WO2023136837A1 - Use of tivozanib and durvalumab for treating hepatocellular carcinoma (hcc) - Google Patents

Use of tivozanib and durvalumab for treating hepatocellular carcinoma (hcc) Download PDF

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Publication number
WO2023136837A1
WO2023136837A1 PCT/US2022/012623 US2022012623W WO2023136837A1 WO 2023136837 A1 WO2023136837 A1 WO 2023136837A1 US 2022012623 W US2022012623 W US 2022012623W WO 2023136837 A1 WO2023136837 A1 WO 2023136837A1
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subject
hcc
tivozanib
treatment
durvalumab
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PCT/US2022/012623
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French (fr)
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Michael James FERRARESSO
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Aveo Pharmaceuticals, Inc.
Medimmune Limited
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Priority to PCT/US2022/012623 priority Critical patent/WO2023136837A1/en
Publication of WO2023136837A1 publication Critical patent/WO2023136837A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2827—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against B7 molecules, e.g. CD80, CD86
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • the field of the invention is medicine, oncology, and the treatment of hepatocellular carcinoma.
  • Tivozanib is a potent and selective small -molecule vascular endothelial growth factor (VEGF) receptor (VEGFR) tyrosine kinase inhibitor (VEGF TKI) that has been approved by the European Medicines Agency and U.S. Food and Drug Administration for the treatment of advanced or refractory renal cell carcinoma (RCC).
  • VEGF vascular endothelial growth factor
  • VEGFR vascular endothelial growth factor receptor
  • VEGF TKI vascular endothelial growth factor receptor
  • RRCC refractory renal cell carcinoma
  • tivozanib inhibits phosphorylation of VEGFR-1, VEGFR-2 and VEGFR-3 and inhibits other kinases including c ⁇ kit and PDGFR p at clinically relevant concentrations.
  • tivozanib inhibited angiogenesis, vascular permeability, and tumor growth of various tumor cell types.
  • Durvalumab is a human monoclonal antibody that blocks the interaction of PD-Ll with PD-1 on T cells and CD80 (B7.1) on immune cells. Interaction between PD-1 and PD-Ll normally results in the inhibition of the cellular immune response. Durvalumab is approved for the treatment of metastatic urothelial carcinoma and non-small cell lung cancer.
  • HCC hepatocellular carcinoma
  • the present disclosure provides improved methods for treating subjects with hepatocellular carcinoma by administering tivozanib and durvalumab in combination.
  • the disclosure provides a method of treating a hepatocellular carcinoma (HCC) in a subject in need thereof.
  • the method comprises administering to the subject a treatment regimen comprising an effective amount of tivozanib and an effective amount of durvalumab thereby to treat the HCC in the subject.
  • the subject experiences a progression free survival of at least 7 months upon receiving the treatment regimen.
  • the treatment regimen when the treatment regimen is administered to subjects having HCC, the subjects experience a median progression free survival of at least 7 months upon receiving the treatment regimen.
  • the subject experiences a progression free survival of at least 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 2.3, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, or 48 months upon receiving the treatment regimen.
  • the subject has a survival time of at least 13 months from the start of treatment
  • the subjects when the treatment regimen is administered to subjects having HCC, the subjects experience a median progression free survival of at least 7.1, 7.2,
  • the subjects experience a median overall survival of at least 13 months from the start of treatment.
  • the HCC can be advanced and/or metastatic HCC.
  • the subject has not previously received treatment for the HCC, e.g, systemic therapy to treat the HCC.
  • treatment regimen of tivozanib and durvalumab is a first line systemic therapy for the HCC in the subject.
  • the subject has previously received treatment for the HCC.
  • the treatment regimen of tivozanib and durvalumab is a second or later line systemic therapy to treat the HCC in the subject.
  • Hie previous treatment can include treatment with a VEGF inhibitor, e.g., bevacizumab or a VEGF TKI, e.g, sorafenib, regorafenib, cabozantinib, or lenvantmib.
  • the VEGF TKI is nintedanib, anlotinib, fruquintinib, apatinib, sunitinib, pazopanib, axitinib, dasatmib, nilotinib, motesanib, deciramb, donafenib, vandetanib, or sulfatinib.
  • the subject has previously been treated with a checkpoint inhibitor, e.g, aPD-1 or PD-L1 inhibitor.
  • a checkpoint inhibitor e.g, aPD-1 or PD-L1 inhibitor.
  • the subject has been previously treated with atezolizumab, or with pembrolizumab and/or ipilimumab, or with nivolumab and/or ipilimumab.
  • the subject has previously been treated with a VEGF inhibitor and a checkpoint inhibitor, e.g., bevacizumab and atezolizumab, to treat the HCC.
  • a checkpoint inhibitor e.g., bevacizumab and atezolizumab
  • the treatment regimen comprises one or more treatment cycles of 28 days in duration.
  • a treatment cycle involves administering trv ozanib at a dose of 1 mg per day on days 1-21 of the treatment cycle followed by no administration of tiv ozanib on days 22-28 of the treatment cycle.
  • if the subject experiences a grade 3 adverse event tivozanib is administered even 7 other day of treatment cycle.
  • I mg of tivozanib is administered every other day of the treatment cycle.
  • the tivozanib is tivozanib hydrochloride.
  • the treatment cycle comprises administering durvalumab at a dose of 1,500 mg on day 1 of the treatment cycle followed by no administration of durvalumab on days 2-28 of the treatment cycle.
  • the treatment regimen comprises one or more treatment cycles where tivozanib is administered at a dose of 1 mg per day on days 1-21 of the treatment cycle followed by no administration of tivozanib on days 22-28 of the treatment cycle and durvalumab is administered at a dose of 1,500 mg on day 1 of the treatment cycle followed by no administration of durvalumab on days 2-28 of the treatment cycle.
  • the subject has not previously received treatment, e.g., a systemic treatment for the HCC. Accordingly, the treatment regimen is a first line systemic therapy for treating the HCC in the subject.
  • the subject has previously received treatment, e.g., a systemic treatment for the HCC, such as sorafenib; or atezolizumab and bevacizumab; or nivolumab or pembrolizumab with or without ipilimumab.
  • a systemic treatment for the HCC such as sorafenib; or atezolizumab and bevacizumab; or nivolumab or pembrolizumab with or without ipilimumab.
  • the treatment regimen is a second line or later line systemic therapy for treating the HCC in the subject.
  • the tivozanib can be administered orally.
  • the durvalumab can be administered intravenously, for example, over a period 60 minutes and/or at a concentration of 1-15 mg/mL.
  • the subject receives at least 7 treatment cycles and/or receives the treatment regimen for at least 7 months.
  • the subject can receive the treatment regimen until the subject experiences a complete response or until the subject experiences progression of the HCC.
  • methods for extending the progression free survival (PFS) in a subject in need thereof with HCC comprising administering to the subject a treatment regimen comprising a therapeutically effective amount of tivozanib or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of durvalumab.
  • the PFS is extended compared to a subject or subjects with HCC treated with sorafenib or with bevacizumab and atezolizumab.
  • methods for extending the progression free survival (PFS) in subjects in need thereof with HCC comprising administering to the subjects a treatment regimen comprising a therapeutically effective amount of tivozanib or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of durvalumab.
  • the PFS is extended compared to subjects with HCC treated with sorafenib or with bevacizumab and atezolizumab.
  • methods for extending the overall survival (OS) in a subject in need thereof with HCC comprising administering to the subject a treatment regimen comprising a therapeutically effective amount of tivozanib or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of durvalumab.
  • the OS is extended compared to a subject or subject with HCC treated with sorafenib or with bevacizumab and atezolizumab.
  • methods for extending the overall survival (OS) in subjects in need thereof with HCC comprising administering to the subjects a treatment regimen comprising a therapeutically effective amount of tivozanib or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of durvalumab.
  • the OS is extended compared to subjects with HCC treated with sorafenib or with bevacizumab and atezolizumab.
  • the subject is a human.
  • FIG. 1 is a schematic overview of the phase lb/2 study described in Example 1.
  • FIG. 2 depicts the best overall response and treatment duration for the indicated subjects.
  • the present disclosure provides methods of treating hepatocellular carcinoma (HCC) using tivozanib and durvalumab. It has been discovered that tivozanib and durvalumab, when used in combination, are effective at prolonging the survival of subjects suffering from advanced HCC. Surprisingly, the data generated in an ongoing clinical study, discussed herein, is indicative that tivozanib and durvalumab, when used in combination, have greater therapeutic efficacy in treating advanced HCC than other currently available systemic therapies. Therefore, tivozanib and durvalumab, when used in combination, may be useful as a first, second or later line systemic therapy for treating subjects with advanced HCC.
  • HCC hepatocellular carcinoma
  • the singular forms “a,” “an,” and “the,” refer to both the singular as well as plural, unless the context clearly indicates otherwise.
  • the term “a cell” includes single or plural cells and can be considered equivalent to the phrase “at least one cell.”
  • the expression “at least one of’ includes individually each of the recited objects after the expression and the various combinations of two or more of the recited objects unless otherwise understood from the context and use. For convenience, certain terms in the specification, examples, and appended claims are collected in this section.
  • administration is understood to mean to provide to a subject an agent, such as tivozanib and/or durvalumab, by any effective route.
  • routes of administration include, but are not limited to, oral, injection (such as subcutaneous, intramuscular, intradermal, intraperitoneal, intravenous, intra-arterial (including hepatic intraarterial), intra-ductal, intraprostatic, and intratumoral), sublingual, rectal, transdermal. intranasal, vaginal and inhalation routes.
  • administration is systemic.
  • administration is oral.
  • HCC hepatocellular carcinoma
  • HCC hepatocellular carcinoma
  • advanced means that the HCC has metastasized, or otherwise cannot be adequately treated with local therapy alone, such as surgical intervention or radiation therapy, and therefore requires a systemic therapy.
  • “advanced” means that the HCC has recurred after having previously responded to treatment with a local or systemic therapy, for example, treatment with a VEGF TKI such as sorafenib, or a VEGF inhibitor such as bevacizumab and a checkpoint inhibitor, such as atezoli Kursab.
  • VEGF TKI such as sorafenib
  • VEGF inhibitor such as bevacizumab
  • checkpoint inhibitor such as atezoli Kursab.
  • advanced HCC is unlikely to be cured or controlled with treatment and, therefore, palliative therapy is used to slow the growth of the cancer or to relieve symptoms through end of life.
  • advanced HCC includes recurrent HCC.
  • atezolizumab also known by its trade name TECENTR1Q®, is understood to refer to a programmed cell death ligand 1 (PD-L1) blocking antibody.
  • Atezolizumab is an Fc-engineered, humanized, non-glycosylated IgG 1 kappa immunoglobulin that has a calculated molecular mass of 145 kDa.
  • the term “best overall response” is understood to mean the best response recorded from the start of the study treatment until the end of treatment taking into account any requirement for confirmation and is determined according to RECIST 1.1 criteria.
  • bevacizumab also known by its trade name AVASTIN®, is understood to refer to a recombinant humanized monoclonal IgGl antibody that binds to and inhibits the biologic activity of human vascular endothelial growth factor (VEGF) in in vitro and in vivo assay systems.
  • VEGF vascular endothelial growth factor
  • Bevacizumab contains human framework regions and the complementarity-determining regions of a murine antibody that binds to VEGF.
  • Avastin has an approximate molecular weight of 149 kD.
  • checkpoint inhibitor is understood to refer to a class of drugs that works by preventing checkpoint proteins on T-cells and tumor cells from binding with one another, thereby allowing T-cells to kill tumor cells.
  • Checkpoint inhibitors are a systemic therapy for treating cancers. Common checkpoint inhibitors act on checkpoint proteins such as PD-1, PD-L1, or CTLA-4.
  • Checkpoint inhibitors include drugs such as a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA-4 inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor, a TIGIT inhibitor, a VISTA inhibitor, a KIR inhibitor, a 2B4 inhibitor, a CD 160 inhibitor, a CGEN-15049 inhibitor, a CHK1 inhibitor, a CHK2 inhibitor, an A2aR inhibitor, or any combination thereof.
  • PD-L1 inhibitors include, for example, durvalumab, atezolizumab, avelumab, or any combination thereof.
  • Other PD-1 inhibitors include, for example, nivolumab, pembrolizuniab, pidilizuniab, cemiplimab, sintiiimab, REGN2810, PDR001, or any combination thereof.
  • CTLA-4 inhibitors includes, for example, ipilimumab, tremelimumab, AGEN-1884, or any combination thereof.
  • TIM-3 inhibitors include, for example, TSR-022, LY3321367, MBG453, or any combination thereof.
  • TIGIT inhibitors include, for example, BMS-986207, AGEN17, tiragolumab, MK-7684, OMP-313M32, EOS-448, AB154, or combinations thereof.
  • LAG-3 inhibitors include, for example, BMS-986016, REGN3767, IMP321, LAG525, BI754U 1 , favezelimab, or combinations thereof.
  • VISTA inhibitors include, for example, CI-8993, HMBD-002, a PSGL-1 antagonist as described in WO 2018/132476, or combinations thereof.
  • the term ‘‘clinical benefit” is understood to refer to a subject experiencing one or more of: (a) slowing tumor growth, (b) halting tumor growth, (c) tumor regression or disappearance, (d) amelioration of a symptom of the cancer, (e) curing the cancer, and (f) prolonging survival of the subject upon the subject receiving a particular intervention, for example, a surgical intervention or therapeutic intervention.
  • DCR disease control rate
  • drug related adverse event is understood to refer to an adverse event (AE) as defined and classified in the National Cancer Institute - Common Terminology Criteria for Adverse Events (CTCAE), version 4.03, dated June 14, 2010. Any reference to “Grade” of adverse event, refers to the grading system as outlined therein.
  • Durvalumab also known by its trade name IMFINZI®, is understood to refer to a programmed cell death ligand 1 (PD-L1) blocking antibody.
  • Durvalumab is a human immunoglobulin G1 kappa (IgGlK) monoclonal antibody that is produced by recombinant DNA technology in Chinese Hamster Ovary (CHO) cell suspension culture.
  • Durvalumab is available as IMFINZI (durvalumab) Injection for intravenous use, which is a sterile, preservative-free, clear to opalescent, colorless to slightly yellow solution, free from visible particles.
  • Each 500 mg vial of IMFINZI contains 500 mg of durvalumab in 10 mL solution. Each ml contains durvalumab, 50 mg, L-histidine (2 mg), L-histidine hydrochloride monohydrate (2.7 mg), a,a-trehalose dihydrate (104 mg), Polysorbate 80 (0.2 mg), and Water for Injection, USP. Each 120 mg vial of IMFINZI contains 120 mg of durvalumab in 2.4 mL solution Each mL contains durvalumab, 50 mg, L-histidine (2 nig), L-histidine hydrochloride monohydrate (2.7 mg), a,a-trehalose dihydrate (104 mg), Polysorbate 80 (0.2 mg), and Water for Injection, USP.
  • Durvalumab is described in International Patent Application Publication No. WO2011/066389A1.
  • the light chain variable region of durvalumab has the following ammo acid sequence:
  • the heavy chain variable region of durvalumab has the following amino acid sequence:
  • the light chain CDR sequences of durvalumab are RASQRVSSSYLA (CDRL1; SEQ ID NOG), DASSRAT (CDRL2; SEQ ID NO:4), and QQYGSLPWT (CDRL3; SEQ ID NO: 5).
  • the heavy chain CDR sequences of dui v alumab are GFTFSRYWMS (CDRH1 ;
  • the terms ‘"effective amount” or “therapeutically effective amount” are understood to mean a quantity of a specific substance (such as tivozanib and/or durvalumab) sufficient to achieve a desired effect in a subject being treated. For instance, this can be the amount necessary to inhibit or suppress grow th of a tumor.
  • an effective amount is the amount necessary to eliminate, reduce the size, or prevent metastasis of a tumor, such as reduce a tumor size, weight and/or volume by at least 10%, at least 20%, at least 50%, at least 75%, at least 80%, at least 90°.., at least 95%, or even 100%, and/or reduce the number and/or size/volume/weight of metastases by at least 10%, at least 20%, at least 50%, at least 75%, at least 80%, at least 90%, at least 95%, or even 100%, for example as compared to a size/volume/number/ weight prior to treatment.
  • this can be the amount necessary to increase the survival time of a treated subject by at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12. months, at least 18 months, at least 24 months, at least 36 months, at least 48 months, or at least 60 months, for example relative to the survival time in an absence of the treatment provided herein. In some examples, combinations of these effects are achieved.
  • a dosage When administered to a subject, a dosage will generally be used that is expected to achieve target tissue concentrations (for example, in tumors) that have been shown to achieve a desired in vitro effect.
  • An effective amount can be administered in one or more administrations, applications or dosages and is not limited to a particular formulation or administration route.
  • an effective treatment regimen or “therapeutically effective treatment regimen” is understood to refer to a treatment regimen of a substance or substances (e.g., tivozanib and/or durvalumab) sufficient to effect beneficial or desired results, such as to effect a clinical benefit in a subject.
  • An effective treatment regimen of tivozanib and durvalumab can be administered in one or more administrations, applications or dosages and is not. limited to a particular formulation or administration route.
  • an exemplary effective treatment regimen of tivozanib and durvalumab is a regimen that is effective to elicit a complete or partial response according to RECIST (Version 1.1) criteria, as further defined herein.
  • An exemplary effective treatment regimen of tivozanib and durvalumab is administration of at least one treatment cycle, where a treatment cycle comprises (i) administering 1.0 mg tivozanib for 21 days followed by 7 days without administration of tivozanib and (ii) administering 1,500 mg durvalumab for 1 day followed by 27 days without, administration of durvalumab.
  • hepatocellular carcinoma also referred to as malignant hepatoma
  • HCC hepatocellular carcinoma
  • hepatocytes liver cells
  • HCC hepatocellular carcinoma
  • ORR all objective response rate
  • OS all survival
  • the term “pharmaceutical composition” is understood to mean the combination of an active agent (such as tivozanib and/or durvalumab) with a carrier (inert or active) that is suitable for diagnostic or therapeutic use in vivo or ex vivo.
  • an active agent such as tivozanib and/or durvalumab
  • a carrier inert or active
  • progression-free survival is understood to mean the time from randomization into a study to first documentation of objective tumor progression (progressive disease “PD”, radiological) according to RECIST (Version 1.1; see, e.g, Eisenhauer et al. (2009), EUR. J. CANCER, 25:228-247) or death due to any reason, whichever comes first.
  • PFS data is censored on the day following the date of last tumor assessment documenting absence of progressive disease (PD) for subjects who do not have objective tumor progression and are still on study at the time of the analysis, are given antitumor treatment other than the study treatment, or are moved from treatment follow-up prior to documentation of objective tumor progression. Subjects having no tumor assessments after randomization who are not known to have died have PFS censored on the date of randomization.
  • recurrent HCC is understood to refer to HCC that fails to respond to treatment or returns after treatment, “recurs”.
  • a hepatocellular carcinoma is recurrent if it fails to respond to a mode of treatment, e.g., the subject experiences disease progression while undergoing treatment.
  • a hepatocellular carcinoma is recurrent if it returns or progresses after treatment or surgical resection.
  • Recurrent HCC may also respond to an initial treatment, and then return, or initially respond to a treatment, but later in the treatment process, the HCC stops responding to such treatment.
  • recurrent hepatocellular carcinoma refers to HCC that has been previously treated with at least one systemic or local treatment, and has not responded to such treatment or becomes resistant to such treatment, or that continues to progress during or after such treatment.
  • recurrent HCC and advanced HCC are synonymous.
  • the terms “response” or “responding” in the context of a subject’s response to a therapeutic agent (such as tivozanib and/or durvalumab) are understood to refer to the RECIST (Response Evaluation Criteria in Solid Tumors, version 1.1, 2009) criteria for evaluating response of target lesions to a cancer therapy.
  • RECIST Response Evaluation Criteria in Solid Tumors, version 1.1, 2009
  • subjects who respond are categorized as either “complete responders” (disappearance of all target lesions) or “partial responders” (at least a 30% decrease in the sum of the diameters of the target lesions, taking as reference the baseline sum of diameters).
  • a “complete response” refers disappearance of all target lesions
  • a “partial response” refers to at least a 30% decrease in the sum of the diameters of the target lesions, taking as reference the baseline sum of diameters.
  • Non-responders can be placed into one of two categories: stable disease (SD; neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum diameters while on treatment) or progressive disease (PD; at least a 20% increase in the sum of the diameters of the target lesions, taking as reference the smallest sum (this includes the baseline sum if that is the smallest on study: in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm; the appearance of one or more new lesions also qualifies as progression).
  • SD stable disease
  • PD progressive disease
  • the RECIST criteria are discussed in detail in, e.g., Therasse et al., J. NATL.. CANCER INST., 2000: 92:205-216 (RECIST 1 .0), and Eisenhauer et al., EUR. J. CANCER, 2009: 25:228-247 (RECIST 1.1). Accordingly, as described herein, responding to therapy refers to subjects falling within the RECIST categories of complete or partial responder, whereas not responding refers to subjects falling within the RECIST categories of stable disease or progressive disease.
  • the term ‘‘subject” is understood to refer to living multi-cellular vertebrate organisms, a category that includes both human and veterinary subjects, including human and non-human mammals such as pigs, mice, rats, guinea pigs, rabbits, sheep, horses, cows, dogs, cats and non-human primates (such as monkeys, chimpanzees, baboons, and rhesus macaques).
  • human and non-human mammals such as pigs, mice, rats, guinea pigs, rabbits, sheep, horses, cows, dogs, cats and non-human primates (such as monkeys, chimpanzees, baboons, and rhesus macaques).
  • the terms “subject” and “patient” are used interchangeably.
  • the subject is a human.
  • systemic therapy in the context of treating HCC, is understood to refer to chemotherapies and immunotherapies such as checkpoint inhibitors. Because these Apes of drugs are administered by methods that distribute the drugs systemically, e.g., orally, or by injection or i.v., and therefore reach all parts of the body, they are referred to as “systemic therapy.” This is in contrast to treatments for HCC, such as radiation or surgery, which are considered “local therapy” because their impact is generally only seen in the part of the body where they are implemented'' administered, i.e., in the liver.
  • tivozamb is understood to refer to a small molecule having the chemical name N- ⁇ 2-chloro-4-[(6,7-dimethoxy-4-qumolyl)oxy]-phenyl ⁇ -N’-(5-methyl-3- isoxazolyl)urea and having the following chemical structure: including pharmaceutically acceptable salts, solvates, solvates of a pharmaceutically acceptable salt, esters, or polymorphs thereof. See, for example, U.S. Patent Nos. 6,821,987, 7,166,722 and 7,211,587, each of which are incorporated herein by reference in their entirety. Tivozamb is sold under the tradename FOTTVDA® in the United States by Aveo Pharmaceuticals, Inc.
  • tivozanib is N- ⁇ 2-chloro- 4"[(6,7-dimethoxy ⁇ 4-quinolyl)oxy]-phenyl ⁇ N’-(5 ⁇ methyl-3-isoxazolyl)urea or hydrates of a hydrochloride salt.
  • tivozamb is N- ⁇ 2-chloro-4-[(6,7-dimethoxy-4- quinolyl)oxy ] -pheny 1 ⁇ -N’ -(5 -methyl-3 -i soxazoly l)urea monohy drochlori c aci d sal t monohydrate.
  • tivozamb is tivozanib hydrochloride having the chemical name 1 - ⁇ 2-chl oro-4- [ (6,7-dimethoxy quinolin-4-yl)oxy ]phenyl ⁇ -3 -(5 - methyhsoxazol-3-yl)urea hydrochloride hydrate, having the chemical structure the molecular formula C22H19CIN4O5 s HC1 * H2O, and a molecular weight of 509.34.
  • Tivozanib hydrochloride is a white to light brown crystalline powder that is practically insoluble in water. Tivozanib is also referred to by its trade name FOTIVDA ®.
  • Tivozanib is a tyrosine kinase inhibitor that has been demonstrated to inhibit phosphorylation of vascular endothelial growth factor receptor (VEGFR)-], VEGFR-2 and VEGFR-3 and other kinases including c ⁇ kit and PDGFR P at clinically relevant concentrations.
