WO2022240722A1 - Anti-pd-1 antibody dosing for cancer treatment - Google Patents

Anti-pd-1 antibody dosing for cancer treatment Download PDF

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Publication number
WO2022240722A1
WO2022240722A1 PCT/US2022/028278 US2022028278W WO2022240722A1 WO 2022240722 A1 WO2022240722 A1 WO 2022240722A1 US 2022028278 W US2022028278 W US 2022028278W WO 2022240722 A1 WO2022240722 A1 WO 2022240722A1
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antibody
subject
weeks
once
administering
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PCT/US2022/028278
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French (fr)
Inventor
Nooshin HASHEMI SADRAEI
Hansen Wong
Vijay Upreti
Sandeep Dutta
Khamir Mehta
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Amgen Inc.
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Publication of WO2022240722A1 publication Critical patent/WO2022240722A1/en

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • 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

  • PD-1 Programmed Cell Death 1 protein
  • CD279 also known as CD279, SLEB2, and hSLEl
  • NK natural killer
  • B lymphocytes activated T
  • macrophages macrophages
  • DCs dendritic cells
  • monocytes monocytes
  • PD-1 is highly expressed on tumor- specific T cells (Han et ak, Am J Cancer Res 10(3): 727-742 (2020)).
  • PD-1 binds to B7 protein family members, PD-1 Ligand 1 (PD-L1; also referred to as CD279 and B7-H1) and PD-1 Ligand 2 (also known as PD-L2, CD273, and B7-DC).
  • PD-1 Ligand 1 also known as CD279 and B7-H1
  • PD-1 Ligand 2 also known as PD-L2, CD273, and B7-DC
  • PD-L1 is constitutively expressed on T and B cells, macrophages and dendritic cells, whereas PD-L2 expression is typically restricted to activated DC and macrophages (Xing et ak, Oncoimmunology 7(3): el356144 (2017) (doi:
  • PD-1 inhibits both adaptive and innate immune responses.
  • the PD-1/PD-L1 axis is involved in the suppression of T cell immune responses in cancer. Antagonists of this pathway have been clinically validated across a number of solid tumor indications.
  • PD-1 inhibitors, nivolumab, pembrolizumab, and cemiplimab, and PD-L1 inhibitors atezolizumab, avelumab, and durvalumab target the PD-1/PD-L1 pathway, and each has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of various cancers.
  • FDA U.S. Food and Drug Administration
  • a method of treating cancer or tumor in a subject comprising administering to the subject an agent that targets PD-1, e.g., an anti-PD-1 antibody (e.g., an anti-PD-1 antibody comprising six complementarity determining region (CDR) amino acid sequences of SEQ ID NOs: 3-8) in an amount effective to treat the cancer or tumor in the subject.
  • said method comprises administering to the subject an amount of the agent that targets PD-1, e.g., an anti-PD-1 antibody (e.g., an anti-PD-1 antibody comprising six CDR amino acid sequences of SEQ ID NOs: 3-8) in an amount equivalent to about 100 mg to about 150 mg per week.
  • the amount of the anti-PD-1 antibody is equivalent to about 115 mg per week to about 125 mg per week. In various aspects, the amount of the anti-PD-1 antibody is equivalent to about 120 mg per week.
  • the method in exemplary embodiments comprises administering to the subject about 120 mg of the PD-1 antibody once a week, about 240 mg of the PD-1 antibody once every 2 weeks, about 360 mg of the PD-1 antibody once every 3 weeks, about 480 mg of the PD-1 antibody once every 4 weeks, about 600 mg of the PD-1 antibody once every 5 weeks, about 720 mg of the PD-1 antibody once every 6 weeks, about 840 mg of the PD-1 antibody once every 7 weeks, or about 960 mg of the PD-1 antibody once every 8 weeks.
  • the method comprises administering to the subject an anti-PD-1 antibody comprising six CDR amino acid sequences of SEQ ID NOs: 3-8 in an amount equivalent to about 480 mg once every 4 weeks.
  • amount administered to the subject provides: (a) a mean serum concentration of the anti-PD-1 antibody which is achieved by administering 480 mg once every 4 weeks; (b) a mean plasma area under the curve (AUC0- ⁇ ) which is achieved by administering 480 mg once every 4 weeks; (c) a difference between the mean plasma Cmax at steady state and a mean plasma Cmin at steady state which is achieved by administering 480 mg once every 4 weeks; (d) a mean plasma Cmax at steady state which is achieved by administering 480 mg once every 4 weeks, or (e) any combination thereof.
  • the anti-PD-1 antibody comprises in exemplary instances, (a) a heavy chain (HC) complementarity -determining region (CDR) 1 amino acid sequence comprising SEQ ID NO: 3; (b) an HC CDR2 amino acid sequence comprising SEQ ID NO: 4; (c) an HC CDR3 amino acid sequence comprising SEQ ID NO: 5; (d) a light chain (LC) CDR1 amino acid sequence comprising SEQ ID NO: 6; (e) an LC CDR2 amino acid sequence comprising SEQ ID NO: 7; and (f) an LC CDR3 amino acid sequence comprising SEQ ID NO: 8.
  • the anti-PD-1 antibody comprises a heavy chain variable region of SEQ ID NO: 9 and a light chain variable region of SEQ ID NO: 10.
  • the anti-PD-1 antibody comprises a heavy chain of SEQ ID NO: 11 or 13 and a light chain of SEQ ID NO: 12.
  • the anti-PD-1 antibody is zeluvalimab in exemplary aspects.
  • the anti-PD-1 antibody is administered intravenously to the subject.
  • the anti-PD-1 antibody is administered to the subject for at least one cycle, at least three cycles, at least six cycles, or more.
  • the subject does not exhibit a dose limiting toxicity (DLT) during treatment with the anti-PD-1 antibody.
  • DLT dose limiting toxicity
  • the subject does not exhibit any grade 3 or grade 4 adverse events associated with anti-PD-1 antibody
  • the tumor is a solid tumor, e.g., an advanced solid tumor or metastatic solid tumor, a Stage 3 of Stage 4 tumor, a non-resectable tumor, and/or a non-localized tumor.
  • the cancer is a colon cancer, an ovarian cancer, a clear cell renal cell carcinoma, a pancreatic carcinoma, a sarcoma metastatic, sarcomatoid carcinoma, a squamous cell carcinoma (head and neck), or an undifferentiated nasopharyngeal carcinoma.
  • the subject exhibits at least a stable disease (SD) after about 2 or more cycles of treatment with the anti-PD-1 antibody, at least a partial response (PR) after about 2 or more cycles of treatment with the anti-PD-1 antibody, or a complete response (CR) after about 2 or more cycles of treatment with the anti-PD-1 antibody.
  • SD stable disease
  • PR partial response
  • CR complete response
  • the present disclosure further provides a method of treating a cancer or tumor in a subject, said method comprising administering to the subject an anti-PD-1 antibody comprising six complementarity determining region (CDR) amino acid sequences of SEQ ID NOs: 3-8 in combination with a platinum chemotherapy and/or an antimetabolite.
  • an anti-PD-1 antibody comprising six complementarity determining region (CDR) amino acid sequences of SEQ ID NOs: 3-8 in combination with a platinum chemotherapy and/or an antimetabolite.
  • an anti-PD-1 antibody comprising six complementarity determining region (CDR) amino acid sequences of SEQ ID NOs: 3-8 in combination with a platinum chemotherapy and/or an antimetabolite, wherein the anti-PD-1 antibody is administered at a first amount for a first time period and at a second amount different from the first amount for a second time period.
  • CDR complementarity determining region
  • the method comprises administering to the subject for a first time period (e.g., an induction phase): (a) about 360 mg anti-PD-1 antibody once every 3 weeks, (b) about 500 mg/m 2 pemetrexed once every 3 weeks, and (c) about 75 mg/m 2 cisplatin or an amount of carboplatin to achieve a target AUC of about 5 once every 3 weeks, and administering to the subject for a second time period (e.g., a maintenance phase): (d) about 720 mg anti-PD-1 antibody once every 6 weeks and (e) about 500 mg/m 2 pemetrexed to the subject once every 3 weeks, wherein the first time period (e.g., induction phase) is about 12 weeks (e.g., about 4 cycles) and the second time period (e.g., maintenance phase) is up to about 186 weeks (e.g., up to 31 cycles).
  • the anti-PD-1 antibody is zeluvalimab.
  • the method comprises administering to the subject for a first time period (e.g., induction phase): (a) about 360 mg anti-PD-1 antibody once every 3 weeks, (b) about 500 mg/m 2 pemetrexed once every 3 weeks, and (c) about 75 mg/m 2 cisplatin, and administering to the subject for a second time period or a maintenance phase: (d) about 720 mg anti-PD-1 antibody once every 6 weeks and (e) about 500 mg/m 2 pemetrexed to the subject once every 3 weeks, wherein the first time period (e.g., induction phase) is about 12 weeks (e.g., about 4 cycles) and the second time
  • the anti-PD-1 antibody is zeluvalimab.
  • the method comprises administering to the subject for a first time period (e.g., induction phase): (a) about 360 mg anti-PD-1 antibody once every 3 weeks, (b) about 500 mg/m 2 pemetrexed once every 3 weeks, and (c) an amount of carboplatin to achieve a target AUC of about 5, and administering to the subject for a second time period or a maintenance phase: (d) about 720 mg anti-PD-1 antibody once every 6 weeks and (e) about 500 mg/m 2 pemetrexed to the subject once every 3 weeks, wherein the first time period (e.g., induction phase) is about 12 weeks (e.g., about 4 cycles) and the second time period (e.g., maintenance phase) is up to about 186 weeks (e.g., up to 31 cycles).
  • the anti-PD-1 antibody is zeluvalimab.
  • a pharmaceutical composition comprising an anti-PD-1 antibody comprising the six CDR amino acid sequences of SEQ ID NOs: 352-357 at a concentration of about 50 mg/iuL to about 100 mg/mL, a buffer, a disaccharide and a surfactant.
  • the buffer is acetate optionally sodium acetate.
  • the pharmaceutical composition comprises about 5 mM to about 25 mM acetate, optionally, about 10 mM sodium acetate.
  • the pharmaceutical composition comprises about 5.0% (w/v) disaccharide to about 15.0 % (w/v) disaccharide, e.g., about 9.0% (w/v) disaccharide.
  • the pharmaceutical composition comprises about 0.001% (w/v) to about 0.1% (w/v) surfactant, e.g., about 0.01% (w/v) surfactant.
  • the surfactant is PS80.
  • the pharmaceutical composition is a preservative-free solution, and optionally, has a pH of about 5.2. Additionally provided is a vial comprising about 1 to about 5 mL of the presently disclosed pharmaceutical composition.
  • the anti-PD-1 antibody is zeluvalimab.
  • FIG. 1 is a schematic of a randomized, double-blind, placebo controlled phase 3 study of platinum plus pemetrexed chemotherapy with or without AMG 404 as first line treatment in subjects with advanced nonsquamous nonsmall cell lung cancer (NSCLC).
  • AUC area under the concentration-time curve
  • irRECIST Immune-related Response Evaluation Criteria in Solid Tumors
  • iPD progressive disease as determined by the investigator using irRECIST
  • PD-L1 programmed death-ligand 1
  • Q3W every 3 weeks
  • Q6W every 6 weeks
  • TPS tumor proportion score.
  • Footnotes a Treatment with AMG 404/placebo will continue until iPD; intolerance of treatment, initiation of another anticancer therapy, withdrawal of consent, death, or a maximum of 35 cycles. Subjects will be permitted to continue treatment with pemetrexed beyond 35 cycles until iPD as determined by the investigator, intolerance of treatment, initiation of another anticancer therapy, withdrawal of consent, or death. Investigators will use irRECIST to make treatment decisions. b Crossover to AMG 404 monotherapy will be permitted for subjects in the placebo-combination group
  • the method comprises administering to the subject an agent which targets PD-1, including but not limited to an anti-PD-1 antibody (e.g., zeluvalimab; also referred to as AMG 404) in an amount effective for treating the cancer or the solid tumor in the subject.
  • an agent which targets PD-1 including but not limited to an anti-PD-1 antibody (e.g., zeluvalimab; also referred to as AMG 404) in an amount effective for treating the cancer or the solid tumor in the subject.
  • Exemplary agents targeting PD-1 include PD-1 antigen binding proteins (e.g., anti-PD-1 antibodies, antigen binding antibody fragments thereof, and anti-PD-1 antibody protein products) described in International Publication No. WO 2019/140196, which is incorporated herein by reference in its entirety.
  • the PD-1 antigen binding protein binds to human PD- 1, which has the amino acid sequence described in National Center for Biotechnology Information (NCBI) Reference Sequence No. NP 005009.2, or SEQ ID NO: 1, or the mature form (e.g., lacking the signal peptide) thereof which is represented by amino acids 21-288 of SEQ ID NO: 1.
  • NCBI National Center for Biotechnology Information
  • the PD-1 antigen binding protein binds to cynomolgus PD-1, which has the amino acid sequence described inNCBI Reference Sequence No. NP 001271065.1, or SEQ ID NO: 2, orthe mature form thereof. In exemplary instances, the PD-1 antigen binding protein binds to both human PD-1 and cynomolgus PD-1.
  • the anti-PD-1 -antibody comprises the amino acid sequences of SEQ ID NOs: 3-8. In exemplary aspects, the anti-PD-1 -antibody comprises six CDR amino acid sequences of SEQ ID NOs: 3-8.
  • the anti-PD-1- antibody comprises a heavy chain (HC) complementarity -determining region (CDR) 1 amino acid sequence of SEQ ID NO: 3, an HC CDR2 amino acid sequence of SEQ ID NO: 4, an HC CDR3 amino acid sequence of SEQ ID NO: 5, a light chain (LC) CDR1 amino acid sequence of SEQ ID NO: 6, an LC CDR2 amino acid sequence of SEQ ID NO: 7, and an LC CDR3 amino acid sequence of SEQ ID NO: 8.
  • HC heavy chain
  • CDR complementarity -determining region
  • the anti-PD-1 antibody comprises a PD-l-binding domain comprising (a) a heavy chain variable region (VH) that comprises: (i) a VH complementarity determining region one (CDR-H1) comprising the amino acid sequence of SEQ ID NO: 3; (ii) a CDR- H2 comprising the amino acid sequence of SEQ ID NO: 4; and (iii) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; and (b) a light chain variable region (VL) that comprises: (i) a VL complementarity determining region one (CDR-L1) comprising the amino acid sequence of SEQ ID NO: 6; (ii) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (iii) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.
  • VH heavy chain variable region
  • CDR-H1 VH complementarity determining region one
  • CDR-H2
  • the 5 domain comprises: a VH that comprises the amino acid sequence of SEQ ID NO: 9, and a VL that comprises the amino acid sequence of SEQ ID NO: 10.
  • the anti-PD-1- antibody comprises a VH comprising the amino acid sequence of SEQ ID NO: 9 and a VL comprising the amino acid sequence of SEQ ID NO: 10.
  • the anti-PD-1 -antibody comprises a HC comprising the amino acid sequence of SEQ ID NO: 11 or 13 and a LC comprising the amino acid sequence of SEQ ID NO: 12.
  • the anti-PD-1 antibody is zeluvalimab (International Nonproprietary Names for Pharmaceutical Substances (INN): Proposed INN: List 124, WHO Drug Information 34(4): 929-1102 (2020); CAS Registry Number 2315361-37- 4).
  • Zeluvalimab is an immunoglobulin G1 -kappa, anti- [Homo sapiens PDCD1 (programmed cell death 1, PD-1, PD1, CD279)], monoclonal antibody comprising a gammal heavy chain (1-450) [VH (Homo sapiens IGHV3-23*03 (92.8%) -(IGHD) -IGHJ3*01 (92.3%)) CDR-IMGT [8.8.13] (26- 33.50-58.97-109) (1-120) - Homo sapiens IGHGl*03v, Glm3>Glml7, nGlml (CHI R120>K (217) (121-218), hinge 1-15 (219-233), CH2 R83>C (295), N84.4>G (300), V85>C (305) (234- 343), CH3 E12 (359), M14 (361) (344-448), CHS (449- 450)) (121-450)], (223-214')-d
  • the subject is a human subject.
  • the human subject is about 18 years old or older.
  • the human subject has a tumor, e.g., a solid tumor.
  • the subject has a histologically or cytologically confirmed metastatic or locally advanced solid tumor, which optionally is not amendable to curative treatment with surgery or radiation.
  • the human subject has an advanced solid tumor.
  • the solid tumor is a metastatic solid tumor and/or non-localized and/or non-resectable.
  • the solid tumor is a Stage 3 or Stage 4 tumor.
  • the subject has at least one measurable lesion as defined by modified RECIST 1.1 which has not undergone biopsy within 3 months of the screening scan !ln exemplary instances, the human subject has an Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to 2, optionally, 0 or 1, (Oken et al., Am J Clin Oncol 5: 649-655 (1982).
  • EOG Eastern Cooperative Oncology Group
  • the subject meets one or more characteristics of Table 2 and/or does not meet one or more characteristics of Table 3.
  • the tumor is a tumor of a cancer, e.g., a cancer described herein.
  • the subject has an adenocarcinoma (e.g., metastatic adenocarcinoma), adrenocortical carcinoma, anal squamous cell carcinoma, basal cell carcinoma, cholangiocarcinoma, cervix carcinoma, adenocarcinoma of the colon or of the appendix, rectal adenocarcinoma, oesophageal squamous cell carcinoma, gastric adenocarcinoma, testicular germ cell
  • adenocarcinoma e.g., metastatic adenocarcinoma
  • adrenocortical carcinoma e.g., anal squamous cell carcinoma, basal cell carcinoma, cholangiocarcinoma, cervix carcinoma,
  • tumor 6 tumor, gastrointestinal stromal tumor, hepatocellular carcinoma, squamous cell carcinoma, mesothelioma (e.g., malignant mesothelioma), keratinizing squamous cell carcinoma of the nasopharynx, undifferentiated nasopharyngeal carcinoma, neuroendocrine carcinoma, haemangiopericytoma, malignant sweat gland carcinoma, porocarcinoma, pancreatic carcinoma (e.g., pancreatic metastatic carcinoma), clear cell renal cell carcinoma, hepatocellular carcinoma, sarcoma, osteosarcoma, dedifferentiated liposarcoma, pleomorphic malignant fibrous histiocytoma, alveolar soft part sarcoma, angiosarcoma, leiomyosarcoma, soft tissue sarcoma, metastatic sarcoma, endometrial stromal sarcoma, sarcomatoid carcinoma, squa
  • the subject has a tumor of a cancer, including but not limited to, anal cancer, gall bladder cancer, triple negative breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial cancer uterine cancer, tracheal cancer, ovarian cancer, prostate cancer, skin cancer, thymus cancer, transitional cell cancer, vaginal cancer, vulva cancer, neuroendocrine cancer, nasopharynx cancer, HCC, GIST, gastric cancer, biliary tract cancer, or basal cell cancer.
  • a cancer including but not limited to, anal cancer, gall bladder cancer, triple negative breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial cancer uterine cancer, tracheal cancer, ovarian cancer, prostate cancer, skin cancer, thymus cancer, transitional cell cancer, vaginal cancer, vulva cancer, neuroendocrine cancer, nasopharynx cancer, HCC, GIST, gastric cancer, biliary tract cancer, or basal cell cancer.
  • the cancer is a colon cancer, an ovarian cancer, a clear cell renal cell carcinoma, a pancreatic carcinoma, a sarcoma metastatic, sarcomatoid carcinoma, a squamous cell carcinoma (head and neck), or an undifferentiated nasopharyngeal carcinoma.
