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WO2023018677A1 - Combinaison thérapeutique constituée d'un antagoniste de tigit, d'un antagoniste de pd-1 et d'un ou plusieurs agent(s) chimiothérapeutique(s) - Google Patents

Combinaison thérapeutique constituée d'un antagoniste de tigit, d'un antagoniste de pd-1 et d'un ou plusieurs agent(s) chimiothérapeutique(s) Download PDF

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Publication number
WO2023018677A1
WO2023018677A1 PCT/US2022/039767 US2022039767W WO2023018677A1 WO 2023018677 A1 WO2023018677 A1 WO 2023018677A1 US 2022039767 W US2022039767 W US 2022039767W WO 2023018677 A1 WO2023018677 A1 WO 2023018677A1
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seq
amino acid
set forth
acid sequence
antagonist
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PCT/US2022/039767
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English (en)
Inventor
Jane Anne HEALY
Sujata SHRAWANKUMAR JHA
Tanya KEENAN
Abby SIEGEL
Elaine M. PINHEIRO
Alexandra SNYDER
Mingmei CAI
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Merck Sharp & Dohme Llc
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Priority to CN202280066297.4A priority Critical patent/CN118055761A/zh
Priority to KR1020247007568A priority patent/KR20240047393A/ko
Priority to EP22856484.5A priority patent/EP4384152A1/fr
Priority to JP2024508015A priority patent/JP2024532744A/ja
Priority to MX2024001892A priority patent/MX2024001892A/es
Publication of WO2023018677A1 publication Critical patent/WO2023018677A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • 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
    • A61K2039/507—Comprising a combination of two or more separate antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/55—Medicinal preparations containing antigens or antibodies characterised by the host/recipient, e.g. newborn with maternal antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—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]
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • V) rovides methods of treating cancer e.g., esophageal cancer, TNBC, biliary cancer, etc.
  • V) ides kits including a TIGIT antagonist, a PD-1 antagonist, 5-fluorouracil and cisplatin.
  • the present disclosure further provides kits including a TIGIT antagonist, a PD-1 antagonist, and paclitaxel or a pharmaceutically acceptable salt thereof.
  • kits including a TIGIT antagonist, a PD-1 antagonist, capecitabine or pharmaceutically acceptable salt thereof and oxaliplatin.
  • a therapeutic combination for treating cancer e.g., esophageal cancer
  • the therapeutic combination includes a TIGIT antagonist, a PD-1 antagonist, 5-fluorouracil and cisplatin.
  • a therapeutic combination for treating cancer e.g., TNBC
  • the therapeutic combination includes a TIGIT antagonist, a PD-1 antagonist, and paclitaxel or a pharmaceutically acceptable salt thereof.
  • kits comprising: (a) a TIGIT antagonist; (b) a PD-1 antagonist; (c) capecitabine or pharmaceutically acceptable salt thereof; and (d) oxaliplatin.
  • the kit further comprises instructions for administering to a human patient the TIGIT antagonist, the PD-1 antagonist, capecitabine or a pharmaceutically acceptable salt thereof and oxaliplatin.
  • a therapeutic combination for treating cancer in a human patient in need thereof wherein the therapeutic combination comprises an effective amount of: (a) a TIGIT antagonist; (b) a PD-1 antagonist; (c) 5-fluorouracil; and (d) cisplatin.
  • the human patient is administered: (a) about 2 mg/kg pembrolizumab once every three weeks; (b) about 2 mg/kg of an anti-human TIGIT antibody or antigen binding fragment thereof comprising three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112, and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113, and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154, and CDRH3 comprising the amino acid sequence as set forth in SEQ ID NO: 110 once every three weeks; (c) a total of about 3000 mg/m 2 or 4000 mg/m 2 5-fluorouracil per cycle (e.g., about 600 mg/m 2 or 800 mg/m 2 per day five times every
  • the human patient is administered: (a) about 240 mg pembrolizumab once every three weeks; (b) about 240 mg of an anti-human TIGIT antibody or antigen binding fragment thereof comprising three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112, and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113, and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154, and CDRH3 comprising the amino acid sequence as set forth in SEQ ID NO: 110 once every three weeks; and (c) about 80 mg/m 2 or about 90 mg/m 2 paclitaxel once every week.
  • CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111
  • CDRL2 comprising the amino acid
  • the human patient is administered about 500 mg/m 2 to about 1500 mg/m 2 gemcitabine or a pharmaceutically acceptable salt thereof, wherein the gemcitabine or a pharmaceutically acceptable salt thereof is administered every three weeks.
  • the human patient is administered about 800 mg/m 2 to about 1000 mg/m 2 gemcitabine or a pharmaceutically acceptable salt thereof, wherein the gemcitabine or a pharmaceutically acceptable salt thereof is administered every three weeks.
  • the human patient is administered about 800 mg/m 2 or about 1000 mg/m 2 gemcitabine or a pharmaceutically acceptable salt thereof, wherein the gemcitabine or a pharmaceutically acceptable salt thereof is administered every three weeks.
  • the human patient is administered about 10 mg/m 2 to about 50 mg/m 2 cisplatin, wherein the cisplatin is administered once every three weeks. In some embodiments, the human patient is administered about 20 mg/m 2 to about 25 mg/m 2 cisplatin, wherein the cisplatin is administered once every three weeks. In some embodiments, the human patient is administered about 20 or about 25 mg/m 2 cisplatin, wherein the cisplatin is administered once every three weeks.
  • antibody fragment or “antigen binding fragment” refers to a fragment of an antibody that retains the ability to bind specifically to the antigen, e.g., fragments that retain one or more CDR regions and the ability to bind specifically to the antigen.
  • An antibody that “specifically binds to” TIGIT or PD-1 is an antibody that exhibits preferential binding to TIGIT or PD-1 (as appropriate) as compared to other proteins, but this specificity does not require absolute binding specificity.
  • Antigen binding portions include, for example, Fab, Fab’, F(ab’)2, Fd, Fv, fragments including CDRs, and single chain variable fragment antibodies (scFv), and polypeptides that contain at least a portion of an immunoglobulin that is sufficient to confer specific antigen binding to the antigen (e.g., TIGIT or PD-1).
  • An antibody includes an antibody of any class, such as IgG, IgA, or IgM (or sub-class thereof), and the antibody need not be of any particular class. Depending on the antibody amino acid sequence of the constant region of its heavy chains, immunoglobulins can be assigned to different classes.
  • the treatments are a combination of at least one anti- human TIGIT monoclonal antibody or antigen-binding fragment thereof, at least one anti- human PD-1 monoclonal antibody or antigen-binding fragment thereof, 5-fluorouracil and cisplatin; a combination of at least one anti-human TIGIT monoclonal antibody or antigen- binding fragment thereof, at least one anti-human PD-1 monoclonal antibody or antigen- binding fragment thereof, and paclitaxel or a pharmaceutically acceptable salt thereof; a combination of at least one anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof, at least one anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof, gemcitabine or a pharmaceutically acceptable salt thereof and cisplatin; or a combination of at least one anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof, at least one anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof, cape
  • the anti- PD-1 treatment begins after the anti-TIGIT and/or the paclitaxel treatment. In some embodiments, the paclitaxel treatment begins prior to the anti-PD-1 and/or the anti-TIGIT treatment. In other embodiments, the paclitaxel treatment begins after the anti- PD-1 and/or the anti-TIGIT treatment. In certain embodiments, the anti-TIGIT treatment is terminated prior to termination of the anti-PD-1 and/or the paclitaxel treatment. In other embodiments, the anti-TIGIT treatment is terminated after termination of the anti-PD-1 and/or the paclitaxel treatment.
  • the anti-TIGIT treatment, the anti-PD-1 treatment, and the gemcitabine/cisplatin treatment are the same period of time. In some embodiments, the anti-TIGIT treatment begins prior to the anti-PD-1 and/or the gemcitabine/cisplatin treatment. In other embodiments, the anti-TIGIT treatment begins after the anti-PD-1 and/or the gemcitabine/cisplatin treatment. In yet other embodiments, the anti-PD-1 treatment begins prior to the anti-TIGIT and/or the gemcitabine/cisplatin treatment. In still other embodiments, the anti- PD-1 treatment begins after the anti-TIGIT and/or the gemcitabine/cisplatin treatment.