  • VEGFR vascular endothelial growth factor receptor
  • the terms ‘"treating” or “treat” or “treatment” in the context of hepatocellular carcinoma are understood to refer to applying techniques, actions or therapies to a subject that (a) slow' tumor growth, (b) halt tumor growth, (c) promote tumor regression or disappearance, (d) ameliorate a symptom of the cancer, (e) cure the cancer, or (f) prolong survival of the subject, or applying techniques, actions or therapies to a subject in an attempt to achieve any of (a)-(f) regardless of whether the individual actually responds to the technique, action or therapy,
  • the term “untreated,” e.g. , in the context of a subject with HCC, e.g., advanced HCC, is understood to mean that the subject has not previously received a systemic therapy, e.g., chemotherapy or immunotherapy such as a checkpoint inhibitor, to treat the HCC.
  • a systemic therapy e.g., chemotherapy or immunotherapy such as a checkpoint inhibitor
  • An untreated subject may or may not have received a surgical invention or localized radiation; however, if they have had a surgical resection of the HCC tumor(s) or localized radiation, the HCC has recurred and is no longer resectable, or otherwise locally treatable.
  • vascular endothelial growth factor (VEGF) inhibitor is understood to refer to compounds that interfere with VEGF signaling with its receptor (VEGFR).
  • VEGF inhibitors include antibodies such as bevacizurnab and ranibizumab that bind VEGF, interfering with VEGF’s ability to bind its receptor, antibodies that bind VEGFR such as ramucirumab, as well as drugs like aflibercept w-hich contain extracellular VEGF receptor sequences of the human VEGFR1 and VEGFR2, thereby acting as a decoy receptor for VEGF-A.
  • VEGF Inhibitors also include VEGF (or VEGFR) TRI inhibitors which are a class of anti-angiogenic drugs that inhibits the activity of VEGF TKIs such as VEGFR- 1, VEGFR-2, and/or VEGFR-3, and may also inhibit any one or more of c-Met, c-Kit, PDGFR- a, PDGFR-b, FGFR-1, and/or FGFR-2.
  • VEGF or VEGFR
  • VEGFR TRI inhibitors which are a class of anti-angiogenic drugs that inhibits the activity of VEGF TKIs such as VEGFR- 1, VEGFR-2, and/or VEGFR-3, and may also inhibit any one or more of c-Met, c-Kit, PDGFR- a, PDGFR-b, FGFR-1, and/or FGFR-2.
  • VEGF TKIs include regorafenib, nintedanib, lenvantinib, anlotinib, sorafenib, fruquintinib, apatinib, sunitinib, pazopanib, axitinib, dasatinib, niiotinib, motesanib, deciranib, donafenib, vandetanib, sulfatinib, tivozanib, and cabozantinib.
  • compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.
  • the disclosure provides methods of treating a subject having hepatocellular carcinoma (HCC), for example, advanced HCC, with a combination of tivozanib and durvalumab.
  • HCC hepatocellular carcinoma
  • the disclosure also provides a combination of tivozanib (or a pharmaceutically acceptable salt and/or hydrate thereof) and durvalumab for use in the treatment of hepatocellular carcinoma (HCC), for example, advanced HCC,
  • HCC hepatocellular carcinoma
  • the disclosure further provides the use of a combination of tivozanib (or a pharmaceutically acceptable salt and/or hydrate thereof) and durvalumab in the manufacture of a medicament for use in the treatment of hepatocellular carcinoma (HCC), for example, advanced HCC.
  • HCC hepatocellular carcinoma
  • the disclosure provides methods of treating a subject having hepatocellular carcinoma (HCC), such as advanced HCC, with an effective amount of tivozanib and an effective amount of durvalumab, thereby to treat the HCC in the subject.
  • the treatment methods for HCC disclosed herein may be used as a first line systemic therapy to treat subjects with HCC that have not previously received a systemic therapy to treat their HCC.
  • a systemic therapy to treat their HCC.
  • they have not previously received chemotherapy, including VEGF inhibitors or immunotherapies such as immune checkpoint inhibitors to treat their HCC.
  • HCC hepatocellular carcinoma
  • the subject has not previously received a systemic therapy, i.e., chemotherapy and/or immunotherapy, to treat HCC.
  • the subject receives treatment with tivozanib and durvalumab as a first line systemic therapy for advanced HCC, where the subject has not previously received a systemic therapy (i.e., chemotherapy and/or immunotherapy) to treat the HCC.
  • the subject has not previously received a systemic therapy, e.g., chemotherapy and/or immunotherapy, to treat HCC, but may have received local radiation or surgical resection of HCC tumor(s) but the cancer has recurred after local therapy.
  • a systemic therapy e.g., chemotherapy and/or immunotherapy
  • the subject has not previously received a systemic therapy, e.g., chemotherapy and/or immunotherapy, to treat HCC, and also has not received local radiation or surgical resection of HCC tumor(s).
  • the subject has not previously received a local therapy, e.g, surgical resection or radiation, and has not previously received a systemic therapy, e.g., chemotherapy and/or immunotherapy, to treat HCC.
  • a local therapy e.g, surgical resection or radiation
  • a systemic therapy e.g., chemotherapy and/or immunotherapy
  • the subject receives treatment with tivozanib and durvalumab as first line therapy for advanced HCC, where the subject has unresectable HCC and has not previously received systemic therapy to treat the HCC.
  • the subject may have previously received surgery to resect the HCC, but the HCC has recurred and is now non- resectable.
  • the subject has received radiation to treat the HCC, but the HCC has recurred.
  • the subject has not received previous surgery or radiation to treat the HCC.
  • the treatment methods for HCC disclosed herein may be used as second line systemic therapies to treat subjects with HCC that have previously received a systemic therapy to treat their HCC.
  • a subject may have previously received chemotherapy and/or immunotherapy in a first line of treatment for the HCC, but failed to respond, or progressed.
  • a first line of treatment may include a VEGF TKI.
  • a first line of treatment may include a VEGF TKI such as sorafenib, regorafenib, lenvantinib, donafenib or cabozantinib, but not tivozanib.
  • a first line of treatment may include sorafenib.
  • a first line of treatment may include a VEGF inhibitor such as bevacizumab combined with an immune checkpoint inhibitor such as atezoiizumab.
  • a first line of treatment may include a VEGF inhibitor such as bevacizumab combined with an immune checkpoint inhibitor such as sintilimab.
  • a first line of treatment for HCC may include nivolumab with ipilimumab or pembrolizumab with ipilimumab.
  • a first line of treatment for HCC may include ramucirumab.
  • the treatment methods for HCC disclosed herein may be used as third or later line systemic therapies to treat subjects with HCC that have previously received a systemic therapy to treat their HCC.
  • a subject may have previously received chemotherapy and/or immunotherapy, in an earlier line of treatment for the HCC, but failed to respond, or progressed.
  • a first, second or later line of previous treatment may include a VEGF TKI.
  • a first, second or later line of previous treatment may include a VEGF TKI such as sorafenib, regorafenib, lenvantinib, donafenib or cabozantinib, but not tivozanib.
  • a first, second or later line of previous treatment may include sorafenib.
  • a first, second or later line of previous treatment may include a VEGF inhibitor such as bevacizumab combined with an immune checkpoint inhibitor such as atezoiizumab.
  • a first, second or later line of previous treatment may include a VEGF inhibitor such as bevacizumab combined with an immune checkpoint inhibitor such as sintilimab.
  • a first, second or later line of previous treatment for HCC may include nivolumab with ipilimumab or pembrolizumab with ipilimumab.
  • a first, second or later line of previous treatment for HCC may include ramucirumab.
  • the disclosure provides methods of treating a subject having hepatocellular carcinoma (HCC), such as advanced HCC, with an effective amount of tivozanib and an effective amount of durvalumab, thereby 7 to treat the HCC, where the subject has previously received treatment for the HCC.
  • HCC hepatocellular carcinoma
  • the subject was previously treated with a VEGF inhibitor, for example, bevacizumab.
  • a VEGF TK1 for example, cabozantimb or regorafenib.
  • the subject was previously treated with a VEGF TKI, for example, sorafenib.
  • the disclosure provides methods of treating a subject having hepatocellular carcinoma (HCC), such as advanced HCC, with an effective amount of tivozanib and an effective amount of durvalumab, thereby to treat the HCC, where the subject has previously received treatment for the HCC.
  • HCC hepatocellular carcinoma
  • the subject was previously treated with a immune checkpoint inhibitor.
  • the subject was previously treated with a PD-Ll inhibitor, for example, atezoiizumab.
  • the disclosure provides methods of treating a subject having hepatocellular carcinoma (HCC), such as advanced HCC, with an effective amount of tivozanib and an effective amount of durvalumab, thereby to treat the HCC, where the subject has previously received treatment for the HCC, and the treatment was a combination of atezoiizumab and bevacizumab.
  • HCC hepatocellular carcinoma
  • the disclosure provides methods of treating a subject having hepatocellular carcinoma (HCC), such as advanced HCC, with an effective amount of tivozanib and an effective amount of durvalumab, thereby to treat the HCC, where the subject experiences a progression free survival of at least six months upon receiving the treatment with tivozanib and durvalumab.
  • HCC hepatocellular carcinoma
  • the subject has not previously received treatment for the HCC, e.g.. previous systemic treatment, prior to treatment with tivozanib and durvalumab.
  • the disclosure provides methods of treating a subject having hepatocellular carcinoma (HCC), such as advanced HCC, with an effective amount of tivozanib and an effective amount of durvalumab, thereby to treat the HCC, where the subject experiences a progression free survival of at least seven months upon receiving the treatment with tivozanib and durvalumab.
  • HCC hepatocellular carcinoma
  • the subject has not previously received treatment for the HCC, e.g., previous systemic treatment, prior to treatment with tivozanib and durvalumab,
  • the disclosure provides methods of treating a subject having hepatocellular carcinoma (HCC), such as advanced HCC, with an effective amount of tivozanib and an effective amount of durvalumab, thereby to treat the HCC, where the subject experiences a progression free survival of at least six months upon receiving the treatment with tivozanib and durvalumab.
  • HCC hepatocellular carcinoma
  • the subject previously received treatment for the HCC with bevacizumab and atezolizumab, prior to treatment with tivozanib and durvalumab.
  • the disclosure provides methods of treating a subject having hepatocellular carcinoma (HCC), such as advanced HCC, with an effective amount of tivozanib and an effective amount of durvalumab, thereby to treat the HCC, where the subject experiences a progression free survival of at least seven months upon receiving the treatment with tivozanib and durvalumab.
  • HCC hepatocellular carcinoma
  • the subject previously received treatment for the HCC with bevacizumab and atezolizumab, prior to treatment with tivozanib and durvalumab.
  • the disclosure provides methods of treating a subject having hepatocellular carcinoma (HCC), such as advanced HCC, with an effective amount of tivozanib and an effective amount of durvalumab, thereby to treat the HCC, where the subject experiences a progression free survival of at least six months upon receiving the treatment with tivozanib and durvalumab.
  • HCC hepatocellular carcinoma
  • the subject previously received treatment for the HCC with a VEGF inhibitor and a checkpoint inhibitor, prior to treatment with tivozanib and durvalumab.
  • the disclosure provides methods of treating a subject having hepatocellular carcinoma (HCC), such as advanced HCC, with an effective amount of tivozanib and an effective amount of durvalumab, thereby to treat the HCC, where the subject experiences a progression free survival of at least seven months upon receiving the treatment with tivozanib and durvalumab.
  • HCC hepatocellular carcinoma
  • the subject previously received treatment for the HCC with a VEGF inhibitor and a checkpoint inhibitor, prior to treatment with tivozanib and durvalumab.
  • VEGF TKI if the subject has previously received systemic therapy with a VEGF TKI and/or an immune checkpoint inhibitor to treat the HCC, then (a) the VEGF TKI is not tivozanib; (b) the immune checkpoint inhibitor is not durvalumab; or (c) the VEGF TKI is not tivozanib and the immune checkpoint inhibitor is not durvalumab.
  • the subject is treated with tivozanib and durvalumab so long as a clinical benefit is observed in the subject or until unacceptable toxicity occurs.
  • the subject receives treatment until the subject experiences a complete response, or until the subject experiences progression of the HCC, or until a physician elects to discontinue the therapy
  • the subject receives treatment with tivozanib and durvalumab so iong as the subject experiences a partial response while receiving the treatment or experiences stable disease while receiving the treatment.
  • a subject having HCC for example, advanced HCC, who is treated with tivozanib and durvalumab according to the disclosed methods experiences a progression free survival of at least 6.0, 6.1, 6.2, 6.2, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2,
  • the subject has a survival time of at least 10.0, 10.1,
  • the treatment is discontinued, for example, due to unacceptable toxicity, lack of response, or disease progression, but the subject survives for a period of time beyond the time the treatment is discontinued.
  • a subject having HCC who is treated with tivozanib and durvalurnab according to the disclosed methods, where the subject has not previously received treatment, e.g. , systemic treatment, for the HCC experiences a progression free survival of at least 6.0, 6.1 , 6.2, 6.2, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6,
  • the subject has a survival time of at least 10.0, 10, 1 , 10.2, 10.3, 10.4,
  • the treatment is discontinued, for example, due to unacceptable toxicity, lack of response, or disease progression, but the subject survives for a period of time beyond the time the treatment is discontinued.
  • a subject having HCC who is treated with tivozanib and durvalumab according to the disclosed methods, where the subject has received previous treatment for the HCC e.g., systemic treatment, such as a VEGF inhibitor and/or a checkpoint inhibitor experiences a progression free survival of at least 6,0, 6.1, 6.2, 6.2, 6.4,
  • the subject has a survival time of at least 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, I I .1, 11.2, 11.3, 11.4, 1 1.5, 11.6, 11.7, 11.8, 1 1.9, 12.0, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6,
  • the treatment is discontinued, for example, due to unacceptable toxicity, lack of response, or disease progression, but the subject survives for a period of time beyond the time the treatment is discontinued.
  • a subject having HCC who is treated with tivozanib and durvalumab according to the disclosed methods, where the subject has received previous treatment with bevacizumab in combination atezolizumab for the HCC experiences a progression free survival of at least 6.0, 6.1, 6.2, 6.2, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2,
  • the subject has a survival time of at least 10.0, 10.1,
  • the treatment is discontinued, for example, due to unacceptable toxicity, lack of response, or disease progression, but the subject survives for a period of time beyond the time the treatment is discontinued.
  • a population of subjects having HCC who are treated with tivozanib and durvalumab according to the disclosed methods experience a median progression free survival of at least 6.0, 6.1 , 6.2, 6.2, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1 , 7.2,
  • the population of subjects experiences a median overall survival of at least 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1,
  • the population of subjects experiences a median overall survival of at least 10.0, 10.1 , 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 1 1.0, 11.1, 11.2, 11.3, 1 1.4, 11.5, 11.6, 11.7, 1 1.8, 1 1.9, 12.0, 12.1 , 12.2, 12.3, 12.4, 12.5,
  • a population of subjects having HCC who are treated with tivozanib and durvalumab according to the disclosed methods, where the subjects have previous! ⁇ ' received treatment for the HCC e.g., systemic treatment, such as a VEGF inhibitor and/or a.
  • checkpoint inhibitor experiences a median progression free survival of at least 6.0, 6.1, 6.2, 6.2, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0,
  • the population of subjects experiences a median overall survival of at least 10.0, 10.1 , 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 1 1.0, 1 1.1, 1 1 .2, 11.3, 1 1.4, 1 1.5,
  • a population of subjects having HCC who is treated with tivozanib and durvalumab according to the disclosed methods, where the subjects have previously received treatment with bevacizumab and atezolizumab for the HCC experiences a median progression free survival of at least 6.0, 6.1, 6.2, 6.2, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0,
  • the population of subjects experiences a median overall survival of at least 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3, 1 1.4, 11.5, 11.6, 11.7, 1 1.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4, 12.5,
  • the population of subjects with HCC has 7, 8, 9, 10, 11, 12,
  • Exemplary effective amounts, dosages, or treatment regimens of tivozanib include 0.5-3 mg, 0.5-2 mg, 1-3 mg, 0.5-1.5 mg, 1.0-2.0 mg, 1.0-1.5 mg. 1.4-1.6 mg, 0.8-0.9 mg, 0.9-1.0 mg, 0.9-1. 1 mg, 1, 0-1.1 mg, 1.1-1.2 mg, 1.2-1.3 mg, 1.3-1.4 mg, 1.4-1.5 mg, 1.4-1.6 mg, 1.5-1.6 mg, 1.6-1.7 mg, 1.7-1.8 mg, 1.8-1.9 mg, 1.8-2.0 mg or 1.9-2.0 mg daily or every other day.
  • the dose of tivozanib is 1 .5 mg.
  • the dose of tivozanib is 1.34 mg.
  • the dose of tivozanib is 1 mg.
  • the dose of tivozanib is 0.89 mg.
  • the amount of tivozanib administered will depend on variables such as the type and extent of disease or indication to be treated, the overall health of the patient, the pharmaceutical formulation, and the route of administration.
  • the initial dosage can be increased beyond the upper level in order to rapidly achieve the desired blood-level or tissuelevel. Alternatively, the initial dosage can be smaller than the optimum, and the daily dosage may be progressively increased during the course of treatment.
  • Human dosage can be optimized, e.g., in a conventional Phase I dose escalation study. Dosing frequency can vary, depending on factors such as route of administration, dosage amount, and the disease being treated.
  • Exemplary dosing frequencies for tivozanib are once per day, once every other day, once every' three days, once every' four days, once every' five days, once every' six days, once per week and once every’ two weeks.
  • the dosing frequency is every' day for 21 days with 7 days off, that is, administration on days 1-21 of a 28 day treatment cycle, with no administration on days 22-28.
  • the dosing frequency is every' day' for 28 days.
  • the dosing frequency is every' other day' for 28 days.
  • the dosing frequency is every' other day' for 28 days beginning on day one of a 28 day treatment cycle.
  • the dosage of tivozanib is 1.5 mg daily. In another embodiment, the dosage is 1.0 mg daily. Additional exemplary' effective amounts, dosages, or treatment regimens of tivozanib are described in U.S. Patent Nos. 6,821,987, and 7,166,722 and in International Patent Application No. WO 2020/097106. [0105] According to one embodiment, the dosage is 1.0 mg daily of tivozanib hydrochloride (equivalent to 0.89 mg tivozanib free base). According to another embodiment, the dosage is 1.5 mg daily of tivozanib hydrochloride (equivalent to 1.34 mg tivozanib free base). In one embodiment, the dose is 1.34 mg daily of tivozanib free base. In another embodiment, the dose is 0.89 mg daily of tivozanib free base.
  • the dose of tivozanib is 1.5 mg (1.34 mg tivozanib free base) daily for 21 days followed by seven days off (i.e., 0 mg tivozanib for 7 days).
  • a 1.5 mg daily dose of tivozanib (1.34 mg tivozanib free base) for 21 days is reduced to 1.0 mg (0.89 mg tivozanib free base) daily for 21 days when a subject experiences a > Grade 3 drug-related adverse event.
  • a 1.5 mg daily dose of tivozanib (1.34 mg tivozanib free base) for 21 days is reduced to 1.0 mg (0.89 mg tivozanib free base) every other day for 28 days when a subject experiences a> Grade 3 drug-related adverse event.
  • the dose of tivozanib is 1.0 mg daily (0.89 mg tivozanib free base) for 21 days followed by seven days off (i.e., 0 mg tivozanib for 7 days).
  • a 1.0 mg daily dose of tivozanib (0.89 mg tivozanib free base) for 21 days is reduced to 1.0 mg (0.89 mg tivozanib free base) every 7 other day for 28 days when a subject experiences a> Grade 3 drug-related adverse event.
  • the dose is 1.5 mg daily of tivozanib hydrochloride administered for 21 days followed by 7 days without administration, which constitutes a treatment cycle. In one embodiment, the dose is 1.0 mg daily of tivozanib hydrochloride administered for 21 days followed by 7 days without administration, which constitutes a treatment cycle. In one embodiment, the dose is 1.0 mg daily of tivozanib hydrochloride administered for 2.8 days, which constitutes a treatment cycle. In one embodiment, the dose is 1.0 mg of tivozanib hydrochloride administered every other day for 28 days, which constitutes a treatment cycle. In one embodiment, the dose is 1.5 mg every' other day of tivozanib hydrochloride administered for 28 days, which constitutes a treatment cycle.
  • Tivozanib may be administered as an oral tablet or capsule or as an intravenous (IV) infusion.
  • IV intravenous
  • the dosage of tivozanib maybe provided in a single capsule or tablet or in two or more capsules or tablets.
  • tivozanib is administered as a single dose tablet.
  • tivozanib is administered as a tablet or capsule.
  • Exemplary effective amounts, dosages, or treatment regimens of tivozanib include administration on a repeating schedule of one dose (e.g, a single dosage contains 0.5-2.0 mg of tivozanib) per day for three weeks, followed by one week off (i.e., 3 weeks on, 1 week off).
  • tivozanib may be administered on a repeating schedule of 0.5-3 mg, 0.5-2 mg, 0.5-1.5 mg, 1.0-3.0 mg, 1 .0-2.0 mg, 1.0-1 .5 mg, or 1.4-1.6 mg per day for three weeks, followed by one week off (i.e., 3 -weeks on, 1 week off). The period of time beginning from Day 1 of administration to the last day of the week off may be referred to as a treatment cycle.
  • tivozanib may be administered as one dose (e.g., a single dosage contains 0.5-2.0 mg of tivozanib) per day.
  • tivozanib may be administered at a dose of 0.5-3 mg, 0.5-2 mg, 0,5-1.5 mg, 1.0-3.0 mg, 1.0-2.0 mg, 1.0-1, 5 mg or 1.4-1.6 mg, 1 mg, or 1.5 mg daily.
  • tivozanib is administered in an amount of 1.5 mg per day. In another embodiment, tivozanib is administered in an amount of 1.0 mg per day. In another embodiment, tivozanib is administered in an amount of 1.5 mg per day every day for three weeks (i.e., 21 days), followed by one week (i.e., 7 days) with no dose of tivozanib (i.e., 3 weeks on, 1 week off), where three weeks on tivozanib and one week off constitutes a 4 week (28 day) treatment cycle.
  • tivozanib is orally administered in an amount of 1.5 mg daily as a single dose for three weeks, followed by one week off. In another embodiment, tivozanib is administered orally in an amount of 1.0 mg daily as a single dose for three weeks, followed by one week without administration of tivozanib. According to these embodiments, three weeks “on” and one week “off” constitutes a 4 w r eek (28 day) treatment cycle.
  • tivozanib is orally administered in an amount of 1.0 mg every other day for 4 weeks (i.e., 28 days), which constitutes a treatment cycle. In another embodiment, tivozanib is orally administered in an amount of 1.0 mg every’ day for 3 weeks followed by one week off, which constitutes a 28 day treatment cycle.
  • tivozanib is orally administered in an amount of 1.5 mg daily and reduced to 1,0 mg daily when the subject experiences a> Grade 3 drug-related adverse event in the treatment of HCC.
  • the administration period for tivozanib is three weeks (starting from the first 1.5 nig dose), followed by one week without administration of tivozanib.
  • three weeks on and one week off constitutes a 4-week (28 day) treatment cycle.
  • tivozanib is orally administered in an amount of 1.0 mg daily for three weeks, followed by one week off, and reduced to 1.0 mg every' other day when the subject experiences a > Grade 3 drug-related adverse event in the treatment of HCC.
  • the administration period for tivozanib is three weeks (starting from the first 1.0 mg dose), followed by one week without administration of tivozanib.
  • three weeks on (administration from day 1-21) and one week off (no administration on days 22-28) constitutes a 4-week (28 day) treatment cycle.
  • a subject undergoes one, two, three, four, five, six, seven, eight, nine, ten, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 2.5, 26, 27, 28, 29, 30, or more treatment cycles of tivozanib, for example, where the treatment cycle is a four week (28 day) treatment cycle of tivozanib.
  • a treatment cycle (for example, a four-week treatment cycle) is repeated as long as the subject experiences a clinical benefit or until the subject experiences unacceptable toxicity.
  • tivozanib is administered as a capsule.
  • the capsule contains gelatin or gelatin and titanium dioxide.
  • tivozanib is formulated as a pharmaceutical composition with mannitol and magnesium stearate.
  • other pharmaceutically acceptable carriers may be used.
  • Exemplary' effective amounts, dosages, or treatment regimens durvalumab include 200-2,000 mg, 500-1,500 mg, 750-1,250 mg, 1,000-2,000 mg, or 1,2.50-750 mg.
  • the dose of durvalumab is 1,500 nig.
  • a subject receives a fixed dose of 1 ,500 nig durvalumab once every 28 days.
  • a subject receives a fixed dose of 1 ,500 mg durvalumab if the subject’s weight is greater than 30 kg.
  • the amount of durvalumab administered will depend on variables such as the type and extent of disease or indication to be treated, the overall health and weight of the patient, the pharmaceutical formulation, and the route of administration.
