment has been initiated, the dose should be reduced over > 1 month to < 10 mg/day oral prednisone or equivalent before atezolizumab treatment can be restarted.

^b Atezolizumab may be discontinued for more than 12 weeks to allow corticosteroids to be reduced to <10 mg/day of oral prednisone or equivalent. The acceptable length of the extension period should be agreed between the investigator and the sponsor.

^c Restarting atezolizumab may be considered in subjects who benefit from and have fully recovered from an immune-related side effect. Subjects may only be re-offered atezolizumab after approval has been documented by both the investigator (or appropriate designee) and the sponsor.

6.5.2.2.5 Immune-related endocrinopathies

An association has been made between thyroid dysfunction, adrenal insufficiency and hypophysitis, and the administration of atezolizumab. Guidelines for the treatment of endocrine side effects are given in table. 6-15.

Watch for signs and symptoms of hypophysitis. Subjects with unexplained symptoms such as fatigue, myalgia, impotence, mental status changes, or constipation should be investigated for thyroid, pituitary, or adrenal endocrinopathy. The subject should be referred to an endocrinologist if endocrinopathy is suspected. Thyroid stimulating hormone (TSH) and free triiodothyronine (T3) and thyroxine (T4) levels should be measured to determine if there are thyroid abnormalities. TSH, prolactin, and morning cortisol levels will help differentiate primary adrenal insufficiency from primary pituitary insufficiency.

Table 6-15. Treatment guidelines for endocrine side effects Side effect Treatment

Stop atezolizumab for up to 12 weeks after the onset of the side effect ¹³ Refer the patient to an endocrinologist.

Perform brain MBT (protocol for

Hypophysitis (pan-hypophysis).

hypopituitarism) Start treatment with 1-2 mg/kg/day IV

grade 2-3 methylprednisolone or equivalent, and go to

1-2 mg/kg/day oral prednisone or equivalent if improved.

Start hormone replacement therapy if clinically indicated.

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Resume treatment with atezolizumab if the side effect resolves to grade 1. ¹³ Permanently stop treatment with atezolizumab and contact the sponsor if the side effect is not resolved to Grade 1 or greater at the time of atezolizumab withdrawal. ⁰ For recurrent hypophysitis, treat as a grade 4 side effect.

Hypophysitis (Pan-Permanently discontinue atezolizumab and hypopituitarism contact sponsor.

) Grade 4 Refer the patient to an endocrinologist.

Perform MBT of the brain (protocol for the pituitary gland).

Start treatment with 1-2 mg/kg/day IV methylprednisolone or equivalent, and move to 1-2 mg/kg/day PO prednisone or equivalent when improved. ³ Start hormone replacement therapy if clinically indicated. Continue atezolizumab

Asymptomatic Start thyroid hormone replacement for hypothyroidism Monitor TSH weekly Discontinue atezolizumab Start thyroid hormone replacement Monitor TSH weekly Symptomatic Consider referring subject to hypothyroid endocrinologist. Resume atezolizumab when symptoms are controlled and thyroid function improves

Asymptomatic TSH > 0.1 mU/L and < 0.5 mU/L: hyperthyroidism Continue atezolizumab Monitor TSH every 4 weeks TSH < 0.1 mU/L: Follow guidelines for symptomatic hyperthyroidism

Symptomatically Stop atezolizumab and hyperthyroidism If necessary, start treatment with an antithyroid drug such as methimazole or

- 79 041548 carbimazole.

Consider referring the subject to an endocrinologist.

Resume atezolizumab when symptoms are controlled and thyroid function improves

Permanently discontinue atezolizumab and contact sponsor for ^life- threatening immune-related hyperthyroidism

Symptomatic Discontinue atezolizumab ^3rd day Refer subject to endocrinologist Insufficiency Perform appropriate adrenal imaging Start treatment with 102 mg/kg/day IV grade 2-4 methylprednisolone or equivalent, and move to 102 mg/kg/day oral prednisone or equivalent at improvement.

Resume atezolizumab treatment if side effect resolves to grade 1 or greater and subject is stable on replacement therapy (if required) for 12 weeks ^a,b Permanently discontinue atezolizumab treatment and contact sponsor if side effect is not resolved by 1 -grade or higher or the subject will not be stable on replacement therapy within 12 weeks _{of allc}

Hyperglycemia Continue atezolizumab

Grade 1 or 2 Initiate insulin treatment as needed, Grade Observe for glucose control

Stop atezolizumab.

If necessary, start insulin treatment. hyperglycemia

Watch for glucose control. 3rd or 4th

Resume atezolizumab when symptoms resolve and glucose levels stabilize.

in / in, intravenously; TSH, thyroid-stimulating hormone.

^a If corticosteroid treatment has been initiated, dose should be tapered over ε 1 month to δ 10 mg/day po prednisone or equivalent before atezolizumab treatment can be restarted.

^b Atezolizumab may be discontinued for more than 12 weeks so that corticosteroids can be reduced to δ 10 mg/day po prednisone or equivalent. The acceptable length of the extension period should be agreed between the investigator and the sponsor.

^c Restarting atezolizumab may be considered in subjects who benefit from and have fully recovered from an immune-related side effect. Subjects may only be re-offered atezolizumab after approval has been documented by both the investigator (or appropriate designee) and the sponsor.

6.5.2.2.6 Immune-related dermatological side effects

An association has been found between treatment-induced rash and atezolizumab. Most of the rashes were mild and did not require treatment, with or without pruritus. A dermatologist should evaluate persistent and/or severe rash or itching. A biopsy should be considered if it is not contraindicated. Guidelines for the treatment of dermatological side effects are given in table. 6-16.

Table 6-16. Guidelines for the treatment of immune-related dermatological side effects caused by atezolizumab

Side effect severity Treatment of a skin disorder 1st degree Continue atezolizumab. Consider treatment with topical corticosteroids and/or other symptomatic therapy (eg, antihistamines). 2nd degree Continue atezolizumab. Consider referring the subject to a dermatologist. Start treatment with topical corticosteroids. Consider treatment with high potency topical corticosteroids if side effect symptoms do not improve 3rd degree Delay administration of atezolizumab.

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Refer the subject to a dermatologist. Start treatment with 10 mg/day oral prednisone or equivalent, increasing the dose to 1–2 mg/kg/day if side effect symptoms do not improve within 48–72 hours. Resume atezolizumab treatment if the side effect returns to grade 1 or greater within 12 weeks. ^{a b} Permanently stop treatment with atezolizumab and contact the sponsor if the side effect is not resolved to grade 1 or greater within 12 weeks. _a , _b , s 4th degree Permanently discontinue atezolizumab and contact the sponsor.

^d If corticosteroid treatment has been initiated, dose should be reduced over > 1 month to < 10 mg/day oral prednisone or equivalent before atezolizumab treatment can be restarted.

^e Atezolizumab may be discontinued for more than 12 weeks to allow corticosteroids to be reduced to <10 mg/day oral prednisone or equivalent. The acceptable length of the extension period should be agreed between the investigator and the sponsor.

^f Restarting atezolizumab may be considered for subjects who benefit from and have fully recovered from an immune-related side effect. Subjects may only be re-offered atezolizumab after approval has been documented by both the investigator (or appropriate designee) and the sponsor.

6.5.2.2.7 Immune-related ocular side effects

An association has been found between treatment-related ocular side effects and atezolizumab. Guidelines for the treatment of ocular side effects are given in table. 6-17.

Table 6-17. Guidelines for the treatment of immune-related ocular side effects caused by atezolizumab

Side effect severity Treatment of ocular side effect 1st degree Continue atezolizumab. It is highly recommended to send subject to an ophthalmologist. Start treatment with topical corticosteroid eye drops and topical immunosuppressive therapy. If symptoms persist, treat as a grade 2 side effect. 2nd degree Delay administration of atezolizumab. Referral to an ophthalmologist is highly recommended. Start treatment with topical corticosteroid eye drops and topical immunosuppressive therapy. Resume atezolizumab treatment if the side effect returns to grade 1 or greater within 12 weeks. ^a,b Permanently stop treatment with atezolizumab and contact the sponsor if the side effect is not resolved to grade 1 or higher within 12 weeks _a , _b , _c 3rd or 4th degree Permanently discontinue atezolizumab and contact the sponsor. ⁰ Refer the subject to an ophthalmologist. Start treatment with 1-2 mg/kg/day of oral prednisone or equivalent.

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If the side effect returns to grade 1 or greater, administer tapering corticosteroids for > 1 month.

_a If corticosteroid treatment has been started, the dose should be tapered over > 1 month to < 10 mg/day oral prednisone or equivalent before atezolizumab treatment can be restarted.

_b Atezolizumab may be discontinued for more than 12 weeks to allow corticosteroids to be reduced to <10 mg/day of oral prednisone or equivalent. The acceptable length of the extension period should be agreed between the investigator and the sponsor.

_c Restarting atezolizumab may be considered in subjects who benefit from and have fully recovered from an immune-related side effect. Subjects may only be re-offered atezolizumab after approval has been documented by both the investigator (or designee) and the sponsor.

6.5.2.2.8 Immune-related meningoencephalitis

Immune-related meningoencephalitis is a recognized risk associated with atezolizumab. Immune-related meningoencephalitis should be suspected in any subject with signs or symptoms suggestive of meningitis or encephalitis, including but not limited to headache, neck pain, confusion, seizures, motor or sensory dysfunction, and an altered or reduced level of consciousness. Encephalopathy resulting from a metabolic or electrolyte imbalance must be distinguished from potential meningoencephalitis resulting from infection (bacterial, viral, or fungal) or malignant progression, or secondary to a paraneoplastic process.

All subjects being considered for meningoencephalitis should be urgently evaluated by CT scan and/or brain MRI to evaluate for metastasis, inflammation, or edema. If the attending physician considers it safe, a lumbar puncture should be done and a neurologist should be consulted.

Subjects with signs and symptoms of meningoencephalitis, in the absence of an identified alternative etiology, should be treated according to the guidelines in Table 1. 6-18.

Table 6-18. Treatment guidelines for immune-associated meningoencephalitis

Side effect severity Treatment All degrees Permanently discontinue atezolizumab and contact sponsor ³ Refer subject to a neurologist Start treatment with 1-2 mg/kg/day IV methylprednisolone or equivalent, and move to 1-2 mg/kg/day PO prednisone or equivalent when improved. If the side effect condition does not improve within 48 hours of starting corticosteroids, consider adding an immunosuppressive agent If the side effect returns to grade 1 or greater, administer tapering corticosteroids for > 1 month.

in / in, intravenously.

^a Restarting atezolizumab may be considered for subjects who benefit from and have fully recovered from an immune-related side effect. Subjects may only be re-offered atezolizumab after approval has been documented by both the investigator (or appropriate designee) and the sponsor.

6.5.2.2.9 Immune-related motor and sensory neuropathy

Myasthenia gravis and Guillain-Barré syndrome have been observed with atezolizumab as the sole agent. Patients may have signs and symptoms of sensory and/or motor neuropathy. Diagnostic testing is essential for accurate characterization in order to distinguish between alternative etiologies. Guidelines for the treatment of neurological disorders are given in table. 6-19.

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Table 6-19. Guidelines for the treatment of immune-related neurological disorders

By-effect

Treatment

Immunity-Related Neuropathy Grade 1 Continue atezolizumab Investigate etiology Immunity-related neuropathy grade 2 Stop atezolizumab Investigate etiology Start treatment according to local methodological guides. Resume atezolizumab treatment if side effect returns to grade 1 or better within 12 weeks ^{a b} Permanently discontinue atezolizumab treatment and contact sponsor if side effect does not resolve to _grade 1 or better within 12 weeks Immunity-related neuropathy grade 3 or 4 Permanently discontinue atezolizumab and contact sponsor ⁰ Initiate treatment according to local guidelines. Myasthenia gravis and Guillain-Barre syndrome, any degree Permanently discontinue atezolizumab and contact sponsor ⁰ Refer subject to a neurologist. Start treatment according to local guidelines. Consider starting treatment with 1–2 mg/kg/dose of prednisone orally or IV, or equivalent.

and Guillain's syndrome - any degree in / in, intravenously.

^a If corticosteroid treatment has been started, the dose should be tapered over > 1 month to < 10 mg/day oral prednisone or equivalent before atezolizumab treatment can be restarted.

^b Atezolizumab may be discontinued for more than 12 weeks to allow corticosteroids to be reduced to <10 mg/day of oral prednisone or equivalent. The acceptable length of the extension period should be agreed between the investigator and the sponsor.

^c Restarting atezolizumab may be considered for subjects who benefit from and have fully recovered from an immune-related side effect. Subjects may only be re-offered atezolizumab after approval has been documented by both the investigator (or appropriate designee) and the sponsor.

6.5.2.2.10 Immune-related pancreatitis

Abdominal pain symptoms associated with elevated amylase and lipase levels suggestive of pancreatitis have been associated with atezolizumab. The differential diagnosis of acute abdominal pain should include pancreatitis. Appropriate evaluation should include assessment of ductal obstruction, as well as serum amylase and lipase testing. Guidelines for the treatment of pancreatic side effects, including pancreatitis, are given in Table. 6-20.

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Table 6-20. Guidelines for the treatment of pancreatic side effects, including pancreatitis

By-effect Treatment Amylase and/or lipase increase, 1st degree Continue atezolizumab Pre-dose monitoring of amylase and lipase levels Amylase increase o Continue atezolizumab and/or lipase, grade 2 o Monitor amylase and lipase levels weekly For prolonged elevation (eg > 3 weeks), consider treatment 10 mg/day day of oral prednisone or equivalent Amylase and/or lipase increase, grade 3 or 4 Discontinue atezolizumab Refer subject to gastroenterologist Monitor amylase and lipase levels once every other day If no improvement, consider treatment with 1-2 mg/kg/day po prednisone or equivalent Resume atezolizumab if side effect returns to grade 1 or better within 12 weeks ^{a b} Stop treatment with atezolizumab permanently and

- 84 041548

contact the sponsor if the side effect is not resolved to grade 1 or greater within 12 weeks _allc For recurrent side effects, permanently stop atezolizumab and contact the sponsor. ^With Immune-related pancreatitis, grade 2 or 3 Discontinue atezolizumab Refer subject to gastroenterologist Start treatment with 102 mg/kg/day IV methylprednisolone or equivalent, and move to 102 mg/kg/day PO prednisone or equivalent when improved. Resume atezolizumab treatment if side effect returns to grade 1 or better _within 12 weeks ^a,b Permanently discontinue atezolizumab treatment and contact sponsor if side effect does not resolve to grade 1 or better within 12 weeks recurrent side effects permanently discontinue atezolizumab and contact the sponsor. ^With Immune-related pancreatitis, grade 4 Permanently discontinue atezolizumab and contact the sponsor. ⁰ Refer subject to gastroenterologist Start treatment at 1o2 mg/kg/day IV methylprednisolone or equivalent, and switch to 1-2 mg/kg/day oral prednisone or equivalent when improved. If the side effect does not improve within 48 hours of starting corticosteroids, consider adding an immunosuppressive agent. If the side effect returns to Grade 1 or greater, taper corticosteroids for > 1 month.