  • the anti- human PD-1 monoclonal antibody is PDR001. In yet another embodiment, the anti-human PD-1 monoclonal antibody is BGB-A317. In still another embodiment, the anti-human PD-1 monoclonal antibody is MGA012. In some embodiments, an anti-human PD-1 antibody or antigen binding fragment thereof for use in the methods, kits, uses and co-formulations of the invention comprises three light chain CDRs of CDRL1, CDRL2 and CDRL3 and/or three heavy chain CDRs of CDRH1, CDRH2 and CDRH3.
  • the anti-TIGIT antibody or antigen binding fragment thereof comprises a variable heavy chain region comprising the amino acid sequence as set forth in SEQ ID NO:87 and a variable light chain region comprising the amino acid sequence as set forth in SEQ ID NO:88. In one embodiment, the anti-TIGIT antibody or antigen binding fragment thereof comprises a variable heavy chain region comprising the amino acid sequence as set forth in SEQ ID NO: 114 and a variable light chain region comprising the amino acid sequence as set forth in SEQ ID NO:115.
  • the anti-TIGIT antibody or antigen binding fragment thereof comprises a variable heavy chain region comprising a variable heavy chain region comprising the amino acid sequence as set forth in SEQ ID NO:148 and a variable light chain region comprising the amino acid sequence as set forth in SEQ ID NO:152. In one embodiment, the anti-TIGIT antibody or antigen binding fragment thereof comprises a variable heavy chain region comprising the amino acid sequence as set forth in SEQ ID NO:147 and a variable light chain region comprising the amino acid sequence as set forth in SEQ ID NO:150.
  • the anti-TIGIT antibody or antigen binding fragment thereof comprises a variable heavy chain region comprising any of the amino acid sequences as set forth in SEQ ID NOs: 213, 214, 215, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, and 286 and a variable light chain region comprising any of the amino acid sequences as set forth in SEQ ID NOs: 217, 218, and 219.
  • Additional anti-TIGIT antibodies which may be used in the formulations described herein include those disclosed, for example, in PCT International Application No.
  • the antibody or antigen binding fragment thereof of the invention comprises a human heavy chain IgG1 constant domain wherein the IgG1 constant domain is afucosylated. In one embodiment, the antibody or antigen binding fragment thereof of the invention comprises a human heavy chain IgG4 constant domain or a variant thereof, wherein the variant comprises up to 20 modified amino acid substitutions. In another embodiment, the antibody or antigen binding fragment thereof of the invention comprises a human heavy chain IgG4 constant domain, wherein the amino acid at position 228 (using EU numbering scheme) has been substituted from Ser to Pro. In one embodiment, the antibody or antigen binding fragment thereof of the invention comprises a human heavy chain IgG4 constant domain comprising the amino acid sequence as set forth in SEQ ID NO: 292.
  • the anti-human PD-1 monoclonal antibody or antigen binding fragment thereof is nivolumab. In another embodiment of the methods, compositions, kits and uses provided herein, the anti-human PD-1 monoclonal antibody or antigen binding fragment thereof is cemiplimab.
  • the method for treating esophageal cancer comprises administering to a human patient in need thereof: (a) an anti-TIGIT antibody or antigen binding fragment thereof comprising three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112, and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113, and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154, and CDRH3 comprising the amino acid sequence as set forth in SEQ ID NO: 110; (b) nivolumab; (c) 5-fluorouracil represented by Formula (I); and (d) cisplatin represented by Formula (II).
  • CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111
  • CDRL2
  • the method of treating cancer comprises administering to a human patient in need thereof: (a) a TIGIT antagonist; (b) a PD-1 antagonist; and (c) paclitaxel represented by Formula (III) or a pharmaceutically acceptable salt thereof.