  • the initial dosage can be increased beyond the upper level in order to rapidly achieve the desired blood-level or tissuelevel. Alternatively, the initial dosage can be smaller than the optimum, and the daily dosage may be progressively increased during the course of treatment.
  • Human dosage can be optimized, e.g., in a conventional Phase I dose escalation study. Dosing frequency can vary, depending on factors such as route of administration, dosage amount, and the disease being treated.
  • Exemplary dosing frequencies for durvalumab are once ever ⁇ ' 28 days (4 weeks), once every three weeks (21 days), once ever ⁇ ' two weeks (14 days), or once every week (7 days).
  • durvalumab is administered once every 28 days, that is, on day 1 of a 28 day treatment cycle, where no durvalumab is administered on days 2-28.
  • durvalumab is administered once every 14 days (2 weeks), that is, on day 1 of a 14 day treatment cycle, where no durvalumab is administered on days 2-14.
  • durvalumab is administered once every 14 days (2 weeks), that is, on days 1 and 15 of a 28 day treatment cycle, where no durvalumab is administered on days 2-14 and 16-28. In another embodiment, durvalumab is administered once ever ⁇ ' 21 days (3 weeks), that is, on day 1 of a 21 day treatment cycle, where no durvalumab is administered on days 2-2.1.
  • the dosage of durvalumab is determined based on the weight of the subject to which the durvalumab is being administered.
  • exemplary dosages of durvalumab are 1-100 mg/kg, 50-100 mg/kg, 50 -75 mg/kg, 20-40 mg/kg, 15-35 mg/kg, 10-30 mg/kg, or 5-15 mg/kg.
  • the dose of durvalumab is 20 mg/kg.
  • the dose of durvalumab is 10 mg/kg.
  • a subject receives 20 mg/kg of durvalumab once even' 28 days, e.g., on day 1 of a 28 day treatment cycle.
  • a subject receives 10 mg/kg of durvalumab once every 14 days, e.g., on day 1 of a 14 day treatment cycle, or on days 1 and 15 of a 28 day treatment cycle.
  • a subject’s weight is at or below 30 kg ( ⁇ 30 kg)
  • the subject receives weight-based dosing equivalent to 10 mg/kg of durvalumab.
  • the subject receives weight-based dosing equivalent to 10 mg/kg of durvalumab, whereas if the subject’s weight is greater than 30 kg, the subject receives a fixed dose of 1,500 mg of durvalumab.
  • a subject’s weight is at or below 30 kg ( ⁇ 30 kg)
  • the subject receives weight-based dosing equivalent to 10 mg/kg of durvalumab once every 14 days, whereas if the subject’s weight is greater than 30 kg, the subject receives a fixed dose of 1,500 mg of durvalumab once every 28 days.
  • the subject receives weight-based dosing equivalent to 20 mg/kg of durvalumab.
  • a subject’s weight is at or below' 30 kg ( ⁇ 30 kg)
  • the subject receives weight-based dosing equivalent to 20 mg/kg of durvalumab
  • the subject receives a fixed dose of 1 ,500 mg of durvalumab.
  • a subject’s weight is at or below 30 kg ( ⁇ 30 kg)
  • the subject receives weight-based dosing equivalent to 20 mg/kg of durvalumab once every 28 days (e.g., on day 1 of a 28 day treatment cycle)
  • the subject receives a fixed dose of 1 ,500 mg of durvalumab once every 28 days (e.g., on day 1 of a 28 day treatment cycle).
  • a subject’s weight is at or below' 30 kg ( ⁇ 30 kg)
  • the subject receives weight-based dosing equivalent to 20 mg/kg every three weeks (21 days) for four cycles followed by 10 mg/kg every 2 weeks thereafter
  • the subject receives 1,500 mg even' three weeks for four cycles followed by 1,500 mg every four weeks thereafter.
  • a disclosed method comprises administering durvalumab at a dose of 1,500 mg on day 1 followed by no administration of durvalumab on days 2-28.
  • a subject is administered 1,500 mg of durvalumab on day 1 of a 28 day treatment cycle followed by no administration of durvalumab on days 2-28, and the subject is administered 1.0 mg tivozanib (0.89 tivozanib free base) on days 1-21 of the 28 day treatment cycle and is administered no tivozanib on days 22-28 to treat HCC, e.g., advanced HCC, in the subject.
  • the durvalumab is administered intravenously, while the tivozanib is administered orally as a capsule or tablet.
  • the tivozanib and durvalumab are administered as a first systemic therapy to a subject with HCC that has not previously been treated with a systemic therapy.
  • the tivozanib and durvalumab are administered as a second or later line systemic therapy to a subject with HCC that has been previously treated with systemic therapy, for example, a VEGF inhibitor and/or a checkpoint inhibitor, e.g., sorafenib, or e.g., bevacizumab and atezolizumab.
  • the treatment cycle is repeated as many times as necessary' until the patient experiences an unacceptable toxicity' or progresses.
  • a subject is administered 1,500 mg of durvalumab on day 1 of a 28 day treatment cycle followed by no administration of durvalumab on days 2-28, and the subject is administered 1.0 mg tivozanib (0.89 tivozanib free base) on day 1 and every other day thereafter of the 28 day treatment cycle to treat HCC, e.g., advanced HCC, in the subject.
  • the durvalumab is administered intravenously, while the tivozanib is administered orally as a capsule or tablet.
  • the tivozanib and durvalumab are administered as a first line systemic therapy to a subject with HCC that has not previously been treated with a systemic therapy.
  • the tivozanib and durvalumab are administered as a second or later line systemic therapy to a subject with HCC that has been previously treated with systemic therapy, for example, a VEGF inhibitor and'' or a checkpoint inhibitor, e.g., sorafenib, or e.g., bevacizumab and atezolizumab.
  • systemic therapy for example, a VEGF inhibitor and'' or a checkpoint inhibitor, e.g., sorafenib, or e.g., bevacizumab and atezolizumab.
  • the treatment cycle is repeated as many times as necessary until the patient experiences an unacceptable toxicity' or progresses.
  • a subject e.g, a subject weighing 30 kg or less, is administered 20 nig/kg of durvalumab on day 1 of a 28 day treatment cycle followed by no administration of durvalumab on days 2-28, and the subject is administered 1 .0 mg tivozanib (0.89 tivozanib free base) on days 1-21 of the 28 day’ treatment cycle and is administered no tivozanib on days 22-28 to treat HCC, e.g., advanced HCC, in the subject.
  • the durvalumab is administered intravenously, wftile the tivozanib is administered orally as a capsule or tablet.
  • the tivozanib and durvalumab are administered as a first systemic therapy’ to a subject with HCC that has not previously been treated with a systemic therapy.
  • the tivozanib and durvalumab are administered as a second or later line systemic therapy to a subject with HCC that has been previously treated with systemic therapy, for example, a VEGF inhibitor and/or a checkpoint inhibitor, e.g, sorafenib, or e.g. bevacizumab and atezolizumab.
  • the treatment cycle is repeated as many times as necessary until the patient experiences an unacceptable toxicity' or progresses.
  • a subject e.g, a subject weighing 30 kg or less, is administered 20 nig/kg of durvalumab on day 1 of a 28 day treatment cycle followed by no administration of durvalumab on days 2-28, and the subject is administered 1 .0 mg tivozanib (0.89 tivozanib free base) on day 1 and every other day thereafter of the 28 day treatment cycle to treat HCC, e.g, advanced HCC, in the subject.
  • the durvalumab is administered intravenously , while the tivozanib is administered orally as a capsule or tablet.
  • the tivozanib and durvalumab are administered as a first systemic therapy to a subject with HCC that has not previously been treated with a systemic therapy.
  • the tivozanib and durvalumab are administered as a second or later line systemic therapy to a subject with HCC that has been previously treated with systemic therapy, for example, a VEGF inhibitor and/or a checkpoint inhibitor, e.g., sorafenib, or e.g., bevacizumab and atezolizumab.
  • the treatment cycle is repeated as many times as necessary until the patient experiences an unacceptable toxicity or progresses.
  • the durvalumab may be administered as an as an intravenous (IV) infusion, for example, over a period of 60 minutes and/or at a concentration of 10- 100 mg/mL.
  • the concentration of the durvalumab formulation is 50 mg/mL.
  • durvalumab at a concentration of 50 mg/mL is added to an infusion solution of 0.9% sodium chloride injection, USP or 5% dextrose injection USP and diluted to a final concentration of between 1 mg/mL and 15 mg/mL prior to administration to the subject.
  • a subject undergoes one, two, three, four, five, six, seven, eight, nine, ten, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, or more treatment cycles of durvalumab and tivozanib.
  • a treatment cycle (for example, a four-week treatment cycle) is repeated as long as the subject experiences a clinical benefit or until the subject experiences unacceptable toxicity,
  • Example 1 A Phase lb/2, Open-Label, Study of Tivozanib in Combination with Durvalumab in Subjects with Advanced Hepatocellular Carcinoma
  • Sexually active pre-menopausal female subjects must use highly effective contraceptive measures while on study and for at least 90 days after the last dose of study drug.
  • sexually active male subjects must use adequate contraceptive measures, while on study and for at least 90 days after the last dose of study drug. All fertile male and female subjects and their partners must agree to use a highly effective method of contraception.
  • Brain metastases or spinal cord compression Subjects with suspected brain metastases at screening should have an MRI (preferred) or CT scan each preferable with IV contrast of the brain prior to study entry'. Brain metastases will not be recorded on RECIST Target Lesions at baseline.
  • GI Bleeding e.g., esophageal varices or ulcer bleeding
  • Vp4 Mam portal vein thrombosis (Vp4) as documented on imaging.
  • VP4 is defined as portal vein thrombosis in the main trunk of the portal vein or a portal vein branch contralateral to the primarily involved lobe (or both).
  • HBV and HCVHBV positive Patients co-infected with HBV and HCVHBV positive [presence of hepatitis B surface antigen (HBsAg) and/or hepatitis B core antibodies (anti-HBcAb) with detectable HBV ONA (>10I U/ml)]; HCV positive (presence of anti-HCV antibodies).
  • HBV positive Presence of anti-HCV antibodies.
  • Major surgery' as defined by the Investigator
  • Local procedures e.g., core needle biopsy, and prostate biopsy are allowed if completed at least 3 days prior to the administration of the first dose of study treatment.
  • LVEF left ventricular ejection fraction
  • o Any New York Heart Association classification > Class 2 (prefer Class 0 or 1)
  • o Any stenting procedure within the last 3 months o Venous thromboembolism or arterial thromboembolism within the last 3 months o Any IV C tumor thrombosis o Histoty of a hemorrhagic event (GI bleed within 6 months)
  • Uncontrolled hypertension blood pressure >150/95 mmHg on more than 2 antihypertensive medications, on two consecutive measurements obtained at least 24 hours apart.
  • Subjects with a history of hypertension must have been on stable doses of anti-hypertensive drugs for > 2 weeks prior to start of protocol therapy o Myocardial infarction within 3 months prior to start of protocol therapy
  • HCV hepatitis C
  • HBV DN A Patients with a history' or current HBV infection (detectable HBV DN A), should be placed on anti-viral treatment and tested at every cycle for HBV DNA viral load.
  • Prior exposure to tivozanib or durvalumab For subjects who have received prior atezolizumab: o Must not have experienced a toxicity that led to permanent discontinuation of prior immunotherapy o All AEs while receiving prior immunotherapy must have completely resolved or resolved to baseline prior to screening for this study o Must not have experienced a Grade > 3 immune-related AE or an immune- related neurologic or ocular AE of any grade while receiving prior immunotherapy. Participants with an endocrine AE of Grade ⁇ 2 are permitted to enroll if they are stably maintained on appropriate replacement therapy and are asymptomatic.
  • autoimmune or inflammatory' disorders including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis. Graves’ disease, rheumatoid arthritis, hypophysitis, uveitis, e/c,]).
  • Uncontrolled intercurrent illness including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, active interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the subject to give written informed consent
  • a modification of the “3 + 3” schema was used during the dose finding phase. Six subjects were treated at the same dose (Dose Level 1). If ⁇ 2 of the 6 subjects treated experience a DLT within Cycle 1, the trial would continue to the dose expansion phase. If > 2 of the 6 subjects experience a DLT at the Dose Level I the study would proceed to Dose Level -1. If > 2 of the 6 subjects experience a DLT at the Dose Level -1 within Cycle 1 , the study would close.
  • the combination would be considered safe for further study if ⁇ 2 of 6 subjects experience a DLT during the first cycle (28 days) of the dose finding phase of the study.
  • Tivozanib (previously known as AV-951 ) is a potent VEGF-TKI.
  • the tivozanib drug product was a capsule containing 1.0 mg of tivozanib hydrochloride salt equivalent to 0.89 mg of tivozanib free base. Any reference to tivozanib 1.0 mg is to be understood as 1.0 mg of tivozanib hydrochloride salt which is equivalent to 0.89 mg of tivozanib free base.
  • DLT dose-limiting toxicity
  • Tivozanib dose reduction was recommended for subjects with > Grade 3 adverse events. Tivozanib should be held for grade 4 adverse events. For patients on dose level 1 for whom dose reduction is required, the dose of tivozanib should be reduced to .89 mg every other day. If this dose was not tolerated, then tivozanib should be discontinued.
  • Durvalumab is a human mAb of the IgG 1 kappa subclass that blocks the interaction of PD-L1 (but not programmed cell death ligand-2) with PD 1 on T cells and CD80 (B7.1) on immune cells.
  • Durvalumab solution for infusion after dilution was supplied in glass vials containing 500 mg durvalumab at a concentration of 50 mg/mL.
  • the solution contained 50 mg/mL durvalumab.
  • the label-claim volume was 10 ml...
  • durvalumab (1,500 mg even' 28 days) was administered as an intravenous infusion over 60 minutes.
  • Tivozanib or durvalumab may be interrupted independently of each other. If tivozanib or durvalumab was interrupted, treatment with the other therapy (durvalumab or tivozanib, respectively) may continue as scheduled. [0161] Subjects with documented stable disease (SD) or an objective response (complete response [CR] or partial response [PR]) may continue to receive treatment at the same dose and schedule until progression if tolerability is acceptable.
  • SD stable disease
  • CR complete response
  • PR partial response
  • a Dose-Limiting Toxicity was generally defined as the occurrence of any Grade >3 immune or non-immune adverse event (AE) in Cycle 1 that is at least possibly related to the study drug or investigational regimen with 2 exceptions: any grade of vitiligo, alopecia or grade 3 controllable hypertension will not qualify as a DLT.
  • Adverse events that are at least possibly related to durvalumab-containing regimens were assessed as DLTs if they met any of the following specific criteria:
  • ALT aminotransferase
  • AST aspaitate aminotransferase
  • DLT dose-limiting toxicity
  • imAE immmune AE
  • ULN upper limit of normal
  • NCI CTCAE (Version 5.0) was used to grade toxicities occurring during this trial.
  • Subjects experiencing DLTs during Cycle 1 were generally discontinued from further participation in the study but may have continued at a reduced dose (tivozanib only; durvalumab must be interrupted or discontinued) if there was evidence of an objective response or other clinical benefit.
  • the dose expansion phase dose was determined from the cohorts in dose modification of the study.
  • the MTD was the dose at which ⁇ 2 of 6 subjects experience a DLT during the first cycle (2.8 days).
  • An adverse event was defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation subject administered an investigational (medicinal) product and that does not necessarily have a causal relationship with this treatment.
  • An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of investigational product, whether or not considered related to the investigational product.
  • Adverse events included the following types of occurrences:
  • Adverse events were spontaneously reported or elicited during open-ended questioning, examination, or evaluation of a subject.
  • a general grading (severity/intensity) scale is provided at the beginning of the NCI-CTCAE document, and specific event grades are also provided. If a particular AEs severity/intensity is not specifically graded by the guidance document, the Investigator is to revert to the general definitions of Grade I through Grade 5 and use his or her best medical judgment.
  • SAE serious adverse event
  • Is life-threatening defined as an event in which the subject was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more se vere).
  • Is a congenital anomaly /birth defect * Is an important medical event, defined as a medical event(s) that may not be immediately life-threatening or result in death or hospitalization but, based upon appropriate medical and scientific judgment, may jeopardize the subject or may require intervention (e.g., medical, surgical) to prevent one of the other serious outcomes listed in the definition above. Examples of such events include, but are not limited to, intensive treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization.) Potential drug induced liver injury (DILI) is also considered an important medical event. [0177] Suspected transmission of an infectious agent (e.g.
  • New primary 1 cancers are those that are not the primary reason for administration of the study drug and have been identified after the subject’s inclusion in the study.
  • Routine health assessment requiring admission for baseline/trending of health status (e.g., routine colonoscopy).
  • Admission encountered for another life circumstance that carries no bearing on health status and requires no medical/surgical intervention e.g., lack of housing, economic inadequacy, caregiver respite, family circumstances, administrative reason).
  • Subjects experiencing unacceptable toxicities or with confirmed disease progression at any time during the study were discontinued from study treatment. Subjects needing to discontinue durvalumab or tivozanib may have continued treatment with the other drug until disease progression.
  • Once discontinued all subjects were followed for evidence of delayed effects of study drug for 90 days post last dose of study drug. Any adverse events that were thought to be related to study drug that were ongoing at the 30-day follow-up visit were followed through resolution or stabilization or up to a maximum of 90 days post last dose of study drug (whichever comes first). All subjects were followed for date of death.
  • Disease assessment included disease classification (including details of the primary' diagnosis and histological/cytological type and stage of disease) and diagnostic imaging / measurement of target lesions. Subjects were evaluated with the same method of assessment and the same imaging technique throughout the study. Computerized tomography and/or MRI were considered the standard methods for evaluating disease status. The location and dimensions of “target” lesions were determined when possible. Response assessment and updates were performed using criteria outlined in RECIST 1.1.
  • the duration of the response was determined from the day 7 the initial response is observed (using screening/basehne images for comparison) to the day that progression is observed. Duration of disease stabilization w-as also assessed,
  • phase lb dose-escalation portion of the study enrolled n 7 previously untreated subjects.
  • the recommended phase 2 dose (RP2D) of tivozanib was 0.89 mg (equivalent to 1 mg commercially available tivozanib hydrochloride) orally once daily for 21 days followed by 7 days off combined with durvaluniab 1,500 mg administered intravenously every' 4 weeks (i.e., once every' 28 days on day 1).
  • the combination of tivozanib with durvalumab was found to be well tolerated in advanced HCC subjects.
  • Cohort A untreated
  • Cohort B prior treatment with both bevacizumab and atezolizumab
  • TABLE 2 and TABLE 3 depict safety and tolerability results for the subjects in
  • FIG. 2 depicts the best overall response and treatment duration for the indicated subjects. Results demonstrated a median PFS of 7.3 months and a 1-year OS of 76%.
  • the tivozanib/durvaiumab combination is especially promising given that the results presented herein show' the combination has been well tolerated in HCC patients in the study to date and the observed safety profile w'as consistent with the known profile of both agents, whereas toxic side effects were noted in 38% of patients receiving the combination of bevacizurnab and atezolizumab in its previous Phase III study.

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Abstract

Disclosed herein are methods directed to treating hepatocellular carcinoma with tivozanib and durvalumab in combination.

Description

LISE OF TIVOZANIB AND DURVALUMAB FOR TREATING HEPATOCELLULAR
CARCINOMA (HCC)
FIELD OF THE INVENTION
[0001] The field of the invention is medicine, oncology, and the treatment of hepatocellular carcinoma.
BACKGROUND
[0002] Tivozanib is a potent and selective small -molecule vascular endothelial growth factor (VEGF) receptor (VEGFR) tyrosine kinase inhibitor (VEGF TKI) that has been approved by the European Medicines Agency and U.S. Food and Drug Administration for the treatment of advanced or refractory renal cell carcinoma (RCC). In vitro cellular kinase assays have demonstrated that tivozanib inhibits phosphorylation of VEGFR-1, VEGFR-2 and VEGFR-3 and inhibits other kinases including c~kit and PDGFR p at clinically relevant concentrations. In tumor xenograft models in mice and rats, tivozanib inhibited angiogenesis, vascular permeability, and tumor growth of various tumor cell types.
[0003] Durvalumab is a human monoclonal antibody that blocks the interaction of PD-Ll with PD-1 on T cells and CD80 (B7.1) on immune cells. Interaction between PD-1 and PD-Ll normally results in the inhibition of the cellular immune response. Durvalumab is approved for the treatment of metastatic urothelial carcinoma and non-small cell lung cancer.
[0004] Approximately 42,000 new cases of hepatocellular carcinoma (HCC) are diagnosed annually in North America resulting in approximately 30,000 deaths (American Cancer Society, 2021). Advanced HCC is highly resistant to chemotherapy, and approved treatments are limited. Sorafenib, a non-specific VEGF TKI has been the standard first line treatment. Despite the advances made to date, there still exists a need for additional treatments for HCC.
SUMMARY OF THE INVENTION
[0005] The present disclosure provides improved methods for treating subjects with hepatocellular carcinoma by administering tivozanib and durvalumab in combination.
[0006] In one aspect, the disclosure provides a method of treating a hepatocellular carcinoma (HCC) in a subject in need thereof. The method comprises administering to the subject a treatment regimen comprising an effective amount of tivozanib and an effective amount of durvalumab thereby to treat the HCC in the subject. In some embodiments, the subject experiences a progression free survival of at least 7 months upon receiving the treatment regimen. In some embodiments, when the treatment regimen is administered to subjects having HCC, the subjects experience a median progression free survival of at least 7 months upon receiving the treatment regimen.
[0007^ In certain embodiments, the subject experiences a progression free survival of at least 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 2.3, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, or 48 months upon receiving the treatment regimen. In certain embodiments, the subject has a survival time of at least 13 months from the start of treatment,
[0008] In certain embodiments, when the treatment regimen is administered to subjects having HCC, the subjects experience a median progression free survival of at least 7.1, 7.2,
7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1 , 9.2, 9.3,
9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, or 48 months upon receiving the treatment regimen. In certain embodiments, the subjects experience a median overall survival of at least 13 months from the start of treatment.
[0009] The HCC can be advanced and/or metastatic HCC.
[0010] In certain embodiments, the subject has not previously received treatment for the HCC, e.g, systemic therapy to treat the HCC. For example, under certain circumstances, the subject has not previously received chemotherapy treatment for the HCC and/or the subject has not previously received a checkpoint inhibitor to treat the HCC. Accordingly, in some embodiments, the treatment regimen of tivozanib and durvalumab is a first line systemic therapy for the HCC in the subject.
[0011] In certain embodiments, the subject has previously received treatment for the HCC. For example, the treatment regimen of tivozanib and durvalumab is a second or later line systemic therapy to treat the HCC in the subject. Hie previous treatment can include treatment with a VEGF inhibitor, e.g., bevacizumab or a VEGF TKI, e.g, sorafenib, regorafenib, cabozantinib, or lenvantmib. Alternatively, the VEGF TKI is nintedanib, anlotinib, fruquintinib, apatinib, sunitinib, pazopanib, axitinib, dasatmib, nilotinib, motesanib, deciramb, donafenib, vandetanib, or sulfatinib. [0012] In certain embodiments, the subject has previously been treated with a checkpoint inhibitor, e.g, aPD-1 or PD-L1 inhibitor. For example, in certain embodiments, the subject has been previously treated with atezolizumab, or with pembrolizumab and/or ipilimumab, or with nivolumab and/or ipilimumab.
[0013] In certain embodiments, the subject has previously been treated with a VEGF inhibitor and a checkpoint inhibitor, e.g., bevacizumab and atezolizumab, to treat the HCC.
[0014] In certain embodiments, the treatment regimen comprises one or more treatment cycles of 28 days in duration. In certain embodiments, a treatment cycle involves administering trv ozanib at a dose of 1 mg per day on days 1-21 of the treatment cycle followed by no administration of tiv ozanib on days 22-28 of the treatment cycle. In certain embodiments, if the subject experiences a grade 3 adverse event tivozanib is administered even7 other day of treatment cycle. For example, I mg of tivozanib is administered every other day of the treatment cycle. In certain embodiments, the tivozanib is tivozanib hydrochloride. In certain embodiments, the treatment cycle comprises administering durvalumab at a dose of 1,500 mg on day 1 of the treatment cycle followed by no administration of durvalumab on days 2-28 of the treatment cycle.