LCD, gastrointestinal; IV, IV ^a If corticosteroid treatment has been initiated, the dose should be reduced over > 1 month to < 10 mg/day oral prednisone or equivalent before atezolizumab treatment can be restarted.

^b Atezolizumab may be discontinued for more than 12 weeks to allow corticosteroids to be reduced to <10 mg/day of oral prednisone or equivalent. The acceptable length of the extension period should be agreed between the investigator and the sponsor.

^c Restarting atezolizumab may be considered for subjects who benefit from and have fully recovered from an immune-related side effect. Subjects may only be re-offered atezolizumab after approval has been documented by both the investigator (or appropriate designee) and the sponsor.

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6.5.2.2.11 Immune-related myocarditis No fatal cases of atezolizumab-associated myocarditis have been reported. Guidelines for the treatment of immune-related myocarditis are presented in Table. 6-21.

Table 6-21. Treatment guidelines for immune-related myocarditis

By-effect

Treatment

Immune-related myocarditis, 1st degree Refer the patient to a cardiologist Start treatment according to local guidelines. Immune-related myocarditis, 2nd degree Stop atezolizumab for up to 12 weeks after the onset of the side effect and contact the sponsor. Refer patient to cardiologist Initiate treatment according to local guidelines and consider treatment with antiarrhythmic drugs, temporary pacemaker, extracorporeal membrane oxygenation (ECMO), or VAD as appropriate. Consider treatment with 1–2 mg/kg/day IV methylprednisolone or equivalent, and switching to 1–2 mg/kg/day po prednisone or equivalent when improved. ³ Restart treatment with atezolizumab if the side effect resolves to grade 1. ¹³ Permanently stop treatment with atezolizumab and contact the sponsor if the side effect is not resolved to grade 1 or greater at the time of atezolizumab withdrawal. ⁰

Immunity-related myocarditis, grade 3-4 Permanently discontinue atezolizumab and contact the sponsor. ⁰ Refer patient to cardiologist Initiate treatment according to local guidelines and consider treatment with antiarrhythmic drugs, temporary pacemaker, ECMO or VAD as appropriate. Start treatment with 1-2 mg/kg/day IV methylprednisolone or equivalent, and move to 1-2 mg/kg/day PO prednisone or equivalent when improved. ^{a b} If the side effect does not improve within 48 hours of starting corticosteroids, consider adding an immunosuppressive agent. If the side effect returns to Grade 1 or greater, titrate corticosteroids for > 1 month.

^a If corticosteroid treatment has been started, the dose should be tapered over > 1 month to < 10 mg/day oral prednisone or equivalent before atezolizumab treatment can be restarted.

^b Atezolizumab may be discontinued for more than 12 weeks to allow corticosteroids to be reduced to <10 mg/day of oral prednisone or equivalent. The acceptable length of the extension period should be agreed between the investigator and the sponsor.

^c Restarting atezolizumab may be considered for subjects who benefit from and have fully recovered from an immune-related side effect. Subjects may only be re-offered atezolizumab after approval has been documented by both the investigator (or appropriate designee) and the sponsor.

6.5.2.2.12 Embryo-fetal toxicity

Based on its mechanism of action, atezolizumab may cause fetal harm when administered to a pregnant woman. Animal studies have shown that inhibition of the PD-L1/PD-1 pathway can lead to an increased risk of immune-related rejection of the developing fetus, leading to fetal death.

If atezolizumab is used during pregnancy or if the subject becomes pregnant while taking atezolizumab, advise the subject of the potential risk to the fetus. Advise women of childbearing potential to use effective contraception during treatment with atezolizumab and for at least 5 months after the last dose.

7. Concomitant medicinal products and therapies

7.1 Approved therapy

Antiemetics and antidiarrheal drugs are permitted for prophylactic purposes according to standard clinical practice when clinically indicated.

Granulocyte colony stimulating factors (G-CSF or GM-CSF) are permitted if used in accordance with clinical guidelines (eg ASCO or ESMO guidelines).

Bisphosphonates may be used to control bone loss or hypocalcemia if the benefit outweighs the risk at the discretion of the investigator (Section 6.5.2.1.8).

Note: Osteonecrosis of the jaw has been reported in subjects using bisphosphonates. Oral examinations are recommended at screening to determine eligibility and periodically during the study. In addition, subjects should be advised to practice good oral hygiene and report symptoms promptly to the investigator. Frequent monitoring of potential overlapping toxicities with study treatment is recommended.

Transfusions and hormonal replacement should be used as directed in standard practice.

Inhaled or intranasal corticosteroids are acceptable with minimal systemic absorption. Systemic corticosteroids are permitted to control infusion reactions or EPE and should be tapered to <10 mg/day prednisone equivalent until the next dose of atezolizumab. Prophylactic steroid treatment of subjects allergic to contrast agents prior to tumor imaging is permitted.

Individual anticoagulant therapy with heparin is allowed if it can be performed safely and effectively under the following circumstances:

Low dose low molecular weight heparins (LMWHs) are permitted for prophylactic use when clinically indicated, and the benefit outweighs the risk at the discretion of the investigator.

Therapeutic doses of LMWH during the first dose of study treatment are permitted if the subject has no evidence of brain metastasis, has been on a stable dose of LMWH for at least 6 weeks, and has had no complications from a thromboembolic side effect or anticoagulant regimen.

Therapeutic doses of LMWH after the first dose of investigational treatment are clinically approved (eg, for the treatment of DVT) and the benefit outweighs the risk at the discretion of the investigator. For treatment of thromboembolic complications during the study, see Section 6.5.2.1.4.

Accepted clinical guidelines for proper management should be followed when receiving anticoagulant therapy with heparins. This includes, but is not limited to: educating the subject about potential adverse drug reactions, monitoring laboratory values, dose adjustments (eg, due to kidney dysfunction).

For restrictions on oral anticoagulants, see Section 7.2.

Possible drug interactions with cabozantinib are listed in Section 7.3.1. Possible drug interactions with atezolizumab are unknown (See local prescribing information and atezolizumab Investigator Brochure).

7.2 Prohibited or restricted therapy

The following treatments are prohibited until study treatment is permanently discontinued.

Any experimental agent or experimental medical device.

Therapeutic doses of oral anticoagulants (eg, warfarin or other coumarin-related agents, direct thrombin inhibitors or direct FXa inhibitors, or antiplatelet agents, or chronic use of aspirin above low dose levels for cardioprotection according to local established guidelines).

Any non-protocol systemic cancer treatment (eg, chemotherapy, immunotherapy, radionuclides, drugs, or herbal products used specifically to treat the cancer under study).

Co-administration of denosumab with atezolizumab is prohibited due to a potential increased risk of infections.

The following treatments should be avoided until study treatment is permanently discontinued or otherwise indicated:

Local anti-cancer treatment, including palliative irradiation, ablation, embolization, or tumor-targeting surgery, should not be performed until radiological progression has been established according to COOS 1.1. If clinically necessary, the investigator should consult the sponsor prior to the procedure for safety recommendations.

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Erythropoietic stimulant agents (eg, epoetin alfa and darbepoetin alfa) should not be used based on the reported increased risk of tumor recurrence/progression associated with erythropoietin (Wright et al 2007).

Concomitant medicinal agents known to increase the QTc interval in subjects receiving cabozantinib should be avoided until they permanently stop cabozantinib treatment (see_http://www.qtdrugs.org for a list of drugs that may increase QTc interval).

Live vaccines are prohibited during the study and up to 5 months after the last dose of atezolizumab (eg, nasal influenza, measles, mumps, rubella, oral polio, Bacillus Calmette-Guerin, yellow fever, varicella, and typhoid TY21a) . The use of inactivated (killed) vaccines for the prevention of infectious diseases requires the approval of the sponsor.

Chronic co-administration of cabozantinib with strong inducers of the CYP3A4 family (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John's wort) can significantly reduce cabozantinib concentrations and should be avoided. It is recommended to choose alternative concomitant drugs with zero or minimal potential for CYP3A4 induction.

Caution should be exercised when discontinuing treatment with a strong CYP3A4 inducer in a subject who is concomitantly receiving a stable dose of cabozantinib, as this may significantly increase exposure to cabozantinib.

Co-administration of cabozantinib with strong inhibitors of the CYP3A4 family (eg, boceprevir, conivaptan, posaconazole, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, saquinavir, ritonavir, lopinavir, telaprevir, telithromycin, and voriconazole) may increase the concentration of cabozantinib, and the like. should be avoided. Grapefruit, carom and orange can also increase plasma concentrations of cabozantinib and should be avoided.

For more information on potential drug interactions with cabozantinib, see Section 7.3.1.

Consult your local prescribing information and the atezolizumab Investigator Brochure for information on which drugs to avoid while taking atezolizumab.

7.3 Possible drug interactions

7.3.1 Potential drug interactions with cabozantinib

Cytochrome P450: Data from a clinical drug interaction study (study XL184-008) indicate that clinically relevant sustained concentrations of cabozantinib do not appear to have a significant effect on the area under the plasma concentration-time curve (AUC) of co-administered rosiglitazone, a substrate CYP2C8. Therefore, cabozantinib is not expected to appreciably inhibit CYP2C8 in clinical settings, and is not expected to appreciably inhibit other CYP450 isoenzymes that have lower [I]/Ki values compared to CYP2C8 (i.e., CYP2C9, CYP2C19, CYP2D6, CYP1A2 and CYP3A4). In vitro data indicate that cabozantinib is unlikely to induce cytochrome P450 enzymes, except for the possible induction of CYP1A1 at high concentrations of cabozantinib (30 µM).

Cabozantinib is a CYP3A4 substrate and a weak CYP2C9 substrate (but not a CYP2D6, CYP2C8, CYP2C19, CYP2B6, or CYP1A2 substrate) based on in vitro data. The results of a clinical pharmacology study, XL184-006, showed that co-administration of cabozantinib with a strong CYP3A4 inducer, rifampin, resulted in a reduction in cabozantinib exposure (AUC values) of approximately 77% following a single dose of cabozantinib in healthy volunteers. Chronic co-administration of cabozantinib with strong inducers of the CYP3A4 family (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John's wort) can significantly reduce cabozantinib concentrations. Chronic use of strong CYP3A4 inducers should be avoided. Other medicinal products that induce CYP3A4 should be used with caution because these medicinal products may decrease the exposure (AUC) of cabozantinib. It is recommended to choose alternative concomitant drugs with zero or minimal potential for CYP3A4 induction.

The results of a clinical pharmacology study, XL184-007, showed that co-administration of cabozantinib with the strong inhibitor of CYP3A4, ketoconazole, resulted in a 38% increase in cabozantinib exposure (AUC values) after a single dose of cabozantinib in healthy volunteers. Co-administration of cabozantinib with strong inhibitors of the CYP3A4 family (eg, boceprevir, conivaptan, posaconazole, ketoconazole, itraconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, saquinavir, ritonavir, lopinavir, telaprevir, telithromycin, and voriconazole) may increase cabozantinib concentrations . Grapefruit, carom and orange can also increase plasma concentrations of cabozantinib and should be avoided. Strong inhibitors of CYP3A4 should be avoided, and other drugs that inhibit CYP3A4 should be used with caution as these drugs may increase

- 88 041548 exposure (AUC) to cabozantinib. It is recommended to choose alternative concomitant drugs with zero or minimal potential for CYP3A4 inhibition.

Please refer to the drug interaction tables at the following websites for lists of substrates, inducers, and inhibitors of selected CYP450 isoenzyme pathways: http://medicine.iupui.edu/clinpharm/ddis/table.aspx; http://www.fda.qov/Druqs/DevelopmentApprovalProcess/DevelopmentR esources/DruqInteractionsLabelinq/ucm080499.htm).

Protein Binding: Cabozantinib is highly bound (>99.7%) to human plasma proteins. Therefore, high protein formulations should be used with caution with cabozantinib, as there is a possible biasing interaction that could increase free concentrations of cabozantinib and/or the high protein co-administered drug (and a corresponding increase in pharmacologic effect).

Other Interactions: Food may increase cabozantinib exposure levels by 57%, so food recommendations should be followed. In vitro data suggest that cabozantinib is unlikely to be a substrate for P-gp, but it appears to have the potential to inhibit P-gp transport activity. Therefore, cabozantinib may potentially increase plasma concentrations of co-administered P-glycoprotein substrates. Additional details related to these general findings can be found in the researchers' brochure.

The introduction of esomeprazole, a proton pump inhibitor (PPI), did not lead to a clinically significant effect on cabozantinib plasma PK in healthy volunteers. Therefore, concomitant use of gastric pH-modifying agents (i.e., PPIs, H2 receptor antagonists, and antacids) is not contraindicated in subjects receiving cabozantinib.

Additional information on possible drug interactions with cabozantinib can be found in the Investigator's Brochure.

7.3.2 Possible drug interactions with atezolizumab

Cytochrome P450 enzymes, as well as conjugation/glucuronidation reactions, are not involved in the metabolism of atezolizumab. No drug interaction studies have been conducted with atezolizumab. There are no known interactions with other drugs or other forms of interaction. For more information, please refer to your local prescribing information and the atezolizumab Investigator Brochure.

8. Security

8.1 Side effects and laboratory abnormalities

8.1.1 Side effects

An AE is any adverse clinical event in a patient or subject of a clinical investigation who has been enrolled in a clinical trial and may have been prescribed an investigational product, whether or not the event is judged to be treatment-related within the study. Therefore, PE can be any adverse and unintended sign (including laboratory finding), symptom or disease temporally associated with the use of an investigational product, whether or not the event is judged to be treatment-related within the study. Previously identified medical conditions that worsen during the study will be recorded as PE. Abnormal laboratory values, ECG results, or vital signs should be recorded as PE if they meet the criteria described in Section 8.2.

All adverse events that occur after informed consent within 30 days (90 days for PET) after the date of the decision to permanently discontinue study treatment must be recorded at the study center.

At each scheduled and non-scheduled visit, PEs should be identified and evaluated based on study procedures, symptom-related routine and clinical investigations, and subject interview/report.

The investigator's assessment of the relationship between PE and study treatment will be based on the following two definitions:

Not Linked: A case is rated as not related to study treatment if it is related to another cause and/or there is no evidence to support a causal relationship.

Associated: A case is assessed as related to study treatment when there is a reasonable likelihood that the study treatment caused the case. Reasonable probability means that there is evidence to suggest a causal relationship between treatment in the study and the case. This case is called the alleged side effect. A putative side effect implies less certainty of causation than a side effect, which means any drug-induced PE.

8.1.2 Laboratory deviations

All laboratory data required by this protocol and any other clinical studies will be considered. Any abnormal finding that results in a change in the subject's management (eg, dose reduction or delay, or need for additional treatment

- 89 041548 or observation) or which is considered clinically significant by the investigator, will be reported as a PE or PE, as appropriate, as long as it is consistent with the subject's current disease state or consistent with pre-study values.

8.2 Serious side effects

The POC definition and reporting requirement is in accordance with the International Conference on Unification (ICU) Clinical Safety Data Handling Guidelines: Definitions and Standards for Expedited Reporting, Section E2A.

PES is defined as any adverse medical complication that occurs at any dose.

Leads to death.