  • provided herein is a method for treating cancer, comprising administering to a human patient in need thereof: (a) a human anti-human TIGIT monoclonal antibody or antigen binding fragment thereof; (b) a human anti-human PD-1 monoclonal antibody or antigen binding fragment thereof; and (c) paclitaxel or a pharmaceutically acceptable salt thereof.
  • a method for treating cancer comprising administering to a human patient in need thereof: (a) a humanized anti-human TIGIT monoclonal antibody or antigen binding fragment thereof; (b) a humanized anti-human PD-1 monoclonal antibody or antigen binding fragment thereof; and (c) paclitaxel or a pharmaceutically acceptable salt thereof.
  • a combination of a PD-1 Antagonist, a TIGIT Antagonist, Gemcitabine, and Cisplatin are methods of treating cancer (e.g., biliary cancer) using a combination of a TIGIT antagonist, a PD-1 antagonist, gemcitabine and cisplatin.
  • the TIGIT antagonist is an anti-TIGIT antibody or antigen binding fragment thereof.
  • the PD-1 antagonist is an anti-PD-1 antibody or antigen binding fragment thereof.
  • the cancer is selected from the group consisting of endometrial cancer, hepatocellular carcinoma (HCC), cervical cancer, head and neck cancer (HNSCC), biliary cancer, esophageal cancer, and triple negative breast cancer (TNBC).
  • HCC hepatocellular carcinoma
  • HNSCC head and neck cancer
  • TNBC triple negative breast cancer
  • the cancer is biliary cancer.
  • the biliary cancer is locally recurrent unresectable.
  • the biliary cancer is metastatic.
  • the method of treating cancer comprises administering to a human patient in need thereof: (a) a TIGIT antagonist as disclosed in Section titled TIGIT Antagonists; (b) a PD-1 antagonist as disclosed in Section titled PD-1 Antagonists; (c) gemcitabine represented by Formula (IV) or a pharmaceutically acceptable salt thereof; and (d) cisplatin represented by Formula (II).
  • the PD-1 antagonist is an anti-human PD-1 monoclonal antibody or antigen binding fragment thereof.
  • the anti-human PD-1 monoclonal antibody is a human antibody.
  • the anti-human PD-1 monoclonal antibody is a humanized antibody.
  • a method for treating cancer comprising administering to a human patient in need thereof: (a) a human anti-human TIGIT monoclonal antibody or antigen binding fragment thereof; (b) a human anti-human PD-1 monoclonal antibody or antigen binding fragment thereof; (c) gemcitabine represented by Formula (IV) or a pharmaceutically acceptable salt thereof; and (d) cisplatin represented by Formula (II).
  • the cancer is selected from the group consisting of: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinom
  • the anti-TIGIT antibody or antigen binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence as set forth in SEQ ID NO: 148 and a light chain variable region comprising the amino acid sequence as set forth in SEQ ID NO: 152.
  • the anti- TIGIT antibody or antigen binding fragment thereof comprises a light chain comprising or consisting of an amino acid sequence as set forth in SEQ ID NO:294 and a heavy chain comprising or consisting of an amino acid sequence as set forth in SEQ ID NO:295.
  • Dosing and Administration for treating cancer (e.g., esophageal cancer, TNBC, biliary cancer, gastric cancer) using a combination of a TIGIT antagonist (e.g., an anti-TIGIT monoclonal antibody or antigen binding fragment thereof), a PD-1 antagonist (e.g., an anti-PD-1 monoclonal antibody or antigen binding fragment thereof), and one or more chemotherapeutic agents (e.g., 5-fluorouracil, cisplatin, paclitaxel or a pharmaceutically acceptable salt thereof, gemcitabine or a pharmaceutically acceptable salt thereof, capecitabine or a pharmaceutically acceptable salt thereof, and/or oxaliplatin).
  • a TIGIT antagonist e.g., an anti-TIGIT monoclonal antibody or antigen binding fragment thereof
  • a PD-1 antagonist e.g., an anti-PD-1 monoclonal antibody or antigen binding fragment thereof
  • chemotherapeutic agents e.g., 5-flu
  • the dose of the PD-1 antagonist is about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 240 mg, about 250 mg, about 300 mg, about 400 mg, or about 500 mg.