[0015] In certain embodiments, the treatment regimen comprises one or more treatment cycles where tivozanib is administered at a dose of 1 mg per day on days 1-21 of the treatment cycle followed by no administration of tivozanib on days 22-28 of the treatment cycle and durvalumab is administered at a dose of 1,500 mg on day 1 of the treatment cycle followed by no administration of durvalumab on days 2-28 of the treatment cycle. In some embodiments, the subject has not previously received treatment, e.g., a systemic treatment for the HCC. Accordingly, the treatment regimen is a first line systemic therapy for treating the HCC in the subject. In some embodiments, the subject has previously received treatment, e.g., a systemic treatment for the HCC, such as sorafenib; or atezolizumab and bevacizumab; or nivolumab or pembrolizumab with or without ipilimumab. Accordingly, the treatment regimen is a second line or later line systemic therapy for treating the HCC in the subject.
[0016] The tivozanib can be administered orally. The durvalumab can be administered intravenously, for example, over a period 60 minutes and/or at a concentration of 1-15 mg/mL.
[0017] Depending upon the circumstances, the subject receives at least 7 treatment cycles and/or receives the treatment regimen for at least 7 months. The subject can receive the treatment regimen until the subject experiences a complete response or until the subject experiences progression of the HCC.
[0018] In certain embodiments, methods are provided for extending the progression free survival (PFS) in a subject in need thereof with HCC comprising administering to the subject a treatment regimen comprising a therapeutically effective amount of tivozanib or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of durvalumab. In some embodiments, the PFS is extended compared to a subject or subjects with HCC treated with sorafenib or with bevacizumab and atezolizumab.
[0019] In certain embodiments, methods are provided for extending the progression free survival (PFS) in subjects in need thereof with HCC comprising administering to the subjects a treatment regimen comprising a therapeutically effective amount of tivozanib or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of durvalumab. In some embodiments, the PFS is extended compared to subjects with HCC treated with sorafenib or with bevacizumab and atezolizumab.
[0020] In certain embodiments, methods are provided for extending the overall survival (OS) in a subject in need thereof with HCC comprising administering to the subject a treatment regimen comprising a therapeutically effective amount of tivozanib or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of durvalumab. In some embodiments, the OS is extended compared to a subject or subject with HCC treated with sorafenib or with bevacizumab and atezolizumab.
[0021] In certain embodiments, methods are provided for extending the overall survival (OS) in subjects in need thereof with HCC comprising administering to the subjects a treatment regimen comprising a therapeutically effective amount of tivozanib or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of durvalumab. In some embodiments, the OS is extended compared to subjects with HCC treated with sorafenib or with bevacizumab and atezolizumab.
[0022] In each of the foregoing methods, the subject is a human.
[0023] These and other aspects and features of the disclosure are described in the following detailed description and claims. BRIEF DESCRIPTION OF THE DRAWINGS
[0024 ] FIG. 1 is a schematic overview of the phase lb/2 study described in Example 1.
[0025] FIG. 2 depicts the best overall response and treatment duration for the indicated subjects.
DETAILED DESCRIPTION OF THE INVENTION
[0026] The present disclosure provides methods of treating hepatocellular carcinoma (HCC) using tivozanib and durvalumab. It has been discovered that tivozanib and durvalumab, when used in combination, are effective at prolonging the survival of subjects suffering from advanced HCC. Surprisingly, the data generated in an ongoing clinical study, discussed herein, is indicative that tivozanib and durvalumab, when used in combination, have greater therapeutic efficacy in treating advanced HCC than other currently available systemic therapies. Therefore, tivozanib and durvalumab, when used in combination, may be useful as a first, second or later line systemic therapy for treating subjects with advanced HCC.
I. Summary of Terms
[0027] Unless otherwise noted, technical terms are used according to conventional usage. Definitions of common terms in molecular biology may be found in Benjamin Lewin, Genes X published by Jones & Bartlett Publishers, 2009; and Meyers et al. (eds.), The Encyclopedia of Cell Biology and Molecular Medicine, published by Wiley- V CH in 16 volumes, 2008; and other similar references.
[0028] As used herein, the singular forms “a,” “an,” and “the,” refer to both the singular as well as plural, unless the context clearly indicates otherwise. For example, the term “a cell” includes single or plural cells and can be considered equivalent to the phrase “at least one cell.” Similarly, the expression “at least one of’ includes individually each of the recited objects after the expression and the various combinations of two or more of the recited objects unless otherwise understood from the context and use. For convenience, certain terms in the specification, examples, and appended claims are collected in this section.
[0029] As used herein, the term “administration” is understood to mean to provide to a subject an agent, such as tivozanib and/or durvalumab, by any effective route. Exemplary' routes of administration include, but are not limited to, oral, injection (such as subcutaneous, intramuscular, intradermal, intraperitoneal, intravenous, intra-arterial (including hepatic intraarterial), intra-ductal, intraprostatic, and intratumoral), sublingual, rectal, transdermal. intranasal, vaginal and inhalation routes. In some examples, administration is systemic. In yet other examples, administration is oral.
[0030] As used herein, the term “advanced hepatocellular carcinoma (HCC)” is understood to mean hepatocellular carcinoma (HCC) that has reached Stage 3 or Stage 4. In certain embodiments, “advanced” means that the HCC has metastasized, or otherwise cannot be adequately treated with local therapy alone, such as surgical intervention or radiation therapy, and therefore requires a systemic therapy. In certain embodiments, “advanced” means that the HCC has recurred after having previously responded to treatment with a local or systemic therapy, for example, treatment with a VEGF TKI such as sorafenib, or a VEGF inhibitor such as bevacizumab and a checkpoint inhibitor, such as atezoli zumab. In certain embodiments, advanced HCC is unlikely to be cured or controlled with treatment and, therefore, palliative therapy is used to slow the growth of the cancer or to relieve symptoms through end of life. In some contexts, advanced HCC includes recurrent HCC.
[0031] As used herein, “atezolizumab,” also known by its trade name TECENTR1Q®, is understood to refer to a programmed cell death ligand 1 (PD-L1) blocking antibody.
Atezolizumab is an Fc-engineered, humanized, non-glycosylated IgG 1 kappa immunoglobulin that has a calculated molecular mass of 145 kDa.
[0032] As used herein, the term “best overall response” is understood to mean the best response recorded from the start of the study treatment until the end of treatment taking into account any requirement for confirmation and is determined according to RECIST 1.1 criteria.
[0033] As used herein, “bevacizumab,” also known by its trade name AVASTIN®, is understood to refer to a recombinant humanized monoclonal IgGl antibody that binds to and inhibits the biologic activity of human vascular endothelial growth factor (VEGF) in in vitro and in vivo assay systems. Bevacizumab contains human framework regions and the complementarity-determining regions of a murine antibody that binds to VEGF. Avastin has an approximate molecular weight of 149 kD.
[0034] As used herein, the term “checkpoint inhibitor” is understood to refer to a class of drugs that works by preventing checkpoint proteins on T-cells and tumor cells from binding with one another, thereby allowing T-cells to kill tumor cells. Checkpoint inhibitors are a systemic therapy for treating cancers. Common checkpoint inhibitors act on checkpoint proteins such as PD-1, PD-L1, or CTLA-4. Checkpoint inhibitors include drugs such as a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA-4 inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor, a TIGIT inhibitor, a VISTA inhibitor, a KIR inhibitor, a 2B4 inhibitor, a CD 160 inhibitor, a CGEN-15049 inhibitor, a CHK1 inhibitor, a CHK2 inhibitor, an A2aR inhibitor, or any combination thereof.
[0035] PD-L1 inhibitors include, for example, durvalumab, atezolizumab, avelumab, or any combination thereof. Other PD-1 inhibitors include, for example, nivolumab, pembrolizuniab, pidilizuniab, cemiplimab, sintiiimab, REGN2810, PDR001, or any combination thereof. CTLA-4 inhibitors includes, for example, ipilimumab, tremelimumab, AGEN-1884, or any combination thereof. TIM-3 inhibitors include, for example, TSR-022, LY3321367, MBG453, or any combination thereof. TIGIT inhibitors include, for example, BMS-986207, AGEN17, tiragolumab, MK-7684, OMP-313M32, EOS-448, AB154, or combinations thereof. LAG-3 inhibitors include, for example, BMS-986016, REGN3767, IMP321, LAG525, BI754U 1 , favezelimab, or combinations thereof. VISTA inhibitors include, for example, CI-8993, HMBD-002, a PSGL-1 antagonist as described in WO 2018/132476, or combinations thereof.
[0036] As used herein, the term ‘‘clinical benefit” is understood to refer to a subject experiencing one or more of: (a) slowing tumor growth, (b) halting tumor growth, (c) tumor regression or disappearance, (d) amelioration of a symptom of the cancer, (e) curing the cancer, and (f) prolonging survival of the subject upon the subject receiving a particular intervention, for example, a surgical intervention or therapeutic intervention.
[0037] As used herein, the term “disease control rate (DCR)” is understood to mean the percentage of subjects in a study population who achieve complete response (CR), partial response (PR) or stable disease (SD) in response to a cancer treatment, such as tivozanib and/or durvalumab.
[0038] As used herein, the term “drug related adverse event” is understood to refer to an adverse event (AE) as defined and classified in the National Cancer Institute - Common Terminology Criteria for Adverse Events (CTCAE), version 4.03, dated June 14, 2010. Any reference to “Grade” of adverse event, refers to the grading system as outlined therein.
[0039] As used herein, “durvalumab,” also known by its trade name IMFINZI®, is understood to refer to a programmed cell death ligand 1 (PD-L1) blocking antibody. Durvalumab is a human immunoglobulin G1 kappa (IgGlK) monoclonal antibody that is produced by recombinant DNA technology in Chinese Hamster Ovary (CHO) cell suspension culture. Durvalumab is available as IMFINZI (durvalumab) Injection for intravenous use, which is a sterile, preservative-free, clear to opalescent, colorless to slightly yellow solution, free from visible particles. Each 500 mg vial of IMFINZI contains 500 mg of durvalumab in 10 mL solution. Each ml contains durvalumab, 50 mg, L-histidine (2 mg), L-histidine hydrochloride monohydrate (2.7 mg), a,a-trehalose dihydrate (104 mg), Polysorbate 80 (0.2 mg), and Water for Injection, USP. Each 120 mg vial of IMFINZI contains 120 mg of durvalumab in 2.4 mL solution Each mL contains durvalumab, 50 mg, L-histidine (2 nig), L-histidine hydrochloride monohydrate (2.7 mg), a,a-trehalose dihydrate (104 mg), Polysorbate 80 (0.2 mg), and Water for Injection, USP.
[0040] Durvalumab is described in International Patent Application Publication No. WO2011/066389A1. The light chain variable region of durvalumab has the following ammo acid sequence:
EIVLTQSPGTLSLSPGERATLSCRASQRVSSSYLAWYQQKPGQAPRLLIYDASSRATGI PDRFSGSGSGrDFTLTISRLEPEDFAVYYCQQYGSLPWTFGQGTKVEIK (SEQ ID NO:1).
[0041] The heavy chain variable region of durvalumab has the following amino acid sequence:
EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYWMSWVRQAPGKGLEWVANIKQDG SEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGWFGELAFDY WGQGTLVTVSS (SEQ ID NO:2).
[0042] The light chain CDR sequences of durvalumab are RASQRVSSSYLA (CDRL1; SEQ ID NOG), DASSRAT (CDRL2; SEQ ID NO:4), and QQYGSLPWT (CDRL3; SEQ ID NO: 5).
[0043 j The heavy chain CDR sequences of dui v alumab are GFTFSRYWMS (CDRH1 ;
SEQ ID NO:6), NIKQDGSEKYYVDSVKG (CDRH2; SEQ ID NO:7), and EGGWFGELAFDY (CDRH3; SEQ ID NO:8).
[0044] As used herein, the terms ‘"effective amount” or “therapeutically effective amount” are understood to mean a quantity of a specific substance (such as tivozanib and/or durvalumab) sufficient to achieve a desired effect in a subject being treated. For instance, this can be the amount necessary to inhibit or suppress grow th of a tumor. In one embodiment, an effective amount is the amount necessary to eliminate, reduce the size, or prevent metastasis of a tumor, such as reduce a tumor size, weight and/or volume by at least 10%, at least 20%, at least 50%, at least 75%, at least 80%, at least 90°.., at least 95%, or even 100%, and/or reduce the number and/or size/volume/weight of metastases by at least 10%, at least 20%, at least 50%, at least 75%, at least 80%, at least 90%, at least 95%, or even 100%, for example as compared to a size/volume/number/ weight prior to treatment. In some examples, this can be the amount necessary to increase the survival time of a treated subject by at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12. months, at least 18 months, at least 24 months, at least 36 months, at least 48 months, or at least 60 months, for example relative to the survival time in an absence of the treatment provided herein. In some examples, combinations of these effects are achieved.
[00451 When administered to a subject, a dosage will generally be used that is expected to achieve target tissue concentrations (for example, in tumors) that have been shown to achieve a desired in vitro effect. An effective amount can be administered in one or more administrations, applications or dosages and is not limited to a particular formulation or administration route.
[0046] As used here, the term “effective treatment regimen” or “therapeutically effective treatment regimen” is understood to refer to a treatment regimen of a substance or substances (e.g., tivozanib and/or durvalumab) sufficient to effect beneficial or desired results, such as to effect a clinical benefit in a subject. An effective treatment regimen of tivozanib and durvalumab can be administered in one or more administrations, applications or dosages and is not. limited to a particular formulation or administration route. In one embodiment, an exemplary effective treatment regimen of tivozanib and durvalumab is a regimen that is effective to elicit a complete or partial response according to RECIST (Version 1.1) criteria, as further defined herein. An exemplary effective treatment regimen of tivozanib and durvalumab is administration of at least one treatment cycle, where a treatment cycle comprises (i) administering 1.0 mg tivozanib for 21 days followed by 7 days without administration of tivozanib and (ii) administering 1,500 mg durvalumab for 1 day followed by 27 days without, administration of durvalumab.
[0047] As used herein, the term “hepatocellular carcinoma (HCC),” also referred to as malignant hepatoma, is understood to refer to a form of primary liver cancer, i.e., HCC originates in the liver rather than being the result of metastasis of another primary cancer to the liver. HCC develops from liver cells called hepatocytes. It. occurs most commonly in people with chronic liver diseases leading to inflammation and/or scarring of the livers such as cirrhosis or fatty liver disease (steatohepatitis), hepatitis B or C, and alcoholism, although certain congenital and metabolic disorders can be risk factors for HCC.
[0048] As used herein, the term “metastatic hepatocellular carcinoma (HCC)” is understood to refer to primary site liver tumors that have spread from the liver to other parts of the body.
[0049] As used herein, the term “overall objective response rate (ORR)” is understood to mean the proportion of subjects in a study population with confirmed complete response (CR) or confirmed partial response (PR) according to response evaluation criteria in solid tumors (RECIST; Version 1.1), relative to the total population of randomized subjects in a study population. Confirmed responses are those that persist on repeat imaging study at least 4 weeks after the initial documentation of response.
[0050] As used herein, the term “overall survival (OS)” is understood to mean the time from the date of randomization into a study to date of death due to any cause. In the absence of confirmation of death, survival time is censored at the last date the subject is known to be alive. Subjects lacking data beyond randomization have their survival times censored on the date of randomization.
[0051] As used herein, the term “pharmaceutical composition” is understood to mean the combination of an active agent (such as tivozanib and/or durvalumab) with a carrier (inert or active) that is suitable for diagnostic or therapeutic use in vivo or ex vivo.
[0052] As used herein, the term “progression-free survival (PFS)” is understood to mean the time from randomization into a study to first documentation of objective tumor progression (progressive disease “PD”, radiological) according to RECIST (Version 1.1; see, e.g, Eisenhauer et al. (2009), EUR. J. CANCER, 25:228-247) or death due to any reason, whichever comes first. PFS data is censored on the day following the date of last tumor assessment documenting absence of progressive disease (PD) for subjects who do not have objective tumor progression and are still on study at the time of the analysis, are given antitumor treatment other than the study treatment, or are moved from treatment follow-up prior to documentation of objective tumor progression. Subjects having no tumor assessments after randomization who are not known to have died have PFS censored on the date of randomization.
[0053] As used herein, the term “recurrent HCC” is understood to refer to HCC that fails to respond to treatment or returns after treatment, “recurs”. For example, a hepatocellular carcinoma is recurrent if it fails to respond to a mode of treatment, e.g., the subject experiences disease progression while undergoing treatment. As another example, a hepatocellular carcinoma is recurrent if it returns or progresses after treatment or surgical resection. Recurrent HCC may also respond to an initial treatment, and then return, or initially respond to a treatment, but later in the treatment process, the HCC stops responding to such treatment. In certain embodiments, “recurrent” hepatocellular carcinoma refers to HCC that has been previously treated with at least one systemic or local treatment, and has not responded to such treatment or becomes resistant to such treatment, or that continues to progress during or after such treatment. In some embodiments, recurrent HCC and advanced HCC are synonymous.
[0054] As used herein, the terms “response” or “responding” in the context of a subject’s response to a therapeutic agent (such as tivozanib and/or durvalumab) are understood to refer to the RECIST (Response Evaluation Criteria in Solid Tumors, version 1.1, 2009) criteria for evaluating response of target lesions to a cancer therapy. According to the RECIST criteria, subjects who respond are categorized as either “complete responders” (disappearance of all target lesions) or “partial responders” (at least a 30% decrease in the sum of the diameters of the target lesions, taking as reference the baseline sum of diameters). Accordingly, a “complete response” refers disappearance of all target lesions, whereas a “partial response” refers to at least a 30% decrease in the sum of the diameters of the target lesions, taking as reference the baseline sum of diameters. Non-responders can be placed into one of two categories: stable disease (SD; neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum diameters while on treatment) or progressive disease (PD; at least a 20% increase in the sum of the diameters of the target lesions, taking as reference the smallest sum (this includes the baseline sum if that is the smallest on study: in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm; the appearance of one or more new lesions also qualifies as progression). The RECIST criteria are discussed in detail in, e.g., Therasse et al., J. NATL.. CANCER INST., 2000: 92:205-216 (RECIST 1 .0), and Eisenhauer et al., EUR. J. CANCER, 2009: 25:228-247 (RECIST 1.1). Accordingly, as described herein, responding to therapy refers to subjects falling within the RECIST categories of complete or partial responder, whereas not responding refers to subjects falling within the RECIST categories of stable disease or progressive disease. [0055] As used herein, the term ‘‘subject” is understood to refer to living multi-cellular vertebrate organisms, a category that includes both human and veterinary subjects, including human and non-human mammals such as pigs, mice, rats, guinea pigs, rabbits, sheep, horses, cows, dogs, cats and non-human primates (such as monkeys, chimpanzees, baboons, and rhesus macaques). As used herein, the terms “subject” and “patient” are used interchangeably. In some examples, the subject is a human.
[0056] As used herein, the term “systemic therapy” in the context of treating HCC, is understood to refer to chemotherapies and immunotherapies such as checkpoint inhibitors. Because these Apes of drugs are administered by methods that distribute the drugs systemically, e.g., orally, or by injection or i.v., and therefore reach all parts of the body, they are referred to as “systemic therapy.” This is in contrast to treatments for HCC, such as radiation or surgery, which are considered “local therapy” because their impact is generally only seen in the part of the body where they are implemented'' administered, i.e., in the liver.
[0057] As used herein, “tivozamb” is understood to refer to a small molecule having the chemical name N-{2-chloro-4-[(6,7-dimethoxy-4-qumolyl)oxy]-phenyl}-N’-(5-methyl-3- isoxazolyl)urea and having the following chemical structure:
Figure imgf000013_0001
including pharmaceutically acceptable salts, solvates, solvates of a pharmaceutically acceptable salt, esters, or polymorphs thereof. See, for example, U.S. Patent Nos. 6,821,987, 7,166,722 and 7,211,587, each of which are incorporated herein by reference in their entirety. Tivozamb is sold under the tradename FOTTVDA® in the United States by Aveo Pharmaceuticals, Inc. (Cambridge, MA). In certain embodiments, tivozanib is N-{2-chloro- 4"[(6,7-dimethoxy~4-quinolyl)oxy]-phenyl}~N’-(5~methyl-3-isoxazolyl)urea or hydrates of a hydrochloride salt. In certain embodiments, tivozamb is N-{2-chloro-4-[(6,7-dimethoxy-4- quinolyl)oxy ] -pheny 1 } -N’ -(5 -methyl-3 -i soxazoly l)urea monohy drochlori c aci d sal t monohydrate. In certain embodiments, tivozamb is tivozanib hydrochloride having the chemical name 1 - { 2-chl oro-4- [ (6,7-dimethoxy quinolin-4-yl)oxy ]phenyl } -3 -(5 - methyhsoxazol-3-yl)urea hydrochloride hydrate, having the chemical structure
Figure imgf000014_0001
the molecular formula C22H19CIN4O5 s HC1 * H2O, and a molecular weight of 509.34. Tivozanib hydrochloride is a white to light brown crystalline powder that is practically insoluble in water. Tivozanib is also referred to by its trade name FOTIVDA ®. Tivozanib is a tyrosine kinase inhibitor that has been demonstrated to inhibit phosphorylation of vascular endothelial growth factor receptor (VEGFR)-], VEGFR-2 and VEGFR-3 and other kinases including c~kit and PDGFR P at clinically relevant concentrations.
[0058] As used herein, the terms ‘"treating” or “treat” or “treatment” in the context of hepatocellular carcinoma, are understood to refer to applying techniques, actions or therapies to a subject that (a) slow' tumor growth, (b) halt tumor growth, (c) promote tumor regression or disappearance, (d) ameliorate a symptom of the cancer, (e) cure the cancer, or (f) prolong survival of the subject, or applying techniques, actions or therapies to a subject in an attempt to achieve any of (a)-(f) regardless of whether the individual actually responds to the technique, action or therapy,
[0059] As used herein, the term “untreated,” e.g. , in the context of a subject with HCC, e.g., advanced HCC, is understood to mean that the subject has not previously received a systemic therapy, e.g., chemotherapy or immunotherapy such as a checkpoint inhibitor, to treat the HCC. An untreated subject may or may not have received a surgical invention or localized radiation; however, if they have had a surgical resection of the HCC tumor(s) or localized radiation, the HCC has recurred and is no longer resectable, or otherwise locally treatable.
[0060] As used herein, the term “vascular endothelial growth factor (VEGF) inhibitor” is understood to refer to compounds that interfere with VEGF signaling with its receptor (VEGFR). VEGF inhibitors include antibodies such as bevacizurnab and ranibizumab that bind VEGF, interfering with VEGF’s ability to bind its receptor, antibodies that bind VEGFR such as ramucirumab, as well as drugs like aflibercept w-hich contain extracellular VEGF receptor sequences of the human VEGFR1 and VEGFR2, thereby acting as a decoy receptor for VEGF-A. VEGF Inhibitors also include VEGF (or VEGFR) TRI inhibitors which are a class of anti-angiogenic drugs that inhibits the activity of VEGF TKIs such as VEGFR- 1, VEGFR-2, and/or VEGFR-3, and may also inhibit any one or more of c-Met, c-Kit, PDGFR- a, PDGFR-b, FGFR-1, and/or FGFR-2. VEGF TKIs include regorafenib, nintedanib, lenvantinib, anlotinib, sorafenib, fruquintinib, apatinib, sunitinib, pazopanib, axitinib, dasatinib, niiotinib, motesanib, deciranib, donafenib, vandetanib, sulfatinib, tivozanib, and cabozantinib.
[0061] Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.
[0062] In the application, where an element or component is said to be included in and/or selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components, or the element or component can be selected from a group consisting of two or more of the recited elements or components.
[0063] Further, it should be understood that elements and/or features of a composition or a method described herein can be combined in a variety of ways without departing from the spirit and scope of the present invention, whether explicit or implicit herein. For example, where reference is made to a particular compound, that compound can be used in various embodiments of compositions of the present invention and/or in methods of the present invention, unless otherwise understood from the context. In other words, within this application, embodiments have been described and depicted in a way that enables a clear and concise application to be written and drawn, but it is intended and will be appreciated that embodiments may be variously combined or separated without parting from the present teachings and invention(s). For example, it will be appreciated that all features described and depicted herein can be applicable to all aspects of the invent! on(s) described and depicted herein.
10064] It should be understood that the expression "at least one of” includes individually each of the recited objects after the expression and the various combinations of two or more of the recited objects uni ess otherwise understood from the context and use. The expression “and/or” in connection with three or more recited objects should be understood to have the same meaning unless otherwise understood from the context.