  • the cancer treatable by the methods disclosed herein can be any cancer, e.g., any malignant growth or tumor caused by abnormal and uncontrolled cell division that may spread to other parts of the body through the lymphatic system or the blood stream.
  • the cancer in some aspects is one selected from the group consisting of acute lymphocytic cancer, acute myeloid leukemia, alveolar rhabdomyosarcoma, bone cancer, brain cancer, breast cancer, cancer of the anus, anal canal, or anorectum, cancer of the eye, cancer of the intrahepatic bile duct, cancer of the joints, cancer of the neck, gallbladder, or pleura, cancer of the nose, nasal cavity, or middle ear, cancer of the oral cavity, cancer of the vulva, chronic lymphocytic leukemia, chronic myeloid cancer, colon cancer, esophageal cancer (e.g., esophageal squamous cell cancer), cervical cancer, gastrointestinal carcinoid tumor, Hodgkin lymphoma, hypopharynx cancer, kidney cancer, larynx cancer, liver cancer, lung cancer, mesothelioma (e.g., malignant mesothelioma), melanoma, multiple my
  • the prostate cancer is a metastatic castration-resistant prostate cancer (mCRPC).
  • the cancer is selected from the group consisting of: head and neck, ovarian, cervical, bladder and esophageal cancers, pancreatic, gastrointestinal cancer, gastric,
  • NSCLC non-small cell lung cancer
  • the NSCLC is squamous NSCLC.
  • the NSCLC is non-squamous NSCLC.
  • the tumor is non-small cell lung cancer (NSCLC), head and neck cancer, renal cancer, triple negative breast cancer, and gastric cancer.
  • the subject has a tumor (e.g., a solid tumor, a hematological malignancy, or a lymphoid malignancy) and the pharmaceutical composition is administered to the subject in an amount effective to treat the tumor in the subject.
  • the tumor is non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), head and neck cancer, renal cancer, breast cancer, melanoma, ovarian cancer, liver cancer, pancreatic cancer, colon cancer, prostate cancer, gastric cancer, lymphoma or leukemia, and the pharmaceutical composition is administered to the subject in an amount effective to treat the tumor in the subject. Additional cancers, tumors and malignancies treatable by the presently disclosed methods are described in International Publication No. WO 2019/140196.
  • the subject has received prior treatment with an anticancer therapy other than anti-PD-1 antibody therapy.
  • the subject has failed at least one or more prior line of systemic therapy prior to being treated with zeluvalimab.
  • the subject has not received any prior treatment with an anticancer therapy.
  • the subject has not failed a prior therapy.
  • an amount effective for treating the cancer or the solid tumor in the subject is administered to the subject.
  • the term “treat,” as well as words related thereto, do not necessarily imply 100% or complete treatment. Rather, there are varying degrees of treatment of which one of ordinary skill in the art recognizes as having a potential benefit or therapeutic effect.
  • the methods of treating cancer of the present disclosure can provide any amount or any level of treatment.
  • the treatment provided by the method of the present disclosure can include treatment of one or more conditions or symptoms or signs of the cancer being treated.
  • the treatment provided by the methods of the present disclosure can encompass slowing the progression of the cancer.
  • the methods can treat cancer by virtue of enhancing the T cell activity or an immune response against the cancer, reducing tumor or cancer growth, reducing metastasis of tumor cells, increasing cell death of tumor or cancer cells, and the like.
  • the methods treat by way of delaying the onset or recurrence of the cancer by 1 day, 2 days, 4 days, 6 days, 8 days, 10 days, 15 days, 30 days, two months, 4 months, 6 months, 1 year, 2 years, 4 years, or more.
  • the methods treat by way increasing the survival of the subject.
  • the survival of the subject is increased by 30 days, two months, 4 months, 6 months, 1 year, 2 years, 4 years, or more.
  • the treatment provided by the methods of the present disclosure provides a therapeutic response as per Response Evaluation Criteria in Solid Tumors (RECIST) or other like criteria.
  • RECIST is a set of criteria to evaluate the progression, stabilization or responsiveness of tumors and/or cancer cells jointly created by the National Cancer Institute of the United States, the National Cancer Institute of Canada Clinical Trials Group and the European Organisation for Research and Treatment of Cancer. According to RECIST, certain tumors are measured in the beginning of an evaluation (e.g., a clinical trial), in order to provide a baseline for comparison after treatment with a drug.
  • the response assessment and evaluation criteria for tumors are published in Eisenhauer et. al., Eur J Cancer 45:228-247 (2009) and Litiere et.
  • the treatment provided by the methods of the present disclosure provides a therapeutic response as per a modified RECIST tumor response assessment, as follows:
  • the method comprises administering to the subject an anti-PD-1 antibody, e.g., zeluvalimab, in accordance with the present disclosures.
  • a method of treating a cancer to provide a complete response (CR), partial response (PR), or stable disease (SD), as per a modified RECIST 1.1, in a subject comprises administering to the subject zeluvalimab in accordance with the present disclosures.
  • the subject upon treatment, the subject exhibits at least SD.
  • the subject upon treatment, the subject exhibits at least SD after about 2 or more cycles of treatment with zeluvalimab.
  • the subject upon treatment, exhibits at least a PR.
  • the subject exhibits at least a PR or a CR after about 2 cycles of treatment with zeluvalimab.
  • the method comprises administering to the subject an anti-PD-1 antibody comprising six CDR amino acid sequences of SEQ ID NOs: 3-8 (e.g., zeluvalimab) in an amount effective for treating the cancer or the solid tumor in the subject.
  • the amount is equivalent to about 100 mg per week to about 150 mg per week.
  • the amount is equivalent to about 100 mg per week to about 140 mg per week, about 100 mg per week to about 130 mg per week, about 100 mg per week to about 120 mg per week, about 100 mg per week to about
  • 110 mg per week about 110 mg per week to about 150 mg per week, about 120 mg per week to about
  • the amount of the anti-PD-1 antibody comprising six
  • CDR amino acid sequences of SEQ ID NOs: 3-8 is equivalent to about 115 mg per week to about 125 mg per week, about 108 mg per week to about 132 mg per week, or about 114 mg
  • the method comprises administering to the subject about 120 mg of anti-PD-1 antibody comprising six CDR amino acid sequences of SEQ ID NOs: 3-8 (e.g., zeluvalimab) once a week or about 240 mg anti-PD- 1 antibody comprising six CDR amino acid sequences of SEQ ID NOs: 3-8 (e.g., zeluvalimab) once every 2 weeks.
  • the method comprises administering to the subject about 360 mg of anti-PD-1 antibody comprising six CDR amino acid sequences of SEQ ID NOs: 3-8 (e.g., zeluvalimab) once every 3 weeks or about 480 mg anti-PD-1 antibody comprising six CDR amino acid sequences of SEQ ID NOs: 3-8 (e.g., zeluvalimab) once every 4 weeks.
  • the method comprises administering to the subject about 600 mg of anti-PD-1 antibody comprising six CDR amino acid sequences of SEQ ID NOs: 3-8 (e.g., zeluvalimab) once every 5 weeks or about 720 mg anti-PD-1 antibody comprising six CDR amino acid sequences of SEQ ID NOs: 3-8 (e.g., zeluvalimab) once every 6 weeks.
  • the method comprises administering to the subject about 840 mg of anti-PD-1 antibody comprising six CDR amino acid sequences of SEQ ID NOs: 3-8 (e.g., zeluvalimab) once every 7 weeks or about 960 mg anti-PD-1 antibody comprising six CDR amino acid sequences of SEQ ID NOs: 3-8 (e.g., zeluvalimab) once every 8 weeks.
  • the method comprises administering anti-PD-1 antibody comprising six CDR amino acid sequences of SEQ ID NOs: 3-8 (e.g., zeluvalimab) to the subject 120X mg of anti-PD-1 antibody comprising six CDR amino acid sequences of SEQ ID NOs: 3-8 (e.g., zeluvalimab) once every X weeks, wherein X is an integer from 1 to 10.
  • the method comprises administering to the subject an anti-PD-1 antibody comprising six CDR amino acid sequences of SEQ ID NOs: 3-8 (e.g., zeluvalimab) in an amount equivalent to about 480 mg administered once every 4 weeks.
  • the amount administered to the patient is within a 10% range of a pharmacokinetic characteristic achieved with a reference amount.
  • the pharmacokinetic characteristic in various instances, is a mean serum concentration, mean plasma area under the curve (AUC), e.g., AUG-,. a mean plasma C max at steady state, a mean plasma C mm at steady state, a difference between the mean plasma C max at steady state and a mean plasma C mm at steady state.
  • the reference amount is about 100 mg to about 150 mg administered weekly.
  • the reference amount is about 115 mg to about 125 mg administered weekly.
  • the reference amount is about 480 mg administered once every 4 weeks.
  • the amount of the anti-PD-1 antibody comprising the six CDRs of SEQ ID NOs: 3-8 administered to the subject is equivalent to 480 mg administered once every 4 weeks and/or the amount provides: (a) a mean serum concentration of the anti-PD-1 antibody which is achieved by administering 480 mg once every 4 weeks; (b) a mean plasma area under the curve (AUG .,) which is achieved by administering 480 mg once every 4 weeks; (c) a difference between the mean plasma C max at steady state and a mean plasma C mm at steady state which is achieved by administering 480 mg once every 4 weeks; and/or (d) a mean plasma C max at steady state which is achieved by administering 480 mg once every 4 weeks.
  • the agent targeting PD-1 e.g., anti-PD-1 antibody (e.g., zeluvalimab)
  • the anti-PD-1 antibody e.g., zeluvalimab
  • routes of administration is merely provided to illustrate exemplary embodiments and should not be construed as limiting the scope in any way.
  • Formulations suitable for parenteral administration include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non- aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • parenteral means not through the alimentary canal but by some other route such as subcutaneous, intramuscular, intraspinal, or intravenous.
  • the anti-PD-1 antibody (e.g., zeluvalimab) can be administered with a physiologically acceptable diluent in a pharmaceutical carrier, such as a sterile liquid or mixture of liquids, including water, saline, aqueous dextrose and related sugar solutions, an alcohol, such as ethanol or hexadecyl alcohol, a glycol, such as propylene glycol or polyethylene glycol, dimethylsulfoxide, glycerol, ketals such as 2,2- dimethyl- 153-dioxolane-4-methanol, ethers, poly(ethyleneglycol) 400, oils, fatty acids, fatty acid esters or glycerides, or acetylated fatty acid glycerides with or without the addition of a pharmaceutically acceptable surfactant, such as a soap or a detergent, suspending agent, such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or
  • Oils which can be used in parenteral formulations include petroleum, animal, vegetable, or synthetic oils. Specific examples of oils include peanut, soybean, sesame, cottonseed, com, olive, petrolatum, and mineral. Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters.
  • the parenteral formulations in some embodiments contain from about 0.5% to about 25% by weight of the anti-PD-1 antibody (e.g., zeluvalimab) in solution.
  • Preservatives and buffers can be used.
  • such compositions can contain one or more nonionic surfactants having a hydrophile-lipophile balance (HLB) of from about 12 to about 17.
  • HLB hydrophile-lipophile balance
  • the quantity of surfactant in such formulations will typically range from about 5% to about 15% by weight.
  • Suitable surfactants include polyethylene glycol sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
  • the parenteral formulations in some aspects are presented in unit-dose or multi-dose sealed containers, such as
  • injectable formulations are in accordance with the present disclosure.
  • the requirements for effective pharmaceutical carriers for injectable compositions are well-known to those of ordinary skill in the art (see, e.g., Pharmaceutics and Pharmacy Practice , J. B. Lippincott Company, Philadelphia, PA, Banker and Chalmers, eds., pages 238-250 (1982), and I.S7// J Handbook on Injectable Drugs , Toissel, 4th ed., pages 622-630 (1986)).
  • the anti-PD-1 antibody e.g., zeluvalimab
  • the pharmaceutical composition comprises the anti-PD-1 antibody (e.g., zeluvalimab), a buffer, a disaccharide, and a surfactant.
  • the pharmaceutical composition in various instances comprises zeluvalimab in a concentration of about 50 mg/mL to about 100 mg/mL, e.g., about 60 mg/mL to about 100 mg/mL, about 70 mg/mL to about 100 mg/mL, about 80 mg/mL to about 100 mg/mL, about 90 mg/mL to about 100 mg/mL, about 50 mg/mL to about 90 mg/mL, about 50 mg/mL to about 80 mg/mL, about 50 mg/mL to about 70 mg/mL, about 50 mg/mL to about 60 mg/mL, about 60 mg/mL to about 90 mg/mL, about 70 mg/mL to about 80 mg/mL, about 65 mg/mL to about 75 mg/mL.
  • zeluvalimab is present in the pharmaceutical composition at about 70 mg/mL.
  • the buffer is an acetate buffer.
  • the buffer is a sodium acetate buffer.
  • the pharmaceutical composition comprises about 5 mM to about 100 mM buffer, e.g., a sodium acetate buffer, optionally, about 5 mM to about 90 mM buffer, about 5 mM to about 80 mM buffer, about 5 mM to about 70 mM buffer, about 5 mM to about 60 mM buffer, about 5 mM to about 50 mM buffer, about 5 mM to about 40 mM buffer, about 5 mM to about 30 mM buffer, about 5 mM to about 20 mM buffer, about 5 mM to about 10 mM buffer, about 5 mM to about 25 mM buffer, about 5 mM to about 15 mM buffer, or about 10 mM buffer.
  • the pharmaceutical composition comprises about 5.0% (w/v) disaccharide to about 15.0 % (w/v) disaccharide, optionally, about 9.0% (w/v) disaccharide.
  • the disaccharide in various aspects is sucrose.
  • Surfactants are surface active agents that are amphipathic (having a polar head and hydrophobic tail). Surfactants preferentially accumulate at interfaces, resulting in reduced interfacial tension. Use of a surfactant can also help to mitigate formation of large proteinaceous particles.
  • the surfactant present in the compositions of the present disclosure is an amphipathic and/or nonionic surfactant.
  • Exemplary surfactants include polyoxyethylene sorbitan fatty acid esters
  • polysorbate 20 and polysorbate 80 are particularly contemplated.
  • the surfactant is amphipathic and nonionic, e.g., a polysorbate.
  • the surfactant is polysorbate 20 or polysorbate 80 or a mixture thereof.
  • the pharmaceutical composition comprises about 0.001% (w/v) to about 0.1% (w/v) surfactant, including, for instance, about 0.01% (w/v) surfactant.
  • the surfactant in some aspects is PS80.
  • the pharmaceutical composition is a preservative-free solution.
  • the solution has a pH less than about 6.0, optionally, less than about 5.5.
  • the pH is about 4.5 to about 5.5 or about 4.8 to about 5.4 or about 4.9, about 5.2, or about 5.4.
  • the solution has a pH of about 5.2.
  • the solution is housed in a vial or other container, e.g., syringe, IV bag, ampoule.
  • the container comprises about 1 to about 5 mL of the pharmaceutical composition of the present disclosure.
  • the pharmaceutical composition is isotonic with the intended site of administration.
  • the solution is in a form intended for administration parenterally, it can be isotonic with blood.
  • the composition typically is sterile. In certain embodiments, this may be accomplished by filtration through sterile filtration membranes.
  • parenteral compositions generally are placed into a container having a sterile access port, for example, an intravenous solution bag, or vial having a stopper pierceable by a hypodermic injection needle, or a prefilled syringe.
  • the composition may be stored either in a ready -to-use form or in a form (e.g., lyophilized) that is reconstituted or diluted prior to administration.
  • the pharmaceutical composition is a sterile, single-use, preservative- free solution for IV infusion in a vial containing 70 mg/mL zeluvalimab formulated with 10 mM acetate (sodium counterion), 9.0% (w/v) sucrose, 0.01% (w/v) polysorbate 80, pH 5.2.
  • the anti-PD-1 antibody e.g., zeluvalimab
  • intravenous administration e.g., intravenously.
  • the anti-PD-1 antibody e.g., zeluvalimab
  • intravenous infusion to the subject.
  • the infusion in various aspects is administered to the subject in about an hour or less. In certain instances, the infusion is a 60-minute infusion or a 45-minute infusion or a 30-minute infusion or a 15-minute infusion.
  • the methods of the present disclosure comprise repeat administrations of the anti-PD-1 antibody (e.g., zeluvalimab).
  • the anti-PD-1 antibody e.g., zeluvalimab
  • the cycle comprises about 3 weeks or about 19-23 days (e.g., about 19 days, about 20 days, about 21 days,
  • the cycle comprises about 4 weeks, about 1 month or about 24 to about 34 days (e.g., about 24 days, about 25 days, about 26 days, about 27 days, about 28 days, about 29 days, about 30 days, about 31 days, about 32 days, about 33 days, about 34 days).
  • the cycle comprises about 6 weeks, about 1.5 months or about 37 days to about 45 days (e.g., about 37 days, about 38 days, about 39 days, about 40 days, about 41 days, about 42 days, about 43 days, about 44 days, about 45 days).
  • Each cycle may be consecutively numbered and each day of each cycle may be consecutively numbered.
  • treatment may comprise 3 cycles (Cycle 1, Cycle 2 and Cycle 3), wherein each cycle is about 3 weeks, and zeluvalimab is administered on Day 1 of each cycle.
  • zeluvalimab is administered at a dose of 480 mg once every four weeks.
  • the cycle comprises about 4 weeks and 480 mg zeluvalimab is administered on Day 1, Day 8 or Day 15 in Cycle 1, then on Day 1 or Day 15 in Cycle 2 and all cycles subsequent to Cycle 2.
  • the antibody is administered on Day 1 starting in Cycle 2 and all cycles thereafter.
  • zeluvalimab is administered on Day 15 in Cycle 1
  • the anti-PD-1 antibody in various instances is administered on Day 15 in Cycle 2 and all cycles thereafter.
  • zeluvalimab is administered on the first day (Day 1) of each cycle.
  • zeluvalimab is administered on the first day (Day 1) of each cycle, wherein each cycle is about 28 or about 29 days.
  • the methods of the present disclosure comprise repeat administrations of the anti-PD-1 antibody (e.g., zeluvalimab) and the anti-PD-1 antibody (e.g., zeluvalimab) is administered to the subject at a first amount for a first time period and at a second amount for a second time period, wherein the second amount is different from the first amount.
  • the presently disclosed methods comprise two-phases of treatment, e.g., an induction phase and a maintenance phase, wherein the anti-PD-1 antibody (e.g., zeluvalimab) is administered to the subject at a first amount during the induction phase and at a second amount different from the first amount during the maintenance phase.
  • the first amount is lower than the second amount. In exemplary instances, the first amount is about half the second amount. In various aspects, the first amount is about 360 mg.
  • the second amount is about 720 mg.
  • the first time period is shorter than the second time period. For instance, the first time period (e.g., the induction phase) is about 12 weeks or about 3 months and the second time period (e.g., the maintenance phase) is greater than 12 weeks or greater than about 3 months.
  • the second time period (e.g., the maintenance phase) in exemplary aspects is at least or about 4 months, at least or about 6 months, at least or about 9 months, at least or about 12 months or at least or about one year, at least or about 18 months, at least or about 24 months or at least or about 2 years, at least or about 30 months or at least or about 36 months, or longer.
  • the second time period is greater than two years.
  • the anti-PD-1 antibody e.g., zeluvalimab
  • each cycle during the first time period comprises about 3 weeks or about 19-23 days (e.g., about 19 days, about 20 days, about 21 days, about 22 days, about 23 days).
  • the anti-PD-1 antibody e.g., zeluvalimab
  • the first time period comprises about 4 cycles.
  • the anti-PD-1 antibody e.g., zeluvalimab
  • each cycle during the second time period comprises about 6 weeks or about 33-39 days (e.g., about 33 days, about 34 days, about 35 days, about 36 days, about 37 days, about 38 days, about 39 days).