  • the PD-1 antagonist e.g., anti-PD-1 antibody (e.g., anti-PD-1 monoclonal antibody) or antigen binding fragment thereof
  • the dose of the PD-1 antagonist is about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 240 mg, about 250 mg, about 300 mg, about 400 mg, or about 500 mg.
  • the human patient is administered 400 mg a TIGIT antagonist (e.g., anti-TIGIT antibody (e.g., anti-TIGIT monoclonal antibody) or antigen binding fragment thereof) once every three weeks.
  • the TIGIT antagonist e.g., anti-TIGIT antibody (e.g., anti-TIGIT monoclonal antibody) or antigen binding fragment thereof
  • the TIGIT antagonist comprises three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112, and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113, and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154, and CDRH3 comprising the amino acid sequence as set forth in SEQ ID NO: 110,
  • the human patient is administered about 480 mg TIGIT antagonist (e.g., anti-TIGIT antibody (e.g., anti-TIGIT monoclonal antibody) or antigen binding fragment thereof) once every six weeks.
  • the human patient is administered 720 mg TIGIT antagonist (e.g., anti-TIGIT antibody (e.g., anti-TIGIT monoclonal antibody) or antigen binding fragment thereof) once every six weeks.
  • the human patient is administered 2 mg/kg TIGIT antagonist (e.g., anti-TIGIT antibody (e.g., anti-TIGIT monoclonal antibody) or antigen binding fragment thereof) once every six weeks.
  • the PD-1 antagonist, anti- PD-1 antibody or anti-PD-1 monoclonal antibody is pembrolizumab
  • the human patient is administered 400 mg pembrolizumab
  • pembrolizumab is administered once every six weeks.
  • the PD-1 antagonist, anti-PD- 1 antibody or anti-PD-1 monoclonal antibody is pembrolizumab
  • the human patient is administered about 200 mg, about 240 mg, about 400 mg, about 480 mg, about 720 mg, or about 2 mg/kg pembrolizumab
  • pembrolizumab is administered once every six weeks.
  • the human patient is administered about 200 mg pembrolizumab once every six weeks.
  • the TIGIT antagonist e.g., anti-TIGIT antibody, or antigen binding fragment thereof
  • the PD-1 antagonist e.g., anti-PD-1 antibody, or antigen binding fragment thereof
  • the anti-TIGIT antibody or antigen binding fragment thereof and the anti-PD-1 antibody or antigen binding fragment thereof are administered sequentially on the same day (e.g., as separate formulations), in either order.
  • the anti-TIGIT antibody or antigen binding fragment thereof is administered first.
  • a co-formulated product with of about 200 mg pembrolizumab or a pembrolizumab variant and about 600 mg of antibody comprising three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112, and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113, and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154, and CDRH3 comprising the amino acid sequence as set forth in SEQ ID NO: 110 is used for intravenous infusion.
  • a co-formulated product with about 200 mg of pembrolizumab or a pembrolizumab variant and about 700 mg of antibody comprising three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112, and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113, and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154, and CDRH3 comprising the amino acid sequence as set forth in SEQ ID NO: 110 is used for intravenous infusion.
  • CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111
  • CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112
  • CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113
  • the human patient is administered: (a) about 200 mg, about 240 mg, about 2 mg/kg or about 22 mg/mL of an anti-TIGIT antibody or antigen binding fragment thereof comprising three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112, and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113, and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154, and CDRH3 comprising the amino acid sequence as set forth in SEQ ID NO: 110; (b) about 200 mg, about 240 mg, about 2 mg/kg or about 22 mg/mL pembrolizumab; (c) a total of about 3000 mg/m 2 or 4
  • a co-formulation of pembrolizumab and of an anti-TIGIT antibody or antigen binding fragment thereof comprising three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112, and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113 and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154, and CDRH3 comprising the amino acid sequence as set forth in SEQ ID NO: 110 are administered by IV infusion.