[0065] The use of the term ■‘include,” “includes,” “including,” “have,” “has,” “having,” “contain,” “contains,” or “containing,” including grammatical equivalents thereof, should be understood generally as open-ended and non-limiting, for example, not excluding additional unrecited elements or steps, unless otherwise specifically stated or understood from the context.
[0066] Where the use of the term “about” is before a quantitative value, the present invention also includes the specific quantitative value itself, unless specifically stated otherwise. As used herein, the term “about” refers to a ±10% variation from the nominal value unless otherwise indicated or inferred.
[0067] It should be understood that the order of steps or order for performing certain actions is immaterial so long as the present invention remain operable. Moreover, two or more steps or actions may be conducted simultaneously.
[0068] The use of any and all examples, or exemplary language herein, for example, “such as” or “including,” is intended merely to illustrate better the present invention and does not pose a limitation on the scope of the invention unless claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the present invention.
II. Methods of Treatment mid Medical Uses
[0069] The disclosure provides methods of treating a subject having hepatocellular carcinoma (HCC), for example, advanced HCC, with a combination of tivozanib and durvalumab.
[0070] The disclosure also provides a combination of tivozanib (or a pharmaceutically acceptable salt and/or hydrate thereof) and durvalumab for use in the treatment of hepatocellular carcinoma (HCC), for example, advanced HCC,
[0071] The disclosure further provides the use of a combination of tivozanib (or a pharmaceutically acceptable salt and/or hydrate thereof) and durvalumab in the manufacture of a medicament for use in the treatment of hepatocellular carcinoma (HCC), for example, advanced HCC. [0072] According to one embodiment, the disclosure provides methods of treating a subject having hepatocellular carcinoma (HCC), such as advanced HCC, with an effective amount of tivozanib and an effective amount of durvalumab, thereby to treat the HCC in the subject.
[0073] The treatment methods for HCC disclosed herein may be used as a first line systemic therapy to treat subjects with HCC that have not previously received a systemic therapy to treat their HCC. For example, they have not previously received chemotherapy, including VEGF inhibitors or immunotherapies such as immune checkpoint inhibitors to treat their HCC.
[0074] According to one embodiment, provided herein is a method of treating a subject having hepatocellular carcinoma (HCC), such as advanced HCC, with an effective amount of tivozanib and an effective amount of durvalumab, thereby to treat the HCC, where the subject has not previously received treatment for the HCC, For example, the subject has not previously received a systemic therapy, i.e., chemotherapy and/or immunotherapy, to treat HCC. In one embodiment, the subject receives treatment with tivozanib and durvalumab as a first line systemic therapy for advanced HCC, where the subject has not previously received a systemic therapy (i.e., chemotherapy and/or immunotherapy) to treat the HCC.
[0075] In one embodiment, the subject has not previously received a systemic therapy, e.g., chemotherapy and/or immunotherapy, to treat HCC, but may have received local radiation or surgical resection of HCC tumor(s) but the cancer has recurred after local therapy. In one embodiment, the subject has not previously received a systemic therapy, e.g., chemotherapy and/or immunotherapy, to treat HCC, and also has not received local radiation or surgical resection of HCC tumor(s).
[0076] In one embodiment, the subject has not previously received a local therapy, e.g, surgical resection or radiation, and has not previously received a systemic therapy, e.g., chemotherapy and/or immunotherapy, to treat HCC.
[0077] In another embodiment, the subject receives treatment with tivozanib and durvalumab as first line therapy for advanced HCC, where the subject has unresectable HCC and has not previously received systemic therapy to treat the HCC. The subject may have previously received surgery to resect the HCC, but the HCC has recurred and is now non- resectable. In some embodiments, the subject has received radiation to treat the HCC, but the HCC has recurred. In some embodiments, the subject has not received previous surgery or radiation to treat the HCC.
[0078] The treatment methods for HCC disclosed herein may be used as second line systemic therapies to treat subjects with HCC that have previously received a systemic therapy to treat their HCC. For example, a subject may have previously received chemotherapy and/or immunotherapy in a first line of treatment for the HCC, but failed to respond, or progressed. For example, a first line of treatment may include a VEGF TKI. For example, a first line of treatment may include a VEGF TKI such as sorafenib, regorafenib, lenvantinib, donafenib or cabozantinib, but not tivozanib. For example, a first line of treatment may include sorafenib. A first line of treatment may include a VEGF inhibitor such as bevacizumab combined with an immune checkpoint inhibitor such as atezoiizumab. For example, a first line of treatment may include a VEGF inhibitor such as bevacizumab combined with an immune checkpoint inhibitor such as sintilimab. For example, a first line of treatment for HCC may include nivolumab with ipilimumab or pembrolizumab with ipilimumab. For example, a first line of treatment for HCC may include ramucirumab.
[0079] The treatment methods for HCC disclosed herein may be used as third or later line systemic therapies to treat subjects with HCC that have previously received a systemic therapy to treat their HCC. For example, a subject may have previously received chemotherapy and/or immunotherapy, in an earlier line of treatment for the HCC, but failed to respond, or progressed. For example, a first, second or later line of previous treatment may include a VEGF TKI. For example, a first, second or later line of previous treatment may include a VEGF TKI such as sorafenib, regorafenib, lenvantinib, donafenib or cabozantinib, but not tivozanib. For example, a first, second or later line of previous treatment may include sorafenib. For example, a first, second or later line of previous treatment may include a VEGF inhibitor such as bevacizumab combined with an immune checkpoint inhibitor such as atezoiizumab. For example, a first, second or later line of previous treatment may include a VEGF inhibitor such as bevacizumab combined with an immune checkpoint inhibitor such as sintilimab. For example, a first, second or later line of previous treatment for HCC may include nivolumab with ipilimumab or pembrolizumab with ipilimumab. For example, a first, second or later line of previous treatment for HCC may include ramucirumab.
[0080] According to one embodiment, the disclosure provides methods of treating a subject having hepatocellular carcinoma (HCC), such as advanced HCC, with an effective amount of tivozanib and an effective amount of durvalumab, thereby7 to treat the HCC, where the subject has previously received treatment for the HCC. For example, the subject was previously treated with a VEGF inhibitor, for example, bevacizumab. For example, the subject was previously treated with a VEGF TK1, for example, cabozantimb or regorafenib. For example, the subject was previously treated with a VEGF TKI, for example, sorafenib.
[0081] According to one embodiment, the disclosure provides methods of treating a subject having hepatocellular carcinoma (HCC), such as advanced HCC, with an effective amount of tivozanib and an effective amount of durvalumab, thereby to treat the HCC, where the subject has previously received treatment for the HCC. For example, the subject was previously treated with a immune checkpoint inhibitor. For example, the subject was previously treated with a PD-Ll inhibitor, for example, atezoiizumab.
[0082] According to one embodiment, the disclosure provides methods of treating a subject having hepatocellular carcinoma (HCC), such as advanced HCC, with an effective amount of tivozanib and an effective amount of durvalumab, thereby to treat the HCC, where the subject has previously received treatment for the HCC, and the treatment was a combination of atezoiizumab and bevacizumab.
[0083] According to one embodiment, the disclosure provides methods of treating a subject having hepatocellular carcinoma (HCC), such as advanced HCC, with an effective amount of tivozanib and an effective amount of durvalumab, thereby to treat the HCC, where the subject experiences a progression free survival of at least six months upon receiving the treatment with tivozanib and durvalumab. In one embodiment, the subject has not previously received treatment for the HCC, e.g.. previous systemic treatment, prior to treatment with tivozanib and durvalumab.
[0084] According to one embodiment, the disclosure provides methods of treating a subject having hepatocellular carcinoma (HCC), such as advanced HCC, with an effective amount of tivozanib and an effective amount of durvalumab, thereby to treat the HCC, where the subject experiences a progression free survival of at least seven months upon receiving the treatment with tivozanib and durvalumab. In one embodiment, the subject has not previously received treatment for the HCC, e.g., previous systemic treatment, prior to treatment with tivozanib and durvalumab,
[0085] According to one embodiment, the disclosure provides methods of treating a subject having hepatocellular carcinoma (HCC), such as advanced HCC, with an effective amount of tivozanib and an effective amount of durvalumab, thereby to treat the HCC, where the subject experiences a progression free survival of at least six months upon receiving the treatment with tivozanib and durvalumab. In one embodiment, the subject previously received treatment for the HCC with bevacizumab and atezolizumab, prior to treatment with tivozanib and durvalumab.
100861 According to one embodiment, the disclosure provides methods of treating a subject having hepatocellular carcinoma (HCC), such as advanced HCC, with an effective amount of tivozanib and an effective amount of durvalumab, thereby to treat the HCC, where the subject experiences a progression free survival of at least seven months upon receiving the treatment with tivozanib and durvalumab. In one embodiment, the subject previously received treatment for the HCC with bevacizumab and atezolizumab, prior to treatment with tivozanib and durvalumab.
100871 According to one embodiment, the disclosure provides methods of treating a subject having hepatocellular carcinoma (HCC), such as advanced HCC, with an effective amount of tivozanib and an effective amount of durvalumab, thereby to treat the HCC, where the subject experiences a progression free survival of at least six months upon receiving the treatment with tivozanib and durvalumab. In one embodiment, the subject previously received treatment for the HCC with a VEGF inhibitor and a checkpoint inhibitor, prior to treatment with tivozanib and durvalumab.
[00881 According to one embodiment, the disclosure provides methods of treating a subject having hepatocellular carcinoma (HCC), such as advanced HCC, with an effective amount of tivozanib and an effective amount of durvalumab, thereby to treat the HCC, where the subject experiences a progression free survival of at least seven months upon receiving the treatment with tivozanib and durvalumab. In one embodiment, the subject previously received treatment for the HCC with a VEGF inhibitor and a checkpoint inhibitor, prior to treatment with tivozanib and durvalumab.
[0089] In certain embodiments, if the subject has previously received systemic therapy with a VEGF TKI and/or an immune checkpoint inhibitor to treat the HCC, then (a) the VEGF TKI is not tivozanib; (b) the immune checkpoint inhibitor is not durvalumab; or (c) the VEGF TKI is not tivozanib and the immune checkpoint inhibitor is not durvalumab.
[0090] According to certain embodiments, the subject is treated with tivozanib and durvalumab so long as a clinical benefit is observed in the subject or until unacceptable toxicity occurs. In certain embodiments, the subject receives treatment until the subject experiences a complete response, or until the subject experiences progression of the HCC, or until a physician elects to discontinue the therapy
[0091] According to certain embodiments, the subject receives treatment with tivozanib and durvalumab so iong as the subject experiences a partial response while receiving the treatment or experiences stable disease while receiving the treatment.
[0092] In certain embodiments, a subject having HCC, for example, advanced HCC, who is treated with tivozanib and durvalumab according to the disclosed methods experiences a progression free survival of at least 6.0, 6.1, 6.2, 6.2, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2,
7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3,
9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 1 1.0, 11.1,
11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7,
12.8, 12.9, 13.0, 13.1, 13.2, 13.3, 13.4, 13.5, 13.6, 13.7, 13.8, 13.9, 14.0, 14.1, 14.2, 14.3,
14.4, 14.5, 14.6, 14.7, 14.8, 14.9, 15.0, 15.1, 15.2, 15.3, 15.4, 15.5, 15.6, 15.7, 15.8, 15.9,
16.0, 16.1 , 16.2, 16.3, 16.4, 16.5, 16.6, 16.7, 16.8, 16.9, 17.0, 17.1, 17.2, 17.3, 17.4, 17.5,
17.6, 17.7, 17.8, 17.9 18.0, 18.1, 18.2, 18.3, 18.4, 18.5, 18.6, 18.7, 18.8, 18.9, 19.0, 19.1,
19.2, 19.3, 19.4, 19.5, 19.6, 19.7, 19.8, 19.9, 20.0, 20.1, 20.2, 20.3, 20.4, 20.5, 20.6, 20.7,
20.8, 20.9, 21.0, 21, 1 , 21.2, 21.3, 21.4, 21.5, 21.6, 21.7, 21.8, 21.9, 22.0, 22.1, 22.2, 22.3,
22.4, 22.5, 22.6, 22.7, 22.8, 22.9, 23.0, 23.1, 23.2, 23.3, 23.4, 23.5, 23.6, 23.7, 23.8, 23.9,
24.0, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1, 25.2, 25.3, 25.4, 25.5,
25.6, 25.7, 25.8, 25.9, 26.0, 26.1 , 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9, 27.0, 27.1,
27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, 28.0, 28.1 , 28.2, 28.3, 28.4, 28.5, 28.6, 28.7,
28.8, 2.8.9, 29.0, 29.1, 29.2, 2.9.3, 29.4, 29.5, 29.6, 29.7, 29.8, 29.9, 30, 31, 32, 33, 34, 35, 36,
37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, or 48 months upon receiving the tivozanib and durvalumab. In certain embodiments, the subject has a survival time of at least 10.0, 10.1,
10.2, 10.3, 10.4, 10,5, 10.6, 10.7, 10.8, 10.9, 1 1.0, 1 1.1, 11.2, 11.3, 11.4, 1 1.5, 11.6, 11.7,
11.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 13.0, 13.1, 13.2, 13.3,
13.4, 13.5, 13.6, 13.7, 13.8, 13.9, 14.0, 14.1, 14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9,
15.0, 15, 1 , 15.2, 15.3, 15.4, 15.5, 15.6, 15.7. 15.8, 15.9, 16.0, 16.1, 16.2, 16.3, 16.4, 16.5,
16.6, 16.7, 16.8, 16.9, 17.0, 17.1, 17.2, 17.3, 17.4, 17.5, 17.6, 17.7, 17.8, 17.9 18.0, 18.1,
18.2, 18.3, 18.4, 18.5, 18.6, 18.7, 18.8, 18.9, 19.0, 19.1, 19.2, 19.3, 19.4, 19.5, 19.6, 19.7,
19.8, 19.9, 20.0, 20.1 , 20.2, 20.3, 20.4, 20.5, 20.6, 20.7, 20.8, 20.9, 21.0, 21.1, 21.2, 21.3,
21.4, 21.5, 21.6, 21 ,7, 21.8, 21.9, 22.0, 22.1 , 22.2, 22.3, 22.4, 22.5, 22.6, 22.7, 22.8, 22.9,
23.0, 23.1, 23.2, 23.3, 23.4, 23.5, 23.6, 23.7, 23.8, 23.9, 24.0, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1, 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26.0, 26.1,
26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9, 27.0, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7,
27.8, 27.9, 28.0, 28.1 , 28.2, 28.3, 28.4, 28.5, 28.6, 28.7, 28.8, 28.9, 29.0, 29.1, 29.2, 29.3,
29.4, 29.5, 29.6, 29.7, 29.8, 29.9, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,
46, 47, or 48 months from the start of treatment with the tivozanib and durvalurnab. In some embodiments, the treatment is discontinued, for example, due to unacceptable toxicity, lack of response, or disease progression, but the subject survives for a period of time beyond the time the treatment is discontinued.
[0093] In certain embodiments, a subject having HCC who is treated with tivozanib and durvalurnab according to the disclosed methods, where the subject has not previously received treatment, e.g. , systemic treatment, for the HCC, experiences a progression free survival of at least 6.0, 6.1 , 6.2, 6.2, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6,
7.7, 7.8, 7.9, 8.0, 8.1 , 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1 , 9.2, 9.3, 9.4, 9.5, 9.6, 9.7,
9.8, 9.9, 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3, 11.4,
11.5, 11.6, 11.7, 11.8, 1 1.9, 12.0, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 13.0,
13.1, 13.2, 13.3, 13.4, 13.5, 13.6, 13.7, 13.8, 13.9, 14.0, 14.1, 14.2, 14.3, 14.4, 14.5, 14.6,
14.7, 14.8, 14.9, 15.0, 15.1, 15.2, 15.3, 15.4, 15.5, 15.6, 15.7, 15.8, 15.9, 16.0, 16.1, 16.2,
16.3, 16.4, 16.5, 16.6, 16.7, 16.8, 16.9, 17.0, 17.1, 17.2, 17.3, 17.4, 17.5, 17.6, 17.7, 17.8,
17.9 18.0, 18.1, 18.2, 18.3, 18.4, 18.5, 18.6, 18.7, 18.8, 18.9, 19.0, 19.1, 19.2, 19.3, 19.4,
19.5, 19.6, 19.7, 19.8, 19.9, 20.0, 20.1, 20.2, 20.3, 20.4, 20.5, 20.6, 20.7, 20.8, 20.9, 21.0,
21.1 , 21.2, 21.3, 21.4, 21.5, 21.6, 21.7, 21.8, 21.9, 22.0, 22.1 , 22.2, 22.3, 22.4, 22.5, 22.6,
22.7, 22.8, 22.9, 23.0, 23.1, 23.2, 23.3, 23.4, 23.5, 23.6, 23.7, 23.8, 23.9, 24.0, 24.1, 24.2,
24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1, 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8,
25.9, 26.0, 26.1, 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9, 27.0, 27.1 , 27.2, 27.3, 27.4,
27.5, 27.6, 27.7, 2.7.8, 27.9, 28.0, 28.1, 28.2, 28.3, 28.4, 28.5, 28.6, 2.8.7, 28.8, 28.9, 29.0,
29.1, 29.2, 29.3, 29.4, 29.5, 29.6, 29.7, 29.8, 29.9, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40,
41, 42, 43, 44, 45, 46, 47, or 48 months upon receiving the tivozanib and durvalurnab. In certain embodiments, the subject has a survival time of at least 10.0, 10, 1 , 10.2, 10.3, 10.4,
10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12.0,
12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 13.0, 13.1, 13.2, 13.3, 13.4, 13.5, 13.6,
13.7, 13.8, 13.9, 14.0, 14.1, 14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9, 15.0, 15.1, 15.2,
15.3, 15.4, 15.5, 15.6, 15.7, 15.8, 15.9, 16.0, 16.1, 16.2, 16.3, 16.4, 16.5, 16.6, 16.7, 16.8,
16.9, 17.0, 17.1, 17.2, 17.3, 17.4, 17.5, 17.6, 17.7, 17.8, 17.9 18.0, 18.1, 18.2, 18.3, 18.4, 18.5, 18.6, 18.7, 18.8, 18.9, 19.0, 19.1, 19.2, 19.3, 19.4, 19.5, 19.6, 19.7, 19.8, 19.9, 20.0,
20.1, 20.2, 20.3, 20.4, 20.5, 20.6, 20.7, 20.8, 20.9, 21.0, 21 .1, 21.2, 21.3, 21.4, 21.5, 21.6,
21.7, 21.8, 21.9, 22.0, 22.1, 22.2, 22.3, 22.4, 22.5, 22.6, 22.7, 22.8, 22.9, 23.0, 23.1, 23.2,
23.3, 23.4, 23.5, 23.6, 23.7, 23.8, 23.9, 24.0, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8,
24.9, 25.0, 25.1, 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26.0, 26.1, 26.2, 26.3, 26.4,
26.5, 26.6, 26.7, 26.8, 26.9, 27.0, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, 28.0,
28.1, 2.8.2, 28.3, 28.4, 28.5, 2.8.6, 28.7, 28.8, 28.9, 29.0, 29.1, 29.2, 29.3, 29.4, 2.9.5, 29.6,
29.7, 29.8, 29.9, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, or 48 months from the start, of treatment with the tivozanib and durvalumab. In some embodiments, the treatment is discontinued, for example, due to unacceptable toxicity, lack of response, or disease progression, but the subject survives for a period of time beyond the time the treatment is discontinued.
[0094] In certain embodiments, a subject having HCC who is treated with tivozanib and durvalumab according to the disclosed methods, where the subject has received previous treatment for the HCC, e.g., systemic treatment, such as a VEGF inhibitor and/or a checkpoint inhibitor experiences a progression free survival of at least 6,0, 6.1, 6.2, 6.2, 6.4,
6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1 , 8.2, 8.3, 8.4, 8.5,
8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.3, 10.4,
10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 1 1.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12.0,
12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 13.0, 13.1 , 13.2, 13.3, 13.4, 13.5, 13.6,
13.7, 13,8, 13.9, 14.0, 14.1, 14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9, 15.0, 15.1, 15.2,
15.3, 15.4, 15.5, 15.6, 15.7, 15.8, 15.9, 16.0, 16.1, 16.2, 16.3, 16.4, 16.5, 16.6, 16.7, 16.8,
16.9, 17.0, 17.1 , 17.2, 17.3, 17.4, 17.5, 17.6, 17.7, 17.8, 17.9 18.0, 18.1, 18.2, 18.3, 18.4,
18.5, 18.6, 18.7, 18.8, 18.9, 19.0, 19.1, 19.2, 19.3, 19.4, 19.5, 19.6, 19.7, 19.8, 19.9, 20.0,
20.1, 20.2, 20.3, 2.0.4, 20.5, 20.6, 20.7, 20.8, 20.9, 21.0, 21.1, 21.2, 2.1.3, 21.4, 21.5, 21.6,
21.7, 21.8, 21.9, 22.0, 22.1, 22.2, 22.3, 22.4, 22.5, 22.6, 22.7, 22.8, 22.9, 23.0, 23.1, 23.2,
23.3, 23.4, 23.5, 23.6, 23.7, 23.8, 23.9, 24.0, 24.1 , 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8,
24.9, 25.0, 25.1, 25.2, 2.5.3, 25.4, 25.5, 25.6, 2.5.7, 25.8, 25.9, 26.0, 26.1, 26.2, 26.3, 26.4,
26.5, 2.6.6, 26.7, 26.8, 26.9, 2.7.0, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 2.7.9, 28.0,
28.1, 28.2, 28.3, 28.4, 28.5, 28.6, 28.7, 28.8, 28.9, 29.0, 29.1, 29.2, 29.3, 29.4, 29.5, 29.6,
29.7, 29.8, 29.9, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, or 48 months upon receiving the tivozanib and durvalumab. In certain embodiments, the subject has a survival time of at least 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, I I .1, 11.2, 11.3, 11.4, 1 1.5, 11.6, 11.7, 11.8, 1 1.9, 12.0, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6,
12.7, 12.8, 12.9, 13.0, 13.1, 13.2, 13.3, 13.4, 13.5, 13.6, 13.7, 13.8, 13.9, 14.0, 14.1, 14.2,
14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9, 15.0, 15.1 , 15.2, 15.3, 15.4, 15.5, 15.6, 15.7, 1.5.8,
15.9, 16.0, 16.1, 16.2, 16.3, 16.4, 16.5, 16.6, 16.7, 16.8, 16.9, 17.0, 17.1, 17.2, 17.3, 17.4,
17.5, 17.6, 17.7, 17.8, 17.9 18.0, 18.1 , 18.2, 18.3, 18.4, 18.5, 18.6, 18.7, 18.8, 18.9, 19.0,
19.1 , 19.2, 19.3, 19.4, 19.5, 19.6, 19.7, 19.8, 19.9, 20.0, 20.1 , 20.2, 20.3, 20.4, 20.5, 20.6,
20.7, 20.8, 20.9, 21.0, 21.1, 21.2, 21.3, 21.4, 21.5, 21.6, 21.7, 21.8, 21.9, 22.0, 22.1, 22.2,
22.3, 22.4, 22.5, 22.6, 22.7, 22.8, 22.9, 23.0, 23.1, 23.2, 23.3, 23.4, 23.5, 23.6, 23.7, 23.8,
23.9, 24.0, 24.1 , 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1 , 25.2, 25.3, 25.4,
25.5, 25.6, 25.7, 25.8, 25.9, 26.0, 26.1, 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9, 27.0,
27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, 28.0, 28.1, 28.2, 28.3, 28.4, 28.5, 28.6,
28.7, 28.8, 28.9, 29.0, 29.1 , 29.2, 29.3, 29.4, 29.5, 29.6, 29.7, 29.8, 29.9, 30, 31, 32, 33, 34,
35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, or 48 months from the start of treatment with the tivozanib and durvalumab. In some embodiments, the treatment is discontinued, for example, due to unacceptable toxicity, lack of response, or disease progression, but the subject survives for a period of time beyond the time the treatment is discontinued.