  • the anti-PD-1 antibody e.g., zeluvalimab
  • the second time period e.g., the maintenance phase
  • the second time period comprises more than about 4 cycles, optionally, more than 8 cycles, more than 12 cycles, more than 18 cycles, more than 24 cycles, optionally, up to 31 cycles.
  • the presently disclosed method of treating cancer or tumor in a subject comprises administering to the subject about 360 mg anti-PD-1 antibody (e.g., zeluvalimab) once every 3 weeks for 4 cycles, wherein each cycle is about 3 weeks, followed by administering to the subject about 720 mg anti-PD-1 antibody (e.g., zeluvalimab) once every 6 weeks for up to 31 cycles, wherein each cycle is about 6 weeks.
  • the method comprises administering the anti-PD-1 antibody (e.g., zeluvalimab) in combination with a platinum chemotherapy and/or an antimetabolite.
  • the antimetabolite is administered to the subject during the first time period (e.g., the induction phase) and during the second time period (e.g., the maintenance phase).
  • the platinum chemotherapy is administered to the subject only during the first time period (e.g., the induction phase).
  • the antimetabolite is exemplary instances is pemetrexed.
  • the method comprises administering about 500 mg/m 2 pemetrexed.
  • the method comprises administering pemetrexed once every 3 weeks during the first time period and second time period.
  • the method comprises administering the platinum chemotherapy during first time period.
  • the platinum chemotherapy is not administered during the second time period in some aspects.
  • the platinum chemotherapy is carboplatin or cisplatin.
  • about 75 mg/m 2 cisplatin is administered to the subject or an amount of carboplatin that provides an AUC of about 5 is administered to the subject.
  • the amount of carboplatin administered to the subject is determined based on the subject’s age, serum creatine level, gender, height, weight, target AUC or a combination thereof.
  • the amount of carboplatin administered to the subject is calculated according to the Calvert method or the amount is calculated based on the CKD-EPI equation.
  • the Calvert method and the CKD-EPI equation are known in the art. See, e.g., Calvert et
  • the cancer treated by the method is Nonsmall Cell
  • NSCLC Lung Cancer
  • the method comprises administering the anti-PD-1 antibody (e.g., zeluvalimab) in amount that does not lead to a dose limiting toxicity (DLT) during treatment with the anti-PD-1 antibody (e.g., zeluvalimab).
  • the subject does not exhibit a DLT during treatment.
  • the subject does not exhibit any grade 3 or grade 4 adverse events associated with the anti-PD-1 antibody (e.g., zeluvalimab) treatment during the treatment period.
  • the subject does not exhibit any grade 3 or grade 4 adverse events associated with the anti-PD-1 antibody (e.g., zeluvalimab) treatment during the treatment period.
  • the treatment period is at least one month, if not longer, e.g., 2 months, 3, months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 1 year, 1.5 years, 2 years.
  • the anti-PD-1 antibody comprising the six CDR amino acid sequences of SEQ ID NOs: 3-8 is administered alone, and in alternative embodiments, is administered in combination with another therapeutic agent.
  • the other therapeutic aims to treat or prevent cancer.
  • the other therapeutic is a chemotherapeutic agent.
  • the other therapeutic is an agent used in radiation therapy for the treatment of cancer.
  • the anti-PD-1 antibody e.g., zeluvalimab
  • the anti-PD-1 antibody is administered in combination with one or more of platinum coordination compounds, topoisomerase inhibitors, antibiotics, antimitotic alkaloids, antimetabolites, alkylating agents, and difluoronucleosides.
  • the anti-PD-1 antibody e.g., zeluvalimab
  • an alkylating agent or a platinum chemotherapy e.g., carboplatin, cisplatin
  • an antimetabolite e.g., pemetrexed
  • anti-PD-1 antibody comprising the six CDR amino acid sequences of SEQ ID NOs: 3-8 is administered in combination with carboplatin or cisplatin and pemetrexed.
  • the anti-PD-1 antibody comprising the six CDR amino acid sequences of SEQ ID NOs: 3-8 is administered in combination with about 500 mg/m 2 pemetrexed as an intravenous infusion over 10 minutes on Day 1 of each of four 21 -day cycles.
  • the pemetrexed is administered after the anti-PD-1 antibody (e.g., zeluvalimab) and prior to the platinum chemotherapy (e.g., carboplatin or cisplatin).
  • the platinum chemotherapy e.g., carboplatin or cisplatin.
  • about 400 mg/m 2 carboplatin is administered as a single intravenous infusion over 15-60 minutes.
  • about 20 mg/m 2 cisplatin is administered by slow intravenous infusion daily for 5 days per cycle or about 75 to 100 mg/m 2 per cycle once every
  • a method of treating a cancer or tumor in a subject comprises administering to the subject an anti-PD-1 antibody comprising six complementarity determining region (CDR) amino acid sequences of SEQ ID NOs: 3-8 (e.g., zeluvalimab) in combination with a platinum chemotherapy and/or an antimetabolite is provided herein.
  • the platinum chemotherapy is carboplatin or cisplatin.
  • the method comprises administering to the subject about 75 mg/m 2 cisplatin.
  • the method comprises administering to the subject an amount of carboplatin that provides an AUC of about 5.
  • the amount of carboplatin administered to the subject is, in exemplary aspects, determined based on the subject’s age, serum creatine level, gender, height, weight, target AUC or a combination thereof.
  • the amount of carboplatin administered to the subject is calculated according to the Calvert method.
  • the amount of carboplatin administered to the subject is calculated based on the CKD-EPI equation.
  • the antimetabolite is pemetrexed and optionally, the method comprises administering to the subject about 500 mg/m 2 pemetrexed.
  • the anti-PD-1 antibody e.g., zeluvalimab
  • the platinum chemotherapy and/or an antimetabolite is administered to the subject once every 3 weeks.
  • the method comprises administering to the subject about 360 mg anti-PD-1 antibody (e.g., zeluvalimab).
  • the presently disclosed method in various aspects, comprises administering (a) about 360 mg anti-PD-1 antibody (e.g., zeluvalimab) once every 3 weeks and (b) about 500 mg/m 2 pemetrexed to the subject once every 3 weeks.
  • the method comprises administering to the subject about 720 mg anti-PD-1 antibody (e.g., zeluvalimab).
  • the method comprises administering about 720 mg anti-PD-1 antibody (e.g., zeluvalimab) once every 6 weeks.
  • the method of treating a subject comprises administering for a first time period (a) about 360 mg anti-PD-1 antibody (e.g., zeluvalimab) once every 3 weeks and (b) about 500 mg/m 2 pemetrexed to the subject once every 3 weeks followed by administering to the subject for a second time period (c) about 720 mg anti-PD-1 antibody (e.g., zeluvalimab) once every 6 weeks and (d) about 500 mg/m 2 pemetrexed to the subject once every 3 weeks.
  • a first time period (a) about 360 mg anti-PD-1 antibody (e.g., zeluvalimab) once every 3 weeks and (b) about 500 mg/m 2 pemetrexed to the subject once every 3 weeks followed by administering to the subject for a second time period (c) about 720 mg anti-PD-1 antibody (e.g., zeluvalimab) once every 6 weeks and (d) about 500 mg/m 2 pemetrexed to the subject once every
  • the method comprises administering to the subject for a first time period: (a) about 360 mg anti-PD-1 antibody (e.g., zeluvalimab) once every 3 weeks, (b) about 500 mg/m 2 pemetrexed to the subject once every 3 weeks, and (c) about 75 mg/m 2 cisplatin or an amount of carboplatin to achieve a target AUC of about 5, and administering to the subject for a second time period: (d) about 720 mg anti-PD-1 antibody (e.g., zeluvalimab) once every 6 weeks and (e) about 500 mg/m 2 pemetrexed to the subject once every 3 weeks, wherein the first time period (e.g., induction phase) is about 12 weeks (e.g., about 4 cycles) and the second time period (e.g., maintenance phase) is up to about 186 weeks (e.g., up to 31 cycles).
  • first time period e.g., induction phase
  • the second time period e.g.,
  • Exemplary embodiments of the present invention include but are not limited to the following:
  • a method of treating cancer or tumor in a subject comprising administering to the subject an anti-PD-1 antibody comprising six complementarity determining region (CDR) amino acid sequences of SEQ ID NOs: 3-8 in an amount equivalent to about 100 mg to about 150 mg per week.
  • CDR complementarity determining region
  • a method of treating cancer or tumor in a subject comprising administering to the subject an anti-PD-1 antibody comprising six complementarity determining region (CDR)
  • the method of any one of the preceding embodiments comprising administering to the subject about 480 mg of the anti-PD-1 antibody once every 4 weeks.
  • the method of any one of the preceding embodiments, wherein the amount provides: a. a mean serum concentration of the anti-PD-1 antibody which is achieved by administering 480 mg once every 4 weeks; b. a mean plasma area under the curve (AUC».,) which is achieved by administering 480 mg once every 4 weeks; c. a difference between the mean plasma C ma x at steady state and a mean plasma C m m at steady state which is achieved by administering 480 mg once every 4 weeks; d.
  • the anti-PD-1 antibody comprises a. a heavy chain (HC) complementarity -determining region (CDR) 1 amino acid sequence comprising SEQ ID NO: 3; b. an HC CDR2 amino acid sequence comprising SEQ ID NO: 4; c. an HC CDR3 amino acid sequence comprising SEQ ID NO: 5; d. a light chain (LC) CDR1 amino acid sequence comprising SEQ ID NO: 6; e. an LC CDR2 amino acid sequence comprising SEQ ID NO: 7; and f. an LC CDR3 amino acid sequence comprising SEQ ID NO: 8.
  • HC heavy chain
  • CDR complementarity -determining region
  • the anti-PD-1 antibody comprises a heavy chain variable region of SEQ ID NO: 9 and a light chain variable region of SEQ ID NO: 10.
  • the anti-PD-1 antibody is zeluvalimab.
  • the method of any one of the preceding embodiments, wherein the anti-PD-1 antibody is administered intravenously to the subject.
  • the method of any one of the preceding embodiments, wherein the anti-PD-1 antibody is administered to the subject for at least one cycle.
  • the method of embodiment 20, wherein the anti-PD-1 antibody is administered to the subject for at least three cycles.
  • the method of embodiment 21, wherein the anti-PD-1 antibody is administered to the subject for at least six cycles.
  • the method of any one of the preceding embodiments, wherein the subject does not exhibit a dose limiting toxicity (DLT) during treatment with the anti-PD-1 antibody.
  • DLT dose limiting toxicity
  • the method of any one of the preceding embodiments, wherein the subject does not exhibit any grade 3 or grade 4 adverse events associated with anti-PD-1 antibody therapy.
  • the method of any one of the preceding embodiments, wherein the subject does not exhibit any grade 3 or grade 4 adverse events associated with anti-PD-1 antibody therapy.
  • the method of any one of the preceding embodiments, wherein the tumor is a solid tumor.
  • the method of embodiment 26, wherein the solid tumor is an advanced solid tumor or metastatic solid tumor.
  • the method of embodiment 26 or 27, wherein the solid tumor is a Stage 3 of Stage 4 tumor, a non-resectable tumor, and/or a non-localized tumor.
  • the cancer is a colon cancer, an ovarian cancer, a clear cell renal cell carcinoma, a pancreatic carcinoma, a sarcoma metastatic, sarcomatoid carcinoma, a squamous cell carcinoma (head and neck), or an undifferentiated nasopharyngeal carcinoma.
  • the subject exhibits at least a stable disease (SD) after about 2 or more cycles of treatment with the anti-PD-1 antibody.
  • SD stable disease
  • a pharmaceutical composition comprising an anti-PD-1 antibody comprising the six CDR amino acid sequences of SEQ ID NOs: 352-357 at a concentration of about 50 mg/mL to about 100 mg/mL, a buffer, a disaccharide and a surfactant.
  • the pharmaceutical composition of embodiment 34 wherein the buffer is acetate optionally sodium acetate.
  • the pharmaceutical composition of embodiment 34 or 35 comprising about 5 mM to about 25 mM acetate, optionally, about 10 mM sodium acetate.
  • the pharmaceutical composition of embodiment 34 or 35 comprising about 5.0% (w/v) disaccharide to about 15.0 % (w/v) disaccharide.
  • the pharmaceutical composition of embodiment 37 comprising about 9.0% (w/v) disaccharide.
  • the pharmaceutical composition of any one of embodiments 34 to 38 comprising about 0.001% (w/v) to about 0.1% (w/v) surfactant.
  • the pharmaceutical composition of embodiment 39 comprising about 0.01% (w/v) surfactant.
  • the pharmaceutical composition of any one of embodiments 34 to 41 which is a preservative-free solution.
  • the pharmaceutical composition of any one of embodiments 34 to 42 which is a solution having a pH of about 5.2.
  • a vial comprising about 1 to about 5 mL of the pharmaceutical composition of any one of embodiments 34 - 43.
  • a method of treating a cancer or tumor in a subject comprising administering to the subject an anti-PD-1 antibody comprising six complementarity determining region (CDR) amino acid sequences of SEQ ID NOs: 3-8 in combination with a platinum chemotherapy and/or an antimetabolite.
  • the method of embodiment 45 wherein the platinum chemotherapy is carboplatin or cisplatin.
  • the method of embodiment 46 comprising administering to the subject about 75 mg/m 2 cisplatin.
  • the method of embodiment 46 comprising administering to the subject an amount of carboplatin that provides an AUC of about 5.
  • the method of embodiment 48 wherein the amount of carboplatin administered to the subject is determined based on the subject’s age, serum creatine level, gender, height, weight, target AUC or a combination thereof.
  • the method of embodiment 49 wherein the amount of carboplatin administered to the subject is calculated according to the Calvert method.
  • the method of embodiment 49 wherein the amount of carboplatin administered to the subject is calculated based on the CKD-EPI equation.
  • the method of any one or embodiments 45-51, wherein the antimetabolite is pemetrexed.
  • the method of embodiment 52 comprising administering to the subject about 500 mg/m 2 pemetrexed.
  • any one of the preceding embodiments wherein the anti-PD-1 antibody, the platinum chemotherapy and/or an antimetabolite is administered to the subject once every 3 weeks.
  • the method of any one of embodiments 45-54 comprising administering to the subject about 360 mg anti-PD-1 antibody.
  • the method of any one of embodiments 54-55 comprising administering (a) about 360 mg anti-PD-1 antibody once every 3 weeks and (b) about 500 mg/m 2 pemetrexed to the subject once every 3 weeks.
  • the method of any one of embodiments 45-56 comprising administering to the subject about 720 mg anti-PD-1 antibody.
  • the method of embodiment 57 comprising administering about 720 mg anti-PD-1 antibody once every 6 weeks.
  • the method of embodiment 58 comprising administering for a first time period (a) about 360 mg anti-PD-1 antibody once every 3 weeks and (b) about 500 mg/m 2 pemetrexed to the subject once every 3 weeks followed by administering to the subject for a second time period (c) about 720 mg anti-PD-1 antibody once every 6 weeks and (d) about 500 mg/m 2 pemetrexed to the subject once every 3 weeks.
  • the method of embodiment 59 comprising: administering to the subject for a first time period: (a) about 360 mg anti-PD-1 antibody once every 3 weeks, (b) about 500 mg/m 2 pemetrexed to the subject once every 3 weeks, and (c) about 75 mg/m 2 cisplatin or an amount of carboplatin to achieve a target AUC of about 5 once every 3 weeks, and administering to the subject for a second time period: (d) about 720 mg anti-PD-1 antibody once every 6 weeks and (e) about 500 mg/m 2 pemetrexed to the subject once every 3 weeks, wherein the first time period is about 12 weeks and the second time period is up to about 186 weeks.
  • a method of treating a cancer or tumor in a subject comprising administering to the subject an anti-PD-1 antibody comprising six complementarity determining region (CDR) amino acid sequences of SEQ ID NOs: 3-8 in combination with a platinum chemotherapy and/or an antimetabolite, wherein the anti-PD-1 antibody is administered at a first amount for a first time period and at a second amount different from the first amount for a second time period.
  • the method of embodiment 61 wherein the first amount is lower than the second amount.
  • the method of embodiment 61 or 62, wherein the first amount is about 360 mg.
  • the method of any one of embodiments 61-63, wherein the second amount is about 720 mg.
  • the method of any one of embodiments 61-64, wherein the first time period is shorter than the second time period.
  • the method of embodiment 65 wherein the first time period is about 12 weeks or about 3 months.
  • the method of any one of embodiments 61-73 comprising administering the platinum chemotherapy during first time period.
  • the method of embodiment 74 wherein the platinum chemotherapy is not administered during the second time period.
  • the method of embodiment 76 comprising administering to the subject about 75 mg/m 2 cisplatin.
  • the method of embodiment 76 comprising administering to the subject an amount of carboplatin that provides an AUC of about 5.
  • the method of embodiment 78 wherein the amount of carboplatin administered to the subject is determined based on the subject’s age, serum creatine level, gender, height, weight, target AUC or a combination thereof.
  • Zeluvalimab is a fully human, monoclonal immunoglobulin G (IgG) subclass 1 (IgGi) directed against PD-1.
  • This molecule is a heterotetramer consisting of 2 heavy chains (HC) of the IgGi subclass and 2 light chains (LC) of the kappa subclass, which are covalently linked through disulfide bonds.
  • HC heavy chains
  • LC light chains
  • Zeluvalimab is aglycosylated through HC engineering by eliminating the glycosylation site in the CH2 domain (N300G).
  • Zeluvalimab contains 1328 amino acids.
  • the HC is composed of 450 amino acids with a molecular mass of 48,801 Da.
  • the C-terminal lysine is mostly removed from the HC during cell culture.
  • the LC is composed of 214 amino acids with a molecular weight of 23,174 Da.
  • Zeluvalimab is described as Antibody 20C1.009 in International Publication No. WO 2019/140196 and is also referred to as AMG 404.
  • Zeluvalimab is supplied as a sterile, single-use, preservative-free solution for intravenous (IV) infusion in a vial containing 70 mg/mL zeluvalimab.
  • the product is formulated with 10 mM acetate (sodium counterion), 9.0% (w/v) sucrose, 0.01% (w/v) polysorbate 80, pH 5.2.
  • the final container is a type 1 glass tubing vial and contains 1 mL of zeluvalimab.
  • Zeluvalimab is a blocking antibody that binds to PD-1 and inhibits engagement of PD-1 with its ligands.
  • zeluvalimab demonstrated comparable ( ⁇ 2-fold different) high affinity binding to both human and cynomolgus monkey PD-1 with 3 ⁇ 4 values of 0.54 nM and 0.86 nM, respectively.
  • zeluvalimab dose-dependently blocked human PD-L1 and PD- L2 binding to cell surface-expressed human and cynomolgus monkey PD-1. It was shown that zeluvalimab was more effective at inhibiting human PD-1 binding to human PD-L1/-L2 than at inhibiting cynomolgus monkey PD-1 binding to human PD-L1/-L2.
  • Zeluvalimab was administered to subjects with advanced solid tumors as short-term ( ⁇ 0.5 hours) IV infusions Q4W at dose levels of 240 mg, 480 mg, or 1050 mg.
  • the clinical trial study was designed to comprise multiple cohorts. For Cohorts 1, 2, and 4, the doses of 240, 480, and 1050 mg zeluvalimab were examined for safety, tolerability, PK, and PD of zeluvalimab in subjects with advanced solid tumors. Upon completion of Cohort 2 and based on acceptable data, dose expansion proceeded with the planned dose of 480 mg in Cohort 3 for subjects.
  • the Cmax of zeluvalimab occurred at or near the end of infusion with a median of 0.5 to 2.5 hours, as expected with a short-term IV infusion administration.