  • the human patient is administered: (a) about 240 mg of an anti-TIGIT antibody or antigen binding fragment thereof comprising three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112, and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113, and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154, and CDRH3 comprising the amino acid sequence as set forth in SEQ ID NO: 110; (b) about 240 mg pembrolizumab; and (c) about 90 mg/m 2 paclitaxel or a pharmaceutically acceptable salt thereof, wherein each of (a) and (b) is administered once every three weeks, and wherein (c) is administered
  • the human patient is administered: (a) about 100 mg, about 150 mg, about 200 mg, about 250 mg, or about 400 mg, or about 2 mg/kg of an anti-TIGIT antibody or antigen binding fragment thereof comprising three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112, and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113, and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154, and CDRH3 comprising the amino acid sequence as set forth in SEQ ID NO: 110; (b) about 100 mg, about 150 mg, about 200 mg, about 250 mg, or about 400 mg, or about 2 mg/kg pembrolizumab; (c)
  • the human patient is administered: (a) about 200 mg of an anti-TIGIT antibody or antigen binding fragment thereof comprising three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112, and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113, and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154, and CDRH3 comprising the amino acid sequence as set forth in SEQ ID NO: 110; (b) about 200 mg pembrolizumab; (c) about 800 mg/m 2 or 1000 mg/m 2 gemcitabine represented by Formula (IV) or a pharmaceutically acceptable salt thereof; and (d) about 20 mg/m 2 or 25 mg/m 2 cis
  • the human patient is administered: (a) about 400 mg of an anti-TIGIT antibody or antigen binding fragment thereof comprising three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112, and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113, and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154, and CDRH3 comprising the amino acid sequence as set forth in SEQ ID NO: 110; (b) about 400 mg pembrolizumab; (c) about 800 mg/m 2 or about 1000 mg/m 2 gemcitabine represented by Formula (IV) or a pharmaceutically acceptable salt thereof; and (d) about 200 mg/m 2 or about 25 mg/m 2
  • a human patient is administered about 750 mg/m 2 , about 800 mg/m 2 , about 850 mg/m 2 , about 900 mg/m 2 , about 950 mg/m 2 , or about 1000 mg/m 2 capecitabine or a pharmaceutically acceptable salt thereof twice a day.
  • a human patient is administered about 750 mg/m 2 capecitabine or a pharmaceutically acceptable salt thereof twice a day.
  • a human patient is administered about 1000 mg/m 2 capecitabine or a pharmaceutically acceptable salt thereof twice a day.
  • oxaliplatin is administered intravenously (e.g., a 60 minutes to 120 minutes IV infusion).
  • the human patient is administered: (a) about 200 mg, about 240 mg, about 2 mg/kg or about 22 mg/mL of an anti-TIGIT antibody or antigen binding fragment thereof comprising three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112, and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113, and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154, and CDRH3 comprising the amino acid sequence as set forth in SEQ ID NO: 110; (b) about 200 mg, about 240 mg, about 2 mg/kg or about 22 mg/mL pembrolizumab; (c) about 750 mg/m 2 or 1000 mg/m 2
  • the human patient is administered: (a) about 200 mg of an anti-TIGIT antibody or antigen binding fragment thereof comprising three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112, and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113, and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154, and CDRH3 comprising the amino acid sequence as set forth in SEQ ID NO: 110; (b) about 200 mg pembrolizumab; (c) about 750 mg/m 2 or 1000 mg/m 2 capecitabine represented by Formula (V) or a pharmaceutically acceptable salt thereof; and (d) about 100 mg/m 2 or 130 mg/m 2
  • the co-formulation is administered for about 30 minutes every three weeks. In some embodiments, the co- formulation is administered for from about 25 to about 40 minutes every three weeks.
  • at least one of the therapeutic agents e.g., the anti-TIGIT antibody (e.g., anti-TIGIT monoclonal antibody) or binding fragment thereof, the anti-PD-1 antibody (e.g., anti-PD-1 monoclonal antibody) or binding fragment thereof, 5-fluorouracil, cisplatin, or paclitaxel
  • the combination therapy is administered using the same dosage regimen (dose, frequency, and duration of treatment) that is typically employed when the agent is used as monotherapy for treating the same condition.