[0095] In certain embodiments, a subject having HCC who is treated with tivozanib and durvalumab according to the disclosed methods, where the subject has received previous treatment with bevacizumab in combination atezolizumab for the HCC, experiences a progression free survival of at least 6.0, 6.1, 6.2, 6.2, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2,
7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1 , 9.2, 9.3,
9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1,
1 1.2, 11.3, 11.4, 11.5, 1 1.6, 11.7, 11.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7,
12.8, 12.9, 13.0, 13.1 , 13.2, 13.3, 13.4, 13.5, 13.6, 13.7, 13.8, 13.9, 14.0, 14.1, 14.2, 14.3,
14.4, 14.5, 14.6, 14.7, 14.8, 14.9, 15.0, 15.1, 15.2, 15.3, 15.4, 15.5, 15.6, 15.7, 15.8, 15.9,
16.0, 16.1, 16.2, 16.3, 16.4, 16.5, 16.6, 16.7, 16.8, 16.9, 17.0, 17.1, 17.2, 17.3, 17.4, 17.5,
17.6, 17.7, 17.8, 17.9 18.0, 18.1, 18.2, 18.3, 18.4, 18.5, 18.6, 18.7, 18.8, 18.9, 19.0, 19.1 ,
19.2, 19.3, 19.4, 19.5, 19.6, 19.7, 19.8, 19.9, 20.0, 20.1 , 20.2, 20.3, 20.4, 20.5, 20.6, 20.7,
20.8, 20.9, 21.0, 21.1, 21.2, 21.3, 21.4, 21.5, 21.6, 21.7, 21.8, 21.9, 22.0, 22.1, 22.2, 22.3,
22.4, 22.5, 22.6, 22.7, 22.8, 22.9, 23.0, 23.1 , 23.2, 23.3, 23.4, 23.5, 23.6, 23.7, 23.8, 23.9,
24.0, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1 , 25.2, 25.3, 25.4, 2.5.5,
25.6, 25.7. 25.8, 25.9, 26.0, 26.1, 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9, 27.0, 27.1,
27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, 28.0, 28.1, 28.2, 28.3, 28.4, 28.5, 28.6, 28.7, 28.8, 28.9, 29.0, 29.1, 29.2, 29.3, 29.4, 29.5, 29.6, 29.7, 29.8, 29.9, 30, 31, 32, 33, 34, 35, 36,
37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, or 48 months upon receiving the tivozanib and durvalumab. In certain embodiments, the subject has a survival time of at least 10.0, 10.1,
10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 1 1.7,
11.8, 1 1.9, 12.0, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 13.0, 13.1 , 13.2, 13.3,
13.4, 13.5, 13.6, 13.7, 13.8, 13.9, 14.0, 14.1, 14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9,
15.0, 15.1, 15.2, 15.3, 15.4, 15.5, 15.6, 15.7, 15.8, 15.9, 16.0, 16.1, 16.2, 16.3, 16.4, 16.5,
16.6, 16.7, 16.8, 16.9, 17.0, 17.1, 17.2, 17.3, 17.4, 17.5, 17.6, 17.7, 17.8, 17.9 18.0, 18.1,
18.2, 18.3, 18.4, 18.5, 18.6, 18.7, 18.8, 18.9, 19.0, 19.1, 19.2, 19.3, 19.4, 19.5, 19.6, 19.7,
19.8, 19.9, 20.0, 20, 1 , 20.2, 20.3, 20.4, 20.5, 20.6, 20.7, 20.8, 20.9, 21.0, 21.1, 21.2, 21.3,
21.4, 21.5, 21.6, 21.7, 21.8, 21.9, 22.0, 22.1, 22.2, 22.3, 22.4, 22.5, 22.6, 22.7, 22.8, 22.9,
23.0, 23.1 , 23.2, 23.3, 23.4, 23.5, 23.6, 23.7, 23.8, 23.9, 24.0, 24.1, 24.2, 24.3, 24.4, 24.5,
24.6, 24.7, 24.8, 24.9, 25.0, 25.1 , 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26.0, 26.1,
26.2, 2.6.3, 26.4, 26.5, 26.6, 2.6.7, 26.8, 26.9, 27.0, 27.1, 27.2, 27.3, 27.4, 27.5, 2.7.6, 27.7,
27.8, 27.9, 28.0, 28.1, 28.2, 28.3, 28.4, 28.5, 28.6, 28.7, 28.8, 28.9, 29.0, 29.1, 29.2, 29.3,
29.4, 29.5, 29.6, 29.7, 29.8, 29.9, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,
46, 47, or 48 months from the start of treatment with the tivozanib and durvalumab. In some embodiments, the treatment is discontinued, for example, due to unacceptable toxicity, lack of response, or disease progression, but the subject survives for a period of time beyond the time the treatment is discontinued.
[0096] In certain embodiments, a population of subjects having HCC who are treated with tivozanib and durvalumab according to the disclosed methods experience a median progression free survival of at least 6.0, 6.1 , 6.2, 6.2, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1 , 7.2,
7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3,
9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1,
11.2, 11.3, 1 1.4, 11.5, 11.6, 11.7, 1 1.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7,
12.8, 12.9, 13.0, 13.1, 13.2, 13.3, 13.4, 13.5, 13.6, 13.7, 13.8, 13.9, 14.0, 14.1 , 14.2, 14.3,
14.4, 14.5, 14.6, 14.7, 14.8, 14.9, 15.0, 15.1, 15.2, 15.3, 15.4, 15.5, 15.6, 15.7, 15.8, 15.9,
16.0, 16.1, 16.2, 16.3, 16.4, 16.5, 16.6, 16.7, 16.8, 16.9, 17.0, 17.1, 17.2, 17.3, 17.4, 17.5,
17.6, 17.7, 17.8, 17.9 18.0, 18.1 , 18.2, 18.3, 18.4, 18.5, 18.6, 18.7, 18.8, 18.9, 19.0, 19.1,
19.2, 19.3, 19.4, 19.5, 19.6, 19.7, 19.8, 19.9, 20.0, 20.1, 20.2, 20.3, 20.4, 20.5, 20.6, 20.7,
20.8, 20.9, 21.0, 21.1, 21.2, 21.3, 21.4, 21.5, 21.6, 21.7, 21.8, 21.9, 22.0, 22.1, 22.2, 22.3,
22.4, 22.5, 22.6, 22.7, 22.8, 22.9, 23.0, 23.1, 23.2, 23.3, 23.4, 23.5, 23.6, 23.7, 23.8, 23.9, 24.0, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1, 25.2, 25.3, 25.4, 25.5,
25.6, 25.7, 25.8, 25.9, 26.0, 26.1, 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9, 27.0, 27.1 ,
27.2, 27.3, 27,4, 27.5, 27.6, 27.7, 27.8, 27.9, 28.0, 28.1, 28.2, 28.3, 28.4, 28.5, 28.6, 28.7,
28.8, 28.9, 29.0, 29.1, 29.2, 29.3, 29.4, 29.5, 29.6, 29.7, 29.8, 29.9, 30, 31, 32, 33, 34, 35, 36,
37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, or 48 months upon receiving the tivozanib and durvalumab, In certain embodiments, the population of subjects experiences a median overall survival of at least 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1,
11.2, 11.3, 11.4, 11.5, 1 1.6, 11.7, 11.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7,
12.8, 12.9, 13.0, 13.1 , 13.2, 13.3, 13.4, 13.5, 13.6, 13.7, 13.8, 13.9, 14.0, 14.1, 14.2, 14.3,
14.4, 14.5, 14.6, 14.7, 14.8, 14.9, 15.0, 15.1, 15.2, 15.3, 15.4, 15.5, 15.6, 15.7, 15.8, 15.9,
16.0, 16.1, 16.2, 16.3, 16.4, 16.5, 16.6, 16.7, 16.8, 16.9, 17.0, 17.1, 17.2, 17.3, 17.4, 17.5,
17.6, 17.7, 17.8, 17.9 18.0, 18.1, 18.2, 18.3, 18.4, 18.5, 18.6, 18.7, 18.8, 18.9, 19.0, 19.1,
19.2, 19.3, 19.4, 19.5, 19.6, 19.7, 19.8, 19.9, 20.0, 20.1, 20.2, 20.3, 20.4, 20.5, 20.6, 20.7,
20.8, 20.9, 21.0, 21.1, 21.2, 21.3, 21.4, 21.5, 21.6, 21.7, 21.8, 21.9, 22.0, 22.1, 22.2, 22.3,
22.4, 22.5, 22.6, 22.7, 22.8, 22.9, 23.0, 23.1 , 23.2, 23.3, 23.4, 23.5, 23.6, 23.7, 23.8, 23.9,
24.0, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1 , 25.2, 25.3, 25.4, 25.5,
25.6, 25.7, 25.8, 25.9, 26.0, 26.1, 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9, 27.0, 27.1,
27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, 28.0, 28.1, 28.2, 28.3, 28.4, 28.5, 28.6, 28.7,
28.8, 28.9, 29.0, 29.1, 29.2, 29.3, 29.4, 29.5, 29.6, 29.7, 29.8, 29.9, 30, 31 , 32, 33, 34, 35, 36,
37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, or 48 months from the start of treatment with the tivozanib and durvalumab.
[0097] In certain embodiments, a population of subjects having HCC who are treated with tivozanib and durvalumab according to the disclosed methods, where the subjects have not previously received treatment, e.g., systemic treatment, for the HCC, experiences a median progression free survival of at least 6.0, 6.1, 6.2, 6.2, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0,
7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1,
9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9,
H O. 11.1 , 1 1.2, 1 1.3, 11.4, 11.5, 1 1.6, 1 1.7, 1 1.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4, 12.5,
12.6, 12.7, 12.8, 12.9, 13.0, 13.1, 13.2, 13.3, 13.4, 13.5, 13.6, 13.7, 13.8, 13.9, 14.0, 14.1,
14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9, 15.0, 15.1, 15.2, 15.3, 15.4, 15.5, 15.6, 15.7,
15.8, 15.9, 16.0, 16.1 , 16.2, 16.3, 16.4, 16.5, 16.6, 16.7, 16.8, 16.9, 17.0, 17.1, 17.2, 17.3,
17.4, 17.5, 17.6, 17.7, 17.8, 17.9 18.0, 18.1, 18.2, 18.3, 18.4, 18.5, 18.6, 18.7, 18.8, 18.9, 19.0, 19.1, 19.2, 19.3, 19.4, 19.5, 19.6, 19.7, 19.8, 19.9, 20.0, 20.1, 20.2, 20.3, 20.4, 20.5, 20.6, 20.7, 20.8, 20.9, 21.0, 21.1, 21.2, 21.3, 21.4, 21.5, 21.6, 21.7, 21.8, 21.9, 22.0, 22.1,
22.2, 22.3, 22.4, 22.5, 22.6, 22.7, 22.8, 22.9, 23.0, 23.1, 23.2, 23.3, 23.4, 23.5, 23.6, 23.7,
23.8, 23.9, 24.0, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1, 25.2, 25.3,
25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26.0, 26.1, 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9,
27.0, 27.1 , 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, 28.0, 28.1, 28.2, 28.3, 28.4, 28.5,
28.6, 28.7, 28.8, 28.9, 29.0, 29.1 , 29.2, 29.3, 29.4, 29.5, 29.6, 29.7, 29.8, 29.9, 30, 31, 32, 33,
34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, or 48 months upon receiving the tivozanib and durvalumab. In certain embodiments, the population of subjects experiences a median overall survival of at least 10.0, 10.1 , 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 1 1.0, 11.1, 11.2, 11.3, 1 1.4, 11.5, 11.6, 11.7, 1 1.8, 1 1.9, 12.0, 12.1 , 12.2, 12.3, 12.4, 12.5,
12.6, 12.7, 12.8, 12.9, 13.0, 13.1 , 13.2, 13.3, 13.4, 13.5, 13.6, 13.7, 13.8, 13.9, 14.0, 14.1,
14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9, 15.0, 15.1 , 15.2, 15.3, 15.4, 15.5, 15.6, 15.7,
15.8, 15.9, 16.0, 16.1, 16.2, 16.3, 16.4, 16.5, 16.6, 16.7, 16.8, 16.9, 17.0, 17. 1, 17.2, 17.3,
17.4, 17.5, 17.6, 17.7, 17.8, 17.9 18.0, 18.1, 18.2, 18.3, 18.4, 18.5, 18.6, 18.7, 18.8, 18.9,
19.0, 19.1, 19.2, 19.3, 19.4, 19.5, 19.6, 19.7, 19.8, 19.9, 20.0, 20.1, 20.2, 20.3, 20.4, 20.5,
20.6, 20.7, 20.8, 20.9, 21.0, 21.1, 21.2, 21.3, 21.4, 21.5, 21.6, 21.7, 21.8, 21.9, 22.0, 22.1 ,
22.2, 22.3, 22.4, 22.5, 22.6, 22.7, 22.8, 22.9, 23.0, 23.1, 23.2, 23.3, 23.4, 23.5, 23.6, 23.7,
23.8, 23.9, 24.0, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1, 25.2, 25.3,
25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26.0, 26.1, 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9,
27.0, 27.1 , 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, 28.0, 28.1, 28.2, 28.3, 28.4, 28.5,
28.6, 2.8.7, 28.8, 28.9, 29.0, 2.9.1, 29.2, 29.3, 29.4, 29.5, 29.6, 29.7, 29.8, 29.9, 30, 31, 32, 33,
34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, or 48 months from the start of treatment with the tivozanib and durvalumab.
[0098] In certain embodiments, a population of subjects having HCC who are treated with tivozanib and durvalumab according to the disclosed methods, where the subjects have previous!}' received treatment for the HCC, e.g., systemic treatment, such as a VEGF inhibitor and/or a. checkpoint inhibitor experiences a median progression free survival of at least 6.0, 6.1, 6.2, 6.2, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0,
10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 1 1.0, 11.1, 11.2, 1 1.3, 1 1.4, 1 1.5, 11.6,
1 1.7, 11.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 13.0, 13.1, 13.2,
13.3, 13.4, 13.5, 13.6, 13.7, 13.8, 13.9, 14.0, 14.1, 14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8,
14.9, 15.0, 15.1, 15.2, 15.3, 15.4, 15.5, 15.6, 15.7, 15.8, 15.9, 16.0, 16.1, 16.2, 16.3, 16.4, 16.5, 16.6, 16.7, 16.8, 16.9, 17.0, 17.1, 17.2, 17.3, 17.4, 17.5, 17.6, 17.7, 17.8, 17.9 18.0,
18.1, 18.2, 18.3, 18.4, 18.5, 18.6, 18.7, 18.8, 18.9, 19.0, 19.1, 19.2, 19.3, 19.4, 19.5, 19.6,
19.7, 19.8, 19.9, 20,0, 20.1, 20.2, 20.3, 20.4, 20.5, 20.6, 20.7, 20.8, 20.9, 21.0, 21.1, 21.2,
21.3, 21.4, 21.5, 21.6, 21.7, 21.8, 21.9, 22.0, 22.1, 22.2, 22.3, 22.4, 22.5, 22.6, 22.7, 22.8,
22.9, 23.0, 23.1, 23.2, 23.3, 23.4, 23.5, 23.6, 23.7, 23.8, 23.9, 24.0, 24.1, 24.2, 24.3, 24.4,
24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1, 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26.0,
26.1, 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9, 27.0, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6,
27.7, 27.8, 27.9, 28.0, 28.1, 28.2, 28.3, 28.4, 28.5, 28.6, 28.7, 28.8, 28.9, 29.0, 29.1, 29.2,
29.3, 29.4, 29.5, 29.6, 29.7, 29.8, 29.9, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,
44, 45, 46, 47, or 48 months upon receiving the tivozanib and durvalumab. In certain embodiments, the population of subjects experiences a median overall survival of at least 10.0, 10.1 , 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 1 1.0, 1 1.1, 1 1 .2, 11.3, 1 1.4, 1 1.5,
11.6, 11,7, 1 1.8, 1 1.9, 12.0, 12, 1 , 12.2, 12.3, 12.4, 12,5, 12.6, 12.7, 12.8, 12.9, 13.0, 13.1,
13.2, 13.3, 13.4, 13.5, 13.6, 13.7, 13.8, 13.9, 14.0, 14.1, 14.2, 14.3, 14.4, 14.5, 14.6, 14.7,
14.8, 14.9, 15.0, 15.1, 15.2, 15.3, 15.4, 15.5, 15.6, 15.7, 15.8, 15.9, 16.0, 16.1, 16.2, 16.3,
16.4, 16.5, 16.6, 16.7, 16.8, 16.9, 17.0, 17.1 , 17.2, 17.3, 17.4, 17.5, 17.6, 17.7, 17.8, 17.9
18.0, 18.1, 18.2, 18.3, 18.4, 18.5, 18.6, 18.7, 18.8, 18.9, 19.0, 19.1, 19.2, 19.3, 19.4, 19.5,
19.6, 19.7, 19.8, 19.9, 20.0, 20.1 , 20.2, 20.3, 20.4, 20.5, 20.6, 20.7, 20.8, 20.9, 21.0, 21.1,
21.2, 21.3, 21.4, 21.5, 21.6, 21.7, 21.8, 21.9, 22.0, 22.1 , 22.2, 22.3, 22.4, 22.5, 22.6, 22.7,
22.8, 22.9, 23.0, 23.1, 23.2, 23.3, 2.3.4, 23.5, 23.6, 23.7, 23.8, 23.9, 24.0, 24.1 , 24.2, 24.3,
24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1, 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 25.9,
26.0, 26.1, 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9, 27.0, 27.1, 27.2, 27.3, 27.4, 27.5,
27.6, 27.7, 27.8, 27.9, 28.0, 28.1, 28.2, 28.3, 28.4, 28.5, 28.6, 28.7, 28.8, 28.9, 29.0, 29.1 ,
29.2, 29.3, 29.4, 29.5, 29.6, 29.7, 29.8, 29.9, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42,
43, 44, 45, 46, 47, or 48 months from the start of treatment with the tivozanib and durvalumab.
[0099] In certain embodiments, a population of subjects having HCC who is treated with tivozanib and durvalumab according to the disclosed methods, where the subjects have previously received treatment with bevacizumab and atezolizumab for the HCC, experiences a median progression free survival of at least 6.0, 6.1, 6.2, 6.2, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0,
7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1,
9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 1 1.2, 11.3, 11.4, 11.5, 1 1.6, 11.7, 11.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 13.0, 13.1, 13.2, 13.3, 13.4, 13.5, 13.6, 13.7, 13.8, 13.9, 14.0, 14.1,
14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9, 15.0, 15.1, 15.2, 15.3, 15.4, 15.5, 15.6, 15.7,
15.8, 15.9, 16.0, 16.1 , 16.2, 16.3, 16.4, 16.5, 16.6, 16.7, 16.8, 16.9, 17.0, 17.1, 17.2, 17.3,
17.4, 17.5, 17.6, 17.7, 17.8, 17.9 18.0, 18.1 , 18.2, 18.3, 18.4, 18.5, 18.6, 18.7, 18.8, 18.9,
19.0, 19.1 , 19.2, 19.3, 19.4, 19.5, 19.6, 19.7, 19.8, 19.9, 20.0, 20.1, 20.2, 20.3, 20.4, 20.5,
20.6, 20.7, 20.8, 20.9, 21.0, 21.1 , 21.2, 21.3, 21.4, 21.5, 21.6, 21.7, 21.8, 21.9, 22.0, 22.1,
22.2, 22.3, 22.4, 22.5, 22.6, 22.7, 22.8, 22.9, 23.0, 23.1, 23.2, 23.3, 23.4, 23.5, 23.6, 23.7,
23.8, 23.9, 24.0, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1, 25.2, 25.3,
25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26.0, 26.1 , 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9,
27.0, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, 28.0, 28.1 , 28.2, 28.3, 28.4, 28.5,
28.6, 28.7, 28.8, 28.9, 29.0, 29.1 , 29.2, 29.3, 29.4, 29.5, 29.6, 29.7, 29.8, 29.9, 30, 31, 32, 33,
34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, or 48 months upon receiving the tivozanib and durvalumab. In certain embodiments, the population of subjects experiences a median overall survival of at least 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3, 1 1.4, 11.5, 11.6, 11.7, 1 1.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4, 12.5,
12.6, 12.7, 12.8, 12.9, 13.0, 13.1, 13.2, 13.3, 13.4, 13.5, 13.6, 13.7, 13.8, 13.9, 14.0, 14.1 ,
14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9, 15.0, 15.1, 15.2, 15.3, 15.4, 15.5, 15.6, 15.7,
15.8, 15.9, 16.0, 16.1, 16.2, 16.3, 16.4, 16.5, 16.6, 16.7, 16.8, 16.9, 17.0, 17.1, 17.2, 17.3,
17.4, 17.5, 17.6, 17.7, 17.8, 17.9 18.0, 18.1 , 18.2, 18.3, 18.4, 18.5, 18.6, 18.7, 18.8, 18.9,
19.0, 19.1 , 19.2, 19.3, 19.4, 19.5, 19.6, 19.7, 19.8, 19.9, 20.0, 20.1, 20.2, 20.3, 20.4, 20.5,
20.6, 20.7, 20.8, 20.9, 21.0, 21.1, 21.2, 21.3, 21.4, 21.5, 21.6, 21.7, 21.8, 21.9, 22.0, 22.1,
22.2, 22.3, 22.4, 22.5, 22.6, 22.7, 22.8, 22.9, 23.0, 23.1, 23.2, 23.3, 23.4, 23.5, 23.6, 23.7,
23.8, 23.9, 24.0, 24.1 , 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1, 25.2, 25.3,
25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26.0, 26.1 , 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9,
27.0, 27.1, 27.2, 2.7.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, 28.0, 28.1, 2.8.2, 28.3, 28.4, 28.5,
28.6, 28.7, 28.8, 28.9, 29.0, 29.1 , 29.2, 29.3, 29.4, 29.5, 29.6, 29.7, 29.8, 29.9, 30, 31, 32, 33,
34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, or 48 months from the start of treatment with the tivozanib and durvalumab.
[0100] In one embodiment, the population of subjects with HCC has 7, 8, 9, 10, 11, 12,
13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37,
38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62,
63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76. 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87,
88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101 , 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 1 18, 119, 120, 121 , 122, 123, 124, 125, 126,
127, 128, 129, 130, 131 , 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, or 150 members.
III. Dosage and Administration of Tivozanib and Durvalumab
[0101] Exemplary effective amounts, dosages, or treatment regimens of tivozanib include 0.5-3 mg, 0.5-2 mg, 1-3 mg, 0.5-1.5 mg, 1.0-2.0 mg, 1.0-1.5 mg. 1.4-1.6 mg, 0.8-0.9 mg, 0.9-1.0 mg, 0.9-1. 1 mg, 1, 0-1.1 mg, 1.1-1.2 mg, 1.2-1.3 mg, 1.3-1.4 mg, 1.4-1.5 mg, 1.4-1.6 mg, 1.5-1.6 mg, 1.6-1.7 mg, 1.7-1.8 mg, 1.8-1.9 mg, 1.8-2.0 mg or 1.9-2.0 mg daily or every other day. For example, the dose of tivozanib is 1 .5 mg. For example, the dose of tivozanib is 1.34 mg. For example, the dose of tivozanib is 1 mg. For example, the dose of tivozanib is 0.89 mg.
[0102] The amount of tivozanib administered will depend on variables such as the type and extent of disease or indication to be treated, the overall health of the patient, the pharmaceutical formulation, and the route of administration. The initial dosage can be increased beyond the upper level in order to rapidly achieve the desired blood-level or tissuelevel. Alternatively, the initial dosage can be smaller than the optimum, and the daily dosage may be progressively increased during the course of treatment. Human dosage can be optimized, e.g., in a conventional Phase I dose escalation study. Dosing frequency can vary, depending on factors such as route of administration, dosage amount, and the disease being treated.
[0103] Exemplary dosing frequencies for tivozanib are once per day, once every other day, once every' three days, once every' four days, once every' five days, once every' six days, once per week and once every’ two weeks. In one embodiment, the dosing frequency is every' day for 21 days with 7 days off, that is, administration on days 1-21 of a 28 day treatment cycle, with no administration on days 22-28. In another embodiment, the dosing frequency is every' day' for 28 days. In another embodiment, the dosing frequency is every' other day' for 28 days. For example, the dosing frequency is every' other day for 28 days beginning on day one of a 28 day treatment cycle.
[0104] In one embodiment, the dosage of tivozanib is 1.5 mg daily. In another embodiment, the dosage is 1.0 mg daily. Additional exemplary' effective amounts, dosages, or treatment regimens of tivozanib are described in U.S. Patent Nos. 6,821,987, and 7,166,722 and in International Patent Application No. WO 2020/097106. [0105] According to one embodiment, the dosage is 1.0 mg daily of tivozanib hydrochloride (equivalent to 0.89 mg tivozanib free base). According to another embodiment, the dosage is 1.5 mg daily of tivozanib hydrochloride (equivalent to 1.34 mg tivozanib free base). In one embodiment, the dose is 1.34 mg daily of tivozanib free base. In another embodiment, the dose is 0.89 mg daily of tivozanib free base.