  • An approximately dose- proportional increase in exposure over the dose range of 240 to 1050 mg was observed with 4.8- and 5.2-fold increases in cycle 1, and 5.4- and 7.0-fold increases in cycle 2 for Cmax and AUC from time 0 to 28 days postdose (AUCcwsd), respectively, for a 4.4-fold increase in dose.
  • Interim RO results confirm PD-1 target coverage in peripheral blood T-cell subsets and are consistent with zeluvalimab achieving saturating PD-1 occupancy on total CD3+ T cells, CD4+ T cells, and CD8+ T cells by 4 hours post-infusion with maintenance of saturation throughout the dosing interval. Given that saturating peripheral RO has been observed clinically at exposures lower than therapeutic doses of other anti-PD-1 mAbs, peripheral RO data were not expected to provide meaningful information to assess efficacy.
  • Treatment-emergent Adverse Events There were >115 subjects with Treatment-emergent Adverse Events. Treatment-emergent adverse events experienced by 10% or more of the subjects were fatigue in 38 subjects (30.9%), nausea in 31 subjects (25.2%), decreased appetite in 29 subjects (23.6%), vomiting in 20 subjects (16.3%), pyrexia in 18 subjects (14.6%), anaemia in 17 subjects (13.8%), diarrhea in 16 subjects (13.0%), constipation in 15 subjects (12.2%), arthralgia in 14 subjects (11.4%), and abdominal pain in 13 subjects (10.6%).
  • the purpose of this study is to evaluate the efficacy, safety, and tolerability of AMG 404 in combination with pemetrexed and platinum-based chemotherapy (PPPC) compared to placebo in combination with pemetrexed and platinum-based chemotherapy (PPPC) in subjects with advanced nonsquamous NSCLC (without activating EGFR mutations/ ALK gene rearrangements) as first line treatment.
  • PPPC pemetrexed and platinum-based chemotherapy
  • FIG. 1 The overall study design is depicted in Figure 1.
  • Six hundred ninety subjects are enrolled at one of ⁇ 200 worldwide study sites. Following an ⁇ 28-day screening period, patients are randomized 2:1 into two treatment groups: [1] a first treatment group assigned to receive AMG 404 + PPPC; and [2] a second treatment group assigned to receive placebo + PPPC.
  • Subjects are stratified by smoking status (never smoked vs former or current smoker) and PD-L1 status (Tumor Proportion Score (TPS)
  • the study includes an induction treatment followed by a maintenance treatment. An optional crossover for patients receiving placebo is available, as described below.
  • Treatment with AMG 404/placebo will continue until progressive disease (PD) as determined by the investigator using irRECIST (iPD); intolerance of treatment, initiation of another anticancer therapy, withdrawal of consent, death, or a maximum of 35 cycles. Subjects are permitted to continue treatment with pemetrexed beyond 35 cycles until iPD as determined by the investigator, intolerance of treatment, initiation of another anticancer therapy, withdrawal of consent, or death.
  • PD progressive disease
  • iPD irRECIST
  • Subjects are permitted to continue treatment with pemetrexed beyond 35 cycles until iPD as determined by the investigator, intolerance of treatment, initiation of another anticancer therapy, withdrawal of consent, or death.
  • AMG 404 is administered as an intravenous solution for infusion. Like the placebo, it is supplied in vials to be stored at 2 °C to 8 °C. The solution for administration is prepared in 5% dextrose IV infusion bags and the solution comprising the IP is delivered through infusion lines.
  • the study includes an induction treatment followed by a maintenance treatment.
  • the first treatment group is treated every 3 weeks (Q3 W) with [1] 360 mg AMG 404, [2] 500 mg/m 2 pemetrexed, and [3] investigator’s choice of either 75 mg/m 2 cisplatin or area under the concentration-time curve (AUC) 5 carboplatin.
  • the second treatment group is treated Q3 W with [1] placebo, [2] 500 mg/m 2 pemetrexed, and [3] investigator’s choice of either 75 mg/m 2 cisplatin or AUC 5 carboplatin.
  • the dose of carboplatin administered to a subject is determined by
  • the first treatment group is treated with [1] 720 mg AMG 404 every 6 weeks (Q6W), and [2] 500 mg/m 2 pemetrexed Q3W for up to 31 cycles.
  • the second treatment group is treated with [1] placebo Q6W, and [2] 500 mg/m 2 pemetrexed Q3 W for up to 31 cycles.
  • Subjects who have PD per irRECIST while receiving placebo plus chemotherapy will have the opportunity to crossover to receive open label AMG 404 monotherapy after they are unblinded, as long as they meet protocol specified criteria.
  • the decision to crossover, from placebo to AMG 404, is optional and at the discretion of the investigator.
  • Subjects that crossover have a washout period, minimum of 21 days, after their last dose of chemotherapy (regardless of the time of progression) before initiating therapy with open label AMG 404.

Abstract

Provided herein are methods of treating cancer or tumor in a subject, said method comprising administering to the subject an anti-PD-1 antibody. Pharmaceutical compositions comprising anti-PD-1 antibodies are also provided herein.

Description

ANTI-PD-1 ANTIBODY DOSING FOR CANCER TREATMENT
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] The benefit under 35 U.S.C. § 119 (e) ofU.S. Provisional Patent Application No. 63/186,300, filed May 10, 2021, and U.S. Provisional Patent Application No. 63/196,947, filed June 4, 2021, is hereby claimed. The disclosure of each patent application is hereby incorporated by reference herein.
INCORPORATION BY REFERENCE OF MATERIAL SUBMITTED ELECTRONICALLY
[0002] Incorporated by reference in its entirety is a computer-readable nucleotide/amino acid sequence listing submitted concurrently herewith and identified as follows: 18,392 byte ASCII (Text) file named "A-2788-WO01-SEC_Sequence_Listing_ST25.txt"; created on May 5, 2022.
BACKGROUND
[0003] Programmed Cell Death 1 protein (PD-1), also known as CD279, SLEB2, and hSLEl, is a transmembrane protein expressed on activated T, natural killer (NK) and B lymphocytes, macrophages, dendritic cells (DCs) and monocytes. Notably, PD-1 is highly expressed on tumor- specific T cells (Han et ak, Am J Cancer Res 10(3): 727-742 (2020)). PD-1 binds to B7 protein family members, PD-1 Ligand 1 (PD-L1; also referred to as CD279 and B7-H1) and PD-1 Ligand 2 (also known as PD-L2, CD273, and B7-DC). PD-L1 is constitutively expressed on T and B cells, macrophages and dendritic cells, whereas PD-L2 expression is typically restricted to activated DC and macrophages (Xing et ak, Oncoimmunology 7(3): el356144 (2017) (doi:
10.1080/2162402X.2017.1356144)). PD-1 inhibits both adaptive and innate immune responses. The PD-1/PD-L1 axis is involved in the suppression of T cell immune responses in cancer. Antagonists of this pathway have been clinically validated across a number of solid tumor indications. PD-1 inhibitors, nivolumab, pembrolizumab, and cemiplimab, and PD-L1 inhibitors atezolizumab, avelumab, and durvalumab target the PD-1/PD-L1 pathway, and each has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of various cancers.
[0004] Although pembrolizumab and nivolumab have been approved by the US FDA, these approvals were based on relatively low response rates (19% with pembrolizumab and 12% with nivolumab). In addition, randomized studies evaluating nivolumab as second-line or maintenance therapy have failed to meet their primary endpoints of overall survival (OS) (Reck et al, 2018). Thus, improved treatments targeting the PD-1/PD-L1 axis are needed.
SUMMARY
[0005] Presented herein are data demonstrating clinical experience with an anti-PD-1 antibody, called zeluvalimab, from the first in human study, which is currently ongoing and supported a recommended phase 2 dose of 480 mg administered once every 4 weeks. Accordingly, the present
1 disclosure provides a method of treating cancer or tumor in a subject, wherein said method comprises administering to the subject an agent that targets PD-1, e.g., an anti-PD-1 antibody (e.g., an anti-PD-1 antibody comprising six complementarity determining region (CDR) amino acid sequences of SEQ ID NOs: 3-8) in an amount effective to treat the cancer or tumor in the subject. In exemplary embodiments said method comprises administering to the subject an amount of the agent that targets PD-1, e.g., an anti-PD-1 antibody (e.g., an anti-PD-1 antibody comprising six CDR amino acid sequences of SEQ ID NOs: 3-8) in an amount equivalent to about 100 mg to about 150 mg per week. In various instances, the amount of the anti-PD-1 antibody is equivalent to about 115 mg per week to about 125 mg per week. In various aspects, the amount of the anti-PD-1 antibody is equivalent to about 120 mg per week. The method in exemplary embodiments, comprises administering to the subject about 120 mg of the PD-1 antibody once a week, about 240 mg of the PD-1 antibody once every 2 weeks, about 360 mg of the PD-1 antibody once every 3 weeks, about 480 mg of the PD-1 antibody once every 4 weeks, about 600 mg of the PD-1 antibody once every 5 weeks, about 720 mg of the PD-1 antibody once every 6 weeks, about 840 mg of the PD-1 antibody once every 7 weeks, or about 960 mg of the PD-1 antibody once every 8 weeks. In exemplary embodiments, the method comprises administering to the subject an anti-PD-1 antibody comprising six CDR amino acid sequences of SEQ ID NOs: 3-8 in an amount equivalent to about 480 mg once every 4 weeks. In exemplary aspects, amount administered to the subject provides: (a) a mean serum concentration of the anti-PD-1 antibody which is achieved by administering 480 mg once every 4 weeks; (b) a mean plasma area under the curve (AUC0-¥) which is achieved by administering 480 mg once every 4 weeks; (c) a difference between the mean plasma Cmax at steady state and a mean plasma Cmin at steady state which is achieved by administering 480 mg once every 4 weeks; (d) a mean plasma Cmax at steady state which is achieved by administering 480 mg once every 4 weeks, or (e) any combination thereof. The anti-PD-1 antibody comprises in exemplary instances, (a) a heavy chain (HC) complementarity -determining region (CDR) 1 amino acid sequence comprising SEQ ID NO: 3; (b) an HC CDR2 amino acid sequence comprising SEQ ID NO: 4; (c) an HC CDR3 amino acid sequence comprising SEQ ID NO: 5; (d) a light chain (LC) CDR1 amino acid sequence comprising SEQ ID NO: 6; (e) an LC CDR2 amino acid sequence comprising SEQ ID NO: 7; and (f) an LC CDR3 amino acid sequence comprising SEQ ID NO: 8. In exemplary instance, the anti-PD-1 antibody comprises a heavy chain variable region of SEQ ID NO: 9 and a light chain variable region of SEQ ID NO: 10. In exemplary aspects, the anti-PD-1 antibody comprises a heavy chain of SEQ ID NO: 11 or 13 and a light chain of SEQ ID NO: 12. The anti-PD-1 antibody is zeluvalimab in exemplary aspects. In certain aspects, the anti-PD-1 antibody is administered intravenously to the subject. In various instances, the anti-PD-1 antibody is administered to the subject for at least one cycle, at least three cycles, at least six cycles, or more. In exemplary aspects, the subject does not exhibit a dose limiting toxicity (DLT) during treatment with the anti-PD-1 antibody. Optionally, the subject does not exhibit any grade 3 or grade 4 adverse events associated with anti-PD-1 antibody
2 therapy. In various instances, the subject does not exhibit any grade 3 or grade 4 adverse events associated with anti-PD-1 antibody therapy. In some aspects, the tumor is a solid tumor, e.g., an advanced solid tumor or metastatic solid tumor, a Stage 3 of Stage 4 tumor, a non-resectable tumor, and/or a non-localized tumor. Optionally, the cancer is a colon cancer, an ovarian cancer, a clear cell renal cell carcinoma, a pancreatic carcinoma, a sarcoma metastatic, sarcomatoid carcinoma, a squamous cell carcinoma (head and neck), or an undifferentiated nasopharyngeal carcinoma. In various aspects, the subject exhibits at least a stable disease (SD) after about 2 or more cycles of treatment with the anti-PD-1 antibody, at least a partial response (PR) after about 2 or more cycles of treatment with the anti-PD-1 antibody, or a complete response (CR) after about 2 or more cycles of treatment with the anti-PD-1 antibody. The subject in some aspects had prior treatment with an anticancer therapy other than the anti-PD-1 antibody.
[0006] The present disclosure further provides a method of treating a cancer or tumor in a subject, said method comprising administering to the subject an anti-PD-1 antibody comprising six complementarity determining region (CDR) amino acid sequences of SEQ ID NOs: 3-8 in combination with a platinum chemotherapy and/or an antimetabolite. Additionally provided herein is a method of treating a cancer or tumor in a subject, said method comprising administering to the subject an anti-PD-1 antibody comprising six complementarity determining region (CDR) amino acid sequences of SEQ ID NOs: 3-8 in combination with a platinum chemotherapy and/or an antimetabolite, wherein the anti-PD-1 antibody is administered at a first amount for a first time period and at a second amount different from the first amount for a second time period. In various aspects, the method comprises administering to the subject for a first time period (e.g., an induction phase): (a) about 360 mg anti-PD-1 antibody once every 3 weeks, (b) about 500 mg/m2 pemetrexed once every 3 weeks, and (c) about 75 mg/m2 cisplatin or an amount of carboplatin to achieve a target AUC of about 5 once every 3 weeks, and administering to the subject for a second time period (e.g., a maintenance phase): (d) about 720 mg anti-PD-1 antibody once every 6 weeks and (e) about 500 mg/m2 pemetrexed to the subject once every 3 weeks, wherein the first time period (e.g., induction phase) is about 12 weeks (e.g., about 4 cycles) and the second time period (e.g., maintenance phase) is up to about 186 weeks (e.g., up to 31 cycles). In specific embodiments, the anti-PD-1 antibody is zeluvalimab.
[0007] In various aspects, the method comprises administering to the subject for a first time period (e.g., induction phase): (a) about 360 mg anti-PD-1 antibody once every 3 weeks, (b) about 500 mg/m2 pemetrexed once every 3 weeks, and (c) about 75 mg/m2 cisplatin, and administering to the subject for a second time period or a maintenance phase: (d) about 720 mg anti-PD-1 antibody once every 6 weeks and (e) about 500 mg/m2 pemetrexed to the subject once every 3 weeks, wherein the first time period (e.g., induction phase) is about 12 weeks (e.g., about 4 cycles) and the second time
3 period (e.g., maintenance phase) is up to about 186 weeks (e.g., up to 31 cycles). In specific embodiments, the anti-PD-1 antibody is zeluvalimab.
[0008] In various aspects, the method comprises administering to the subject for a first time period (e.g., induction phase): (a) about 360 mg anti-PD-1 antibody once every 3 weeks, (b) about 500 mg/m2 pemetrexed once every 3 weeks, and (c) an amount of carboplatin to achieve a target AUC of about 5, and administering to the subject for a second time period or a maintenance phase: (d) about 720 mg anti-PD-1 antibody once every 6 weeks and (e) about 500 mg/m2 pemetrexed to the subject once every 3 weeks, wherein the first time period (e.g., induction phase) is about 12 weeks (e.g., about 4 cycles) and the second time period (e.g., maintenance phase) is up to about 186 weeks (e.g., up to 31 cycles). In specific embodiments, the anti-PD-1 antibody is zeluvalimab.
[0009] Further provided herein is a pharmaceutical composition comprising an anti-PD-1 antibody comprising the six CDR amino acid sequences of SEQ ID NOs: 352-357 at a concentration of about 50 mg/iuL to about 100 mg/mL, a buffer, a disaccharide and a surfactant. In various aspects, the buffer is acetate optionally sodium acetate. Optionally, the pharmaceutical composition comprises about 5 mM to about 25 mM acetate, optionally, about 10 mM sodium acetate. In various aspects, the pharmaceutical composition comprises about 5.0% (w/v) disaccharide to about 15.0 % (w/v) disaccharide, e.g., about 9.0% (w/v) disaccharide. In various aspects, the pharmaceutical composition comprises about 0.001% (w/v) to about 0.1% (w/v) surfactant, e.g., about 0.01% (w/v) surfactant. Optionally, the surfactant is PS80. In various aspects, the pharmaceutical composition is a preservative-free solution, and optionally, has a pH of about 5.2. Additionally provided is a vial comprising about 1 to about 5 mL of the presently disclosed pharmaceutical composition. In specific embodiments, the anti-PD-1 antibody is zeluvalimab.
BRIEF DESCRIPTION OF THE DRAWING
[0001] Figure 1 is a schematic of a randomized, double-blind, placebo controlled phase 3 study of platinum plus pemetrexed chemotherapy with or without AMG 404 as first line treatment in subjects with advanced nonsquamous nonsmall cell lung cancer (NSCLC). Abbreviations: AUC = area under the concentration-time curve; irRECIST = Immune-related Response Evaluation Criteria in Solid Tumors; iPD = progressive disease as determined by the investigator using irRECIST; PD-L1 = programmed death-ligand 1; Q3W = every 3 weeks; Q6W = every 6 weeks; TPS = tumor proportion score. Footnotes: a Treatment with AMG 404/placebo will continue until iPD; intolerance of treatment, initiation of another anticancer therapy, withdrawal of consent, death, or a maximum of 35 cycles. Subjects will be permitted to continue treatment with pemetrexed beyond 35 cycles until iPD as determined by the investigator, intolerance of treatment, initiation of another anticancer therapy, withdrawal of consent, or death. Investigators will use irRECIST to make treatment decisions. b Crossover to AMG 404 monotherapy will be permitted for subjects in the placebo-combination group
4 who have iPD as determined by the investigator using irRECIST. cUpon permanent discontinuation from the study treatment for any reason, a safety follow-up visit will be performed 30 days (+ 7 days) after the last administration of study treatment.
DETAILED DESCRIPTION
[0002] Provided herein are methods of treating a subject with cancer and methods of treating a subject with a solid tumor. In exemplary embodiments, the method comprises administering to the subject an agent which targets PD-1, including but not limited to an anti-PD-1 antibody (e.g., zeluvalimab; also referred to as AMG 404) in an amount effective for treating the cancer or the solid tumor in the subject.