Is directly life-threatening (i.e., in the opinion of the investigator, PE directly exposes the subject to the risk of death; it does not include a reaction that, if it occurred in a more severe form, could lead to death).

Requires inpatient hospitalization or results in prolongation of existing hospitalization.

Causes a significant inability or a significant impairment of the ability to function normally.

This is a congenital anomaly or birth defect.

Is an important clinical event that may not be directly life-threatening, cause death, or require hospitalization, but may be considered a PPE when, based on appropriate medical judgment, it endangers the subject or may require medical or surgical intervention to prevent one of the outcomes, listed above.

Once the investigator becomes aware of a POC that meets the criteria for a POC, the investigator documents the POC to the extent that information about it is available.

A POC, regardless of causation, must be reported to the sponsor or designee within 24 hours of the investigator becoming aware of the case by submitting the completed POC Report Form and any other pertinent POC information listed on the POC Reporting Form ( or in the instructions for completing the PPA Reporting Form), and acknowledging receipt of the report. PPA reporting forms and contact information will be provided to study centers.

PPAs that must be recorded on the PPA Reporting Form include the following:

All PETs that occur after informed consent and 30 days (90 days for PET) after the date of the decision to permanently discontinue treatment within the study (or the date the subject is screened out).

Any PSE is assessed as being related to study treatment or study procedures, even if PSE occurs more than 30 days after the date of the decision to permanently discontinue study treatment.

Note: If the subject does not meet the eligibility criteria at the time of screening, then the POC need only be reported from the time the subject signs the informed consent until the day the subject is determined not to be eligible to participate in the study.

POCs occurring after the start of investigational treatment 30 days (90 days for PEOIT) after the date of the decision to permanently discontinue investigational treatment should also be recorded on the CRF page.

The minimum information required for POC reporting includes investigator identity, center number, subject number, and case description. Other important information that needs to be provided in a timely manner is the term(s) of the POC, the reason the case is considered serious (i.e. severity criterion), and the investigator's assessment of the association of the case with treatment within the study. Additional information on the POC, including medications or other therapeutic measures used to treat the side effect, actions taken during study treatment related to the side effect, and outcome/treatment of the side effect will be recorded on the POC form.

In all cases, the investigator should continue to monitor the clinical situation and report any relevant facts regarding the progression or outcome of PES. In addition, the investigator may be required to provide additional information at the request of the sponsor's staff or designee.

The following additional points will be noted when reporting on the POC:

When a diagnosis of PSE is known or suspected, the investigator will report the diagnosis or syndrome as the primary term for PSE, not as signs or symptoms. Signs and symptoms may be described in the side effect description.

Death will not be reported as a POC but as a result of a specific POC if the side effect prior to death is not known. The terms unexplained death or death of unknown etiology may be used when the cause is unknown. In these circumstances, the cause of death should be investigated and the diagnosis changed once the etiology has been determined. If an autopsy has been performed, an autopsy report must be provided.

While most hospitalizations require POC reporting, some hospitalizations do not require POC reporting, as follows:

Elective or previously planned surgeries or procedures for pre-existing conditions that have not worsened since the start of treatment (eg, previously scheduled ventral hernia repair). However, SPE should be reported for any surgical or procedural complications resulting in prolonged hospitalization.

Pre-specified hospitalizations during the study for follow-up.

Side effects that result in a hospital stay of less than 24 hours and that do not require hospitalization (eg, an emergency room visit for hematuria that leads to a diagnosis of cystitis and home prescription of oral antibiotics).

8.3 Side effects of particular interest for atezolizumab

Adverse events of particular interest (AEOI) for atezolizumab consist of immune-mediated adverse events associated with ICTI, incidents of possible drug-induced liver injury, and suspected transmission of the infectious agent during study treatment (Table 8-1).

The PEOI will be reported to the sponsor or designee using the POC reporting form, regardless of whether the event is major or non-serious; all PEOIs must be reported within 24 hours using the POC submission process as described in Section 8.2.

Guidance on the treatment of immune-mediated side effects associated with atezolizumab is provided in the protocol (Section 6.5.2.2) and can also be found in the local prescribing information and the atezolizumab Investigator Brochure.

Table. 8-1: Side effects of particular interest for atezolizumab

Cases of potential DILI that include elevated ALT or AST in combination with elevated bilirubin or clinical jaundice as defined by High's Law and based on the following observations:

Treatment-related ALT or ACT > 3 x baseline in combination with total bilirubin > 2 x ULN (of which > 35% is conjugated bilirubin)

Occurrence during treatment ALT or ACT > 3 x baseline in combination with clinical jaundice

Suspected transmission of an infectious agent during study treatment, as indicated below

Any organism, virus, or infectious particle (eg, a prion protein that transmits transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is considered an infectious agent. Transmission of an infectious agent may be suspected based on clinical symptoms or laboratory findings that indicate infection in an exposed patient. This term is used only if contamination of the investigational medicinal product is suspected.

Pneumonia

Colitis

Endocrinopathy: diabetes mellitus, pancreatitis, adrenal insufficiency, hyperthyroidism and hypophysitis

Hepatitis, including ACT or ALT > 10 x ULN

Systemic lupus erythematosus

Neurological disorders: Guillain-Barré syndrome, myasthenic syndrome or myasthenia gravis, and meningoencephalitis

Complications indicative of hypersensitivity, infusion reactions, cytokine release syndrome, influenza-like illness, systemic inflammatory response syndrome, and systemic immune activation

Nephritis

Ocular toxicity (eg, uveitis, retinitis)

Myositis

Myopathies, including rhabdomyolysis

Cardiac disorders > grade 2 (eg, atrial fibrillation, myocarditis, pericarditis)

Vasculitis

ALT, alanine aminotransferase; ACT, aspartate aminotransferase; DILI, drug-induced liver injury; HPN, upper limit of normal.

8.3.1 General information on immune-related adverse events

The immunomodulatory properties of immune checkpoint inhibitors, such as the antu-PD-LI antibody atezolizumab, are capable of breaking immunological tolerance and generating a subset of PEs (called ISPEs) with an autoimmune inflammatory pathomechanism. ISPEs can

- 91 041548 affect every organ or tissue (Michot et al. 2016). Most ESPEs occur within the first 12 weeks of ICTO exposure, but some may appear with a delayed onset. Diagnosis of ISPE should be based on exposure to ICTI and a reasonable immunological mechanism for the observed PE. Where possible, histological examination or other immunological diagnostic evaluations should be used to confirm the diagnosis. Other causes should be ruled out, including PE from tumor progression.

The spectrum of ISPEs is broad and can be either general or organ-specific. Examples of common AEs in subjects treated with ICTI are fatigue, fever, and chills. Organ-specific EPs consist of dermatitis (rash, pruritus, vitiligo, oral mucositis, and gingivitis), enterocolitis (diarrhea with abdominal pain and clinical or radiographic evidence of colonic inflammation), and endocrinopathies (pituitary, thyroid, adrenals, testes). Diagnosis of endocrine dysfunction is challenging with relatively non-specific symptoms. Additional laboratory tests of the endocrine systems may be useful: prolactin (pituitary-hypothalamus function), T4 and TSH (pituitary-thyroid function), luteinizing hormone (LH) and follicle-stimulating hormone (FSH) (pituitary-gonadal function), adrenocorticotropic hormone (ACTH), and cortisol (pituitary-adrenal function).

Additional organ-specific EAEs include hepatitis (increased AST/ALT levels, hepatomegaly, periportal edema, periportal lymphadenopathy, periportal lymphocyte infiltrates, and surrounding primary bile ducts) and pneumonia (acute interstitial pneumonia). Less common cases of ESPE include neurological syndromes (myasthenia gravis, Guillain-Barré syndrome, aseptic meningitis), ocular PE (uveitis), renal PE (interstitial nephritis), cardiac PE (myocarditis), and pancreatic PE (increased lipase levels).

Clinical treatment of ISPE is aimed at suppressing the immune response with non-steroidal and steroidal anti-inflammatory drugs. Treatment algorithms for high-grade ESPE have been developed and should be followed for subjects suspected of having ESPE due to exposure to ICTI (Naidoo et al. 2015).

8.4 Follow-up for side effects

All PETs and PEOIs that continue 30 days after the last dose of study treatment, and AEs assessed as Grade 3 or 4 that led to discontinuation of treatment that continue 30 days after the date of the decision to stop study treatment, must the following occurs:

PE cured

PE improved to Grade 2 or below

The investigator determines that the complication has become stable or irreversible.

This follow-up requirement also applies to related SPEs that occur >30 days after the date of the decision to discontinue study treatment.

In addition, PETs must be recorded in the CRF up to 90 days after the decision to discontinue study treatment.

The status of all other PEs that continue 30 days after the date of the decision to discontinue study treatment will be documented from the post-treatment follow-up visit.

8.5 Other safety aspects

8.5.1 Pregnancy

The use of medically acceptable methods of contraception is very important during the study and for 5 months after the last dose of study treatment. If the subject becomes pregnant during the study, the subject will be excluded from the study treatment. She will be monitored until the end of her pregnancy and the baby must be monitored for at least 12 months after birth. If the female partner of a male subject becomes pregnant during the study, the sponsor will request that the pregnant partner be monitored for the remainder of her pregnancy and that the child be monitored for at least 6 months after birth.

The investigator must inform the sponsor of the pregnancy. Pregnancy reporting forms will be provided to study centers upon request. The outcome of the pregnancy (for the subject or for the subject's partner) and the health status of any resulting offspring must be communicated to the sponsor or his designee. Any birth defect or congenital anomaly should be reported as a PET, and any other adverse complication that occurs during pregnancy should be reported as a PET or PSE, as appropriate.

8.5.2 Errors in the use of the medicinal product / overdose

A drug misuse is defined as the administration of a study drug outside or above established dosing regimens in accordance with a specific protocol.

Any overdose, misuse, abuse, or misuse of a study drug (excluding missed doses) resulting in an AE or PET must be reported within 24 hours to the sponsor or their designee. Forms for reporting drug use errors will be provided to study centers.

In the event of an overdose, a medical supervisor or sponsor's designee should be contacted immediately to discuss further action. Any PE resulting from overdose should be treated in accordance with accepted clinical practice.

Please refer to the Investigator's Brochure for additional cabozantinib overdose recommendations.

Statistical aspects

The details of the planned analyzes will be documented in a separate Statistical Analysis Plan (SPA). Aggregate data will generally be presented by dose group/group and as a whole (for all subjects). No formal statistical tests are planned for this study. Confidence intervals will be calculated for the selected measured parameters.

9.1 Power and sample size

9.1.1 Dose escalation step

The number of subjects in each dose escalation group was selected based on the well-designed design of the Phase 1 dose escalation study. Subjects are enrolled in groups on a 3 plus 3 basis, with each group initially consisting of 3 subjects and potentially expanding to 6 subjects depending on the number of patients observed. CCT. From 9 to 36 subjects can be enrolled at this stage, depending on the number of boost groups and subjects required to establish the MTD or recommended dose and schedule for the expansion stage.

9.1.2 Expansion stage

The purpose of expansion groups is to evaluate the ORR to assess whether the actual response rate with a given combination regimen is better than that expected with monotherapy. Thus, two-sided 80% and 60% Blife-Steel-Casell CIs will be constructed for the ORR, providing 90 and 80% one-sided confidence intervals, respectively, in interpreting the lower bound. The sample size of 30 subjects for expansion groups was chosen to ensure that the lower bound of the two-tailed 80% CI did not exceed 12 percentage points from the point estimate. An example of 80% and 60% 2-tailed CIs with one-tailed interpretations of the lower bound is shown in Table 9-1 for the range of potential values for the observed ORR.

80% 2-way CI

60% 2-way CI

Observe Observe Table 9-1. Blyfe-Steel-Casell Confidence Intervals Example for N=30 ORR for Expansion Groups with One-Sided Interpretations of the Lower Bound

responses given (Total N=30) given CHOO NDP VRT True ORR ^a (90% CI) NDP VRT True ORR ^a (80% CI) 17 0.57 0.44 0.69 > 44% 0.47 0.66 > 47% 15 0.50 0.38 0.62 > 38% 0.41 0.59 > 41% 12 0.40 0.28 0.53 > 28% 0.31 0.47 > 31% eleven 0.37 0.25 0.50 > 25% 0.28 0.44 > 28% 10 0.33 0.23 0.46 > 23% 0.25 0.41 > 25% 9 0.30 0.19 0.42 > 19% 0.24 0.38 > 24% 8 0.27 0.16 0.38 > 16% 0.19 0.34 > 19% 7 0.23 0.15 0.34 > 15% 0.16 0.31 > 16% 6 0.20 0.11 0.31 > 11% 0.13 0.28 > 13% 5 0.17 0.09 0.28 > 9% 0.12 0.24 > 12% 4 0.13 0.06 0.25 > 6% 0.08 0.19 > 8%

CI, confidence interval; LDP, lower confidence limit; ORR, objective response rate; ULR, upper confidence limit.

^a Per each one-sided interpretation of the lower bound.

The planned enrollment of 30 subjects in expansion groups 5 and 7 will be divided between 15 subjects with ICTIO-refractory disease (P3 as the best response to prior ICTIO therapy) and 15 subjects with ICTIO-resistant disease (PO, OR, MD as the best response to previous therapy). ICTIO). The sample size of 15 subjects was chosen to ensure that the lower bound of the 2-tailed 80% CI did not exceed 19 percentage points from the point estimate. An example of 80% and 60% 2-tailed CIs with one-tailed interpretations of the lower bound is shown in Table 1. 9-2 for the range of potential values for the observed ORR. If subjects who are difficult to respond to ICTI and/or resistant to ICTI achieve a clinically significant ORR, as

- 93 041548 as determined by the Study Review Committee, approximately 50 subjects (i.e., up to 80 subjects in each group) could be added to group 5 and/or 7 to further explore the safety and clinical utility of the combination with these treatment options, having a highly unmet need and a novel mechanism of action of resensitization to ICTIO therapy. Study Review Committee decisions regarding the clinical significance of the achieved OER in expansion groups 5 and 7 will be based on a lower bound of 80% CI for the entire cohort of 30 subjects, or 15 subjects with ICTIO-refractory disease and 15 subjects with ICTIO-resistant disease, with need. As a guideline, the Study Review Committee may use a target NRR of 20-25% for expansion group 5, and 15-20% for expansion group 7. In general, this generally corresponds to an 80% confidence in the true MRR of > 11% for n=15 or >13% for n=30. The expansion of group 5 and/or 7 to 50 additional subjects may be limited to either ICTIO-refractory or ICTIO-resistant subjects, or may include subjects from both groups depending on the observed ORR.

Table 9-2: Example of N=15 Blyfe-Steele-Casell Confidence Intervals for ORR for Expansion Groups of 15 Subjects with One-Sided Interpretations of the Lower Bound

Observed responses (Total N=15) Observe- given CHOO 80% 2-way CI 60% 2-way CI NDP VRT True ORR ^a (90% CI) NDP VRT True ORR ^a (80% CI) 9 0.60 0.42 0.77 > 43% 0.46 0.70 > 46% 7 0.47 0.28 0.64 > 28% 0.33 0.61 > 33% 6 0.40 0.23 0.57 > 23% 0.30 0.54 > 30% 5 0.33 0.20 0.51 > 20% 0.23 0.46 > 23% 4 0.27 0.12 0.44 > 12% 0.16 0.39 > 16% 3 0.20 0.10 0.36 > 10% 0.11 0.33 > 11% 2 0.13 0.06 0.28 > 6% 0.08 0.23 > 8% 1 0.07 0.01 0.23 > 1% 0.03 0.16 > 3%

CI, confidence interval; LDP, lower confidence limit; ORR, objective response rate; ULR, upper confidence limit.