[0106] According to one embodiment, the dose of tivozanib is 1.5 mg (1.34 mg tivozanib free base) daily for 21 days followed by seven days off (i.e., 0 mg tivozanib for 7 days).
[0107] According to one embodiment, a 1.5 mg daily dose of tivozanib (1.34 mg tivozanib free base) for 21 days is reduced to 1.0 mg (0.89 mg tivozanib free base) daily for 21 days when a subject experiences a > Grade 3 drug-related adverse event.
[0108] According to one embodiment, a 1.5 mg daily dose of tivozanib (1.34 mg tivozanib free base) for 21 days is reduced to 1.0 mg (0.89 mg tivozanib free base) every other day for 28 days when a subject experiences a> Grade 3 drug-related adverse event.
[0109] According to one embodiment, the dose of tivozanib is 1.0 mg daily (0.89 mg tivozanib free base) for 21 days followed by seven days off (i.e., 0 mg tivozanib for 7 days).
[0110] According to one embodiment, a 1.0 mg daily dose of tivozanib (0.89 mg tivozanib free base) for 21 days is reduced to 1.0 mg (0.89 mg tivozanib free base) every7 other day for 28 days when a subject experiences a> Grade 3 drug-related adverse event.
[0111] In one embodiment, the dose is 1.5 mg daily of tivozanib hydrochloride administered for 21 days followed by 7 days without administration, which constitutes a treatment cycle. In one embodiment, the dose is 1.0 mg daily of tivozanib hydrochloride administered for 21 days followed by 7 days without administration, which constitutes a treatment cycle. In one embodiment, the dose is 1.0 mg daily of tivozanib hydrochloride administered for 2.8 days, which constitutes a treatment cycle. In one embodiment, the dose is 1.0 mg of tivozanib hydrochloride administered every other day for 28 days, which constitutes a treatment cycle. In one embodiment, the dose is 1.5 mg every' other day of tivozanib hydrochloride administered for 28 days, which constitutes a treatment cycle.
[0112] Tivozanib may be administered as an oral tablet or capsule or as an intravenous (IV) infusion. When administered as an oral tablet or capsule, the dosage of tivozanib maybe provided in a single capsule or tablet or in two or more capsules or tablets. In one embodiment, tivozanib is administered as a single dose tablet. In one embodiment, tivozanib is administered as a tablet or capsule. [0113] Exemplary effective amounts, dosages, or treatment regimens of tivozanib include administration on a repeating schedule of one dose (e.g, a single dosage contains 0.5-2.0 mg of tivozanib) per day for three weeks, followed by one week off (i.e., 3 weeks on, 1 week off). For example, tivozanib may be administered on a repeating schedule of 0.5-3 mg, 0.5-2 mg, 0.5-1.5 mg, 1.0-3.0 mg, 1 .0-2.0 mg, 1.0-1 .5 mg, or 1.4-1.6 mg per day for three weeks, followed by one week off (i.e., 3 -weeks on, 1 week off). The period of time beginning from Day 1 of administration to the last day of the week off may be referred to as a treatment cycle. In other embodiments, tivozanib may be administered as one dose (e.g., a single dosage contains 0.5-2.0 mg of tivozanib) per day. For example, tivozanib may be administered at a dose of 0.5-3 mg, 0.5-2 mg, 0,5-1.5 mg, 1.0-3.0 mg, 1.0-2.0 mg, 1.0-1, 5 mg or 1.4-1.6 mg, 1 mg, or 1.5 mg daily.
[0114] In one embodiment, tivozanib is administered in an amount of 1.5 mg per day. In another embodiment, tivozanib is administered in an amount of 1.0 mg per day. In another embodiment, tivozanib is administered in an amount of 1.5 mg per day every day for three weeks (i.e., 21 days), followed by one week (i.e., 7 days) with no dose of tivozanib (i.e., 3 weeks on, 1 week off), where three weeks on tivozanib and one week off constitutes a 4 week (28 day) treatment cycle.
[0115] In one embodiment, tivozanib is orally administered in an amount of 1.5 mg daily as a single dose for three weeks, followed by one week off. In another embodiment, tivozanib is administered orally in an amount of 1.0 mg daily as a single dose for three weeks, followed by one week without administration of tivozanib. According to these embodiments, three weeks “on” and one week “off” constitutes a 4 wreek (28 day) treatment cycle.
[0116] In one embodiment, tivozanib is orally administered in an amount of 1.0 mg every other day for 4 weeks (i.e., 28 days), which constitutes a treatment cycle. In another embodiment, tivozanib is orally administered in an amount of 1.0 mg every’ day for 3 weeks followed by one week off, which constitutes a 28 day treatment cycle.
[0117] In one embodiment, tivozanib is orally administered in an amount of 1.5 mg daily and reduced to 1,0 mg daily when the subject experiences a> Grade 3 drug-related adverse event in the treatment of HCC. In this embodiment, the administration period for tivozanib is three weeks (starting from the first 1.5 nig dose), followed by one week without administration of tivozanib. According to this embodiment, three weeks on and one week off constitutes a 4-week (28 day) treatment cycle.
[0118] In one embodiment, tivozanib is orally administered in an amount of 1.0 mg daily for three weeks, followed by one week off, and reduced to 1.0 mg every' other day when the subject experiences a > Grade 3 drug-related adverse event in the treatment of HCC. In this embodiment, the administration period for tivozanib is three weeks (starting from the first 1.0 mg dose), followed by one week without administration of tivozanib. According to this embodiment, three weeks on (administration from day 1-21) and one week off (no administration on days 22-28) constitutes a 4-week (28 day) treatment cycle.
[0119] According to one embodiment, a subject undergoes one, two, three, four, five, six, seven, eight, nine, ten, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 2.5, 26, 27, 28, 29, 30, or more treatment cycles of tivozanib, for example, where the treatment cycle is a four week (28 day) treatment cycle of tivozanib. According to one embodiment, a treatment cycle (for example, a four-week treatment cycle) is repeated as long as the subject experiences a clinical benefit or until the subject experiences unacceptable toxicity.
[0120] In a further embodiment, tivozanib is administered as a capsule. In a further embodiment, the capsule contains gelatin or gelatin and titanium dioxide.
[0121] In a further embodiment, tivozanib is formulated as a pharmaceutical composition with mannitol and magnesium stearate. In other embodiments, other pharmaceutically acceptable carriers may be used.
[0122] Exemplary' effective amounts, dosages, or treatment regimens durvalumab include 200-2,000 mg, 500-1,500 mg, 750-1,250 mg, 1,000-2,000 mg, or 1,2.50-750 mg. For example, the dose of durvalumab is 1,500 nig. For example, in one embodiment, a subject receives a fixed dose of 1 ,500 nig durvalumab once every 28 days. In one embodiment, a subject receives a fixed dose of 1 ,500 mg durvalumab if the subject’s weight is greater than 30 kg.
[0123] The amount of durvalumab administered will depend on variables such as the type and extent of disease or indication to be treated, the overall health and weight of the patient, the pharmaceutical formulation, and the route of administration. The initial dosage can be increased beyond the upper level in order to rapidly achieve the desired blood-level or tissuelevel. Alternatively, the initial dosage can be smaller than the optimum, and the daily dosage may be progressively increased during the course of treatment. Human dosage can be optimized, e.g., in a conventional Phase I dose escalation study. Dosing frequency can vary, depending on factors such as route of administration, dosage amount, and the disease being treated.
[0124] Exemplary dosing frequencies for durvalumab are once ever}' 28 days (4 weeks), once every three weeks (21 days), once ever}' two weeks (14 days), or once every week (7 days). For example, in one embodiment durvalumab is administered once every 28 days, that is, on day 1 of a 28 day treatment cycle, where no durvalumab is administered on days 2-28. In another embodiment, durvalumab is administered once every 14 days (2 weeks), that is, on day 1 of a 14 day treatment cycle, where no durvalumab is administered on days 2-14. In another embodiment, durvalumab is administered once every 14 days (2 weeks), that is, on days 1 and 15 of a 28 day treatment cycle, where no durvalumab is administered on days 2-14 and 16-28. In another embodiment, durvalumab is administered once ever}' 21 days (3 weeks), that is, on day 1 of a 21 day treatment cycle, where no durvalumab is administered on days 2-2.1.
[0125] In some embodiments, the dosage of durvalumab is determined based on the weight of the subject to which the durvalumab is being administered. For example, exemplary dosages of durvalumab are 1-100 mg/kg, 50-100 mg/kg, 50 -75 mg/kg, 20-40 mg/kg, 15-35 mg/kg, 10-30 mg/kg, or 5-15 mg/kg. For example, the dose of durvalumab is 20 mg/kg. For example, the dose of durvalumab is 10 mg/kg. In one embodiment, a subject receives 20 mg/kg of durvalumab once even' 28 days, e.g., on day 1 of a 28 day treatment cycle. In one embodiment, a subject receives 10 mg/kg of durvalumab once every 14 days, e.g., on day 1 of a 14 day treatment cycle, or on days 1 and 15 of a 28 day treatment cycle.
[0126] In one embodiment, if a subject’s weight is at or below 30 kg (<30 kg), then the subject receives weight-based dosing equivalent to 10 mg/kg of durvalumab. In one embodiment, if a subject’s weight is at or below' 30 kg (<30 kg), then the subject receives weight-based dosing equivalent to 10 mg/kg of durvalumab, whereas if the subject’s weight is greater than 30 kg, the subject receives a fixed dose of 1,500 mg of durvalumab. In one embodiment, if a subject’s weight is at or below 30 kg (<30 kg), then the subject receives weight-based dosing equivalent to 10 mg/kg of durvalumab once every 14 days, whereas if the subject’s weight is greater than 30 kg, the subject receives a fixed dose of 1,500 mg of durvalumab once every 28 days. [0127] In one embodiment, if a subject’s weight is at or below 30 kg (<30 kg), then the subject receives weight-based dosing equivalent to 20 mg/kg of durvalumab. In one embodiment, if a subject’s weight is at or below' 30 kg (<30 kg), then the subject receives weight-based dosing equivalent to 20 mg/kg of durvalumab, whereas if the subject’s weight is greater than 30 kg, the subject receives a fixed dose of 1 ,500 mg of durvalumab. In one embodiment, if a subject’s weight is at or below 30 kg (<30 kg), then the subject receives weight-based dosing equivalent to 20 mg/kg of durvalumab once every 28 days (e.g., on day 1 of a 28 day treatment cycle), whereas if the subject’s weight is greater than 30 kg, the subject receives a fixed dose of 1 ,500 mg of durvalumab once every 28 days (e.g., on day 1 of a 28 day treatment cycle).
[0128] In one embodiment, if a subject’s weight is at or below' 30 kg (<30 kg), then the subject receives weight-based dosing equivalent to 20 mg/kg every three weeks (21 days) for four cycles followed by 10 mg/kg every 2 weeks thereafter, whereas if the subject’s weight is above 30 kg, then the subject receives 1,500 mg even' three weeks for four cycles followed by 1,500 mg every four weeks thereafter.
[0129] In certain embodiments, a disclosed method comprises administering durvalumab at a dose of 1,500 mg on day 1 followed by no administration of durvalumab on days 2-28. In one embodiment, a subject is administered 1,500 mg of durvalumab on day 1 of a 28 day treatment cycle followed by no administration of durvalumab on days 2-28, and the subject is administered 1.0 mg tivozanib (0.89 tivozanib free base) on days 1-21 of the 28 day treatment cycle and is administered no tivozanib on days 22-28 to treat HCC, e.g., advanced HCC, in the subject. In one embodiment, the durvalumab is administered intravenously, while the tivozanib is administered orally as a capsule or tablet. In one embodiment, the tivozanib and durvalumab are administered as a first systemic therapy to a subject with HCC that has not previously been treated with a systemic therapy. In another embodiment, the tivozanib and durvalumab are administered as a second or later line systemic therapy to a subject with HCC that has been previously treated with systemic therapy, for example, a VEGF inhibitor and/or a checkpoint inhibitor, e.g., sorafenib, or e.g., bevacizumab and atezolizumab. In one embodiment, the treatment cycle is repeated as many times as necessary' until the patient experiences an unacceptable toxicity' or progresses.
[0130] In another embodiment, a subject is administered 1,500 mg of durvalumab on day 1 of a 28 day treatment cycle followed by no administration of durvalumab on days 2-28, and the subject is administered 1.0 mg tivozanib (0.89 tivozanib free base) on day 1 and every other day thereafter of the 28 day treatment cycle to treat HCC, e.g., advanced HCC, in the subject. In one embodiment, the durvalumab is administered intravenously, while the tivozanib is administered orally as a capsule or tablet. In one embodiment, the tivozanib and durvalumab are administered as a first line systemic therapy to a subject with HCC that has not previously been treated with a systemic therapy. In another embodiment, the tivozanib and durvalumab are administered as a second or later line systemic therapy to a subject with HCC that has been previously treated with systemic therapy, for example, a VEGF inhibitor and'' or a checkpoint inhibitor, e.g., sorafenib, or e.g., bevacizumab and atezolizumab. In one embodiment, the treatment cycle is repeated as many times as necessary until the patient experiences an unacceptable toxicity' or progresses.
[0131] In one embodiment, a subject, e.g, a subject weighing 30 kg or less, is administered 20 nig/kg of durvalumab on day 1 of a 28 day treatment cycle followed by no administration of durvalumab on days 2-28, and the subject is administered 1 .0 mg tivozanib (0.89 tivozanib free base) on days 1-21 of the 28 day’ treatment cycle and is administered no tivozanib on days 22-28 to treat HCC, e.g., advanced HCC, in the subject. In one embodiment, the durvalumab is administered intravenously, wftile the tivozanib is administered orally as a capsule or tablet. In one embodiment, the tivozanib and durvalumab are administered as a first systemic therapy’ to a subject with HCC that has not previously been treated with a systemic therapy. In another embodiment, the tivozanib and durvalumab are administered as a second or later line systemic therapy to a subject with HCC that has been previously treated with systemic therapy, for example, a VEGF inhibitor and/or a checkpoint inhibitor, e.g, sorafenib, or e.g. bevacizumab and atezolizumab. In one embodiment, the treatment cycle is repeated as many times as necessary until the patient experiences an unacceptable toxicity' or progresses.
[0132] In one embodiment, a subject, e.g, a subject weighing 30 kg or less, is administered 20 nig/kg of durvalumab on day 1 of a 28 day treatment cycle followed by no administration of durvalumab on days 2-28, and the subject is administered 1 .0 mg tivozanib (0.89 tivozanib free base) on day 1 and every other day thereafter of the 28 day treatment cycle to treat HCC, e.g, advanced HCC, in the subject. In one embodiment, the durvalumab is administered intravenously , while the tivozanib is administered orally as a capsule or tablet. In one embodiment, the tivozanib and durvalumab are administered as a first systemic therapy to a subject with HCC that has not previously been treated with a systemic therapy. In another embodiment, the tivozanib and durvalumab are administered as a second or later line systemic therapy to a subject with HCC that has been previously treated with systemic therapy, for example, a VEGF inhibitor and/or a checkpoint inhibitor, e.g., sorafenib, or e.g., bevacizumab and atezolizumab. In one embodiment, the treatment cycle is repeated as many times as necessary until the patient experiences an unacceptable toxicity or progresses.
[0133] In one embodiment, the durvalumab may be administered as an as an intravenous (IV) infusion, for example, over a period of 60 minutes and/or at a concentration of 10- 100 mg/mL. In one embodiment, the concentration of the durvalumab formulation is 50 mg/mL. In one embodiment, durvalumab at a concentration of 50 mg/mL is added to an infusion solution of 0.9% sodium chloride injection, USP or 5% dextrose injection USP and diluted to a final concentration of between 1 mg/mL and 15 mg/mL prior to administration to the subject.
|0134] According to one embodiment, a subject undergoes one, two, three, four, five, six, seven, eight, nine, ten, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, or more treatment cycles of durvalumab and tivozanib. According to one embodiment, a treatment cycle (for example, a four-week treatment cycle) is repeated as long as the subject experiences a clinical benefit or until the subject experiences unacceptable toxicity,
EXAMPLES
[0135] The invention is further illustrated by the following examples. The following examples are provided for illustration purposes only, and are not to be construed as limiting the scope or content of the invention in any way.
Example 1: A Phase lb/2, Open-Label, Study of Tivozanib in Combination with Durvalumab in Subjects with Advanced Hepatocellular Carcinoma
[0136] This study was designed to test the hypothesis that tivozanib and durvalumab can be combined for the treatment of subjects with HCC. The purpose of the study was, in part, to determine the maximum dose of tivozanib that can be safely combined with durvalumab, and to evaluate the tolerability and safety profile of this combination. Given the different mechanisms of action and lack of overlapping toxicities, this combination may provide an alternative therapy to subjects with HCC. OBJECTIVES
[0137] Primary Objectives
* To establish the safety and tolerability of tivozanib in combination with durvalumab in subjects with advanced hepatocellular carcinoma (HCC) that are untreated or pretreated with both bevacizumab and atezolizumab in a prior line of therapy.
[0138] Secondary Objectives
» To estimate the response rate of tivozanib in combination with durvalumab in subjects with untreated advanced HCC and after treatment with both bevacizumab and atezolizumab.
* To estimate the progression free survival (PFS) of tivozanib in combination with durvalumab in subjects with untreated advanced HCC and after treatment with both bevacizumab and atezolizumab.
® To estimate the overall survival (OS) of tivozanib in combination with durvalumab in subjects with untreated advanced HCC and after treatment with both bevacizumab and atezolizumab.
[0139] Exploratory Objectives
« To estimate durvalumab pharmacokinetics (PK) in the presence of tivozanib.
* To estimate the effect of PD-L1 expression on activity of the combination.
ELIGIB1 LETT ASSESSMENT AND ENROLLMENT
[0140] Subject enrollment/regi strati on took place before study drug administration (Day
1). All eligibility criteria was met at the time of enrol Iment/registrati on. Eligible subjects were of either sex, age > 18 years, and with histologically or cytologically confirmed untreated HCC or after treatment with both bevacizumab and atezolizumab. Patients must have met at least the following inclusion criteria.
* > 18 years old
* Histologically or cytologically confirmed unresectable locally advanced or metastatic hepatocellular carcinoma. Measurable or evaluable disease by RECIST 1.1 criteria. Patients can be either untreated or have progressed on both bevacizumab and atezolizumab. * Child-Pugh Class A
« ECOG performance status < 1 (see Oken et cd. (1982) Am J Clin Oncol (CCT) 5:649- 655)
« Life expectancy > 3 months
® Body weight > 30 kg
* Measured creatinine clearance (crCL) >40 mL/min or calculated crCL >40 mL/min as determined by Cockcroft-Gault (using actual body weight) o Males CrCL = [Weight (kg) * (140 - Age)] / [72 * serum creatinine (mg/dL)] o Females CrCL = [Weight (kg) * (140 -- Age)] / [85 * serum creatinine (mg/dL)]
» Sexually active pre-menopausal female subjects (and female partners of male subjects) must use highly effective contraceptive measures while on study and for at least 90 days after the last dose of study drug. Sexually active male subjects must use adequate contraceptive measures, while on study and for at least 90 days after the last dose of study drug. All fertile male and female subjects and their partners must agree to use a highly effective method of contraception.
[0141] Subjects must not have met any of the following exclusion criteria to be eligible for participation in the study.
® Subjects who have received prior systemic treatment for HCC except for both bevacizumab and atezolizumab.
* Female subjects who are pregnant or breastfeeding or male or female subjects of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of study drug.
* Brain metastases or spinal cord compression. Subjects with suspected brain metastases at screening should have an MRI (preferred) or CT scan each preferable with IV contrast of the brain prior to study entry'. Brain metastases will not be recorded on RECIST Target Lesions at baseline.
* Any’ of the following hematologic abnormalities: o Hemoglobin < 9.0 g/dL o Absolute neutrophil count (ANC) < 1,500 per mm3 o Platelet count < 75,000 per mm3
« Any of the following serum chemistry or urinalysis abnormalities: o Total bilirubin > 2 x ULN (>2.5 mg/dL in subjects with Gilbert’s syndrome) o AST or ALT > 5 x ULN o Alkaline phosphatase > 2.5 x ULN (or > 5 x ULN for subjects with liver or bone metastasis) o Serum creatinine > 1.5 * ULN o > 2+ proteinuria
* History of hepatic encephalopathy within past 12 months or requirement for medications to prevent or control encephalopathy (e.g., no lactulose, rifaximin, etc. if used for purposes of hepatic encephalopathy).
* GI Bleeding (e.g., esophageal varices or ulcer bleeding) within 12 months.
® Clinically meaningful ascites defined as ascites requiring non-pharmacologic intervention (e.g., paracentesis) to maintain symptomatic control, within 6 months prior to the first scheduled dose. Subjects on stable doses of diuretics for ascites for > 2. months are eligible.
« Mam portal vein thrombosis (Vp4) as documented on imaging. VP4 is defined as portal vein thrombosis in the main trunk of the portal vein or a portal vein branch contralateral to the primarily involved lobe (or both).
* For subjects who require ongoing therapeutic anti-coagulation or anti-platelet therapy; the subject must be off either therapy for at least 7 days prior to the first dose of investigational product. Low-dose aspirin for cardiac prophylaxis/protection is permitted per local institutional standards.
* Patients co-infected with HBV and HCVHBV positive [presence of hepatitis B surface antigen (HBsAg) and/or hepatitis B core antibodies (anti-HBcAb) with detectable HBV ONA (>10I U/ml)]; HCV positive (presence of anti-HCV antibodies). * Major surgery' (as defined by the Investigator) within 28 days prior to first dose or still recovering from prior surgery. Local procedures (e.g., core needle biopsy, and prostate biopsy) are allowed if completed at least 3 days prior to the administration of the first dose of study treatment.
* Significant cardiovascular disease, including: o Clinically symptomatic heart failure. Subjects with a history of heart failure must have an ECHO or MUGA scan to document left ventricular ejection fraction (LVEF) > 45% prior to start of protocol therapy. o Any New York Heart Association classification > Class 2 (prefer Class 0 or 1) o Any stenting procedure within the last 3 months o Venous thromboembolism or arterial thromboembolism within the last 3 months o Any IV C tumor thrombosis o Histoty of a hemorrhagic event (GI bleed within 6 months) o Uncontrolled hypertension: blood pressure >150/95 mmHg on more than 2 antihypertensive medications, on two consecutive measurements obtained at least 24 hours apart. Subjects with a history of hypertension must have been on stable doses of anti-hypertensive drugs for > 2 weeks prior to start of protocol therapy o Myocardial infarction within 3 months prior to start of protocol therapy
» Subjects with delayed healing of wounds, ulcers, and/or bone fractures.
® Serious/active infection or infection requiring parenteral antibiotics.
» Inadequate recovery from any prior surgical procedure: major surgical procedure within 4 weeks prior to start of protocol therapy.
® Inability to comply with protocol requirements.
* History of another primary malignancy except for:
Malignancy treated with curative intent and with no known active disease > 5 years before the first dose of study drug and low' potential risk for recurrence Adequately treated non-melanoma skin cancer of lentigo maligna without evidence of disease
* Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Subjects positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
® Patients with a history' or current HBV infection (detectable HBV DN A), should be placed on anti-viral treatment and tested at every cycle for HBV DNA viral load.
* Palliative radiotherapy' with a limited field of radiation within 2 weeks or with wide field of radiation or to more than 30% of the bone marrow' within 4 weeks before the first dose of study intervention.
® Treatment with systemic hormonal therapy within 3 weeks prior to start, of protocol therapy, with the exception of: o Hormonal therapy for appetite stimulation or contraception o Nasal, ophthalmic, inhaled and topical steroid preparations o Oral replacement therapy for adrenal insufficiency o Low-dose maintenance steroid therapy (equivalent of prednisone 10 mg/day) for other conditions o Hormone replacement therapy such as testosterone
* Strong CYP3A4 inducers within 2. weeks prior to start of, or during, protocol therapy'
« Prior exposure to tivozanib or durvalumab. For subjects who have received prior atezolizumab: o Must not have experienced a toxicity that led to permanent discontinuation of prior immunotherapy o All AEs while receiving prior immunotherapy must have completely resolved or resolved to baseline prior to screening for this study o Must not have experienced a Grade > 3 immune-related AE or an immune- related neurologic or ocular AE of any grade while receiving prior immunotherapy. Participants with an endocrine AE of Grade < 2 are permitted to enroll if they are stably maintained on appropriate replacement therapy and are asymptomatic.