[0003] Agents Targeting PD-1
[0004] Exemplary agents targeting PD-1 include PD-1 antigen binding proteins (e.g., anti-PD-1 antibodies, antigen binding antibody fragments thereof, and anti-PD-1 antibody protein products) described in International Publication No. WO 2019/140196, which is incorporated herein by reference in its entirety. In exemplary aspects, the PD-1 antigen binding protein binds to human PD- 1, which has the amino acid sequence described in National Center for Biotechnology Information (NCBI) Reference Sequence No. NP 005009.2, or SEQ ID NO: 1, or the mature form (e.g., lacking the signal peptide) thereof which is represented by amino acids 21-288 of SEQ ID NO: 1. In exemplary aspects, the PD-1 antigen binding protein binds to cynomolgus PD-1, which has the amino acid sequence described inNCBI Reference Sequence No. NP 001271065.1, or SEQ ID NO: 2, orthe mature form thereof. In exemplary instances, the PD-1 antigen binding protein binds to both human PD-1 and cynomolgus PD-1. In exemplary embodiments, the anti-PD-1 -antibody comprises the amino acid sequences of SEQ ID NOs: 3-8. In exemplary aspects, the anti-PD-1 -antibody comprises six CDR amino acid sequences of SEQ ID NOs: 3-8. In exemplary embodiments, the anti-PD-1- antibody comprises a heavy chain (HC) complementarity -determining region (CDR) 1 amino acid sequence of SEQ ID NO: 3, an HC CDR2 amino acid sequence of SEQ ID NO: 4, an HC CDR3 amino acid sequence of SEQ ID NO: 5, a light chain (LC) CDR1 amino acid sequence of SEQ ID NO: 6, an LC CDR2 amino acid sequence of SEQ ID NO: 7, and an LC CDR3 amino acid sequence of SEQ ID NO: 8. In certain embodiments, the anti-PD-1 antibody comprises a PD-l-binding domain comprising (a) a heavy chain variable region (VH) that comprises: (i) a VH complementarity determining region one (CDR-H1) comprising the amino acid sequence of SEQ ID NO: 3; (ii) a CDR- H2 comprising the amino acid sequence of SEQ ID NO: 4; and (iii) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; and (b) a light chain variable region (VL) that comprises: (i) a VL complementarity determining region one (CDR-L1) comprising the amino acid sequence of SEQ ID NO: 6; (ii) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (iii) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8. In certain embodiments, the PD-l-binding
5 domain comprises: a VH that comprises the amino acid sequence of SEQ ID NO: 9, and a VL that comprises the amino acid sequence of SEQ ID NO: 10. In certain embodiments, the anti-PD-1- antibody comprises a VH comprising the amino acid sequence of SEQ ID NO: 9 and a VL comprising the amino acid sequence of SEQ ID NO: 10. In certain embodiments, the anti-PD-1 -antibody comprises a HC comprising the amino acid sequence of SEQ ID NO: 11 or 13 and a LC comprising the amino acid sequence of SEQ ID NO: 12. In various instances, the anti-PD-1 antibody is zeluvalimab (International Nonproprietary Names for Pharmaceutical Substances (INN): Proposed INN: List 124, WHO Drug Information 34(4): 929-1102 (2020); CAS Registry Number 2315361-37- 4). Zeluvalimab is an immunoglobulin G1 -kappa, anti- [Homo sapiens PDCD1 (programmed cell death 1, PD-1, PD1, CD279)], monoclonal antibody comprising a gammal heavy chain (1-450) [VH (Homo sapiens IGHV3-23*03 (92.8%) -(IGHD) -IGHJ3*01 (92.3%)) CDR-IMGT [8.8.13] (26- 33.50-58.97-109) (1-120) - Homo sapiens IGHGl*03v, Glm3>Glml7, nGlml (CHI R120>K (217) (121-218), hinge 1-15 (219-233), CH2 R83>C (295), N84.4>G (300), V85>C (305) (234- 343), CH3 E12 (359), M14 (361) (344-448), CHS (449- 450)) (121-450)], (223-214')-disulfide with kappa light chain (l'-214') [V-KAPPA (Homo sapiens IGKV1-12*01 (96.8%) -IGKJ4*01 (100%)) CDR-IMGT [6.3.9](27- 32.50-52.89-97) (l'-107') -Homo sapiens IGKC*01 (100%), Km3 A45.1 (153), V101 (191) (108'-214’)]; dimer (229-229":232-232")-bisdisulfide, produced in Chinese hamster ovary (CHO) cells, non-glycosylated immunomodulator, antineoplastic.
[0005] Subjects, Cancer, and Efficacy
[0006] In various instances of the presently disclosed methods, the subject is a human subject. In various aspects, the human subject is about 18 years old or older. In exemplary instances, the human subject has a tumor, e.g., a solid tumor. In various aspects, the subject has a histologically or cytologically confirmed metastatic or locally advanced solid tumor, which optionally is not amendable to curative treatment with surgery or radiation. In exemplary instances, the human subject has an advanced solid tumor. In various aspects, the solid tumor is a metastatic solid tumor and/or non-localized and/or non-resectable. In various instances, the solid tumor is a Stage 3 or Stage 4 tumor. In exemplary instances, the subject has at least one measurable lesion as defined by modified RECIST 1.1 which has not undergone biopsy within 3 months of the screening scan !ln exemplary instances, the human subject has an Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to 2, optionally, 0 or 1, (Oken et al., Am J Clin Oncol 5: 649-655 (1982).
In exemplary aspects, the subject meets one or more characteristics of Table 2 and/or does not meet one or more characteristics of Table 3. In various aspects, the tumor is a tumor of a cancer, e.g., a cancer described herein. In various aspects, the subject has an adenocarcinoma (e.g., metastatic adenocarcinoma), adrenocortical carcinoma, anal squamous cell carcinoma, basal cell carcinoma, cholangiocarcinoma, cervix carcinoma, adenocarcinoma of the colon or of the appendix, rectal adenocarcinoma, oesophageal squamous cell carcinoma, gastric adenocarcinoma, testicular germ cell
6 tumor, gastrointestinal stromal tumor, hepatocellular carcinoma, squamous cell carcinoma, mesothelioma (e.g., malignant mesothelioma), keratinizing squamous cell carcinoma of the nasopharynx, undifferentiated nasopharyngeal carcinoma, neuroendocrine carcinoma, haemangiopericytoma, malignant sweat gland carcinoma, porocarcinoma, pancreatic carcinoma (e.g., pancreatic metastatic carcinoma), clear cell renal cell carcinoma, hepatocellular carcinoma, sarcoma, osteosarcoma, dedifferentiated liposarcoma, pleomorphic malignant fibrous histiocytoma, alveolar soft part sarcoma, angiosarcoma, leiomyosarcoma, soft tissue sarcoma, metastatic sarcoma, endometrial stromal sarcoma, sarcomatoid carcinoma, squamous cell carcinoma of the skin, malignant neoplasm of ampulla of Vater or of the thymus small intestine adenocarcinoma, gastrointestinal stromal tumor, transitional cell cancer of the renal pelvis and ureter, vaginal adenocarcinoma, or a squamous cell carcinoma of the vulva. In various instances, the subject has a tumor of a cancer, including but not limited to, anal cancer, gall bladder cancer, triple negative breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial cancer uterine cancer, tracheal cancer, ovarian cancer, prostate cancer, skin cancer, thymus cancer, transitional cell cancer, vaginal cancer, vulva cancer, neuroendocrine cancer, nasopharynx cancer, HCC, GIST, gastric cancer, biliary tract cancer, or basal cell cancer.
[0007] In various instances, the cancer is a colon cancer, an ovarian cancer, a clear cell renal cell carcinoma, a pancreatic carcinoma, a sarcoma metastatic, sarcomatoid carcinoma, a squamous cell carcinoma (head and neck), or an undifferentiated nasopharyngeal carcinoma. The cancer treatable by the methods disclosed herein can be any cancer, e.g., any malignant growth or tumor caused by abnormal and uncontrolled cell division that may spread to other parts of the body through the lymphatic system or the blood stream. The cancer in some aspects is one selected from the group consisting of acute lymphocytic cancer, acute myeloid leukemia, alveolar rhabdomyosarcoma, bone cancer, brain cancer, breast cancer, cancer of the anus, anal canal, or anorectum, cancer of the eye, cancer of the intrahepatic bile duct, cancer of the joints, cancer of the neck, gallbladder, or pleura, cancer of the nose, nasal cavity, or middle ear, cancer of the oral cavity, cancer of the vulva, chronic lymphocytic leukemia, chronic myeloid cancer, colon cancer, esophageal cancer (e.g., esophageal squamous cell cancer), cervical cancer, gastrointestinal carcinoid tumor, Hodgkin lymphoma, hypopharynx cancer, kidney cancer, larynx cancer, liver cancer, lung cancer, mesothelioma (e.g., malignant mesothelioma), melanoma, multiple myeloma, nasopharynx cancer, non-Hodgkin lymphoma, ovarian cancer, pancreatic cancer, peritoneum, omentum, and mesentery cancer, pharynx cancer, prostate cancer, rectal cancer, renal cancer (e.g., renal cell carcinoma (RCC)), small intestine cancer, soft tissue cancer, stomach cancer, testicular cancer, thyroid cancer, ureter cancer, and urinary bladder cancer. In various aspects, the prostate cancer is a metastatic castration-resistant prostate cancer (mCRPC). In particular aspects, the cancer is selected from the group consisting of: head and neck, ovarian, cervical, bladder and esophageal cancers, pancreatic, gastrointestinal cancer, gastric,
7 breast, endometrial and colorectal cancers, hepatocellular carcinoma, glioblastoma, bladder, lung cancer, e.g., non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma. In various aspects, the NSCLC is squamous NSCLC. In alternative aspects, the NSCLC is non-squamous NSCLC. In particular embodiments, the tumor is non-small cell lung cancer (NSCLC), head and neck cancer, renal cancer, triple negative breast cancer, and gastric cancer. In exemplary aspects, the subject has a tumor (e.g., a solid tumor, a hematological malignancy, or a lymphoid malignancy) and the pharmaceutical composition is administered to the subject in an amount effective to treat the tumor in the subject. In other exemplary aspects, the tumor is non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), head and neck cancer, renal cancer, breast cancer, melanoma, ovarian cancer, liver cancer, pancreatic cancer, colon cancer, prostate cancer, gastric cancer, lymphoma or leukemia, and the pharmaceutical composition is administered to the subject in an amount effective to treat the tumor in the subject. Additional cancers, tumors and malignancies treatable by the presently disclosed methods are described in International Publication No. WO 2019/140196.
[0008] In various aspects, the subject has received prior treatment with an anticancer therapy other than anti-PD-1 antibody therapy. In various instances, the subject has failed at least one or more prior line of systemic therapy prior to being treated with zeluvalimab. In various instances, the subject has not received any prior treatment with an anticancer therapy. In various aspects, the subject has not failed a prior therapy.
[0009] In exemplary embodiments, an amount effective for treating the cancer or the solid tumor in the subject is administered to the subject. As used herein, the term “treat,” as well as words related thereto, do not necessarily imply 100% or complete treatment. Rather, there are varying degrees of treatment of which one of ordinary skill in the art recognizes as having a potential benefit or therapeutic effect. In this respect, the methods of treating cancer of the present disclosure can provide any amount or any level of treatment. Furthermore, the treatment provided by the method of the present disclosure can include treatment of one or more conditions or symptoms or signs of the cancer being treated. Also, the treatment provided by the methods of the present disclosure can encompass slowing the progression of the cancer. For example, the methods can treat cancer by virtue of enhancing the T cell activity or an immune response against the cancer, reducing tumor or cancer growth, reducing metastasis of tumor cells, increasing cell death of tumor or cancer cells, and the like. In exemplary aspects, the methods treat by way of delaying the onset or recurrence of the cancer by 1 day, 2 days, 4 days, 6 days, 8 days, 10 days, 15 days, 30 days, two months, 4 months, 6 months, 1 year, 2 years, 4 years, or more.
[0010] In exemplary aspects, the methods treat by way increasing the survival of the subject. In various instances, the survival of the subject is increased by 30 days, two months, 4 months, 6 months, 1 year, 2 years, 4 years, or more.
8 [0011] In various aspects, the treatment provided by the methods of the present disclosure provides a therapeutic response as per Response Evaluation Criteria in Solid Tumors (RECIST) or other like criteria. RECIST is a set of criteria to evaluate the progression, stabilization or responsiveness of tumors and/or cancer cells jointly created by the National Cancer Institute of the United States, the National Cancer Institute of Canada Clinical Trials Group and the European Organisation for Research and Treatment of Cancer. According to RECIST, certain tumors are measured in the beginning of an evaluation (e.g., a clinical trial), in order to provide a baseline for comparison after treatment with a drug. The response assessment and evaluation criteria for tumors are published in Eisenhauer et. al., Eur J Cancer 45:228-247 (2009) and Litiere et. al, Journal of Clinical Oncology 37(13): 1102-1110 (2019) DOI: 10.1200/JC0.18.01100. In various instances, the treatment provided by the methods of the present disclosure provides a therapeutic response as per a modified RECIST tumor response assessment, as follows:
Figure imgf000011_0001
9
Figure imgf000012_0001
CR=complete response; NA=not available; ND=not done; PR=partial response; RECIST Response Evaluation Criteria in Solid Tumors; UE = unable to evaluate a Decrease assessed relative to baseline. Increase assessed relative to nadir. b Response: CR and PR require a confirmation assessment after >4 weeks, may also wait until the next scheduled imaging c Progression: Progressive disease requires a confirmation assessment 4 to 6 weeks after initial radiographic progressive disease is observed d Subjects with non-index lesions only
[0012] Accordingly, methods of slowing the progression of a cancer in a subject, enhancing the T cell activity or an immune response against a cancer in a subject, reducing tumor or cancer growth in a subject, reducing metastasis of tumor cells in a subject, increasing cell death of tumor or cancer cells in a subject, and/or delaying the onset or recurrence of a cancer in a subject are provided herein. In various aspects, the method comprises administering to the subject an anti-PD-1 antibody, e.g., zeluvalimab, in accordance with the present disclosures. Also, a method of treating a cancer to provide a complete response (CR), partial response (PR), or stable disease (SD), as per a modified RECIST 1.1, in a subject is provided. In various aspects, the method comprises administering to the subject zeluvalimab in accordance with the present disclosures. In exemplary instances, upon treatment, the subject exhibits at least SD. Optionally, the subject exhibits at least SD after about 2 or more cycles of treatment with zeluvalimab. In exemplary aspects, upon treatment, the subject exhibits at least a PR. Optionally, the subject exhibits at least a PR or a CR after about 2 cycles of treatment with zeluvalimab.
[0013] Dosing
[0014] In exemplary embodiments, the method comprises administering to the subject an anti-PD-1 antibody comprising six CDR amino acid sequences of SEQ ID NOs: 3-8 (e.g., zeluvalimab) in an amount effective for treating the cancer or the solid tumor in the subject. In various instances, the amount is equivalent to about 100 mg per week to about 150 mg per week. For example, the amount is equivalent to about 100 mg per week to about 140 mg per week, about 100 mg per week to about 130 mg per week, about 100 mg per week to about 120 mg per week, about 100 mg per week to about
110 mg per week, about 110 mg per week to about 150 mg per week, about 120 mg per week to about
150 mg per week, about 130 mg per week to about 150 mg per week, or about 140 mg per week to about 150 mg per week. In various aspects, the amount of the anti-PD-1 antibody comprising six
CDR amino acid sequences of SEQ ID NOs: 3-8 (e.g., zeluvalimab) is equivalent to about 115 mg per week to about 125 mg per week, about 108 mg per week to about 132 mg per week, or about 114 mg
10 per week to about 126 mg per week, or about 120 mg per week. In exemplary instances, the method comprises administering to the subject about 120 mg of anti-PD-1 antibody comprising six CDR amino acid sequences of SEQ ID NOs: 3-8 (e.g., zeluvalimab) once a week or about 240 mg anti-PD- 1 antibody comprising six CDR amino acid sequences of SEQ ID NOs: 3-8 (e.g., zeluvalimab) once every 2 weeks. In exemplary aspects, the method comprises administering to the subject about 360 mg of anti-PD-1 antibody comprising six CDR amino acid sequences of SEQ ID NOs: 3-8 (e.g., zeluvalimab) once every 3 weeks or about 480 mg anti-PD-1 antibody comprising six CDR amino acid sequences of SEQ ID NOs: 3-8 (e.g., zeluvalimab) once every 4 weeks. In various instances, the method comprises administering to the subject about 600 mg of anti-PD-1 antibody comprising six CDR amino acid sequences of SEQ ID NOs: 3-8 (e.g., zeluvalimab) once every 5 weeks or about 720 mg anti-PD-1 antibody comprising six CDR amino acid sequences of SEQ ID NOs: 3-8 (e.g., zeluvalimab) once every 6 weeks. In various aspects, the method comprises administering to the subject about 840 mg of anti-PD-1 antibody comprising six CDR amino acid sequences of SEQ ID NOs: 3-8 (e.g., zeluvalimab) once every 7 weeks or about 960 mg anti-PD-1 antibody comprising six CDR amino acid sequences of SEQ ID NOs: 3-8 (e.g., zeluvalimab) once every 8 weeks. In various aspects, the method comprises administering anti-PD-1 antibody comprising six CDR amino acid sequences of SEQ ID NOs: 3-8 (e.g., zeluvalimab) to the subject 120X mg of anti-PD-1 antibody comprising six CDR amino acid sequences of SEQ ID NOs: 3-8 (e.g., zeluvalimab) once every X weeks, wherein X is an integer from 1 to 10. In exemplary embodiments, the method comprises administering to the subject an anti-PD-1 antibody comprising six CDR amino acid sequences of SEQ ID NOs: 3-8 (e.g., zeluvalimab) in an amount equivalent to about 480 mg administered once every 4 weeks. By “equivalent” is meant that the amount administered to the patient is within a 10% range of a pharmacokinetic characteristic achieved with a reference amount. The pharmacokinetic characteristic in various instances, is a mean serum concentration, mean plasma area under the curve (AUC), e.g., AUG-,. a mean plasma Cmax at steady state, a mean plasma Cmm at steady state, a difference between the mean plasma Cmax at steady state and a mean plasma Cmm at steady state. In exemplary aspects, the reference amount is about 100 mg to about 150 mg administered weekly. In exemplary aspects, the reference amount is about 115 mg to about 125 mg administered weekly. In exemplary aspects, the reference amount is about 480 mg administered once every 4 weeks. In various aspects, the amount of the anti-PD-1 antibody comprising the six CDRs of SEQ ID NOs: 3-8 administered to the subject is equivalent to 480 mg administered once every 4 weeks and/or the amount provides: (a) a mean serum concentration of the anti-PD-1 antibody which is achieved by administering 480 mg once every 4 weeks; (b) a mean plasma area under the curve (AUG .,) which is achieved by administering 480 mg once every 4 weeks; (c) a difference between the mean plasma Cmax at steady state and a mean plasma Cmm at steady state which is achieved by administering 480 mg once every 4 weeks; and/or (d) a mean plasma Cmax at steady state which is achieved by administering 480 mg once every 4 weeks.
11 [0015] Routes of Administration, Pharmaceutical Compositions, and Regimens
[0016] The agent targeting PD-1, e.g., anti-PD-1 antibody (e.g., zeluvalimab), can be administered to the subject via any suitable route of administration. For example, the anti-PD-1 antibody (e.g., zeluvalimab) can be administered to a subject via parenteral, nasal, oral, pulmonary, topical, vaginal, or rectal administration. The following discussion on routes of administration is merely provided to illustrate exemplary embodiments and should not be construed as limiting the scope in any way.
[0017] Formulations suitable for parenteral administration include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non- aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. The term, “parenteral” means not through the alimentary canal but by some other route such as subcutaneous, intramuscular, intraspinal, or intravenous. The anti-PD-1 antibody (e.g., zeluvalimab) can be administered with a physiologically acceptable diluent in a pharmaceutical carrier, such as a sterile liquid or mixture of liquids, including water, saline, aqueous dextrose and related sugar solutions, an alcohol, such as ethanol or hexadecyl alcohol, a glycol, such as propylene glycol or polyethylene glycol, dimethylsulfoxide, glycerol, ketals such as 2,2- dimethyl- 153-dioxolane-4-methanol, ethers, poly(ethyleneglycol) 400, oils, fatty acids, fatty acid esters or glycerides, or acetylated fatty acid glycerides with or without the addition of a pharmaceutically acceptable surfactant, such as a soap or a detergent, suspending agent, such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agents and other pharmaceutical adjuvants.
[0018] Oils, which can be used in parenteral formulations include petroleum, animal, vegetable, or synthetic oils. Specific examples of oils include peanut, soybean, sesame, cottonseed, com, olive, petrolatum, and mineral. Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters.
[0019] The parenteral formulations in some embodiments contain from about 0.5% to about 25% by weight of the anti-PD-1 antibody (e.g., zeluvalimab) in solution. Preservatives and buffers can be used. In order to minimize or eliminate irritation at the site of injection, such compositions can contain one or more nonionic surfactants having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations will typically range from about 5% to about 15% by weight. Suitable surfactants include polyethylene glycol sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol. The parenteral formulations in some aspects are presented in unit-dose or multi-dose sealed containers, such as
12 ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient, for example, water, for injections, immediately prior to use. Extemporaneous injection solutions and suspensions in some aspects are prepared from sterile powders, granules, and tablets of the kind previously described.