^a Per each one-sided interpretation of the lower bound.

9.2 Population analysis

9.2.1 Safety population

The safety population will consist of all subjects who received any treatment in the study. Because enrollment is determined by receipt of study treatment, the enrollment group is not defined as different from the safety assessment group.

9.2.2 Dose escalation population

The dose escalation population will include subjects who have not been replaced in accordance with Section 3.9.

9.2.3 Other populations

Additional analysis populations may be defined in the PSA.

9.3 Scheduled tests

9.3.1 Safety and tolerability analysis

Safety will primarily be assessed by evaluation of PE and laboratory tests. Tolerability will be assessed by assessing changes in study treatment and treatment discontinuation.

9.3.1.1 Side effects

The side effect designations recorded in the CRF will be matched against the preferred terms using the Medical Regulatory Dictionary of Terms (MSTRO). The investigator categorizes the severity of PE using the HSCT v4 and ranks each event as unrelated or treatment related within the study. Adverse events leading to discontinuation of study treatment will also be assessed by the investigator as related or unrelated to the study disease.

Data for PE, ISPE, PETI, and PE will be tabulated into groups according to organ system class and preferred general morbidity term; worst reported severity; and links to treatment within the study.

At each level of generalization, the subject will only be counted once for each PE preference term he or she experiences at that level (i.e. multiple episodes of complications with the same preference terms will only be counted once).

All reported deaths will be summarized by treatment group, cause of death, and study treatment dependency.

A timeline will also be prepared to describe the recruitment and expansion of dose escalation groups, substitution of subjects, observed CCTs, COG decisions, and the final rationale for the recommended dose of the expansion stage.

9.3.1.2 Laboratory test results

Individual lab test results will be pooled across treatment groups to assess the worst grade of HBMT after baseline and deviations or changes from baseline.

9.3.1.3 Study treatment

Study treatment parameters will be presented separately for each agent, cabozantinib and atezolizumab. The number of subjects experiencing dose reduction, delay, interruption, modification and/or discontinuation due to side effect will be provided depending on each agent. The duration and intensity of study treatment will also be tabulated.

9.3.2 Preliminary antitumor activity assays

The objective of the expansion stage is to estimate the OER, defined as the proportion of subjects with a confirmed OR or OER according to CCAS 1.1, as determined by the investigator. Likewise, the ORR will be determined for each modified CRRR for the immune response, which is determined by the investigator as the measurand under investigation. ORR will be assessed independently in each of the expansion and dose escalation groups.

The best overall tumor response, based on a score of targeted, non-targeted, and new lesions, will be presented as the proportion of subjects in each of the following categories: PO, OR, MD, PT, and not estimable, and includes OR. In expansion groups, two-tailed 80% and 60% CIs of Blife-SteelCasella will be constructed for ORRs providing 90% and 80% one-sided confidence intervals, respectively, when interpreting the lower bound to assess the preliminary efficacy of combination therapy compared with the expected efficacy of treatment with one agent already administered. research. Confidence intervals at the 95% level will also be presented to comply with the standard presentation rules.

Median PFS and OS with corresponding 2-tailed 95% CIs will be estimated using Kaplan-Meier methods.

Duration of response is defined as the time from the first documented objective response (CR or OR) as assessed by the investigator, which is subsequently confirmed to whichever comes first - radiological confirmation of progression or death, or exclusion due to the absence of these events or due to the start of off-protocol cancer treatment. therapy. Medians and confidence intervals will be estimated using Kaplan-Meier analysis, limited to patients who received a validated objective response.

9.3.3 Interim analysis

The COG will review the accumulated data from dose escalation groups.

No formal interim review is planned for the expansion phase. However, safety and antitumor outcomes will be reviewed on an ongoing basis.

10. Other tests

10.1 Pharmacokinetic analyzes

Plasma concentration of cabozantinib will be analyzed by the sponsor or designee using an approved bioassay method.

Possible degradation products of cabozantinib may also be evaluated in blood samples for PK collected during the study. Descriptive statistics (eg, count, mean and/or median, standard deviation, and coefficient of variation) will be used to describe concentration versus time data. Where appropriate, these data can be analyzed using population PK models and/or combined with data from other studies in a meta-analysis. The effect of exposure on biomarkers, clinical safety parameters (eg selected AEs) or clinical response may also be studied. The results of the PK analysis will also be evaluated in conjunction with available safety data.

Concentrations of atezolizumab and/or atezolizumab breakdown products may also be measured in blood samples for PK if considered important for safety and/or efficacy analysis in this study.

10.2 Biomarker analysis

Analyzes will be summarized, which may include, but are not limited to: MET, AXL, PD-L1, and possible correlation with clinical response and other analyzes (eg, sequencing, FACS).

The foregoing invention has been described in detail by way of illustration and examples for the purpose of clarity and understanding. The present invention has been described with reference to various specific and preferred embodiments and methods. However, it should be understood that numerous changes and modifications can be made without departing from the spirit and scope of the invention. One skilled in the art will appreciate that it is within the scope of the appended claims

- 95 041548 changes and modifications may be made. Therefore, it should be understood that the above description is intended to be illustrative and not limiting. Therefore, the scope of the present invention should not be determined on the basis of the above description, but instead it should be determined on the basis of the following appended claims, together with all equivalents to which such claims pertain.

Appendix A: Evaluation Schedule for the Dose Escalation Stage:

Graphs of required assessments for the dose escalation step are presented in this Appendix.

As described in Section 3.5.1.1, the COG may decide to use an introductory cabozantinib dosing schedule for some groups during the dose escalation phase. Below are separate tables for two possible dosing schedules: the standard dosing schedule (Table A-1) and the introductory dosing schedule for cabozantinib (Table A-2). All other evaluations must be performed according to the schedule provided regardless of the dosing schedule.

Most assessments and study procedures (including administration according to treatment) will be performed in cycles. Cycle 1 Day 1 (C1D1) is defined as the date of the first dose of any investigational treatment. The overall cycle is typically a 21-day period starting on the date of the atezolizumab infusion and ending on the day before the next atezolizumab infusion. However, under some circumstances, the dose of atezolizumab may not be administered during the cycle:

If an introductory dosing schedule of cabozantinib is used during the dose escalation phase, the period during which cabozantinib is administered prior to the first dose of atezolizumab will be defined as Cycle 1.

If atezolizumab treatment is discontinued but cabozantinib treatment is allowed to continue with sponsor notification, each subsequent 21-day period beginning on the date of the decision to discontinue atezolizumab will be defined as a cycle. If the decision to stop atezolizumab is made less than 21 days after the last infusion, then the next cycle will begin on the 22nd day after the last infusion.

Cycles may last longer than 21 days if atezolizumab administration is delayed. During atezolizumab dose deferral, subjects should return to the center for scheduled safety visits every three weeks after the last dose of atezolizumab. Additionally, the study site should arrange for unscheduled weekly visits (or more frequently if clinically necessary) to monitor the subject's safety and suitability for retreatment with the investigational treatment. Other unscheduled visits are permitted as needed (see Section 5.5 for more details).

Evaluative imaging (CT, MRI, bone tomograms) should be performed at protocol-defined intervals based on the first dose of study treatment (defined as Week 1, Day 1 [H1D1]); at all subsequent points in time, the same nomenclature will apply to these estimates and will not be changed as a result of modifications or deletions of treatment administration.

Unless otherwise noted, in the absence of side effects, all scheduled visits will occur within the time periods for the visit schedule specified in the protocol. If the subject experiences side effects, investigational treatment may be modified or delayed as described in Section 6.5. If a subject is unable to complete a study evaluation within a specified period of time due to a reason beyond their control (e.g., center closure, personal emergency, bad weather, vacation), the evaluation should be conducted as close as possible to the required schedule. Laboratory kits for serum chemistry, hematology and urinalysis are defined in Section 5.6.5.

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Table A-1. Evaluation schedule for dose escalation stage: Standard dosing schedule:

Before registration After registration Evaluation: Screening ³ (Before the first dose) Cycle 1 ( + 3 days) Cycle 2 (+3 days) Cycles 3 - 8 (+ 3 days) Cycles 9 or more (+ 5 days) 30 days follow-up after treatment (+14 days) Extended after- blowing observation Day 1 Day 10 Day 21 Day 1 Day 10 Day 21 Informed consent (Section 5.1) ^xb Demographics, clinical and cancer history (Section 5.6.1) 5 28 days Clinical examination ^e + mass (Section 5.6.2) <28 days X before introduction X X x ^d Day 1 of each cycle or every three weeks after last dose atezolizumab (if infusions are delayed). X General condition according to VKOG (Section 5.6.2, 5 28 days (+ total X X X x ^d Day 1 of each cycle or every three X Appendix E) status on the Karnofsky scale for subjects with RCC) weeks after last dose atezolizumab (if infusions are delayed). Vital Signs (Section 5.6.3) 5 28 days X ^e X X X ^e Day 1 of each cycle or every three weeks after the last dose of atezolizumab (if infusions are delayed). ^e X 12-lead ECG (Section 5.6.4) ^f 5 14 days X ^d before injection X X Day 1 of every 4th cycle starting on CZD1 (i.e. CZD1, C 7 D1, etc.) or every 12 weeks after the last dose of atezolizumab (if infusions are delayed) X Hematology and biochemistry in the central laboratory (Section 5.6.5) 14 days X ^{h Di} before injection X X X ^h d Day 1 of each cycle or every three weeks after the last dose of atezolizumab (if X infusions are delayed).

Table A-1. Evaluation schedule for the dose escalation stage:

Standard dosing schedule:

Before registration After registration Evaluation: Screening ³ (Before the first dose) Cycle 1 (±3 days) Cycle 2 (+3 days) Cycles 3-8 (± 3 days) Cycles 9 or more (± 5 days) 30-day follow-up after treatment (+14 days) Extended after- blowing observation Day 1 Day 10 Day 21 Day 1 Day 10 Day 21 Screening for hepatitis, in the central laboratory (Section 5.6.5) X PT/LSM and PTT' in the central laboratory (Section 5.6.5) X 3 before injection X _x d Day 1 of every 3rd cycle starting from CZD1 (i.e. CZD1, C6D1, etc.) or every nine weeks after the last dose of atezolizumab (if infusions are delayed) X Urinalysis at the local laboratory (Section 5.6.5) 14 days X ^g ' ^h before the introduction X X ¹¹ to Day 1 of each cycle or every three weeks after the last dose of atezolizumab (if X

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delayed infusions). Urinalysis including CMB at the central laboratory (Section 5.6.5) 14 days X up introductions X xd Day 1 every other cycle starting with CZD1 (i.e. CZD1, C5D1, etc.) or every six weeks after the last dose atezolizumab (if infusions are delayed) X Pregnancy test at local laboratory (Section 5.6.5) serum X before introduction (serum rotka urine) Day 1 of each cycle or every three weeks after the last dose of atezolizumab (if infusions are delayed). (serum or urine) X Testing of thyroid function in a central laboratory (Section 5.6.5) 14 days X ^g BEFORE administration X _x d Day 1 of every 3rd cycle starting from CZD1 (i.e. CZD1, C6D1, etc.) or every nine weeks after the last dose of atezolizumab (if infusions are delayed) X Archival tumor tissue sample ¹¹ (Section 5.6.7) X

Table A-1: Count! Standard graphics Evaluation: Tumor assessment: CT/MRI Thoracic, abdominal, gas areas (Section 5.6.8) I to assessments for dosir Before registration Screening ¹⁵ (Before the first dose) 5_28 days for the dose escalation stage: After registration 30-day Cycles 9 and thereafter Extended Cycles 3-8 (± 3 Cycle 1 (+ 3 days) Cycle 2 (+ 3 days) more (+ 5 follow-up days) days) after treatment observation (+14 days) Day Day Day Day Day Day 1 10 21 1 10 21 CT scan of the chest, abdomen, pelvis, or CT scan of the chest with MRI of the abdomen and pelvis will be performed for all subjects at screening and every 6 weeks (+ 5 days) after the first dose (at H7D1, H13D1, etc.). At the end of the 12 months of the study, these evaluations will be conducted every 12 weeks (± 7 days). To ensure image comparability, the same imaging modalities and acquisition protocols used in screening should be used for subsequent tumor evaluations. CT/MRI should be performed according to the schedule defined by the protocol, regardless of whether treatment is reduced, interrupted, delayed or discontinued, and tumor evaluation is independent of the atezolizumab schedule. Tumor imaging will continue until radiological confirmation of disease progression in accordance with CCAS 1.1, as determined by the investigator. For subjects who discontinue investigational treatment prior to radiological confirmation of disease progression in accordance with CCAS 1.1, if possible, regular scheduled imaging evaluations should be continued until radiological confirmation of progression according to COOS 1.1 or initiation of the next anticancer therapy. 40 or CCAS 1.1 EL at a point in time to be confirmed by reassessments > 4 weeks after the response criteria were first met. For subjects with a COOS 1.1 PB who are continuing study treatment, tumor measurements must be confirmed > 4 weeks after the initial PB criteria have been met. For subjects who continue treatment after confirmatory tumor scans, regularly scheduled imaging will continue. Tumor Assessment: MRI/CT Brain (Section 5.6.8) <28 days Brain MRI (or CT) will be performed at screening for all subjects with RCC, and for subjects with CM who have a history or clinical symptoms of brain metastasis. After the first dose, an MRI (or CT) brain scan is required only for subjects with documented, previously treated brain metastases. Evaluations will be performed every 12 weeks (7 days) after the first dose (at H13D1, H26D1, etc.). The timing of these assessments is independent of the timing of atezolizumab. To ensure image comparability, the same imaging modalities and acquisition protocols used in screening should be used for subsequent tumor evaluations. (Note: To be eligible for the study, brain metastases must have been treated and stable for at least 4 weeks prior to the first dose of study treatment. Subjects without documented brain metastases at screening evaluation are not required to undergo brain imaging after the start of study treatment, unless clinically indicated). CT/MRI should be performed according to the schedule defined by the protocol, regardless of whether treatment is reduced, interrupted, delayed or discontinued, and tumor evaluation is independent of the atezolizumab schedule. Tumor imaging will continue until radiological confirmation of disease progression in accordance with CCAS 1.1, as determined by the investigator. For subjects who discontinue investigational treatment prior to radiological confirmation of disease progression in accordance with CCAS 1.1, if possible, routinely scheduled imaging assessments should be continued until radiographic confirmation.