* Must not have required the use of additional immunosuppression other than corticosteroids for the management of an AE, not have experienced recurrence of an AE if re-challenged, and not currently require maintenance doses of > 10 mg prednisone or equivalent per day.
* History of allogeneic organ transplantation.
» Active or prior documented autoimmune or inflammatory' disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis. Graves’ disease, rheumatoid arthritis, hypophysitis, uveitis, e/c,]). The following are exceptions to this criterion: o Subjects with vitiligo or alopecia o Subjects with hypothyroidism (e.g, following Hashimoto syndrome) stable on hormone replacement o Any chronic skin condition that does not require systemic therapy o Subjects without active disease in the last 5 years may be included but only after consultation with Medical Monitor o Subjects with celiac disease controlled by diet alone
® Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, active interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the subject to give written informed consent
» History of leptomeningeal carcinomatosis.
« History’ of active primary immunodeficiency. * Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) > 470 ms calculated from 3 ECGs (within 15 minutes at 5 minutes apart).
® Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients,
® Concurrent enrollment in another clinical study, unless it is an observational (non interventional) clinical study or during the follow-up period of an interventional study.
» Receipt of live attenuated vaccine within 30 days prior to the first dose of study drug. Subjects, if enrolled, should not receive live vaccine whilst receiving study drug and up to 30 days after the last dose of study drug.
* Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion: o Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection) o Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent o Steroids as premedication for hypersensitivity reactions {e.g., CT scan premedication)
* Previous study drug assignment in the present study.
STUDY DESIGN
[0142] This was a Phase lb/2, open-label study of tivozanib in combination with durvalumab. This study was designed to evaluate the safety, tolerability, and preliminary antineoplastic activity of tivozanib in combination with durvalumab in subjects with advanced HCC. An overview of the study design is depicted in FIG. 1.
[0143] Subjects were enrolled into dose cohorts in a sequential manner. Enrollment to the next cohort occurred only after acceptable tolerance has been demonstrated throughout Cycle 1 (28 days), and only after consultation with the medical monitor. The number of cohorts enrolled and maximum dose administered depended on observed tolerability.
[0144] This study included 2 parts: a dose finding phase and a dose expansion phase. [0145] In the dose finding phase, six subjects were enrolled at tivozanib .89 nig daily for 21 days and durvalumab 1 ,500 mg every 28 days. In other words, on Day 1 of Cycle 1, tivozanib was administered once daily for 3 weeks followed by 1 week off (1 cycle = 28 days), and durvalumab was administered every 28 days starting on Day 1 of Cycle I .
[0146] A modification of the “3 + 3” schema was used during the dose finding phase. Six subjects were treated at the same dose (Dose Level 1). If < 2 of the 6 subjects treated experience a DLT within Cycle 1, the trial would continue to the dose expansion phase. If > 2 of the 6 subjects experience a DLT at the Dose Level I the study would proceed to Dose Level -1. If > 2 of the 6 subjects experience a DLT at the Dose Level -1 within Cycle 1 , the study would close.
[0147] The combination would be considered safe for further study if < 2 of 6 subjects experience a DLT during the first cycle (28 days) of the dose finding phase of the study.
[0148] Upon determination of MTD during the dose finding phase, there was an expansion cohort of up to 35 additional subjects at MTD (dose expansion phase). The study will enroll a total of approximately 20 patients in each of two cohorts, untreated (Cohort A) and after treatment with both bevacizumab and atezolizumab (Cohort B).
STUDY DRUG/ADMINISTRA TION
[0149] Tivozanib (previously known as AV-951 ) is a potent VEGF-TKI.
[0150] The tivozanib drug product was a capsule containing 1.0 mg of tivozanib hydrochloride salt equivalent to 0.89 mg of tivozanib free base. Any reference to tivozanib 1.0 mg is to be understood as 1.0 mg of tivozanib hydrochloride salt which is equivalent to 0.89 mg of tivozanib free base.
[0151] On Day 1 of Cycle 1, tivozanib .89 mg was administered once daily (Dose Level 1) for 3 weeks followed by 1 week off (1 cycle = 28 days) to 6 subjects in dose cohort 1. If >1 subject had a dose-limiting toxicity (DLT) DLT in cohort 1, a second cohort of 6 subjects would be enrolled at .89 mg every other day (Dose Level -1) without interruption (14 doses per 28 days) with durvalumab, Tivozanib dosing repeats every' cycle in the absence of disease progression or unacceptable toxicity.
[0152] Tivozanib dose reduction was recommended for subjects with > Grade 3 adverse events. Tivozanib should be held for grade 4 adverse events. For patients on dose level 1 for whom dose reduction is required, the dose of tivozanib should be reduced to .89 mg every other day. If this dose was not tolerated, then tivozanib should be discontinued.
[0153] Durvalumab is a human mAb of the IgG 1 kappa subclass that blocks the interaction of PD-L1 (but not programmed cell death ligand-2) with PD 1 on T cells and CD80 (B7.1) on immune cells.
[0154] Durvalumab solution for infusion after dilution was supplied in glass vials containing 500 mg durvalumab at a concentration of 50 mg/mL. The solution contained 50 mg/mL durvalumab. 26 mM histidine/histidine hydrochloride, 275 mM trehalose dihydrate, and 0.02% weight/volume (w/v) polysorbate 80; it had a pH of 6.0 and a density of 1.054 g/mL. The label-claim volume was 10 ml...
[0155] In both parts of the study, on Day 1, durvalumab (1,500 mg even' 28 days) was administered as an intravenous infusion over 60 minutes. A dose of 1,500 mg was administered using an IV bag containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final durvalumab concentration ranging from 1 to 15 mg/mL and delivered through an IV administration set with a 0.2- or 0.22-pm filter. The infusion was given over 1 hour.
[0156] Subjects received durvalumab 1,500 mg via IV infusion every' 28 days starting on Day 1 of Cycle 1 . Subjects received 1 treatment of durvalumab in each treatment cycle, starting on Day 1.
[0157] If a subject’s weight falls to 30 kg or below (< 30 kg), then the subject should receive weight-based dosing equivalent to 20 mg/kg of durvalumab every' 2.8 days after consultation between Investigator and Medical Monitor, until the weight improves to above 30 kg (>30 kg), at which point the subject should start receiving the fixed dosing of durvalumab 1,500 mg every 28 days.
[0158] Subj ects were to be treated until progression per RECIST 1.1 or until unacceptable toxicity.
[0159] Durvalumab administration may be delayed or withheld. However, dose reduction was not permitted.
[0160] Tivozanib or durvalumab may be interrupted independently of each other. If tivozanib or durvalumab was interrupted, treatment with the other therapy (durvalumab or tivozanib, respectively) may continue as scheduled. [0161] Subjects with documented stable disease (SD) or an objective response (complete response [CR] or partial response [PR]) may continue to receive treatment at the same dose and schedule until progression if tolerability is acceptable.
EVALUATIONS Dose Limiting Toxicity
[0162] A Dose-Limiting Toxicity (DLT) was generally defined as the occurrence of any Grade >3 immune or non-immune adverse event (AE) in Cycle 1 that is at least possibly related to the study drug or investigational regimen with 2 exceptions: any grade of vitiligo, alopecia or grade 3 controllable hypertension will not qualify as a DLT. Adverse events that are at least possibly related to durvalumab-containing regimens were assessed as DLTs if they met any of the following specific criteria:
* Hematologic toxicity: o Grade >3 neutropenia complicated by fever >38.5°C o Grade 4 neutropenia (lasting more than 7 days) o Grade >3 thrombocytopenia with significant bleeding o Grade 4 thrombocytopenia (regardless of duration) o Grade 4 anemia (regardless of duration)
* Non-hematologic toxicity:
Figure imgf000047_0001
Figure imgf000048_0001
ALT=alanine aminotransferase; AST=aspaitate aminotransferase; DLT=dose-limiting toxicity; imAE=immune AE; ULN=upper limit of normal
[0163] Any events not described above that lead to the permanent discontinuation of durvalumab and/or tivozanib according to the toxicity management guidelines were also a
DLT.
[0164] The NCI CTCAE (Version 5.0) was used to grade toxicities occurring during this trial.
[0165] Subjects experiencing DLTs during Cycle 1 were generally discontinued from further participation in the study but may have continued at a reduced dose (tivozanib only; durvalumab must be interrupted or discontinued) if there was evidence of an objective response or other clinical benefit.
[0166] Subjects experiencing DLTs at any other time during their participation in the study received subsequent dosing with study drug at a reduced dose or were discontinued from further participation in the study at the discretion of the Investigator.
[0167] The dose expansion phase dose (MTD) was determined from the cohorts in dose modification of the study. The MTD was the dose at which < 2 of 6 subjects experience a DLT during the first cycle (2.8 days).
[0168] Patients who received <75% of the study drug in Cycle 1, because the infusion had to be discontinued due to a Grade 1 or 2 infusion reaction or due to missed doses of tivozanib, and did not experience a DLT were not considered evaluable in the assessment of the overall DLT rate for the particular dose level cohort and were replaced.
[0169] Patients who withdrew or were withdrawn from study treatment prior to completing the DLT assessment window for any reason other than a study drug-related toxicity through Cycle 1, were not considered evaluable for DLTs and were replaced.
Safety Assessment
[0170] An adverse event (AE) was defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation subject administered an investigational (medicinal) product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of investigational product, whether or not considered related to the investigational product.
[0171] Adverse events included the following types of occurrences:
* Suspected adverse drug reactions.
• Other medical experiences, regardless of their relationship with the study drug, such as injury’, surgery', accidents, extensions of symptoms or apparently unrelated illnesses, and significant abnormalities in clinical laboratory' values or vital signs, psychological testing or physical examination findings.
® Reactions from study drug overdose, abuse, withdrawal, sensitivity', toxicity or failure of the study drug’s expected pharmacological action. [0172] The causal relationship to study drug was determined by a physician and was used to assess all AE. The casual relationship can be related (there is a reasonable causal relationship between study drug administration and the AE) or not related (there is not a reasonable causal relationship between study drug administration and the AE). The term "reasonable causal relationship" means there is evidence to suggest a causal relationship.
[0173] Adverse events were spontaneously reported or elicited during open-ended questioning, examination, or evaluation of a subject.
[0174] In this protocol, symptoms and signs of exacerbation or worsening of primary' malignancy will usually be captured in the context of efficacy assessment. Therefore, symptoms, or signs of exacerbation or worsening of the primary malignancy will not be considered as AEs unless the event is considered possibly or probably' related to the study' drug (the worsening is not consistent with the anticipated natural progression of the disease), or the subject is discontinued from study drug due to clinical progression without documented progressive disease. [0175] The Investigator was required to grade the severity/intensity of each AE according to the CTCAE (V ersion 5.0). A general grading (severity/intensity) scale is provided at the beginning of the NCI-CTCAE document, and specific event grades are also provided. If a particular AEs severity/intensity is not specifically graded by the guidance document, the Investigator is to revert to the general definitions of Grade I through Grade 5 and use his or her best medical judgment.
[0176] A serious adverse event (SAE) was any untoward medical occurrence that at any dose:
* Results in death.
* Is life-threatening (defined as an event in which the subject was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more se vere).
» Requires inpatient hospitalization or causes prolongation of existing hospitalization.
® Results in persistent or significant disability/incapacity.
* Is a congenital anomaly /birth defect. * Is an important medical event, defined as a medical event(s) that may not be immediately life-threatening or result in death or hospitalization but, based upon appropriate medical and scientific judgment, may jeopardize the subject or may require intervention (e.g., medical, surgical) to prevent one of the other serious outcomes listed in the definition above. Examples of such events include, but are not limited to, intensive treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization.) Potential drug induced liver injury (DILI) is also considered an important medical event. [0177] Suspected transmission of an infectious agent (e.g. , pathogenic or nonpathogenic) via the study drug was an SAE. Development of a new cancer must have been handled as an SAE. New primary1 cancers are those that are not the primary reason for administration of the study drug and have been identified after the subject’s inclusion in the study.
[0178] The following hospitalizations were not considered SAEs: * A visit to the emergency room or other hospital department < 24 hours, that does not result in admission (unless considered an important medical or life-threatening event).
* Elective surgery planned prior to signing consent.
« Admissions as per protocol for a planned medical/ surgical procedure.
* Routine health assessment requiring admission for baseline/trending of health status (e.g., routine colonoscopy).
® Medical/surgical admission other than to remedy ill health and planned prior to entry into the study (appropriate documentation is required in these cases).
* Admission encountered for another life circumstance that carries no bearing on health status and requires no medical/surgical intervention (e.g., lack of housing, economic inadequacy, caregiver respite, family circumstances, administrative reason).
[0179] Subjects experiencing unacceptable toxicities or with confirmed disease progression at any time during the study were discontinued from study treatment. Subjects needing to discontinue durvalumab or tivozanib may have continued treatment with the other drug until disease progression. [0180] Once discontinued, all subjects were followed for evidence of delayed effects of study drug for 90 days post last dose of study drug. Any adverse events that were thought to be related to study drug that were ongoing at the 30-day follow-up visit were followed through resolution or stabilization or up to a maximum of 90 days post last dose of study drug (whichever comes first). All subjects were followed for date of death.
Disease/Response Assessment
[0181] Data on disease classification and the duration of disease stabilization or any objective response, as well as the time to disease progression, was collected for all subjects. Subjects underwent disease assessment at screening (within 30 days prior to the start of Cycle 1) and every' 8 weeks on treatment.
[0182] Disease assessment included disease classification (including details of the primary' diagnosis and histological/cytological type and stage of disease) and diagnostic imaging / measurement of target lesions. Subjects were evaluated with the same method of assessment and the same imaging technique throughout the study. Computerized tomography and/or MRI were considered the standard methods for evaluating disease status. The location and dimensions of “target” lesions were determined when possible. Response assessment and updates were performed using criteria outlined in RECIST 1.1.
[0183] In the event of an objective response, the duration of the response was determined from the day7 the initial response is observed (using screening/basehne images for comparison) to the day that progression is observed. Duration of disease stabilization w-as also assessed,
[0184] To be assigned a status of partial response (PR) or complete response (CR), changes in tumor measurements must have been confirmed by repeat studies performed no less than 4 weeks after the criteria for response are first met. In the case of stable disease (SD), follow-up measurements must have met the SD criteria at least once after study entry at a minimal interval of 4 weeks.
[0185] Patients off study' were contacted every7 3 months for survival status.
[0186] Disease status was summarized by cycle and dose group, including changes from baseline. Wherever possible, duration of objective tumor response, duration of CR, duration of PR, duration of SD, and progression free survival (PFS) and overall survival (OS) were assessed and presented for all subjected treated at MTD, using the Kaplan- Meier procedure. Overall objective tumor response (ORR) was defined as the proportion of evaluable subjects who have a best overall response classification of CR or PR during the study. A 95% confidence interval (CI) about the overall objective tumor response rate (CR + PR) and disease control rate (CR + PR + SD) were calculated. The untreated and previously treated patients will be presented separately.
Phase lb
[0187] The phase lb dose-escalation portion of the study enrolled n=7 previously untreated subjects.
[0188] There were no > grade 3 AEs in Cycle 1. 6 of 7 subjects experienced an adverse drug reaction. The most common AEs (each seen in 2/7 patients) were: cough; diarrhea; fatigue; hypertension; and PPE. 1 subject experienced a treatment-related SAE for grade 3 GI hemorrhage, winch resolved. Two of the 7 patients were found to be partial responders, while 3 exhibited stable disease and 2 exhibited progressive disease during the study.
[0189] The recommended phase 2 dose (RP2D) of tivozanib was 0.89 mg (equivalent to 1 mg commercially available tivozanib hydrochloride) orally once daily for 21 days followed by 7 days off combined with durvaluniab 1,500 mg administered intravenously every' 4 weeks (i.e., once every' 28 days on day 1). The combination of tivozanib with durvalumab was found to be well tolerated in advanced HCC subjects.
Phase 2
[0190] For the phase 2 portion of the study, Cohort A (untreated) completed enrollment and Cohort B (prior treatment with both bevacizumab and atezolizumab) is currently enrolling.
[0191] TABLE 1 depicts the baseline characteristics of the subjects (N=20) in Cohort A.
TABLE 1
Figure imgf000054_0001
[0192] TABLE 2 and TABLE 3 depict safety and tolerability results for the subjects in
Cohort A,
TABLE 2
Figure imgf000054_0002
hepatic encephalopathy
TABLE 3
Figure imgf000054_0003
[0193] Grade 3 TRAEs occurred in n==3 patients (2 hypertension [HTN], 1 GI hemorrhage). There were no Grade 4 or 5 TRAEs. The most common Grade 1 and 2 TRAEs were HTN, fatigue, diarrhea, nausea and hypothyroidism.
[0194] TABLE 4 depicts efficacy results for the evaluable subjects (N=18; N=2 subjects not yet reached first scan censored for PFS and OS) in Cohort A. NE = not estimable.
TABLE 4
Figure imgf000055_0001
[0195] FIG. 2 depicts the best overall response and treatment duration for the indicated subjects. Results demonstrated a median PFS of 7.3 months and a 1-year OS of 76%.
[0196] This PFS suggests tivozanib in combination with dtirvalumab may be a promising new treatment for patients with advanced HCC as the median PFS in a previous Phase III study for the combination of atezolizumab, an anti-PD-Ll antibody, and bevacizurnab, a VEGF-A monoclonal antibody in advanced HCC patients was only 6.8 months and 1 year overall survival was only 67.2%. The tivozanib/durvaiumab combination is especially promising given that the results presented herein show' the combination has been well tolerated in HCC patients in the study to date and the observed safety profile w'as consistent with the known profile of both agents, whereas toxic side effects were noted in 38% of patients receiving the combination of bevacizurnab and atezolizumab in its previous Phase III study.
INCORPORATION BY REFERENCE
[0197] The entire disclosure of each of the patent documents and scientific articles cited herein is incorporated by reference for all purposes. EQUIVALENTS
[0198] The invention can be embodied in other specific forms with departing from the essential characteristics thereof. The foregoing embodiments therefore are to be considered illustrative rather than limiting on the invention described herein. The scope of the invention is indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

We claim:
1. A method of treating a hepatocellular carcinoma (HCC) in a subject in need thereof comprising administering to the subject a treatment regimen comprising:
(i) a therapeutically effective amount of tivozanib or a pharmaceutically acceptable salt thereof, and
(ii) a therapeutically effective amount of durvalumab, thereby to treat the HCC in the subject, wherein the subject experiences a progression free survival (PFS) of at least 7 months upon receiving the treatment regimen.
2. A method of treating a hepatocellular carcinoma (HCC) in a subject in need thereof comprising administering to the subject a treatment regimen comprising:
(i) a therapeutically effective amount of tivozanib or a pharmaceutically acceptable salt thereof, and
(ii) a therapeutically effective amount of durvalumab, thereby to treat the HCC in the subject, wherein when the treatment regimen is administered to subjects having HCC, the subjects experience a median progression free survival (PFS) of at least 7 months upon receiving the treatment regimen.
3. A method of extending progression free survival (PFS) in a subject in need thereof with a hepatocellular carcinoma (HCC), comprising administering to the subject a treatment regimen comprising a therapeutically effective amount of tivozanib or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of durvalumab.
4. A method of extending overall survival (OS) in a subject in need thereof with a hepatocellular carcinoma (HCC), comprising administering to the subject a treatment regimen comprising a therapeutically effective amount of tivozanib or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of durvalumab.
5. The method of any one of claims 1-4, wherein the HCC is advanced HCC.
6. The method of any one of claims 1-5, wherein the HCC is metastatic HCC.
7. The method of any one of claims 1-6, wherein the subject has not previously received treatment for the HCC.
8. Tire method of any one of claims 1-7, wherein the subject has not previously received systemic therapy to treat the HCC.
9. ’The method of any one of claims 1-8, wherein the subject has not previously received chemotherapy treatment for the HCC.
10. The method of any one of claims 1-9, wherein the subject has not previously received a checkpoint inhibitor to treat the HCC.
11. The method of any one of claims 1-10, wherein the treatment regimen is a first line systemic therapy for the HCC m the subject.
12. The method of any one of claims 1-6, wherein the subject has previously received treatment for the HCC.
13. The method of any one of claims 1-6 or 12, wherein the treatment regimen is a second or later line systemic therapy for the HCC in the subject.
14. Tire method of claim 12 or 13, wherein the subject has been previously treated with a VEGF inhibitor.
15. The method of claim 14, wherein VEGF inhibitor is bevacizumab.
16. ’The method of claim 14, wherein the VEGF inhibitor is a VEGF TKI inhibitor.
17. ’The method of claim 16, wherein the VEGF TKI inhibitor is sorafenib.
18. ’The method of claim 16, wherein the VEGF TKI inhibitor is cabozantinib, regorafenib, nintedanib, lenvantinib, anlotinib, fruquintinib, apatinib, sunitinib, pazopanib, axitmib, dasatinib, nilotinib, motesanib, deciranib, donafenib, vandetanib, or sulfatinib.
19. The method of any one of claims 1-6 or 12-18, wherein the subject has been previously treated with a checkpoint inhibitor.
20. The method of claim 19, wherein the checkpoint inhibitor is a PD-1 or PD-L1 inhibitor.
21. The method of claim of claim 19 or 20, wherein the checkpoint inhibitor is atezolizumab.
22. The method of claim 19 or 20, wherein the checkpoint inhibitor is nivolumab and/or ipilimumab.
23. ’The method of claims 19 or 20, wherein the checkpoint inhibitor is pembrolizumab and/or ipilimumab.
24. The method of any one of claims 1-6 or 12-23, wherein the subject has been previously treated with bevacizumab and atezolizumab.
25. The method of any one of claims 1-24, wherein the treatment regimen comprises one or more treatment cycles of 28 days in duration.
26. The method of claim 25, wherein the treatment cycle comprises administering tivozanib at a dose of 1 mg per day on days 1-21 of the treatment cycle followed by no administration of tivozanib on days 22-28 of the treatment cycle.
27. The method of any one of claims 1-26, wherein tivozanib is administered orally.
28. The method of any one of claims 1-27, wherein tivozanib is tivozanib hydrochloride.
29. The method of any one of claims 25-28, wherein the treatment cycle comprises administering durvalumab at a dose of 1,500 mg on day 1 of the treatment cycle followed by no administration of durvalumab on days 2-28 of the treatment cycle.
30. The method of any one of claims 1-2.9, wherein durvalumab is administered intravenously.
31. The method of claim 30, wherein durvalumab is administered over a period of 60 minutes.
32. The method of any one of claims 1-31, wherein durvalumab is administered at. a concentration of 1 mg/mL - 15 mg/mL.
33. The method of any one of claims 25-32, wherein the subject receives at least 7 treatment cycles.
34. The method of any one of claims 1-33, wherein the subject receives the treatment regimen for at least 7 months.
35. The method of any one of claims 1-34, wherein the subject receives the treatment regimen until the subject experiences a complete response or experiences progression of the HCC.
36. The method of any one of claims 1-35, wherein the subject is a human.
37. The method of any one of claims 25-36, wherein if the subject experiences a grade 3 adverse event tivozanib is administered every other day of treatment cycle.
38. The method of any one of claims 1-37, wherein the subject experiences a progression free survival of at least 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1 , 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, or 48 months.
39. The method of any one of claims 1 -38, wherein the subject has a survival time of at least 13 months from the start of treatment.
40. ’The method of any one of claims 1-39, wherein the subject experiences no Grade 4 and/or Grade 5 treatment related adverse events (TRAEs).
41. The method of any one of claims 2-40, wherein the subjects experience a median progression free survival of at least 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1 , 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1 , 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 2.6, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, or 48 months.
42. The method of any one of claims 2-41, wherein the subjects experience a median overall survival of at least 13 months.
43. The method of any one of claims 1 -42, wherein the PFS of the subject is extended compared to a subject or subjects with HCC treated with sorafenib, or with bevacizumab and atezolizumab.
44. The method of any one of claims 1-43, wherein the overall survival (OS) of the subject is extended compared to the OS of a subject or subjects with HCC treated with sorafenib, or with bevacizumab and atezolizumab.
45. The method of any one of claims 1-44, wherein the subject has not previously received tivozanib and/or durvalumab.
PCT/US2022/012623 2022-01-14 2022-01-14 Use of tivozanib and durvalumab for treating hepatocellular carcinoma (hcc) WO2023136837A1 (en)

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WO2021173903A1 (en) * 2020-02-26 2021-09-02 Five Prime Therapeutics, Inc. Cd80 extracellular domain fc fusion protein therapy

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