[0020] Injectable formulations are in accordance with the present disclosure. The requirements for effective pharmaceutical carriers for injectable compositions are well-known to those of ordinary skill in the art (see, e.g., Pharmaceutics and Pharmacy Practice , J. B. Lippincott Company, Philadelphia, PA, Banker and Chalmers, eds., pages 238-250 (1982), and I.S7//J Handbook on Injectable Drugs , Toissel, 4th ed., pages 622-630 (1986)).
[0021] In various aspects, the anti-PD-1 antibody (e.g., zeluvalimab) is administered to the subject as a pharmaceutical composition for intravenous administration, e.g., intravenous injection or infusion. In exemplary aspects, the pharmaceutical composition comprises the anti-PD-1 antibody (e.g., zeluvalimab), a buffer, a disaccharide, and a surfactant. The pharmaceutical composition in various instances comprises zeluvalimab in a concentration of about 50 mg/mL to about 100 mg/mL, e.g., about 60 mg/mL to about 100 mg/mL, about 70 mg/mL to about 100 mg/mL, about 80 mg/mL to about 100 mg/mL, about 90 mg/mL to about 100 mg/mL, about 50 mg/mL to about 90 mg/mL, about 50 mg/mL to about 80 mg/mL, about 50 mg/mL to about 70 mg/mL, about 50 mg/mL to about 60 mg/mL, about 60 mg/mL to about 90 mg/mL, about 70 mg/mL to about 80 mg/mL, about 65 mg/mL to about 75 mg/mL. In various aspects, zeluvalimab is present in the pharmaceutical composition at about 70 mg/mL.
[0022] In exemplary aspects, the buffer is an acetate buffer. In exemplary aspects, the buffer is a sodium acetate buffer. Optionally, the pharmaceutical composition comprises about 5 mM to about 100 mM buffer, e.g., a sodium acetate buffer, optionally, about 5 mM to about 90 mM buffer, about 5 mM to about 80 mM buffer, about 5 mM to about 70 mM buffer, about 5 mM to about 60 mM buffer, about 5 mM to about 50 mM buffer, about 5 mM to about 40 mM buffer, about 5 mM to about 30 mM buffer, about 5 mM to about 20 mM buffer, about 5 mM to about 10 mM buffer, about 5 mM to about 25 mM buffer, about 5 mM to about 15 mM buffer, or about 10 mM buffer.
[0023] In various instances, the pharmaceutical composition comprises about 5.0% (w/v) disaccharide to about 15.0 % (w/v) disaccharide, optionally, about 9.0% (w/v) disaccharide. The disaccharide in various aspects is sucrose.
[0024] Surfactants are surface active agents that are amphipathic (having a polar head and hydrophobic tail). Surfactants preferentially accumulate at interfaces, resulting in reduced interfacial tension. Use of a surfactant can also help to mitigate formation of large proteinaceous particles. In some aspects, the surfactant present in the compositions of the present disclosure is an amphipathic and/or nonionic surfactant. Exemplary surfactants include polyoxyethylene sorbitan fatty acid esters
13 (e.g. polysorbate 20, polysorbate 80), alkylaryl polyethers, e.g. oxyethylated alkyl phenol (e.g. Triton™ X-100), and poloxamers (e.g. Pluronics®, e.g. Pluronic® F68), and combinations of any of the foregoing, either within a class of surfactants or among classes of surfactants. Polysorbate 20 and polysorbate 80 (and optionally mixtures thereof) are particularly contemplated. In exemplary aspects, the surfactant is amphipathic and nonionic, e.g., a polysorbate. In exemplary aspects, the surfactant is polysorbate 20 or polysorbate 80 or a mixture thereof. In various instances, the pharmaceutical composition comprises about 0.001% (w/v) to about 0.1% (w/v) surfactant, including, for instance, about 0.01% (w/v) surfactant. The surfactant in some aspects is PS80. In various aspects, the pharmaceutical composition is a preservative-free solution. In exemplary aspects, the solution has a pH less than about 6.0, optionally, less than about 5.5. In certain aspects, the pH is about 4.5 to about 5.5 or about 4.8 to about 5.4 or about 4.9, about 5.2, or about 5.4. In various instances, the solution has a pH of about 5.2. In some aspects, the solution is housed in a vial or other container, e.g., syringe, IV bag, ampoule. Optionally, the container comprises about 1 to about 5 mL of the pharmaceutical composition of the present disclosure.
[0025] In various instances, the pharmaceutical composition is isotonic with the intended site of administration. For example, if the solution is in a form intended for administration parenterally, it can be isotonic with blood. The composition typically is sterile. In certain embodiments, this may be accomplished by filtration through sterile filtration membranes. In certain embodiments, parenteral compositions generally are placed into a container having a sterile access port, for example, an intravenous solution bag, or vial having a stopper pierceable by a hypodermic injection needle, or a prefilled syringe. In certain embodiments, the composition may be stored either in a ready -to-use form or in a form (e.g., lyophilized) that is reconstituted or diluted prior to administration.
[0026] In various instances, the pharmaceutical composition is a sterile, single-use, preservative- free solution for IV infusion in a vial containing 70 mg/mL zeluvalimab formulated with 10 mM acetate (sodium counterion), 9.0% (w/v) sucrose, 0.01% (w/v) polysorbate 80, pH 5.2.
[0027] In various aspects, the anti-PD-1 antibody (e.g., zeluvalimab) is administered to the subject by intravenous administration, e.g., intravenously. In various instance, the anti-PD-1 antibody (e.g., zeluvalimab) is administered to the subject by intravenous infusion to the subject. The infusion in various aspects is administered to the subject in about an hour or less. In certain instances, the infusion is a 60-minute infusion or a 45-minute infusion or a 30-minute infusion or a 15-minute infusion.
[0028] In exemplary embodiments, the methods of the present disclosure comprise repeat administrations of the anti-PD-1 antibody (e.g., zeluvalimab). The anti-PD-1 antibody (e.g., zeluvalimab), in various aspects, is given to the subject once a cycle. In various aspects, the cycle comprises about 3 weeks or about 19-23 days (e.g., about 19 days, about 20 days, about 21 days,
14 about 22 days, about 23 days). In various instances, the cycle comprises about 4 weeks, about 1 month or about 24 to about 34 days (e.g., about 24 days, about 25 days, about 26 days, about 27 days, about 28 days, about 29 days, about 30 days, about 31 days, about 32 days, about 33 days, about 34 days). In various instances, the cycle comprises about 6 weeks, about 1.5 months or about 37 days to about 45 days (e.g., about 37 days, about 38 days, about 39 days, about 40 days, about 41 days, about 42 days, about 43 days, about 44 days, about 45 days). Each cycle may be consecutively numbered and each day of each cycle may be consecutively numbered. For instance, treatment may comprise 3 cycles (Cycle 1, Cycle 2 and Cycle 3), wherein each cycle is about 3 weeks, and zeluvalimab is administered on Day 1 of each cycle. In various aspects, zeluvalimab is administered at a dose of 480 mg once every four weeks. In various aspects, the cycle comprises about 4 weeks and 480 mg zeluvalimab is administered on Day 1, Day 8 or Day 15 in Cycle 1, then on Day 1 or Day 15 in Cycle 2 and all cycles subsequent to Cycle 2. In various aspects, if zeluvalimab is administered on Day 1 or Day 8 in Cycle one, then the antibody is administered on Day 1 starting in Cycle 2 and all cycles thereafter. Alternatively, if zeluvalimab is administered on Day 15 in Cycle 1, then the anti-PD-1 antibody in various instances is administered on Day 15 in Cycle 2 and all cycles thereafter. In various aspects, zeluvalimab is administered on the first day (Day 1) of each cycle. In various instances, zeluvalimab is administered on the first day (Day 1) of each cycle, wherein each cycle is about 28 or about 29 days.
[0029] In exemplary embodiments, the methods of the present disclosure comprise repeat administrations of the anti-PD-1 antibody (e.g., zeluvalimab) and the anti-PD-1 antibody (e.g., zeluvalimab) is administered to the subject at a first amount for a first time period and at a second amount for a second time period, wherein the second amount is different from the first amount. In various aspects, the presently disclosed methods comprise two-phases of treatment, e.g., an induction phase and a maintenance phase, wherein the anti-PD-1 antibody (e.g., zeluvalimab) is administered to the subject at a first amount during the induction phase and at a second amount different from the first amount during the maintenance phase. In various aspects, the first amount is lower than the second amount. In exemplary instances, the first amount is about half the second amount. In various aspects, the first amount is about 360 mg. Optionally, the second amount is about 720 mg. In exemplary instances, the first time period is shorter than the second time period. For instance, the first time period (e.g., the induction phase) is about 12 weeks or about 3 months and the second time period (e.g., the maintenance phase) is greater than 12 weeks or greater than about 3 months. The second time period (e.g., the maintenance phase) in exemplary aspects is at least or about 4 months, at least or about 6 months, at least or about 9 months, at least or about 12 months or at least or about one year, at least or about 18 months, at least or about 24 months or at least or about 2 years, at least or about 30 months or at least or about 36 months, or longer. In exemplary instances, the second time period is greater than two years. In various instances, the anti-PD-1 antibody (e.g., zeluvalimab) is
15 administered to the subject once a cycle during the first time period (e.g., the induction phase). In various aspects, each cycle during the first time period (e.g., the induction phase) comprises about 3 weeks or about 19-23 days (e.g., about 19 days, about 20 days, about 21 days, about 22 days, about 23 days). In various aspects, the anti-PD-1 antibody (e.g., zeluvalimab) is administered to the subject once a cycle during the first time period (e.g., the induction phase), wherein the cycle is about 3 weeks, and the first time period (e.g., the induction phase) comprises about 4 cycles.
[0030] In various instances, the anti-PD-1 antibody (e.g., zeluvalimab) is administered to the subject once a cycle during the second time period (e.g., the maintenance phase). In various aspects, each cycle during the second time period (e.g., the maintenance phase) comprises about 6 weeks or about 33-39 days (e.g., about 33 days, about 34 days, about 35 days, about 36 days, about 37 days, about 38 days, about 39 days). In various aspects, the anti-PD-1 antibody (e.g., zeluvalimab) is administered to the subject once a cycle during the second time period (e.g., the maintenance phase), wherein the cycle is about 6 weeks, and the second time period (e.g., the maintenance phase) comprises more than about 4 cycles, optionally, more than 8 cycles, more than 12 cycles, more than 18 cycles, more than 24 cycles, optionally, up to 31 cycles. In exemplary instances, the presently disclosed method of treating cancer or tumor in a subject comprises administering to the subject about 360 mg anti-PD-1 antibody (e.g., zeluvalimab) once every 3 weeks for 4 cycles, wherein each cycle is about 3 weeks, followed by administering to the subject about 720 mg anti-PD-1 antibody (e.g., zeluvalimab) once every 6 weeks for up to 31 cycles, wherein each cycle is about 6 weeks. In various instances, the method comprises administering the anti-PD-1 antibody (e.g., zeluvalimab) in combination with a platinum chemotherapy and/or an antimetabolite. Optionally, the the antimetabolite is administered to the subject during the first time period (e.g., the induction phase) and during the second time period (e.g., the maintenance phase). In various instances, the platinum chemotherapy is administered to the subject only during the first time period (e.g., the induction phase). The antimetabolite is exemplary instances is pemetrexed. In various aspects, the method comprises administering about 500 mg/m2 pemetrexed. In various instances, the method comprises administering pemetrexed once every 3 weeks during the first time period and second time period. In exemplary aspects, the method comprises administering the platinum chemotherapy during first time period. The platinum chemotherapy is not administered during the second time period in some aspects. Optionally, the platinum chemotherapy is carboplatin or cisplatin. In various aspects, about 75 mg/m2 cisplatin is administered to the subject or an amount of carboplatin that provides an AUC of about 5 is administered to the subject. In various instances, the amount of carboplatin administered to the subject is determined based on the subject’s age, serum creatine level, gender, height, weight, target AUC or a combination thereof. The amount of carboplatin administered to the subject is calculated according to the Calvert method or the amount is calculated based on the CKD-EPI equation. The Calvert method and the CKD-EPI equation are known in the art. See, e.g., Calvert et
16 al., J Clin Oncology 7 (11): 1748-56 (1989), and Janowitz et al., J Clin Oncol. Jul
7: JCO2017727578 (2017). In various aspects, the cancer treated by the method is Nonsmall Cell
Lung Cancer (NSCLC), e.g., advanced non-squamous NSCLC.
[0031] Safety
[0032] In some aspects, the method comprises administering the anti-PD-1 antibody (e.g., zeluvalimab) in amount that does not lead to a dose limiting toxicity (DLT) during treatment with the anti-PD-1 antibody (e.g., zeluvalimab). Optionally, the subject does not exhibit a DLT during treatment. In various instances, the subject does not exhibit any grade 3 or grade 4 adverse events associated with the anti-PD-1 antibody (e.g., zeluvalimab) treatment during the treatment period. In various aspects, the subject does not exhibit any grade 3 or grade 4 adverse events associated with the anti-PD-1 antibody (e.g., zeluvalimab) treatment during the treatment period. In various instances, the treatment period is at least one month, if not longer, e.g., 2 months, 3, months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 1 year, 1.5 years, 2 years.
[0033] Combination Therapy
[0034] In some embodiments, the anti-PD-1 antibody comprising the six CDR amino acid sequences of SEQ ID NOs: 3-8 (e.g., zeluvalimab) is administered alone, and in alternative embodiments, is administered in combination with another therapeutic agent. In some aspects, the other therapeutic aims to treat or prevent cancer. In some embodiments, the other therapeutic is a chemotherapeutic agent. In some embodiments, the other therapeutic is an agent used in radiation therapy for the treatment of cancer. Accordingly, in some aspects, the anti-PD-1 antibody (e.g., zeluvalimab) is administered in combination with one or more of platinum coordination compounds, topoisomerase inhibitors, antibiotics, antimitotic alkaloids, antimetabolites, alkylating agents, and difluoronucleosides. In various instances, the anti-PD-1 antibody (e.g., zeluvalimab) is administered in combination with an alkylating agent or a platinum chemotherapy (e.g., carboplatin, cisplatin) and/or an antimetabolite (e.g., pemetrexed). In exemplary aspects, anti-PD-1 antibody comprising the six CDR amino acid sequences of SEQ ID NOs: 3-8 (e.g., zeluvalimab) is administered in combination with carboplatin or cisplatin and pemetrexed. In various instances, the anti-PD-1 antibody comprising the six CDR amino acid sequences of SEQ ID NOs: 3-8 (e.g., zeluvalimab) is administered in combination with about 500 mg/m2 pemetrexed as an intravenous infusion over 10 minutes on Day 1 of each of four 21 -day cycles. In various instances, the pemetrexed is administered after the anti-PD-1 antibody (e.g., zeluvalimab) and prior to the platinum chemotherapy (e.g., carboplatin or cisplatin). In various aspects, about 400 mg/m2 carboplatin is administered as a single intravenous infusion over 15-60 minutes. In various aspects, about 20 mg/m2 cisplatin is administered by slow intravenous infusion daily for 5 days per cycle or about 75 to 100 mg/m2 per cycle once every
17 4 weeks on Day 1 or about 50 to about 70 mg/m2 IV per cycle once every 3 to 4 weeks. In various aspects, four cycles of intravenously administered cisplatin (75 mg per square meter of body-surface area) or carboplatin (area under the concentration-time curve, 5 mg per milliliter per minute) plus pemetrexed (500 mg per square meter), are administered intravenously every 3 weeks, followed by pemetrexed (500 mg per square meter) every 3 weeks. Accordingly, a method of treating a cancer or tumor in a subject comprises administering to the subject an anti-PD-1 antibody comprising six complementarity determining region (CDR) amino acid sequences of SEQ ID NOs: 3-8 (e.g., zeluvalimab) in combination with a platinum chemotherapy and/or an antimetabolite is provided herein. In various instances, the platinum chemotherapy is carboplatin or cisplatin. In exemplary instances, the method comprises administering to the subject about 75 mg/m2 cisplatin. In various aspects, the method comprises administering to the subject an amount of carboplatin that provides an AUC of about 5. The amount of carboplatin administered to the subject is, in exemplary aspects, determined based on the subject’s age, serum creatine level, gender, height, weight, target AUC or a combination thereof. Optionally, the amount of carboplatin administered to the subject is calculated according to the Calvert method. Alternatively, the amount of carboplatin administered to the subject is calculated based on the CKD-EPI equation. In various instances, the antimetabolite is pemetrexed and optionally, the method comprises administering to the subject about 500 mg/m2 pemetrexed. In exemplary aspects, the anti-PD-1 antibody (e.g., zeluvalimab), the platinum chemotherapy and/or an antimetabolite is administered to the subject once every 3 weeks. In various instances, the method comprises administering to the subject about 360 mg anti-PD-1 antibody (e.g., zeluvalimab). The presently disclosed method in various aspects, comprises administering (a) about 360 mg anti-PD-1 antibody (e.g., zeluvalimab) once every 3 weeks and (b) about 500 mg/m2 pemetrexed to the subject once every 3 weeks. In some aspects, the method comprises administering to the subject about 720 mg anti-PD-1 antibody (e.g., zeluvalimab). Optionally, the method comprises administering about 720 mg anti-PD-1 antibody (e.g., zeluvalimab) once every 6 weeks. In various instances, the method of treating a subject comprises administering for a first time period (a) about 360 mg anti-PD-1 antibody (e.g., zeluvalimab) once every 3 weeks and (b) about 500 mg/m2 pemetrexed to the subject once every 3 weeks followed by administering to the subject for a second time period (c) about 720 mg anti-PD-1 antibody (e.g., zeluvalimab) once every 6 weeks and (d) about 500 mg/m2 pemetrexed to the subject once every 3 weeks. In exemplary aspects, the method comprises administering to the subject for a first time period: (a) about 360 mg anti-PD-1 antibody (e.g., zeluvalimab) once every 3 weeks, (b) about 500 mg/m2 pemetrexed to the subject once every 3 weeks, and (c) about 75 mg/m2 cisplatin or an amount of carboplatin to achieve a target AUC of about 5, and administering to the subject for a second time period: (d) about 720 mg anti-PD-1 antibody (e.g., zeluvalimab) once every 6 weeks and (e) about 500 mg/m2 pemetrexed to the subject once every 3 weeks, wherein the first time period (e.g., induction phase) is about 12 weeks (e.g., about 4 cycles) and the second time period (e.g., maintenance phase) is up to about 186 weeks (e.g., up to 31 cycles).
18 [0035] Additional combinations comprising zeluvalimab are described in International Publication No. WO 2019/140196.
Exemplary Embodiments
[0036] Exemplary embodiments of the present invention include but are not limited to the following:
1. A method of treating cancer or tumor in a subject, said method comprising administering to the subject an anti-PD-1 antibody comprising six complementarity determining region (CDR) amino acid sequences of SEQ ID NOs: 3-8 in an amount equivalent to about 100 mg to about 150 mg per week.
2. The method of embodiment 1, wherein the amount of the anti-PD-1 antibody is equivalent to about 115 mg per week to about 125 mg per week.
3. The method of embodiment 2, wherein the amount of the anti-PD-1 antibody is equivalent to about 120 mg per week.
4. The method of any one of the preceding embodiments, comprising administering to the subject about 120 mg of the PD- 1 antibody once a week.
5. The method of any one of the preceding embodiments, comprising administering to the subject about 240 mg of the PD-1 antibody once every 2 weeks.
6. The method of any one of the preceding embodiments, comprising administering to the subject about 360 mg of the PD-1 antibody once every 3 weeks.