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progression according to COOS 1.1 or the start of the next anticancer therapy. Scanning bones (Section 5.6.8) <28 days Technetium Bone Scan (TBS) will be performed at screening for subjects who have a history or clinical symptoms (eg, bone pain) of bone metastases. After initiation of investigational treatment, bone scans are required only for subjects with documented bone lesions or if clinically marked by signs and symptoms suggestive of new bone metastases. Evaluations after the first dose will be performed according to normal clinical practice (approximately every 12 weeks for the first 12 months and every 24 weeks thereafter). The timing of these assessments is independent of the timing of atezolizumab. Bone scans should be used to guide confirmatory imaging with CT/MRI if necessary (these CT/MRI results will be used to evaluate COOS vl.1), and bone scan results alone should not be used to determine progression in this study. Bone scan evaluations will end on the day of the last CT/MRI scan. If the bone scan schedule does not match the last CT/MRI scan, no additional bone scan is required after the last CT/MRI scan.

Table A-1: Evaluation schedule for dose escalation stage: Standard dosing schedule:

Before registration After registration Evaluation: Screening ³ (Before the first dose) Cycle 1 (+3 days) Cycle 2 (+3 days) cycles 3-8 (+ 3 days) Cycles 9 and more (+ 5 days) 30 days follow-up after treatment (+14 days) Extended wind-blown observation Day 1 Day 10 Day 21 Day 1 Day 10 Day 21 Blood samples for PK' (Section 5.6.6.1) C1D1 (before treatment, approximately 5 minutes after atezolizumab infusion and 2 hours, 4 hours, and 6-8 hours after cabozantinib) and before dosing at C1D10, C2D1, and CZD1. blood sample- Pharmacogenetic (Section 5.6.7) before the introduction X 1 Blood sample Immune cell profiling by FACS (Section 5.6.7) Before dosing at C1D1, C1D10, and C2D1 (may be performed at selected centers) blood sample - serum/plasma biomarkers (Section 5.6.7) Before dosing in C1D1, C1D10, C2D1 and CZD1. An optional sample may be obtained at the first sign of processing, depending on the investigator. blood sample - Before dosing in C1D1, C1D10, C2D1 and CZD1.

cellular and/or plasma pharmacogenomics (Section 5.6.7) An optional sample may be obtained at the first sign of progression, depending on the investigator. Concomitant treatment (Section 7) Document concomitant medicinal products taken within 28 days prior to the first dose of study treatment, up to 30 days after the date of the decision to discontinue study treatment. Side effects (Sections 8.1, 8.2 and 8.3.1) Document new or worsening AEs with informed consent within 30 days (90 days for PEOI) after the date of the decision to permanently discontinue study treatment. PE information will be collected during study visits and may also be obtained at any time by telephone or spontaneous reporting by the subject. At the date of the first dose of study treatment, AEs will be documented before and after dosing. Some AEs and all PPEs that continue 30 days after the study permanent discontinuation date should be treated until recovery or until the Investigator determines that the complication is stable or irreversible (see Section 8.4).

Table A-1: Evaluation schedule for dose escalation stage: Standard dosing schedule:

Evaluation: Screening ³ (Before the first dose) Cycle 1 (±3 days) Cycle 2 (+3 days) Cycles 3-8 (± 3 days) Cycles 9 or more (± 5 days) 30 days follow-up after treatment (+14 days) Extended follow-up Day 1 Day 10 Day 21 Day 1 Day 10 Day 21 Dose administration of atezolizumab' (Section 6.2) X X Atezolizumab will be given by IV infusion at the clinic every 3 weeks (-2 days) on Day 1 of each cycle until treatment is Cabozantinib dose administration (Section 6.2) Cabozantinib will be administered in the clinic at C1D1 and then taken once daily at home until study treatment is discontinued

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^a The results of screening evaluations should be reviewed prior to the first dose of investigational treatment to confirm that the subject meets the eligibility criteria.

^b Informed consent may be obtained more than 28 days prior to the first dose of study treatment, but must be provided before any study-specific procedures are performed; however, assessments performed as part of routine care prior to informed consent may be used as screening assessments if permitted by the centre's IEC/EU rules.

^c Symptom-based clinical evaluation will be performed at C1D1 prior to the first dose of investigational treatment and at subsequent safety visits.

^d Assessments scheduled in C2D1 should not be performed if the same assessment was completed within 3 days at the end of Cycle 1.

^e Vital signs should be assessed within 60 min prior to infusion of atezolizumab, and additional assessment of vital signs should be performed during and after infusion as clinically indicated.

^f Additional ECGs should be performed as clinically indicated.

^g This evaluation is intended to confirm suitability for treatment after screening and prior to the first dose at C1D1. If this assessment was performed at screening within 14 days (7 days for a pregnancy test) prior to C1D1, this assessment should not be performed at C1D1 unless the subject's clinical condition has changed (e.g., the appearance of new symptoms indicative of clinical worsening) . If the assessment is conducted at C1D1, the results must be available and verified by the investigator prior to any treatment.

^h Samples for serum chemistry, hematology, and urinalysis should be collected and results reviewed within 72 hours prior to any administration of atezolizumab during the study.

¹¹ Local laboratory tests for these panels can be obtained and used if the results are required by the investigator at short notice (see Section 5.6.5 and the Laboratory Manual for more details on laboratory tests).

' The screening will test for hepatitis B surface antigen and hepatitis C antibody (in HCV RNA reflex testing if the antibody test is positive).

^k Tumor tissue (archival) will be obtained prior to the first dose whenever possible. Formalin-fixed paraffin tumor blocks (FFPE) are preferred, but in cases where this is not possible, 12 unstained fresh cut FFPE preparations should be obtained. See the Transitional Medicine Laboratory Manual for specific instructions.

¹¹ After C1D1, PK specimens should be collected approximately 8 hours or more after the previous dose of cabozantinib, and if cabozantinib will be administered on that day, PK specimens should be collected prior to cabozantinib administration. The investigator will ask the subject for the date and time of the most recent previous dose of cabozantinib, and this information will be recorded on the appropriate page of the CRF.

^m Doses of atezolizumab should not be given less than 19 days apart.

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Table A-2. Evaluation schedule for the dose escalation stage:

Cabozantinib introductory dosing schedule:

Before registration After registration Evaluation: Screening ³ (Before the first Dose) Cycle 1 (±3 days) Cycle 2 (±3 days) Cycles 3 - 8 (± 3 days) Cycles 9 or more (± 5 days) 30 days follow-up after treatment (+14 days) Extended follow-up Day 1 Day 10 Day 21 Day 1 Day 10 Day 21 Informed consent (Section 5.1) xb Demographics, clinical and cancer history (Section 5.6.1) 28 days Clinical examination ^e + mass a (Section 5.6.2) 28 days X before dosing X X X Day 1 of each cycle ⁰ or every three weeks after the last dose of atezolizumab (if delayed X HCOG general status (Section 5.6.2, Appendix E) Vital signs (Section 5.6.3) 12-lead ECG (Section 5.6.4) ^f Hematology and biochemistry in the central laboratory (Section 5.6.5) 28 days (+ general condition on the Karnofsky scale for subjects with RCC) 28 days 14 14 days < 14 days X9 h before dosing X xh-i before the introduction doses X X infusion). Day 1 of each cycle ⁰ or every three weeks after the last dose of atezolizumab (if infusions are delayed). Day 1 of each cycle or every three weeks after the last dose of atezolizumab (if infusions are delayed). Day 1 of every 4th cycle starting with C4D1 (i.e. C4D1, C8D1, etc.) or every 12 weeks after the last dose of atezolizumab (if infusions are delayed) Day 1 of each cycle or every three weeks after the last dose of atezolizumab ( if infusions are delayed). ^{h t} X

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Table A-2: Evaluation schedule for the dose escalation phase: Cabozantinib introductory dosing schedule

Before registration After registration Evaluation: Screening ³ (before the first dose) Cycle 1 (±3 days) Cycle 2 (+3 days) cycles 3-8 (± 3 days) Cycles 9 or more (± 5 days) 30 days follow-up after treatment (+14 days) Extended follow-up Day 1 Day 10 Day 21 Day 1 Day 10 Day 21 Screening for hepatitis, in the central laboratory (Section 5.6.5) X PV/LSM and PIT in the central laboratory (Section 5.6.5) 14 days X 9 before dosing X X Day 1 of every 3rd cycle, starting with Ts4D1 (i.e. Ts4D1, Ts7D1, etc.) or once every nine weeks after the last dose of atezolizumab X

(if infusion delayed) General analysis urine in local laboratories (Section 5.6.5) 14 days X ¹ before dose X ¹ BEFORE dosing X Day 1 of each cycle or every three weeks after the last dose of atezolizumab (if infusions are delayed) ¹ X Biochemical analysis of urine including MBCM in the central laboratory (Section 5.6.5) 14 days X 9 before dosing X X Day 1 time through the cycle starting with C4D1 (i.e. C4D1, C6D1, etc.) or every six weeks after last dose of atezolizumab (if infusions delayed) X Test for pregnancy in local laboratories (Section 5.6.5) < 7 days serum X ^d before dosing (serum) (serum or urine) Day 1 of each cycle or every three weeks after the last dose X

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Table A-2: Evaluation schedule for the dose escalation phase: Cabozantinib introductory dosing schedule

Before registration After registration Evaluation: Screening ³ (Before the first dose) Cycle 1 (±3 days) Cycle 2 (+3 days) Cycles 3-8 (± 3 days) Cycles 9 or more (± 5 days) 30 days follow-up after treatment (+14 days) Extended Field-Blowing Observation Day 1 Day 10 Day 21 Day 1 Day 10 Day 21 Tumor assessment: CT/MRI Thoracic, abdominal, pelvic regions (Section 5.6.8) 28 days CT scan of the chest, abdomen, pelvis, or CT scan of the chest with MRI of the abdomen and pelvis will be performed for all subjects at screening and every 6 weeks (± 5 days) after the first dose (at H7D1, H13D1, etc.). At the end of the 12 months of the study, these evaluations will be conducted every 12 weeks (± 7 days). To ensure image comparability, the same imaging modalities and acquisition protocols used in screening should be used for subsequent tumor evaluations. CT/MRI should be performed according to the schedule defined by the protocol, regardless of whether treatment is reduced, interrupted, delayed or discontinued, and tumor evaluation is independent of the atezolizumab schedule. Tumor imaging will continue until radiological confirmation of disease progression in accordance with CCAS 1.1, as determined by the investigator. For subjects who discontinue investigational treatment prior to radiological confirmation of disease progression in accordance with CCAS 1.1, if possible, regular scheduled imaging evaluations should be continued until radiological confirmation of progression according to COOS 1.1 or initiation of the next anticancer therapy.

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The ER or LR according to CCES 1.1 at a point in time must be confirmed by reassessments > 4 weeks after the response criteria were first met. For subjects with a COOS 1.1 PB who are continuing study treatment, tumor measurements must be confirmed > 4 weeks after the initial PB criteria have been met. For subjects who continue treatment after confirmatory tumor scans, regularly scheduled imaging will continue. Evaluation Tumors: MRI/CT Brain (Section 5.6.8) 28 days Brain MRI (or CT) will be performed at screening for all subjects with RCC, and for subjects with CM who have a history or clinical symptoms of brain metastasis. After the first dose, an MRI (or CT) brain scan is required only for subjects with documented, previously treated brain metastases. Assessments will be performed every 12 weeks (± 7 days) after the first dose (at H13D1, H26D1, etc.). The timing of these evaluations is independent of the timing of atezolizumab. To ensure image comparability, the same imaging modalities and acquisition protocols used in screening should be used for subsequent tumor evaluations. (Note: To be eligible for the study, brain metastases must have been treated and stable for at least 4 weeks prior to the first dose of study treatment. Subjects without documented brain metastases at screening evaluation are not required to undergo brain imaging after the start of study treatment, unless clinically indicated). CT/MRI should be performed according to the schedule defined by the protocol, regardless of whether treatment is reduced, interrupted, delayed or discontinued, and tumor evaluation is independent of the atezolizumab schedule. Tumor imaging will continue until radiological confirmation of disease progression in accordance with CCAS 1.1, as determined by the investigator. For subjects who

stop investigational treatment until radiological confirmation of disease progression in accordance with COOS 1.1, if possible, continue to conduct routine imaging assessments as scheduled until radiographic confirmation of progression according to COOS 1.1 or initiation of the next anticancer therapy. Bone scan (Section 5.6.8) <28 days Technetium Bone Scan (TBS) will be performed at screening for subjects who have a history or clinical symptoms (eg, bone pain) of bone metastases. After initiation of investigational treatment, bone scans are required only for subjects with documented bone lesions or if clinically marked by signs and symptoms suggestive of new bone metastases. Evaluations after the first dose will be performed according to normal clinical practice (approximately every 12 weeks for the first 12 months and every 24 weeks thereafter). The timing of these evaluations is independent of the timing of atezolizumab. Bone scans should be used to guide confirmatory imaging with CT/MRI if necessary (these CT/MRI results will be used to evaluate COOS vl. 1), and bone scan results alone should not be used to determine progression in this study. Bone scan evaluations will end on the day of the last CT/MRI scan. If the bone scan schedule does not match the last CT/MRI scan, no additional bone scan is required after the last CT/MRI scan.

Table A-2: Evaluation schedule for the dose escalation phase: Introductory dosing schedule for cabozantinib ___________

Before registration After registration Evaluation: Screening ³ (Before the first dose) Cycle 1 (±3 days) Cycle 2 (+3 days) cycles 3-8 (± 3 days) Cycles 9 or more (± 5 days) 30 days follow-up after treatment (+14 days) Extended follow-up Day 1 Day 10 Day 21 Day 1 Day 10 Day 21 Blood samples for PK' (Section 5.6.6.1) C1D1 (before treatment, and 2 hours, 4 hours and 6-8 hours after administration of cabozantinib) and before dosing at C2D1, C2D10, and CZD1. blood sample- Pharmacogenetic (Section 5.6.7) X before dosing Blood sample Immune cell profiling by FACS (Section 5.6.7) Prior to dosing in C1D1, C2D1, and C2D10 (can be performed at selected centers) blood sample - serum/plasma biomarkers (Section 5.6.7) Before dosing in C1D1, C2D1, C2D10 and CZD1 An optional sample may be obtained at the first sign of progression, depending on the investigator. blood sample - cellular and/or plasma Before dosing in C1D1, C2D1, C2D10 and CZD1 An optional sample may be obtained at the first sign of progression, depending on the investigator.

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pharmacogenomics (Section 5.6.7) Concomitant treatment (Section 7) Document concomitant medicinal products taken within 28 days prior to the first dose of study treatment, up to 30 days after the date of the decision to discontinue study treatment. Side effects (Sections 8.1, 8.2 and 8.3.1) Document new or worsening AEs with informed consent within 30 days (90 days for PEOI) after the date of the decision to permanently discontinue study treatment. PE information will be collected during study visits and may also be obtained at any time by telephone or spontaneous reporting by the subject. At the date of the first dose of study treatment, AEs will be documented before and after dosing. Some AEs and all PPEs that continue 30 days after the study permanent discontinuation date should be treated until recovery or until the Investigator determines that the complication is stable or irreversible (see Section 8.4).

Table A-2: Evaluation schedule for the dose escalation stage: Introductory cabozantinib dosing schedule:

^a The results of screening evaluations should be reviewed prior to the first dose of investigational treatment to confirm that the subject meets the eligibility criteria.

^b Informed consent may be obtained more than 28 days prior to the first dose of study treatment, but must be provided before any study-specific procedures are performed; however, assessments performed as part of routine care prior to informed consent may be used as screening assessments if permitted by the center's IEC/EC policies.

Symptom-based clinical examination will be carried out at C1D1 prior to the first dose

- 105 041548 study treatment and at follow-up visits to assess safety. Evaluations scheduled in EAC1 should not be performed if the same evaluation was completed within 3 days at the end of Cycle 2.

^e Vital signs should be assessed within 60 min prior to infusion of atezolizumab, and additional assessment of vital signs should be performed during and after infusion as clinically indicated.

f Additional ECGs should be performed as clinically indicated.

^g This evaluation is intended to confirm suitability for treatment after screening and prior to the first dose at C1D1. If this assessment was performed at screening within 14 days (7 days for a pregnancy test) prior to C1D1, this assessment should not be performed at C1D1 unless the subject's clinical condition has changed (e.g., the appearance of new symptoms indicative of clinical worsening) . If the assessment is conducted at C1D1, the results must be available and verified by the investigator prior to any treatment.

^h Local laboratory testing for these panels can be obtained and used if results are required by the investigator on short notice (see Section 5.6.5 and Laboratory Manual for more details on laboratory testing).

Samples for serum chemistry, hematology, and urinalysis should be collected and results reviewed within 72 hours prior to any atezolizumab infusion during the study.

The screening will test for hepatitis B surface antigen and hepatitis C antibody (in HCV RNA reflex testing if the antibody test is positive).

^k Tumor tissue (archival) will be obtained prior to the first dose whenever possible. Formalin-fixed paraffin tumor blocks (FFPE) are preferred, but in cases where this is not possible, 12 unstained fresh cut FFPE preparations should be obtained. See the Transitional Medicine Laboratory Manual for specific instructions.

¹ After C1D1, PK specimens should be collected approximately 8 hours or more after the previous dose of cabozantinib, and if cabozantinib will be administered on that day, PK specimens should be collected prior to cabozantinib administration. The investigator will ask the subject for the date and time of the most recent previous dose of cabozantinib, and this information will be recorded on the appropriate page of the CRF.

^m Doses of atezolizumab should not be given less than 19 days apart.

Appendix B: Estimate Schedule for the Expansion Stage

The schedule of required assessments for the expansion stage is presented in this Annex in the table below. Because the sampling times for PK and biomarkers differ slightly for the standard dosing schedule and cabozantinib introductory dosing schedule, duplicate rows for these estimates are presented in the table; lines of the introductory dosing schedule for cabozantinib are shown in gray for clarity.

Most assessments and study procedures (including administration according to treatment) will be performed in cycles. Cycle 1 Day 1 (C1D1) is defined as the date of the first dose of any investigational treatment. Cycles may last longer than 21 days if atezolizumab administration is delayed. The overall cycle is typically a 21-day period starting on the date of the atezolizumab infusion and ending on the day before the next atezolizumab infusion. However, if atezolizumab treatment is discontinued but cabozantinib treatment is allowed to continue with sponsor notification, each subsequent 21-day period beginning on the date of the decision to discontinue atezolizumab will be defined as a cycle. If the decision to stop atezolizumab is made less than 21 days after the last infusion, then the next cycle will begin on the 22nd day after the last infusion.

During atezolizumab dose deferral, subjects should return to the center for scheduled safety visits every three weeks after the last dose of atezolizumab. In addition, the study site should arrange for unscheduled weekly visits (or more frequently if clinically necessary) to monitor the subject's safety and suitability for retreatment with the investigational treatment. Other unscheduled visits are permitted as needed (see Section 5.5 for more details).

Evaluative imaging (CT, MRI, bone tomograms) should be performed at protocol-defined intervals based on the first dose of study treatment (defined as Week 1, Day 1 [H1A1]); at all subsequent points in time, the same nomenclature will apply to these estimates and will not be changed as a result of modifications or deletions of treatment administration.

Unless otherwise noted, in the absence of side effects, all scheduled visits will occur within the time periods for the visit schedule specified in the protocol. If the subject experiences side effects, investigational treatment may be modified or delayed as described in Section 6.5. If a subject is unable to complete a study evaluation within a specified period of time for reasons beyond their control (for example, center closure,

- 106 041548 personal emergency, bad weather, vacation), assessment should be done as close to the scheduled time as possible. Laboratory kits for serum chemistry, hematology and urinalysis are defined in Section 5.6.5.

Appendix B: Estimate Schedule for the Expansion Stage

Before registration After registration Evaluation: Screening ^a (Before the first dose) Cycle 1 (± 3 days) Cycles 2 to 8 (±3 days) Cycles 9 or more (15 days) 30-day follow-up after treatment (+14 days) Extended after- blowing observation Informed consent (Section 5.1) x b Demographics, clinical and < 28 days cancer history (Section 5.6.1) Clinical examination + mass (Section 5.6.2) VKOG General status (Section 5.6.2, Appendix E) 28 days (with growth) 28 days (+ general state on a scale Karnovsky FOR subjects with PAC) C1D1 (before dosing) C1D1 Day 1 of each cycle or every three weeks after the last dose of atezolizumab (if infusions are delayed) Day 1 of each cycle or every three weeks after the last dose of atezolizumab (if infusions are delayed) X X

Appendix B: Estimate Schedule for the Expansion Stage

Before registration After registration Evaluation: Screening ^a (Before the first dose) Cycle 1 (± 3 days) Cycles 2 to 8 (± 3 days) Cycles 9 or more (± 5 days) 30-day follow-up after treatment (+14 days) Extended follow-up Indicators vital signs (Section 5.6.3) < 28 days C1D1 ^Y Day 1 of each cycle or every three weeks after the last dose of atezolizumab (if infusions are delayed) ^d X 12-lead ECG (Section 5.6A) ^e < 14 days C1D1 ^£ before dosing Day 1 of every 4th cycle starting on CZD1 (i.e. CZD1, C7D1, etc.) or every 12 weeks after the last dose of atezolizumab (if infusions are delayed). X Hematology and Biochemistry in central laboratory < 14 days C1D19' ^N before dosing Day 1 of each cycle or every three weeks after the last dose of atezolizumab (if infusions are delayed) ^g ' ^h X

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(Section 5.6.5) Only for CRRPJ: testosterone (Section 5.6.5) and PSA (Section 5.6.8.3) 28 days (PSA and testoseron) PSA only: Day 1 of every ^3'd cycle for the first 6 months and Day 1 of every ^5'h of cycle thereafter Screening for Hepatitis B central laboratory (Section 5.6.5) X PT/LSM and PTT in the central laboratory (Section 5.6.5) < 14 days C1D1 ^D before dosing Day 1 of every 3rd cycle starting on CZD1 (i.e. CZD1, C6D1, etc.) or every nine weeks after the last dose of atezolizumab (if infusions are delayed). X General analysis urine at the local laboratory (Section 5.6.5) 14 days SD1 ^d before dosing Day 1 of each cycle or every three weeks after the last dose of atezolizumab (if infusions are delayed) ^g X Biochemical analysis of urine including MBCM in the central laboratory (Section 5.6.5) 14 days SD1 ^£ before dosing Day 1 every other cycle starting with CZD1 (i.e. CZD1, C5D1, etc.) or every six weeks after the last dose of atezolizumab (if infusions are delayed). X Test for pregnancy in local laboratories (Section 5.6.5) < 7 days (serum) C1D1 ^£ before dosing (serum) Day 1 of each cycle or every three weeks after the last dose of atezolizumab (if infusions delayed) (urine) Checking thyroid function in central laboratory (Section 5.6.5) 14 days C1D1 ^£ before dosing Day 1 of every 3rd cycle starting with CZD1 (i.e. CZD1, C6D1, etc.) or every nine weeks after the last dose atezolizumab (if infusions are delayed). X

Appendix B: Estimate Schedule for the Expansion Stage

Before registration After registration Evaluation: Screening ^a (Before the first dose) Cycle 1 (±3 days) Cycles 2 to 8 (± 3 days) Cycles 9 or more (+ 5 days) 30-day follow-up after treatment (+14 days) Extended follow-up Archival tumor tissue sample ⁷ (Section 5.6.7) X Optional biopsy tumors (Section 5.6.7) After the first dose of study treatment (6 weeks or later) if archived tissue can be assessed. If archival samples are not assessable, then tissues may be collected prior to the first dose of investigational treatment. Tumor assessment: CT/MRI Thoracic, abdominal, pelvic 5 28 days CT scan of the chest, abdomen, pelvis, or CT scan of the chest with MRI of the abdomen and pelvis will be performed for all subjects at screening and every 6 weeks (± 5 days) after the first dose (at H7D1, H13D1, etc.). At the end of the 12 months of the study, these evaluations will be conducted every 12 weeks (± 7 days). To provide image comparability, same imaging techniques and protocols

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areas (Section 5.6.8) preparations that are used in screening should be used for subsequent tumor evaluations. CT/MRI should be performed according to the schedule defined by the protocol, regardless of whether treatment is reduced, interrupted, delayed or discontinued, and tumor evaluation is independent of the atezolizumab schedule. Tumor imaging will continue until radiological confirmation of disease progression in accordance with CCAS 1.1, as determined by the investigator. For subjects who discontinue investigational treatment prior to radiological confirmation of disease progression in accordance with CCAS 1.1, if possible, regular scheduled imaging evaluations should be continued until radiological confirmation of progression according to COOS 1.1 or initiation of the next anticancer therapy. 40 or CCAS 1.1 EL at a point in time to be confirmed by reassessments > 4 weeks after the response criteria were first met. For subjects with a COOS 1.1 PB who are continuing study treatment, tumor measurements must be confirmed > 4 weeks after the initial PB criteria have been met. For subjects who continue treatment after confirmatory tumor scans, regularly scheduled imaging will continue. Tumor assessment: MRUCT Brain (Section 5.6.8) 5 28 days Brain MRI (or CT) will be performed at screening for all subjects with RCC and NSCLC, and for subjects with UC and CRPC who have a history or clinical symptoms of brain metastasis. After the first dose, an MRI (or CT) scan of the brain is required only for subjects with documented, previously treated brain metastases. Evaluations will be performed every 12 weeks (± 7 days) after the first dose (at H13D1, H2 6D1, etc.). The timing of these evaluations is independent of the timing of atezolizumab. To ensure image comparability, the same imaging modalities and acquisition protocols used in screening should be used for subsequent tumor evaluations. (Note: To be eligible for the study, brain metastases must have been treated and stable for at least 4 weeks prior to the first dose of study treatment. Subjects without documented brain metastases at screening evaluation are not required to undergo brain imaging after the start of study treatment, unless clinically indicated). CT/MRI should be performed according to the schedule defined by the protocol, regardless of whether treatment is reduced, interrupted, delayed or discontinued, and tumor evaluation is independent of the atezolizumab schedule. Tumor imaging will continue until radiological confirmation of disease progression in accordance with CCAS 1.1, as determined by the investigator. For subjects who discontinue investigational treatment prior to radiological confirmation of disease progression in accordance with CCAS 1.1, if possible, regular scheduled imaging evaluations should be continued until radiological confirmation of progression according to COOS 1.1 or initiation of the next anticancer therapy.

Appendix B: Estimate Schedule for the Expansion Stage

Before registration After registration Evaluation: Screening ^a (before the first dose) Cycle 1 (±3 days) Cycles 2 to 8 (± 3 days) Cycles 9 or more (± 5 days) 30-day follow-up after treatment (+14 days) Extended follow-up Bone scan (Section 5.6.8) 28 days Technetium Bone Scan (TBS) will be performed at screening for all subjects with CRPC and for subjects with RCC, UC, or NSCLC who have a history or clinical symptoms (eg, bone pain) of bone metastases. After initiation of investigational treatment, bone scans are required only for subjects with documented bone lesions or if clinically marked by signs and symptoms suggestive of new bone metastases. Evaluations after the first dose will be performed according to normal clinical practice (approximately every 12 weeks for the first 12 months and every 24 weeks thereafter). Bone scanning should be used to guide confirmatory imaging with CT/MRI if necessary (these

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CT/MRI results will be used to evaluate CCSE vl.l), and bone scan results alone should not be used to determine progression in this study. Bone scan evaluations will end on the day of the last CT/MRI scan. If the bone scan schedule does not match the last CT/MRI scan, no additional bone scan is required after the last CT/MRI scan. Evaluation of pharmacokinetics and biomarkers of blood samples for a standard dosing schedule PK blood samples ^to (Section 5.6.6.1) C1D1 (before treatment, approximately 5 minutes after infusion of atezolizumab and 2 hours after administration of cabozantinib) and before dosing in C2D1, CZD1. blood sample- Pharmacogenetics (Section 5.6.7) before the introduction doses X Blood Sample - Immune Cell Profiling with FACS ¹ (Section Before dosing in C1D1, C2D1. (can be performed at selected centers) 5.6.7) Blood Sample - Serum/Plasma Biomarkers ¹ (Section 5.6.7) Before dosing in C1D1, C2D1, and CZD1 An optional sample may be obtained at the first sign of progression, depending on the investigator. Blood Sample - Cellular and/or Plasma Pharmacogenomics ¹ (Section 5.6.7) Before dosing in C1D1, C2D1, and CZD1 An optional sample may be obtained at the first sign of progression, depending on the investigator. Evaluation of pharmacokinetics and biomarkers of blood samples for the introductory dosing schedule of cabozantinib PK blood samples ^to (Section 5.6.6.1) C1D1 (before treatment and 2 hours after dosing with cabozantinib) and before dosing in C2D1, CZD1. blood sample- Pharmacogenetic (Section 5.6.7) before the introduction doses X

Appendix B: Estimate Schedule for the Expansion Stage

Before registration After registration Evaluation: Screening ^a (before the first dose) Cycle 1 (±3 days) Cycles 2 to 8 (±3 days) Cycles 9 or more (± 5 days) 30-day follow-up after treatment (+14 days) Extended follow-up Blood Sample - Immune Cell Profiling with FACS ¹ (Section 5.6.7) Before dosing in C1D1, C2D1. (can be performed at selected centers) Blood Sample - Serum/Plasma Biomarkers ¹ (Section 5.6.7) Before dosing in C1D1, C2D1, and CZD1 An optional sample may be obtained at the first sign of progression, depending on the investigator. Blood Sample - Cellular and/or Plasma Pharmacogenomics ¹ (Section 5.6.7) Before dosing in C1D1, C2D1, and CZD1 An optional sample may be obtained at the first sign of progression, depending on the investigator. Concomitant Treatment (Section 7) Document concomitant medicinal products taken within 28 days prior to the first dose of study treatment, up to 30 days after the date of the decision to discontinue study treatment. Side effects Document new or worsening AEs with informed consent in

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(Sections 8.1, 8.2 and 8.3.1) within 30 days (90 days for PEOI) after the date of the decision to permanently discontinue study treatment. PE information will be collected during study visits and may also be obtained at any time by telephone or spontaneous reporting by the subject. At the date of the first dose of study treatment, AEs will be documented before and after dosing. Some AEs and all PPEs that continue 30 days after the study permanent discontinuation date should be treated until recovery or until the Investigator determines that the complication is stable or irreversible (see Section 8.4). Dose Administration atezolizumab' (Section 6.2) Atezolizumab will be administered IV at the clinic. Standard dosing schedule: first infusion in C1D1; introductory cabozantinib dosing schedule: first C2D1 infusion. Follow-up infusions of atezolizumab will be given every three weeks (-2 days) on Day 1 of each cycle until study treatment ends. Cabozantinib dose administration (Section 6.2) Cabozantinib will be administered in the clinic at C1D1 and then taken once daily at home until study treatment is discontinued Accounting dispensed/returned oral medicinal treatment and Cabozantinib should be given subjects every 3 weeks.

reception compliance (Section 6.3)

Appendix B: Estimate Schedule for the Expansion Stage

Before registration After registration

Evaluation: Screening ^a (before the first dose) Cycle 1 (± 3 days) Cycles 2 to 8 (± 3 days) Cycles 9 and more (± 5 days) 30 days post-treatment follow-up (+14 days) Extended after- blowing observation Complementary cancer treatment and survival status (Sections 5.3 and 5.6.10) (+ 7 days) after 30 days Every 12 weeks post-treatment follow-up visit until death

a Results of screening evaluations should be reviewed prior to the first dose of investigational treatment to confirm that the subject meets the eligibility criteria.