7. The method of any one of the preceding embodiments, comprising administering to the subject about 480 mg of the PD-1 antibody once every 4 weeks.
8. The method of any one of the preceding embodiments, comprising administering to the subject about 600 mg of the PD-1 antibody once every 5 weeks.
9. The method of any one of the preceding embodiments, comprising administering to the subject about 720 mg of the PD-1 antibody once every 6 weeks.
10. The method of any one of the preceding embodiments, comprising administering to the subject about 840 mg of the PD-1 antibody once every 7 weeks.
11. The method of any one of the preceding embodiments, comprising administering to the subject about 960 mg of the PD-1 antibody once every 8 weeks.
12. A method of treating cancer or tumor in a subject, said method comprising administering to the subject an anti-PD-1 antibody comprising six complementarity determining region (CDR)
19 amino acid sequences of SEQ ID NOs: 3-8 in an amount equivalent to about 480 mg once every 4 weeks. The method of any one of the preceding embodiments, comprising administering to the subject about 480 mg of the anti-PD-1 antibody once every 4 weeks. The method of any one of the preceding embodiments, wherein the amount provides: a. a mean serum concentration of the anti-PD-1 antibody which is achieved by administering 480 mg once every 4 weeks; b. a mean plasma area under the curve (AUC».,) which is achieved by administering 480 mg once every 4 weeks; c. a difference between the mean plasma Cmax at steady state and a mean plasma Cmm at steady state which is achieved by administering 480 mg once every 4 weeks; d. a mean plasma Cmax at steady state which is achieved by administering 480 mg once every 4 weeks. The method of any one of the preceding embodiments, wherein the anti-PD-1 antibody comprises a. a heavy chain (HC) complementarity -determining region (CDR) 1 amino acid sequence comprising SEQ ID NO: 3; b. an HC CDR2 amino acid sequence comprising SEQ ID NO: 4; c. an HC CDR3 amino acid sequence comprising SEQ ID NO: 5; d. a light chain (LC) CDR1 amino acid sequence comprising SEQ ID NO: 6; e. an LC CDR2 amino acid sequence comprising SEQ ID NO: 7; and f. an LC CDR3 amino acid sequence comprising SEQ ID NO: 8. The method of embodiment 15, wherein the anti-PD-1 antibody comprises a heavy chain variable region of SEQ ID NO: 9 and a light chain variable region of SEQ ID NO: 10. The method of embodiment 16, wherein the anti-PD-1 antibody comprises a heavy chain of SEQ ID NO: 11 or 13 and a light chain of SEQ ID NO: 12.
20 The method of any one of the preceding embodiments, wherein the anti-PD-1 antibody is zeluvalimab. The method of any one of the preceding embodiments, wherein the anti-PD-1 antibody is administered intravenously to the subject. The method of any one of the preceding embodiments, wherein the anti-PD-1 antibody is administered to the subject for at least one cycle. The method of embodiment 20, wherein the anti-PD-1 antibody is administered to the subject for at least three cycles. The method of embodiment 21, wherein the anti-PD-1 antibody is administered to the subject for at least six cycles. The method of any one of the preceding embodiments, wherein the subject does not exhibit a dose limiting toxicity (DLT) during treatment with the anti-PD-1 antibody. The method of any one of the preceding embodiments, wherein the subject does not exhibit any grade 3 or grade 4 adverse events associated with anti-PD-1 antibody therapy. The method of any one of the preceding embodiments, wherein the subject does not exhibit any grade 3 or grade 4 adverse events associated with anti-PD-1 antibody therapy. The method of any one of the preceding embodiments, wherein the tumor is a solid tumor. The method of embodiment 26, wherein the solid tumor is an advanced solid tumor or metastatic solid tumor. The method of embodiment 26 or 27, wherein the solid tumor is a Stage 3 of Stage 4 tumor, a non-resectable tumor, and/or a non-localized tumor. The method of any one of the preceding embodiments, wherein the cancer is a colon cancer, an ovarian cancer, a clear cell renal cell carcinoma, a pancreatic carcinoma, a sarcoma metastatic, sarcomatoid carcinoma, a squamous cell carcinoma (head and neck), or an undifferentiated nasopharyngeal carcinoma. The method of any one of the preceding embodiments, wherein the subject exhibits at least a stable disease (SD) after about 2 or more cycles of treatment with the anti-PD-1 antibody.
21 The method of embodiment 30, wherein the subject exhibits at least a partial response (PR) after about 2 or more cycles of treatment with the anti-PD-1 antibody. The method of embodiment 31, wherein the subject exhibits a complete response (CR) after about 2 or more cycles of treatment with the anti-PD-1 antibody. The method of any one of the preceding embodiments, wherein the subject had prior treatment with an anticancer therapy other than the anti-PD-1 antibody. A pharmaceutical composition comprising an anti-PD-1 antibody comprising the six CDR amino acid sequences of SEQ ID NOs: 352-357 at a concentration of about 50 mg/mL to about 100 mg/mL, a buffer, a disaccharide and a surfactant. The pharmaceutical composition of embodiment 34, wherein the buffer is acetate optionally sodium acetate. The pharmaceutical composition of embodiment 34 or 35, comprising about 5 mM to about 25 mM acetate, optionally, about 10 mM sodium acetate. The pharmaceutical composition of embodiment 34 or 35, comprising about 5.0% (w/v) disaccharide to about 15.0 % (w/v) disaccharide. The pharmaceutical composition of embodiment 37, comprising about 9.0% (w/v) disaccharide. The pharmaceutical composition of any one of embodiments 34 to 38, comprising about 0.001% (w/v) to about 0.1% (w/v) surfactant. The pharmaceutical composition of embodiment 39, comprising about 0.01% (w/v) surfactant. The pharmaceutical composition of any one of embodiments 34 to 40, wherein the surfactant is PS80. The pharmaceutical composition of any one of embodiments 34 to 41, which is a preservative-free solution. The pharmaceutical composition of any one of embodiments 34 to 42, which is a solution having a pH of about 5.2. A vial comprising about 1 to about 5 mL of the pharmaceutical composition of any one of embodiments 34 - 43.
22 A method of treating a cancer or tumor in a subject, said method comprising administering to the subject an anti-PD-1 antibody comprising six complementarity determining region (CDR) amino acid sequences of SEQ ID NOs: 3-8 in combination with a platinum chemotherapy and/or an antimetabolite. The method of embodiment 45, wherein the platinum chemotherapy is carboplatin or cisplatin. The method of embodiment 46, comprising administering to the subject about 75 mg/m2 cisplatin. The method of embodiment 46, comprising administering to the subject an amount of carboplatin that provides an AUC of about 5. The method of embodiment 48, wherein the amount of carboplatin administered to the subject is determined based on the subject’s age, serum creatine level, gender, height, weight, target AUC or a combination thereof. The method of embodiment 49, wherein the amount of carboplatin administered to the subject is calculated according to the Calvert method. The method of embodiment 49, wherein the amount of carboplatin administered to the subject is calculated based on the CKD-EPI equation. The method of any one or embodiments 45-51, wherein the antimetabolite is pemetrexed. The method of embodiment 52, comprising administering to the subject about 500 mg/m2 pemetrexed. The method of any one of the preceding embodiments, wherein the anti-PD-1 antibody, the platinum chemotherapy and/or an antimetabolite is administered to the subject once every 3 weeks. The method of any one of embodiments 45-54, comprising administering to the subject about 360 mg anti-PD-1 antibody. The method of any one of embodiments 54-55, comprising administering (a) about 360 mg anti-PD-1 antibody once every 3 weeks and (b) about 500 mg/m2 pemetrexed to the subject once every 3 weeks. The method of any one of embodiments 45-56, comprising administering to the subject about 720 mg anti-PD-1 antibody.
23 The method of embodiment 57, comprising administering about 720 mg anti-PD-1 antibody once every 6 weeks. The method of embodiment 58, comprising administering for a first time period (a) about 360 mg anti-PD-1 antibody once every 3 weeks and (b) about 500 mg/m2 pemetrexed to the subject once every 3 weeks followed by administering to the subject for a second time period (c) about 720 mg anti-PD-1 antibody once every 6 weeks and (d) about 500 mg/m2 pemetrexed to the subject once every 3 weeks. The method of embodiment 59, comprising: administering to the subject for a first time period: (a) about 360 mg anti-PD-1 antibody once every 3 weeks, (b) about 500 mg/m2 pemetrexed to the subject once every 3 weeks, and (c) about 75 mg/m2 cisplatin or an amount of carboplatin to achieve a target AUC of about 5 once every 3 weeks, and administering to the subject for a second time period: (d) about 720 mg anti-PD-1 antibody once every 6 weeks and (e) about 500 mg/m2 pemetrexed to the subject once every 3 weeks, wherein the first time period is about 12 weeks and the second time period is up to about 186 weeks. A method of treating a cancer or tumor in a subject, said method comprising administering to the subject an anti-PD-1 antibody comprising six complementarity determining region (CDR) amino acid sequences of SEQ ID NOs: 3-8 in combination with a platinum chemotherapy and/or an antimetabolite, wherein the anti-PD-1 antibody is administered at a first amount for a first time period and at a second amount different from the first amount for a second time period. The method of embodiment 61, wherein the first amount is lower than the second amount. The method of embodiment 61 or 62, wherein the first amount is about 360 mg. The method of any one of embodiments 61-63, wherein the second amount is about 720 mg. The method of any one of embodiments 61-64, wherein the first time period is shorter than the second time period. The method of embodiment 65, wherein the first time period is about 12 weeks or about 3 months.
24 The method of embodiment 65 or 66, wherein the second time period is at least or about one year. The method of embodiment 67, wherein the second time period is at least or about two years. The method of embodiment 68, wherein the second time period is greater than two years. The method of any one of embodiments 61-69, comprising administering the antimetabolite during the first time period and the second time period. The method of embodiment 70, wherein the antimetabolite is pemetrexed. The method of embodiment 71, comprising administering about 500 mg/m2 pemetrexed. The method of any one of the preceding embodiments, comprising administering pemetrexed once every 3 weeks during the first time period and second time period. The method of any one of embodiments 61-73, comprising administering the platinum chemotherapy during first time period. The method of embodiment 74, wherein the platinum chemotherapy is not administered during the second time period. The method of any one of the preceding embodiments, wherein the platinum chemotherapy is carboplatin or cisplatin. The method of embodiment 76, comprising administering to the subject about 75 mg/m2 cisplatin. The method of embodiment 76, comprising administering to the subject an amount of carboplatin that provides an AUC of about 5. The method of embodiment 78, wherein the amount of carboplatin administered to the subject is determined based on the subject’s age, serum creatine level, gender, height, weight, target AUC or a combination thereof. The method of embodiment 79, wherein the amount of carboplatin administered to the subject is calculated according to the Calvert method. The method of embodiment 79, wherein the amount of carboplatin administered to the subject is calculated based on the CKD-EPI equation. The method of any one of the preceding embodiments, wherein the cancer is Non-Small Cell Lung Cancer (NSCLC).
25 83. The method of embodiment 82, wherein the NSCLC is advanced non-squamous NSCLC.
84. The method of any one of embodiments 45-83, wherein the anti-PD-1 antibody is zeluvalimab.
[0037] The following examples are given merely to illustrate the present invention and not in any way to limit its scope.
EXAMPLES EXAMPLE 1
[0038] A Phase 1 Study to Evaluate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AMG 404, a Programmed Death-1 (PD-1) Antibody, in Patients With Advanced Solid Tumors (NCT03853109) was initiated and is currently ongoing.
[0039] Investigational Product: Zeluvalimab
[0040] Zeluvalimab is a fully human, monoclonal immunoglobulin G (IgG) subclass 1 (IgGi) directed against PD-1. This molecule is a heterotetramer consisting of 2 heavy chains (HC) of the IgGi subclass and 2 light chains (LC) of the kappa subclass, which are covalently linked through disulfide bonds. Zeluvalimab is aglycosylated through HC engineering by eliminating the glycosylation site in the CH2 domain (N300G). Zeluvalimab contains 1328 amino acids. The HC is composed of 450 amino acids with a molecular mass of 48,801 Da. The C-terminal lysine is mostly removed from the HC during cell culture. The LC is composed of 214 amino acids with a molecular weight of 23,174 Da. Zeluvalimab is described as Antibody 20C1.009 in International Publication No. WO 2019/140196 and is also referred to as AMG 404.
[0041] Zeluvalimab is supplied as a sterile, single-use, preservative-free solution for intravenous (IV) infusion in a vial containing 70 mg/mL zeluvalimab. The product is formulated with 10 mM acetate (sodium counterion), 9.0% (w/v) sucrose, 0.01% (w/v) polysorbate 80, pH 5.2. The final container is a type 1 glass tubing vial and contains 1 mL of zeluvalimab.
[0042] Zeluvalimab is a blocking antibody that binds to PD-1 and inhibits engagement of PD-1 with its ligands. In preclinical studies, zeluvalimab demonstrated comparable (< 2-fold different) high affinity binding to both human and cynomolgus monkey PD-1 with ¾ values of 0.54 nM and 0.86 nM, respectively. In a separate study, zeluvalimab dose-dependently blocked human PD-L1 and PD- L2 binding to cell surface-expressed human and cynomolgus monkey PD-1. It was shown that zeluvalimab was more effective at inhibiting human PD-1 binding to human PD-L1/-L2 than at inhibiting cynomolgus monkey PD-1 binding to human PD-L1/-L2.
[0043] Zeluvalimab was administered to subjects with advanced solid tumors as short-term (~0.5 hours) IV infusions Q4W at dose levels of 240 mg, 480 mg, or 1050 mg.
26 [0044] Cohorts
[0045] The clinical trial study was designed to comprise multiple cohorts. For Cohorts 1, 2, and 4, the doses of 240, 480, and 1050 mg zeluvalimab were examined for safety, tolerability, PK, and PD of zeluvalimab in subjects with advanced solid tumors. Upon completion of Cohort 2 and based on acceptable data, dose expansion proceeded with the planned dose of 480 mg in Cohort 3 for subjects.
A summary of the some of the cohorts is provided in Table 1. Upon completion of a subset of subjects in Cohort 4 and based on the data obtained, dose expansion proceeded at the RP2D in Cohorts 6-9 (with a safety lead-in in Cohort 5. Some patients of some cohorts failed at least one (or more) prior line of systemic therapy.
TABLE 1
Figure imgf000029_0001
IV = intravenously (over approximately 0.5 hours); PD-L1 = programmed death-ligand 1; Q4W = every 4 weeks; a as determined after review of available data obtained in Cohorts 1 to 4.
[0046] Subjects
[0047] The inclusion criteria for subjects set forth in Table 2 were applied in this clinical trial study:
TABLE 2
Figure imgf000029_0002
27
Figure imgf000030_0001
[0048] The exclusion criteria for subjects set forth in Table 3 were applied in this clinical trial study:
TABLE 3
28
Figure imgf000031_0001
29
Figure imgf000032_0003
[0049] Primary and Second Outcome Measures
[0050] The purpose of this clinical trial was to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of zeluvalimab in human subjects with advanced solid tumors. The primary and secondary outcome measures of this study are provided in Tables 4 and 5, respectively.
TABLE 4
Figure imgf000032_0001
TABLE 5
Figure imgf000032_0002
[0051] Interim Results
30 [0052] This clinical study is currently ongoing with over 120 patients enrolled. A discussion of interim results is provided below. Based on the safety, tolerability, pharmacokinetic (PD), and pharmacodynamic (PD) data obtained from multiple cohorts, the RP2D was determined as 480 mg Q4W.
[0053] Pharmacokinetics (PK)
[0054] Interim PK results for zeluvalimab from 42 subjects with advanced solid tumors after zeluvalimab administration as short-term (~0.5 hours) IV infusions Q4W were available for dose levels of 240 mg (3 subjects), 480 mg (29 subjects), and 1050 mg (10 subjects). Select PK parameters results are shown in Table 6.
TABLE 6
Figure imgf000033_0002
Figure imgf000033_0001
a Dose was administered on the first day of the 28-day cycle. bData were calculated using nominal sampling times and presented as geometric mean (arithmetic mean, %CV) except tmax where data were reported as median (min - max) for N subjects unless otherwise noted. For AUCo d, individual parameter data were included in summary statistics only if concentration data for an individual were available for time points up to 28 days postdose, respectively. c N = 2; d N = 27; e N = 8; f N = 15; g N = 4
31 [0055] The Cmax of zeluvalimab occurred at or near the end of infusion with a median of 0.5 to 2.5 hours, as expected with a short-term IV infusion administration. An approximately dose- proportional increase in exposure over the dose range of 240 to 1050 mg was observed with 4.8- and 5.2-fold increases in cycle 1, and 5.4- and 7.0-fold increases in cycle 2 for Cmax and AUC from time 0 to 28 days postdose (AUCcwsd), respectively, for a 4.4-fold increase in dose. Interim results suggest minimal accumulation of Cmax and AUCcwsd (< 2-fold) from cycle 1 to cycle 2, consistent for an mAb administered IV Q4W with an estimated tia.zof approximately 4 weeks, based on population PK modeling of the observed PK data. Additionally, the estimated ti/2,z of approximately 4 weeks supports Q4W dosing and potentially longer dosing intervals.
[0056] Currently, over 120 subjects have been enrolled in this study. The characteristics of the PK in additional patients have been analyzed and were determined to be essentially the same as those shown in Table 6.
[0057] Pharmacodynamics
[0058] Interim pharmacodynamic data as assessed by zeluvalimab receptor occupancy (RO) on peripheral blood T cells were available for cohorts across the studied dose range of 240 to 1050 mg. Briefly, %RO of zeluvalimab was measured using a validated flow cytometry assay in peripheral blood collected from subjects pre- and post-administration of zeluvalimab. Fluorochrome-labeled competing and noncompeting anti-PD-1 antibodies were used to measure free and total PD-1 receptor levels on total CD3+ T cells, CD4+ T cells, and CD8+ T cells in lysed, washed peripheral blood. Interim RO results confirm PD-1 target coverage in peripheral blood T-cell subsets and are consistent with zeluvalimab achieving saturating PD-1 occupancy on total CD3+ T cells, CD4+ T cells, and CD8+ T cells by 4 hours post-infusion with maintenance of saturation throughout the dosing interval. Given that saturating peripheral RO has been observed clinically at exposures lower than therapeutic doses of other anti-PD-1 mAbs, peripheral RO data were not expected to provide meaningful information to assess efficacy. However, these results at the 240- and 480-mg dose levels were consistent with the expected saturation of RO for these doses given the potent inhibition of PD- 1/PD- L1 interactions in vitro with low nanomolar half-maximal inhibitory concentration (ICso) values and interim observed zeluvalimab exposures in subjects. Interim PK/PD modeling indicates that high intratumoral RO (approximately > 90% at steady state) is predicted with 480 mg Q4W dosing based on observed serum exposures of zeluvalimab in subjects, Kcjof zeluvalimab binding to PD-1 and estimated antibody biodistribution coefficient for solid tumors (Shah and Betts, MAbs. 2013;5:297- 305 (2013)). In conjunction with nonclinical pharmacology findings and interim human PK results, these results provide increased confidence towards achieving an efficacious dose with doses planned in the FIH study.
[0059] Safety
32 [0060] Over 100 subjects were enrolled in the study. Interim data were available for subjects with advanced or metastatic solid tumors in the safety analysis set who had received at least 1 dose of zeluvalimab: 3 subjects in cohort 1 (240 mg), 9 subjects in cohort 2 (480 mg), 20 subjects in cohort 3 (480 mg), 21 subjects in cohort 4 (1050 mg), 20 subjects in cohort 6 (480 mg), 40 subjects in cohort 7 (480 mg), 8 subjects in cohort 8 (480 mg), and 2 subjects in cohort 9 (480 mg). No DLTs were observed in any of the 123 subjects administered zeluvalimab. The study subjects received a mean of 4.9 cycles of zeluvalimab therapy each, with a median of 3.0 zeluvalimab administrations.