^b Informed consent may be obtained more than 28 days prior to the first dose of study treatment, but must be provided before any study-specific procedures are performed; however, assessments performed as part of routine care prior to informed consent may be used as screening assessments if permitted by the center's IEC/EC rules.

^c Symptom-based clinical evaluation will be performed at C1D1 prior to the first dose of investigational treatment and at subsequent safety visits.

^d Vital signs should be assessed within 60 minutes prior to infusion of atezolizumab, and additional assessment of vital signs should be performed during and after infusion as clinically indicated.

^e Additional ECGs should be performed when clinically indicated.

^f This evaluation is intended to confirm suitability for treatment after screening and prior to the first dose. If this evaluation was performed at screening within 14 days (7 days for a pregnancy test) prior to the first dose (C1D1), this evaluation should not be performed at C1D1 unless the subject's clinical condition has changed (e.g., the appearance of new symptoms indicating for clinical deterioration). If the assessment is conducted at C1D1, the results must be available and verified by the investigator prior to any treatment.

^g Samples for serum chemistry, haematology, and urinalysis should be collected and results reviewed within 72 hours prior to any infusion of atezolizumab during the study.

^h Local laboratory testing for these panels can be obtained and used if results are required by the investigator in a short timeframe (see Section 5.6.5 and Laboratory Manual).

- 111 041548 for more information about laboratory tests).

The screening will test for hepatitis B surface antigen and hepatitis C antibody (in HCV RNA reflex testing if the antibody test is positive).

Tumor tissue (archival) will be obtained prior to the first dose of study treatment, whenever possible. Paraffin tumor blocks with formalin fixation (FFPE) are preferred, but in cases where this is not possible, 12 unstained fresh cut FFPE preparations should be obtained (see Transitional Medicine Laboratory Manual for specific instructions).

^k After C1D1, PK specimens should be collected approximately 8 hours or more after the previous dose of cabozantinib, and if cabozantinib will be administered on that day, PK specimens should be collected prior to cabozantinib administration. The investigator will ask the subject for the date and time of the most recent previous dose of cabozantinib, and this information will be recorded on the appropriate page of the CRF.

^l An additional blood sample should be collected if an optional tumor tissue sample is obtained and such tissue sample collection does not coincide with the scheduled blood collection for biomarker analysis.

^m Doses of atezolizumab should not be given less than 19 days apart.

Appendix C: Maintenance Phase

When enough data has been collected to adequately assess all of the study's measurable parameters, and upon notification of the sponsor, subjects remaining on study treatment will enter the maintenance phase. Once the maintenance phase has begun, the sponsor reviews the safety and efficacy profile of the drug in this study to be sufficiently prepared for regulatory procedures.

During the maintenance phase, subjects will continue to receive study treatment until the protocol's withdrawal criteria are met (Section 3.8 protocol). Subjects should undergo periodic safety evaluations (including local laboratory analyzes) and tumor evaluations; the nature and frequency of such assessments should be consistent with the standard of care. It is the investigator's responsibility to ensure that visits to subjects are frequent enough and that adequate assessments are made to ensure the safety of the subject.

To continue collecting important safety information for subjects still included in the study, reporting on PETs, PEOs and other reported adverse events (mistakes in pregnancy and medication with residuals) should continue in accordance with the protocol (Section 8.2.1) .

Additionally, the following PEs, whether they are serious or not, should be reported using the same process as for reporting POCs, as described in the protocol in Section 8.2 (although reporting deadlines for POCs do not apply to non-serious POCs). cases reported in these categories):

Adverse effects (including ESAEs), serious or not, leading to interruption of study treatment

Adverse events (including EIEs), whether serious or not, leading to dose modification of investigational treatment (i.e., causing interruption, delay, or reduction of investigational treatment)

Accounting for the study drug should continue as described in Section 6.4.

See the maintenance phase score chart below.

Subjects may be required to visit the study center more frequently to obtain study treatment supplies rather than standard of care clinic visits for safety assessments and tumor evaluations.

Observation center visits will be conducted at a reduced frequency to ensure compliance with PPCR, adherence to protocols, adequate site safety surveillance, study drug accountability, and reporting of POCs and other accountable events.

During the maintenance phase, no data should be entered into the CRF. Samples for the central research laboratory should not be collected. Do not report results to the study management vendor at the local laboratory.

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Graph Graph for the Maintenance Phase

Evaluation Study period / visit As long as the subject is receiving study treatment (Until treatment is permanently discontinued) After treatment observation visit Study Medicinal Accounting Each time a study drug is dispensed s/ ^a Investigational treatment Atezolizumab: Once every three for 3 weeks (-2 days); cabozantinib: Daily Investigational treatment may be continued until the termination criterion (Section 3.6) is met. Subjects may be allowed to discontinue treatment with one component of the combination and continue with the other, with sponsor notification. Safety rating: Clinical examination and studies in the local laboratory according to the standard Frequency according to standard of care Reporting on PETs, PEOIs and other reportable complications (pregnancy and medication errors with residuals) Provide reports to the sponsor in accordance with Section 8.2. Reporting PEs (including EPEs), whether serious or not: Submit reports to the sponsor following the same process as for POC reporting in accordance with Section 8.2. leads to discontinuation of investigational treatment leads to a change in the dose of investigational treatment (i.e. causes interruption, delay or reduction of investigational treatment) The POC reporting deadline requirements do not apply to non-serious complications listed in these categories. Tumor evaluations: Imaging methods according to the standard of care Frequency according to standard of care

PE, side effect; ISPE, immune-related side effects; PSE, serious side effect; SL, standard of care.

The data will not be entered into electronic individual registration cards. Do not transfer local lab results to study management vendor at local lab, X-ray images to study center imaging vendor.

^{a A} post-treatment visit may be required to return any unused medications still in the subject's possession.

Appendix D: Previous Autoimmune Diseases and Immune Deficiencies

Subjects should be carefully questioned regarding their acquired or congenital immunodeficiency or a history of autoimmune disease. Subjects with any history of immunodeficiency or autoimmune disease listed in the table below are excluded from participation in the study. Possible exceptions to this exclusion may include:

Subjects who have a history of atopic disease or childhood arthralgias when clinical doubt regarding an autoimmune disease is weak

Subjects with a history of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone, controlled type 1 diabetes mellitus and on an insulin schedule, or asthma requiring intermittent bronchodilators

Subjects with transient autoimmune manifestations of an acute infectious disease that has been cured by treatment of the infectious agent (eg, acute Lyme arthritis)

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Contact sponsor regarding uncertainty regarding autoimmune exclusions.

Autoimmune diseases and immunodeficiencies

Острый диссеминирующий энцефаломиелит Болезнь Аддисона Анкило зирующий спондилоартрит Синдром антифосфолипидного антитела Апластическая анемия Аутоиммунная гемолитическая анемия Аутоиммунный гепатит Аутоиммунный гипопаратиреоз Аутоиммунный гипофизит Аутоиммунный миокардит Аутоиммунный оофорит Аутоиммунный орхит Аутоиммунная тромбоцитопеническая пурпура Болезнь Бехчета Буллезный пемфигоид Синдром хронической усталости Хроническая воспалительная демиелинизирующая полинейропатия Синдром Черджа- Strauss Crohn's disease Dermatomyositis Type 1 diabetes mellitus Vegetovascular dystonia Acquired epidermolysis bullosa Gestational pemphigoid Giant cell arteritis Goodpasture's syndrome Graves' disease Guillain-Barré syndrome Hashimoto's disease IgA nephropathy Inflammatory bowel disease Interstitial cystitis Kawasaki's disease Lambert's Myasthenia Eaton Lupus erythematosus Lyme disease - chronic Meniere's syndrome Moray ulcer Annular scleroderma Multiple sclerosis Myasthenia gravis Neuromyotonia Dancing Syndrome eye Neuritis of the eye nerve Atrophic form autoimmune thyroiditis Pemphigus Pernicious anemia Polyarteritis nodosa Polyarthritis Polyglandular autoimmune syndrome Primary biliary cirrhosis Psoriasis Reiter's syndrome Rheumatoid arthritis Sarcoidosis Scleroderma Sjögren's syndrome Muscular syndrome stiffness Takayasu's arteritis Ulcerative colitis Vitiligo Woga's disease Koyanagi-Harada Wegener's granulomatosis

Appendix E: General Condition Criteria

VCOG scale of general condition Karnovsky General Condition Scale Degree Descriptions Percent Description 0 Normal activity. Fully active, able to perform all pre-morbid functions without restriction. 100 Normal, no complaints, no signs of illness. 90 Able to conduct normal activities; minor signs or symptoms of the disease. 1 Symptoms, but outpatient. Restricted to physically strenuous activities, but ambulatory and able to perform light or sedentary work (eg, light housework, office work). 80 Normal activity with effort; some signs or symptoms of the disease. 70 Takes care of himself, unable to carry out normal activities or engage in active work. 2 In bed < 50% of the time. Ambulatory and able to care for himself, but unable to do any work. Up to and around more than 50% of waking hours. 60 Requires occasional assistance, but is able/capable of taking care of himself for most of his needs. 50 Requires significant assistance and frequent medical attention. 3 In bed > 50% of the time. Capable of limited self-care, confined to bed or chair for more than 50% of waking hours. 40 Disabled, requires special care and assistance. thirty Severe disability, hospitalization is scheduled. Death is not inevitable. 4 100% bed rest. Completely disabled. Can't continue to take care of himself. Completely chained to 20 Very ill, hospitalized. Death is not inevitable. 10 Dying, death processes fast bed or chair. are progressing. 5 Dead. 0 Dead.

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Appendix F: Response Evaluation Criteria for Solid Tumors

Version 1.1 (COOSO 1.1) Adapted from Eisenhauer et al 2009

Definitions

Baseline: Baseline is defined as the most recent assessment performed prior to receiving study treatment. Baseline assessments must be completed within the period specified in the eligibility criteria protocol.

Measurable lesions: With the exception of lymph nodes, as described below, measurable lesions are defined as lesions that can be accurately measured in at least 1 direction (record longest diameter) as >10 mm by CT scan (if CT scan slice thickness exceeds 5 mm, then the minimum size for a measurable lesion is twice the slice thickness).

To be considered pathologically enlarged and measurable, a lymph node must be >15 mm in the short axis when assessed by CT (CT slice thickness no greater than 5 mm is recommended). At baseline and at follow-up, only the short axis will be measured and recorded.

MRI may be a substitute for contrast-enhanced CT for lesions in some anatomical sites, but not for lesions in the lungs. The minimum measurement size is the same as for CT (10 mm) if the scan is performed with a slice thickness of 5 mm and no gap. If MRI is performed with thicker slices, the size of the measured lesion at baseline should be twice the slice thickness. In the case of interlayer gaps, this must also be taken into account when determining the size of measurable lesions at baseline.

Non-measurable lesions: All other lesions (or lesions of disease), including small lesions (largest diameter < 10 mm or pathological lymph nodes with a short axis > 10 to < 15 mm), are considered non-measurable. Lymph nodes with a short axis < 10 mm are considered non-pathologic and are not recorded or monitored. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, cutaneous lymphangitis/pulmonitis, and abdominal masses (without CT or MRI) are considered immeasurable.

Target lesions: All measurable lesions up to a maximum of 2 lesions per organ and up to 5 lesions in total, representing all organs involved, should be identified as target lesions and measured and recorded at baseline. Target lesions should be selected based on their size (lesions with the longest diameter), be representative of all organs involved, and be those that are amenable to reproducible repeated measurements. It may happen that sometimes the largest damage cannot be measured reproducibly, in which case the next largest damage that can be reproducibly measured should be chosen. Target lesions will be measured at each assessment (longest axis for non-lymph node lesions, shortest axis for measurable malignant lymph node lesions).

Non-target lesions: All other lesions (or disease lesions), including all non-measurable lesions (including pathological lymph nodes with a short axis > 10 to < 15 mm) and all measurable lesions greater than or greater than 5 target lesions lesions should be identified as non-target lesions and noted at baseline. Measurements of these lesions are not required, but the presence, absence or, in rare cases, unequivocal progression of each should be noted throughout the follow-up period. Lymph nodes with a short axis < 10 mm are considered non-pathologic and should not be noted or observed.

To be considered as progression of non-target lesions in the presence of measurable disease, unequivocal progression is defined as a significant worsening of non-target disease such that even in the presence of CV or PR of the target disease, the overall tumor burden is significantly increased such that therapy should be discontinued.

Special note

Lesions on clinical examination will not be used to answer in this study.

Cystic lesions

Cystic lesions that meet the x-ray criteria for simple cysts should not be considered malignant lesions (neither measurable nor non-measurable), as they are, by definition, simple cysts.

Cystic lesions that are considered to be cystic metastases may be considered measurable lesions if they meet the definition of measurability described above. However, if non-cystic lesions are present in the same subject, they are preferred for selection as target lesions.

Bone lesions

Bone scans, PET scans, or x-rays are not considered adequate imaging modalities for measuring bony lesions.

Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue components that can be assessed using cross-sectional imaging techniques such as CT or MRI may be considered measurable lesions if the soft tissue component meets the definition of measurability described higher.

Powerful lesions of the bones are not measurable.

Lesions with preliminary local treatment

Lesions located in a previously irradiated area or in an area subjected to other local-regional therapy are not considered to be measurable.

Visualization methods

The same scoring method and the same method that is used to characterize each identified and marked lesion at baseline should be used during each subsequent evaluation. All measurements must be taken and recorded in metric form using a ruler or caliper. Imaging-based evaluation is preferred over evaluation by clinical examination unless the observed lesion(s) can be visualized but only evaluated by clinical examination (meaning biopsy-proven visible lesion(s) on the chest ).

Chest x-ray: Chest x-ray will not be used to evaluate response in this study.

Conventional CT and MRI: This guideline determines the measurability of lesions on CT scans based on the assumption that the CT slice thickness is 5 mm or less. If the slice thickness exceeds 5 mm on a CT scan, the minimum measurable lesion size is twice the slice thickness. MRI is also acceptable in certain situations (for example, for body scans), with the exception of the lungs.

The use of MRI remains a challenge. MRI has excellent contrast, spatial and temporal resolution; however, there are many imaging variables that play a role in MRI that significantly affect image quality, lesion visibility, and measurement. In addition, the availability of MRI varies widely. As with CT, if MRI is performed, the specifications of the scan sequences used must be optimized to assess the type and location of disease. In addition, as with CT, the imaging modality used at follow-up should be the same as at baseline, and lesions should be measured/assessed in the same pulse mode. The COOS guidelines do not specify specific pulsed MRI parameters for all scanners, body parts, and diseases. Best of all, the same type of scanner should be used and the imaging protocol should be followed as close as possible to previous scans. Body scanning should be performed, if possible, by breath-hold scanning techniques.

Positron emission tomography will not be used to evaluate response in this study.

Ultrasound: Ultrasound will not be used to evaluate response in this study.

A bone scan will be used to assess the presence or absence of the osseous component of osseous lesions. A CT or MRI will be used to confirm the bone scan results. MRI is the preferred method of confirmation.

Tumor markers: Tumor markers can be assessed for change but will not be used to determine disease progression in this study.

Cytology, Histology: The origin of any effusion that appears or worsens during treatment will be considered malignant until cytological confirmation.

Estimation by points in time

The frequency and schedule of tumor evaluations are defined in the protocol. The schedule must be adhered to whether treatment is reduced, interrupted, delayed or discontinued.

At baseline, tumors and lymph nodes are classified and documented as target or non-target lesions according to the definitions above. Several off-target lesions may be noted involving the same organ as a single entity (eg, multiple liver metastases). For all assessments after baseline (subsequent), the baseline classification (target, non-target) should be followed, and lesions should be noted and described in a consistent order over time (e.g. recorded in the same order in primary documents).

At each assessment, the sum of the diameters (longest for non-lymph node lesions, short axis for lymph node lesions) will be calculated and included in the primary documents. The baseline sum of diameters (SvD) will be used as a baseline to further characterize any objective tumor regression by measurable disease. The smallest SV (nadir) since (and including) the baseline value will be used as the basis for progression estimation.

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After measurements at baseline, the target lesions should be of documented actual size, if possible, even if the lesions become very small. If, in the opinion of the radiologist, the lesion is likely to have disappeared, 0 mm should be recorded. If a lesion is present but too small to be measured, an indicator too small to be measured should be included in the source documents.

For target lesions, measurements should be taken and recorded in metric form. All tumor measurements should be recorded in millimeters.

Non-target lesions should be assessed qualitatively (present, cured, or unequivocal progression) and new lesions, if any, should be documented separately.

At each assessment, the progression status should be determined based on the status at the point in time for target lesions, non-target lesions, and new lesions.

The discovery of new lesions should not be due to differences in scanning technique, changes in imaging modality, or findings thought to be something other than a tumor. Necrosis of pre-existing lesions as part of response to treatment should be ruled out until a new cystic lesion is identified. A lesion identified during follow-up at an anatomic site that was not scanned at baseline is considered a new lesion. If a new lesion is questionable due to its small size, repeat scans should confirm that there is definitely new lesion and progression should be recognized using the date of the original scan.

Time point progression cannot be based solely on bone scan results. Bone scanning should be used to guide confirmatory imaging with CT/MRI if needed. These CT/MRI results will be used to determine progression.

Response Criteria Times

Time Point Response (TMR) of target lesions Complete Response (RT) Disappearance of all target lesions. All pathological lymph nodes) (whether targeted or non-targeted) should have reduction in the short axis to < 10 mm.

Partial response (PR)

At least 30% reduction in SV of target lesions based on baseline

Court.

Stable disease (SD)

Not a sufficient decrease to qualify as an OR, nor a sufficient increase to qualify as an OR.

Progressive disease (PD)

At least 20% increase in SV of target lesions, based on the lowest (nadir) SV from (and including) baseline. In addition to a relative increase of 20%, the SuD must also show an absolute increase of at least 5 mm.

Not applicable (NA)

No target lesion was identified at baseline.

Impossible to rate (BUT)

One or more of the target lesions are not visualized, and the rest of the SV compared to the nadir SV does not reach the established criterion value for the PZ.

SV, baseline sum of diameters (longest for non-lymph node lesions; short axis for lymph node lesions).

If the subject's target lesion meets both the OR criteria and the PV at that point in time, the response of the target lesion is an OR.

If the SDR nadir is 0 (i.e., the subject previously had a LR for the target lesion), the reappearance of any previous target lesion to any extent is a CL.

Time Point Response (TMR) of non-target lesions

Full answer (PO)

Disappearance of all non-target lesions. All lymph nodes must be non-pathological in size (< 10 mm in the short axis).

Non-software/Non-software

Persistent one or more non-target lesions.

Progressive disease (PD)

Unambiguous progression of non-target lesions. Unequivocal progression should generally not outweigh the status of the target lesion. It should be representative of the overall change in disease status, not just the increase in one lesion.

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Not applicable (NA)

Screening revealed no non-target lesions.

Impossible to rate (BUT)

One or more non-target lesions are not visualized, and the remaining non-target lesions do not meet the TL criteria.

Time point response (TMR) of new lesions

There is a lesion found at the observation visit, either for the first time or reappearing (i.e., the lesion was already at baseline, disappeared at the observation visit, and reappeared later).

Note: The appearance of one or more new lesions on CT or MRI is considered progression unless these findings are unequivocally associated with a change in imaging technique or modality. When scanning bones, there are not enough new lesions to qualify them as PZ. Confirmation must be obtained by performing a CT or MRI of the area of doubt to confirm the results of the bone scan. MRI is the preferred method of confirmation.

No

No new lesions found at follow-up visits.

Impossible to rate (BUT)

The subject was not evaluated or not fully evaluated for the presence of new lesions.

Evaluation of the overall response by time points

OMV of the target lesion OMV of a non-target lesion OMV new lesion General OMV BY Software or NP No BY* By No-software/no-software No PR* By BUT No PR* Cho Any other than software No PR* 03 Any other than software No 03 But Any other than software No But No or Yes PZ Any PZ or NO No or Yes Any PZ PZ or NO Any Any Eat PZ** NP BY No By* NP No-software/no-software No No-software/no-software NP BUT No BUT

Software, complete answer; CHO, partial response; SD, stable disease; PD, progressive disease, HO, cannot be assessed; NA, not applicable (no such lesions on screening); Any, PO, PO, SZ, PZ, NA or NO.

The total response at a given point in time is independent of the total response determined at any previous or subsequent point in time (i.e., the confirmation requirement is not taken into account when determining responses at a point in time).

*Subjects with an overall response of CR or PR should undergo re-evaluation of the tumor, performed at least 4 weeks after the first achievement of the response criterion. However, the presence or absence of an acknowledgment is not taken into account when determining the response at a point in time.

* * If a lesion disappears and reappears at a subsequent time point, it should continue to be measured. However, the subject's response at the time a lesion reappears will depend on the status of his/her other lesions. For example, if a subject's tumor has reached PD status and the lesion reappears, then the subject will be treated as PD at the time of reappearance. In contrast, if the tumor status was PR or SC and one lesion that disappeared then reappeared, its maximum diameter should be added to the sum of the remaining lesions to calculate the response.

Confirmation

The main purpose of confirming an objective response is to avoid overestimating the observed level of response. For subjects with an overall PR or LR response at a given time point, changes in tumor dimension should be confirmed by repeat assessments, which should be performed at least 4 weeks after the response criteria were first met. However, the presence or absence of an acknowledgment is not taken into account when determining the response at a point in time. Longer intervals defined by the protocol may also be appropriate.

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Best Overall Answer

The best overall response, including validation requirements, will be derived from a statistical analysis of a number of responses over time points and should not be taken into account in determining the response at each time point.

Appendix G: Immunity-Related Response Criteria (modified by COOS)

Immunity-associated response criteria (modified CCSR) adapted from Wolchock et al. 2009 and Nishino et al. 2013.

Key aspects of the modified QOOSE for assessing the immune-related response:

New defeats:

New lesions after baseline do not necessarily define radiological progression.

New measurable lesions are added to the total tumor burden and monitored in subsequent tumor evaluations.

Immeasurable new lesions preclude complete response status.

Non-target lesions:

Progression of off-target lesions does not determine radiological progression.

Disappearance of all non-target lesions is required for complete response status.

Radiological progression:

Based on measurable disease only

Defined by >20% increase in sum of lesion diameters (LDS; including measurable new lesions)

Radiologic progression that is not confirmed > 4 weeks from first recording is not radiological progression by immune response criteria

The best response may occur after any number of radiological progression evaluations.

Evaluation of the overall response by time points associated with immunity, according to the modified criteria of CCFR Change in immunity Non-Targeted New New non-associated ADS Total target lesion measurable measurable Tumor immune lesion lesion lesion load (Including associated lesions VMF lesions lesions Including measurable VMF

OMV new lesions)

By By No No -100% ISPO Cho Any Any Any < -30% ischo NW Any Any Any > -30% to < satellite PZ Any Any Any > +20% isPZ

Software, complete answer; CHO, partial response; SD, stable disease; PD, progressive disease, immune-related IS; SDOP, the sum of the diameters of the lesions; OMV, time point response.

Time-point responses and the best overall response to the modified CCSR, including validation requirements, will be obtained during statistical analysis based on the tumor scores performed by the investigator.

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Appendix H: Guide to

Classification of immune-related infusion reactions according to R&D OTKPO version 4.0

1st degree

Soft temporary reaction; interruption of infusion is not assigned; no intervention scheduled 2nd degree

Infusion interruption ordered, but there is a rapid response to symptomatic treatment (eg, antihistamines, NSAIDs, narcotics, intravenous (IV) fluids); Initiated prophylactic treatment for < 24 hours for immune-related infusion reactions

Guidelines for the management of immune-related infusion reactions

Monitoring of indicators of • vital functions according to clinical indications

Interruption of infusion

Provide adequate supportive care (examples: antihistamines, acetaminophen, NSAIDs, IV fluids, narcotics)

Monitor vital signs as clinically indicated

Atezolizumab infusion may be restarted at a lower infusion rate if symptoms resolve immediately after initiation of maintenance therapy

Premedication is required for the next scheduled infusion of atezolizumab.

Consider discontinuing atezolizumab completely if a grade 2 infusion reaction occurs despite appropriate premedication

3rd degree

Prolonged (i.e., not responding quickly to symptomatic treatment and / or short-term interruption of the infusion);

recurrence of symptoms after initial improvement; hospitalized for other clinical complications Grade 4 Life-threatening consequences; urgent intervention is scheduled.

Interruption of infusion

Provide adequate supportive care (examples: antihistamines, acetaminophen, NSAIDs, IV fluids, narcotics, corticosteroids, epinephrine, oxygen, or ventilation) Monitor vital signs as clinically indicated Hospitalization is ordered for clinical complications (examples: renal failure, pulmonary infiltrates) Permanently discontinue IV, IV atezolizumab; NSAIDs, non-steroidal anti-inflammatory drugs; PO, orally.

Appropriate medical personnel and resuscitation equipment should be available during atezolizumab infusion therapy:

Premedication for subsequent atezolizumab infusions:

Premedication may be administered approximately 1.5 hours prior to atezolizumab infusions.

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Claims (17)

Examples: Diphenhydramine 50 mg orally and acetaminophen 500-1000 mg orally or similar drugs at equivalent doses Reference: Doessegger and Banholzer 2015 CLAIM 1. A method of treating locally advanced solid tumors or metastatic solid tumors, comprising administering to a patient in need of such treatment a compound of formula I or a pharmaceutically acceptable compound thereof. salt, or a pharmaceutical composition containing a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein R ¹ is halogen; R ² is halogen and Q is CH or N; in combination with atezolizumab, where local advanced solid tumors or metastatic solid tumors are castration recurrent prostate cancer (CRPC). 2. The method according to claim 1, wherein the compound of formula I is compound 1 or a pharmaceutically acceptable salt thereof. Compound 1 3. The method according to claim 2, characterized in that the compound 1 is administered in the form of a salt of L-malic acid. 4. The method according to claim 2, characterized in that the compound 1 is administered in the form of a salt of D-malic acid. 5. The method according to any one of claims 2 to 4, characterized in that atezolizumab is administered intravenously (IV). 6. The method according to any one of claims 2 to 5, characterized in that compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab are administered simultaneously or sequentially. 7. The method according to claim 2, characterized in that up to and including 1200 mg of atezolizumab is administered to the patient once every three weeks in combination with 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50 , 45, 40, 35, 30, 25, 20, 15, 10 or 5 mg of Compound 1, or a pharmaceutically acceptable salt thereof, once daily on an empty stomach. 8. The method according to claim 7, characterized in that up to and including 1200 mg of atezolizumab is administered to the patient once every three weeks in combination with 60, 40 or 20 mg of compound 1, or a pharmaceutically acceptable salt thereof, once a day on an empty stomach. 9. The method according to claim 2, characterized in that up to and including 1100 mg of atezolizumab is administered to the patient once every three weeks in combination with 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50 , 45, 40, 35, 30, 25, 20, 15, 10 or 5 mg of Compound 1, or a pharmaceutically acceptable salt thereof, once daily on an empty stomach. 10. The method according to claim 9, characterized in that up to and including 1100 mg of atezolizumab is administered to the patient once every three weeks in combination with 60, 40 or 20 mg of compound 1, or its pharmaceutically acceptable salt, once a day on an empty stomach. 11. The method according to claim 2, characterized in that up to and including 1000 mg of atezolizumab is administered to the patient once every three weeks in combination with 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50 , 45, 40, 35, 30, 25, 20, 15, 10 or 5 mg of Compound 1, or a pharmaceutically acceptable salt thereof, once daily on an empty stomach. 12. The method according to claim 11, characterized in that up to and including 1000 mg of atezolizumab is administered to the patient once every three weeks in combination with 60, 40 or 20 mg of compound 1, or a pharmaceutically acceptable salt thereof, once a day on an empty stomach. 13. The method according to claim 2, characterized in that up to and including 900 mg of atezolizumab is administered to the patient once every three weeks in combination with 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50 , 45, 40, 35, 30, 25, 20, 15, 10 or 5 mg of Compound 1, or a pharmaceutically acceptable salt thereof, once daily on an empty stomach. 14. The method according to claim 13, characterized in that up to and including 900 mg of atezolizumab is administered to the patient once every three weeks in combination with 60, 40 or 20 mg of compound 1, or its pharmaceutically acceptable salt, once a day on an empty stomach. 15. The method according to any one of claims 7 to 14, characterized in that compound 1 or a pharmaceutically acceptable salt thereof and atezolizumab are administered simultaneously or sequentially. - 121 041548 16. The method according to any one of claims 6 to 15, characterized in that atezolizumab is administered intravenously by infusion over 60 or 30 minutes. 17. The method according to any one of claims 1 to 16, characterized in that patients treated with said combination show stabilization of the disease. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky per., 2 - 122 -