[0061] There were >115 subjects with Treatment-emergent Adverse Events. Treatment-emergent adverse events experienced by 10% or more of the subjects were fatigue in 38 subjects (30.9%), nausea in 31 subjects (25.2%), decreased appetite in 29 subjects (23.6%), vomiting in 20 subjects (16.3%), pyrexia in 18 subjects (14.6%), anaemia in 17 subjects (13.8%), diarrhea in 16 subjects (13.0%), constipation in 15 subjects (12.2%), arthralgia in 14 subjects (11.4%), and abdominal pain in 13 subjects (10.6%).
[0062] A summary of treatment-emergent adverse events is provided in Table 7.
33 TABLE 7
Figure imgf000036_0001
[0063] Overall, these interim safety data from the first >120 subjects exposed to zeluvalimab suggest the drug is reasonably safe and tolerable.
[0064] Efficacy
[0065] As of a data cutoff date almost 2 years from the actual study start date, interim efficacy data were available for over 100 subjects with a best overall response value who were dosed with zeluvalimab. Among all cohorts, 10 subjects (9.8%) had a confirmed partial response, and 44 subjects had stable disease (43.1%). Among cohorts 6, 7, and 8 there were 54 subjects with a best overall response value who were dosed with zeluvalimab. Of these 54 subjects, 8 subjects (14.8%) had a confirmed complete response, and 24 subjects had stable disease (44.4%).
EXAMPLE 2
[0066] A Randomized, Double-Blind, Placebo Controlled Phase 3 Study of Platinum Plus Pemetrexed Chemotherapy With or Without AMG 404 as First Line Treatment in Subjects With Advanced Nonsquamous Nonsmall Cell Lung Cancer (NSCLC).
[0067] The purpose of this study is to evaluate the efficacy, safety, and tolerability of AMG 404 in combination with pemetrexed and platinum-based chemotherapy (PPPC) compared to placebo in combination with pemetrexed and platinum-based chemotherapy (PPPC) in subjects with advanced nonsquamous NSCLC (without activating EGFR mutations/ ALK gene rearrangements) as first line treatment.
[0068] The overall study design is depicted in Figure 1. Six hundred ninety subjects are enrolled at one of ~200 worldwide study sites. Following an ~28-day screening period, patients are randomized 2:1 into two treatment groups: [1] a first treatment group assigned to receive AMG 404 + PPPC; and [2] a second treatment group assigned to receive placebo + PPPC. Subjects are stratified by smoking status (never smoked vs former or current smoker) and PD-L1 status (Tumor Proportion Score (TPS)
< 1%, 1% < TPS < 50%, and TPS > 50%. As shown in Figure 1 and described below, the study includes an induction treatment followed by a maintenance treatment. An optional crossover for patients receiving placebo is available, as described below. Treatment with AMG 404/placebo will continue until progressive disease (PD) as determined by the investigator using irRECIST (iPD); intolerance of treatment, initiation of another anticancer therapy, withdrawal of consent, death, or a maximum of 35 cycles. Subjects are permitted to continue treatment with pemetrexed beyond 35 cycles until iPD as determined by the investigator, intolerance of treatment, initiation of another anticancer therapy, withdrawal of consent, or death. Investigators use Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) described in, e.g., Tazdait et ah, EurJ Cancer 88:38- 47 (2018), to make treatment decisions. Following treatment, subjects participate in a safety follow up and a long-term follow-up. Upon permanent discontinuation from the study treatment for any
35 reason, a safety follow-up visit will be performed 30 days (+ 7 days) after the last administration of study treatment.
[0069] Investigational and Non-Investigational Products
[0070] AMG 404 is administered as an intravenous solution for infusion. Like the placebo, it is supplied in vials to be stored at 2 °C to 8 °C. The solution for administration is prepared in 5% dextrose IV infusion bags and the solution comprising the IP is delivered through infusion lines.
[0071] The non-investigational products of this study are described in Table 8.
TABLE 8
Figure imgf000038_0001
[0072] Induction Treatment
[0073] The study includes an induction treatment followed by a maintenance treatment. During induction treatment, the first treatment group is treated every 3 weeks (Q3 W) with [1] 360 mg AMG 404, [2] 500 mg/m2 pemetrexed, and [3] investigator’s choice of either 75 mg/m2 cisplatin or area under the concentration-time curve (AUC) 5 carboplatin. The second treatment group is treated Q3 W with [1] placebo, [2] 500 mg/m2 pemetrexed, and [3] investigator’s choice of either 75 mg/m2 cisplatin or AUC 5 carboplatin. The dose of carboplatin administered to a subject is determined by
36 the AUC calculation described in Calvert et al., Carboplatin dosage: prospective evaluation of a simple formula based on renal function. Journal of Clinical Oncology 1989, 7 (11): 1748-56, to achieve a target AUC of 5. The induction treatment for both treatment groups is 4 cycles of treatment.
[0074] Maintenance Treatment
[0075] During maintenance treatment, the first treatment group is treated with [1] 720 mg AMG 404 every 6 weeks (Q6W), and [2] 500 mg/m2 pemetrexed Q3W for up to 31 cycles. The second treatment group is treated with [1] placebo Q6W, and [2] 500 mg/m2 pemetrexed Q3 W for up to 31 cycles.
[0076] Optional Crossover
[0077] Subjects who have PD per irRECIST while receiving placebo plus chemotherapy will have the opportunity to crossover to receive open label AMG 404 monotherapy after they are unblinded, as long as they meet protocol specified criteria. The decision to crossover, from placebo to AMG 404, is optional and at the discretion of the investigator. Subjects that crossover have a washout period, minimum of 21 days, after their last dose of chemotherapy (regardless of the time of progression) before initiating therapy with open label AMG 404.
[0078] Subjects
[0079] The inclusion criteria for subjects set forth in Table 9 were applied in this clinical trial study:
TABLE 9
Figure imgf000039_0001
* described in Schwartz et al., Eur J Cancer. 45:261-267 (2009); and Schwartz et al., Eur J Cancer 62:132-137 (2016).
37 [0080] The exclusion criteria for subjects set forth in Table 10 were applied in this clinical trial study:
TABLE 10
Figure imgf000040_0001
[0081] A list of prohibited concomitant medications is provided in Table 11.
TABLE 11
Figure imgf000040_0002
[0082] Primary and Second Outcome Measures
[0083] The primary and secondary objectives and endpoints of this study are provided in Table 12.
TABLE 12
38
Figure imgf000041_0001
39
Figure imgf000042_0001
[0084] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.
[0085] The use of the terms “a” and “an” and “the” and similar referents in the context of describing the disclosure (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms “comprising,” “having,” “including,” and “containing” are to be construed as open-ended terms including the indicated component(s) but not excluding other elements (i.e., meaning “including, but not limited to,”) unless otherwise noted.
[0086] Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range and each endpoint, unless otherwise indicated herein, and each separate value and endpoint is incorporated into the specification as if it were individually recited herein.
[0087] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the disclosure and does not pose a limitation on the scope of the disclosure unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the disclosure.
[0088] Preferred embodiments of this disclosure are described herein, including the best mode known to the inventors for carrying out the disclosure. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the disclosure to be practiced otherwise than as specifically described herein. Accordingly, this disclosure includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the disclosure unless otherwise indicated herein or otherwise clearly contradicted by context.
40

Claims

WHAT IS CLAIMED IS:
1. An anti-PD-1 antibody comprising six complementarity determining region (CDR) amino acid sequences of SEQ ID NOs: 3-8 for use in a method of treating cancer or tumor in a subject, said method comprising administering to the subject the anti-PD-1 antibody in an amount equivalent to about 100 mg to about 150 mg per week.
2. The anti-PD-1 antibody of claim 1, wherein the amount of the anti-PD-1 antibody is equivalent to about 115 mg per week to about 125 mg per week, optionally, wherein the amount of the anti-PD- 1 antibody is equivalent to about 120 mg per week.
3. The anti-PD-1 antibody of claim 1 or 2, wherein the method comprises administering to the subject (a) about 120 mg of the PD-1 antibody once a week, (b) about 240 mg of the PD-1 antibody once every 2 weeks, (c) about 360 mg of the PD-1 antibody once every 3 weeks, (d) about 480 mg of the PD-1 antibody once every 4 weeks, (e) about 600 mg of the PD-1 antibody once every 5 weeks, (f) about 720 mg of the PD-1 antibody once every 6 weeks, (g) about 840 mg of the PD-1 antibody once every 7 weeks, or (h) about 960 mg of the PD-1 antibody once every 8 weeks.
4. An anti-PD-1 antibody comprising six complementarity determining region (CDR) amino acid sequences of SEQ ID NOs: 3-8 for use in a method of treating cancer or tumor in a subject, said method comprising administering to the subject the anti-PD-1 antibody in an amount equivalent to about 480 mg once every 4 weeks.
5. The anti-PD-1 antibody of any one of the preceding claims, wherein the method comprises administering to the subject about 480 mg of the anti-PD-1 antibody once every 4 weeks.
6. The anti-PD-1 antibody of any one of the preceding claims, wherein the amount provides: a. a mean serum concentration of the anti-PD-1 antibody which is achieved by administering 480 mg once every 4 weeks; b. a mean plasma area under the curve (AUC».,) which is achieved by administering 480 mg once every 4 weeks; c. a difference between the mean plasma Cmax at steady state and a mean plasma Cmm at steady state which is achieved by administering 480 mg once every 4 weeks; d. a mean plasma Cmax at steady state which is achieved by administering 480 mg once every 4 weeks.
41
. The anti-PD-1 antibody of any one of the preceding claims, wherein the anti-PD-1 antibody comprises (A) a. a heavy chain (HC) complementarity-determining region (CDR) 1 amino acid sequence comprising SEQ ID NO: 3; b. an HC CDR2 amino acid sequence comprising SEQ ID NO: 4; c. an HC CDR3 amino acid sequence comprising SEQ ID NO: 5; d. a light chain (LC) CDR1 amino acid sequence comprising SEQ ID NO: 6; e. an LC CDR2 amino acid sequence comprising SEQ ID NO: 7; and f. an LC CDR3 amino acid sequence comprising SEQ ID NO: 8.
(B) a heavy chain variable region of SEQ ID NO: 9 and a light chain variable region of SEQ ID NO: 10,
(C) a heavy chain of SEQ ID NO: 11 or 13 and a light chain of SEQ ID NO: 12, or
(D) a combination thereof. . The anti-PD-1 antibody of any one of the preceding claims, wherein the anti-PD-1 antibody is zeluvalimab. . The anti-PD-1 antibody of any one of the preceding claims, wherein the method comprises (a) intravenously administering to the subject the anti-PD-1 antibody, (b) administering the anti-PD-1 antibody to the subject for at least one cycle, (c) administering the anti-PD-1 antibody to the subject for at least three cycles, (d) administering anti-PD-1 antibody to the subject for at least six cycles, or (e) a combination thereof. 0. The anti-PD-1 antibody of any one of the preceding claims, wherein the subject (a) does not exhibit a dose limiting toxicity (DLT) during treatment with the anti-PD-1 antibody, (b) does not exhibit any grade 3 or grade 4 adverse events associated with anti-PD-1 antibody therapy, (c) does not exhibit any grade 3 or grade 4 adverse events associated with anti-PD-1 antibody therapy, or (d) a combination thereof. l.The anti-PD-1 antibody of any one of the preceding claims, wherein the tumor is a solid tumor, optionally, an advanced solid tumor or metastatic solid tumor.
42 The anti-PD-1 antibody of claim 11, wherein the solid tumor is a Stage 3 of Stage 4 tumor, a non- resectable tumor, and/or a non-localized tumor. The anti-PD-1 antibody of any one of the preceding claims, wherein the cancer is a colon cancer, an ovarian cancer, a clear cell renal cell carcinoma, a pancreatic carcinoma, a sarcoma metastatic, sarcomatoid carcinoma, a squamous cell carcinoma (head and neck), or an undifferentiated nasopharyngeal carcinoma. The anti-PD-1 antibody of any one of the preceding claims, wherein the subject (a) exhibits at least a stable disease (SD) after about 2 or more cycles of treatment with the anti-PD-1 antibody, (b) exhibits at least a partial response (PR) after about 2 or more cycles of treatment with the anti-PD- 1 antibody, (c) exhibits a complete response (CR) after about 2 or more cycles of treatment with the anti-PD-1 antibody, (d) had prior treatment with an anticancer therapy other than the anti-PD-1 antibody, or (e) a combination thereof. A pharmaceutical composition comprising an anti-PD-1 antibody comprising the six CDR amino acid sequences of SEQ ID NOs: 352-357 at a concentration of about 50 mg/mL to about 100 mg/mL, a buffer, a disaccharide and a surfactant. The pharmaceutical composition of claim 15, wherein the buffer is acetate optionally sodium acetate, optionally, comprising about 5 mM to about 25 mM acetate, optionally, about 10 mM sodium acetate. The pharmaceutical composition of claim 15 or 16, comprising about 5.0% (w/v) disaccharide to about 15.0 % (w/v) disaccharide, optionally, about 9.0% (w/v) disaccharide. The pharmaceutical composition of any one of claims 15 to 17, comprising about 0.001% (w/v) to about 0.1% (w/v) surfactant, optionally, about 0.01% (w/v) surfactant. The pharmaceutical composition of any one of claims 15 to 18, wherein the surfactant is PS80. The pharmaceutical composition of any one of claims 34 to 41, which is (a) a preservative-free solution, (b) a solution having a pH of about 5.2, or (c) a combination thereof. A vial comprising about 1 to about 5 mL of the pharmaceutical composition of any one of claims 15 - 20. An anti-PD-1 antibody comprising six complementarity determining region (CDR) amino acid sequences of SEQ ID NOs: 3-8 for use in a method of treating a cancer or tumor in a subject, said
43 method comprising administering to the subject the anti-PD-1 antibody in combination with a platinum chemotherapy and/or an antimetabolite. The anti-PD-1 antibody of claim 45, wherein the platinum chemotherapy is carboplatin or cisplatin, optionally, wherein the method comprises administering to the subject about 75 mg/m2 cisplatin or administering to the subject an amount of carboplatin that provides an AUC of about 5. The anti-PD-1 antibody of claim 23, wherein the amount of carboplatin administered to the subject is (a) determined based on the subject’s age, serum creatine level, gender, height, weight, target AUC or a combination thereof, (b) calculated according to the Calvert method, (c) calculated based on the CKD-EPI equation, or (d) a combination thereof. The anti-PD-1 antibody of any one or claims 22-24, wherein the antimetabolite is pemetrexed, optionally, wherein the method comprises administering to the subject about 500 mg/m2 pemetrexed. The anti-PD-1 antibody of any one of claims 22-25, wherein the anti-PD-1 antibody, the platinum chemotherapy and/or an antimetabolite is administered to the subject once every 3 weeks. The anti-PD-1 antibody of any one of claims 22-26, wherein the method comprises administering (i) about 360 mg anti-PD-1 antibody to the subject, (ii) (a) about 360 mg anti-PD-1 antibody once every 3 weeks and (b) about 500 mg/m2 pemetrexed to the subject once every 3 weeks, (iii) about 720 mg anti-PD-1 antibody to the subject, (iv) about 720 mg anti-PD-1 antibody once every 6 weeks, (v) for a first time period (a) about 360 mg anti-PD-1 antibody once every 3 weeks and (b) about 500 mg/m2 pemetrexed to the subject once every 3 weeks followed by administering to the subject for a second time period (c) about 720 mg anti-PD-1 antibody once every 6 weeks and (d) about 500 mg/m2 pemetrexed to the subject once every 3 weeks, or (vi) a combination thereof. The method of claim 27, comprising: administering to the subject for a first time period: (a) about 360 mg anti-PD-1 antibody once every 3 weeks, (b) about 500 mg/m2 pemetrexed to the subject once every 3 weeks, and (c) about 75 mg/m2 cisplatin or an amount of carboplatin to achieve a target AUC of about 5 once every 3 weeks, and administering to the subject for a second time period: (d) about 720 mg anti-PD-1 antibody once every 6 weeks and (e) about 500 mg/m2 pemetrexed to the subject once every 3 weeks,
44 wherein the first time period is about 12 weeks and the second time period is up to about 186 weeks. 9. An anti-PD-1 antibody comprising six complementarity determining region (CDR) amino acid sequences of SEQ ID NOs: 3-8 for use in a method of treating a cancer or tumor in a subject, said method comprising administering to the subject the anti-PD-1 antibody in combination with a platinum chemotherapy and/or an antimetabolite, wherein the anti-PD-1 antibody is administered at a first amount for a first time period and at a second amount different from the first amount for a second time period. 0. The anti-PD-1 antibody of claim 29, wherein the first amount is lower than the second amount, optionally, wherein the first amount is about 360 mg and/or the second amount is about 720 mg. l.The anti-PD-1 antibody of any one of claims 29 or 30, wherein the first time period is shorter than the second time period, optionally, wherein the first time period is about 12 weeks or about 3 months and or the second time period is at least or about one year. 2. The anti-PD-1 antibody of claim 31, wherein the second time period is at least or about two years. 3. The anti-PD-1 antibody of claim 31, wherein the second time period is greater than two years.4. The anti-PD-1 antibody of any one of claims 29-33, comprising administering the antimetabolite during the first time period and the second time period, optionally, wherein the antimetabolite is pemetrexed. 5. The anti-PD-1 antibody of claim 34, comprising administering about 500 mg/m2 pemetrexed. 6. The anti-PD-1 antibody of any one of the preceding claims, comprising administering pemetrexed once every 3 weeks during the first time period and second time period.
7. The anti-PD-1 antibody of any one of claims 29-36, comprising administering the platinum chemotherapy during first time period, optionally, wherein the platinum chemotherapy is not administered during the second time period 8. The anti-PD-1 antibody of any one of the preceding claims, wherein the platinum chemotherapy is carboplatin or cisplatin, optionally, wherein the method comprises administering to the subject about 75 mg/m2 cisplatin. 9. The anti-PD-1 antibody of claim 38, comprising administering to the subject an amount of carboplatin that provides an AUC of about 5.
45 The anti-PD-1 antibody of claim 39, wherein the amount of carboplatin administered to the subject is (a) determined based on the subject’s age, serum creatine level, gender, height, weight, target AUC or a combination thereof, (b) calculated according to the Calvert method, (c) calculated based on the CKD-EPI equation, or (d) a combination thereof. The anti-PD-1 antibody of any one of the preceding claims, wherein the cancer is Non-Small Cell Lung Cancer (NSCLC), optionally, wherein the NSCLC is advanced non-squamous NSCLC The anti-PD-1 antibody of any one of claims 22-41, wherein the anti-PD-1 antibody is zeluvalimab. A combination of (a) an anti-PD-1 antibody comprising six complementarity determining region (CDR) amino acid sequences of SEQ ID NOs: 3-8 and (b) a platinum chemotherapy and/or an antimetabolite, for use in a method of treating a cancer or tumor in a subject, said method comprising administering to the subject the anti-PD-1 antibody in combination with the platinum chemotherapy and/or the antimetabolite. A combination of (a) an anti-PD-1 antibody comprising six complementarity determining region (CDR) amino acid sequences of SEQ ID NOs: 3-8 and (b) a platinum chemotherapy and/or an antimetabolite, for use in a method of treating a cancer or tumor in a subject, said method comprising administering to the subject the anti-PD-1 antibody in combination with the platinum chemotherapy and/or the antimetabolite, wherein the anti-PD-1 antibody is administered at a first amount for a first time period and at a second amount different from the first amount for a second time period.
46
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