  • a combination therapy disclosed herein is administered to a patient who has not previously been treated with a biotherapeutic or chemotherapeutic agent, i.e., is treatment-na ⁇ ve.
  • the combination therapy is administered to a patient who failed to achieve a sustained response after prior therapy with the biotherapeutic or chemotherapeutic agent, i.e., is treatment-experienced.
  • the therapeutic combination disclosed herein may be used in combination with one or more other active agents, including but not limited to, other anti-cancer agents that are used in the prevention, treatment, control, amelioration, or reduction of risk of a particular disease or condition (e.g., cancer).
  • Such other active agents may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with one or more of the therapeutic agents in the combinations disclosed herein.
  • the one or more additional active agents may be co-administered with the TIGIT antagonist (e.g., anti-TIGIT antibody (e.g., anti-TIGIT monoclonal antibody) or antigen binding fragment thereof), the PD-1 antagonist (e.g., anti-PD-1 antibody (e.g., anti-PD-1 monoclonal antibody) or antigen binding fragment thereof), or one or more chemotherapeutic agents (e.g., 5-fluorouracil, cisplatin, or paclitaxel).
  • the TIGIT antagonist e.g., anti-TIGIT antibody (e.g., anti-TIGIT monoclonal antibody) or antigen binding fragment thereof
  • the PD-1 antagonist e.g., anti-PD-1 antibody (e.g., anti-PD-1 monoclonal antibody) or
  • compositions comprising a PD-1 antagonist and/or a TIGIT antagonist and any one of a hyaluronan degrading enzyme, hyaluronidase, soluble hyaluronidase, soluble PH20 polypeptide, or a variant of any of the foregoing enzymes.
  • the pharmaceutical composition comprises a PD-1 antagonist and a soluble PH20 polypeptide or a variant thereof.
  • the pharmaceutical composition comprises a PD-1 antagonist, a TIGIT antagonist, gemcitabine or a pharmaceutically acceptable salt thereof, cisplatin and a soluble PH20 polypeptide or a variant thereof.
  • the pharmaceutical composition comprises a PD-1 antagonist, a TIGIT antagonist, capecitabine or a pharmaceutically acceptable salt thereof, oxaliplatin and a soluble PH20 polypeptide or a variant thereof.
  • the pharmaceutically acceptable carriers, excipients, or stabilizers are non-toxic to the cell or mammalian being exposed thereto at the dosage and concentrations employed.
  • the pharmaceutically acceptable carrier is an aqueous pH buffered solution.
  • pharmaceutically acceptable carriers include buffers, such as phosphate, citrate, acetate, and other organic acids; antioxidants, such as ascorbic acid; low molecular weight (e.g., fewer than about 10 amino acid residues) polypeptide; proteins, such as serum albumin, gelatin, or immunoglobulin; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, glutamine, asparagine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrins; chelating agents, such as EDTA; sugar alcohols, such as mannitol or sorbitol; salt-forming counterions, such as sodium; and/
  • a kit comprises dosages of each component sufficient for a certain period of treatment (e.g., 3, 6, 12, or 24 weeks, etc.).
  • a kit can comprise a dosage of about 200 mg pembrolizumab, a dosage of about 200 mg anti-TIGIT antibody, and a dosage of about 80 mg/m 2 or about 90 mg/m 2 paclitaxel or a pharmaceutically acceptable salt thereof, which are sufficient for a 3-week treatment.
  • the TIGIT antagonist is an anti-TIGIT antibody (e.g., anti- TIGIT monoclonal antibody) or antigen-binding fragment thereof.
  • the PD-1 antagonist is an anti-PD-1 antibody (e.g., anti-PD-1 monoclonal antibody) or antigen- binding fragment thereof.
  • the PD-1 antagonist is an anti-PD-L1 monoclonal antibody or antigen-binding fragment thereof.
  • the anti-PD-1 antibody (e.g., anti-PD-1 monoclonal antibody) or antigen binding fragment thereof is pembrolizumab.
  • the anti-PD-1 antibody e.g., anti-PD-1 monoclonal antibody or antigen binding fragment thereof is nivolumab. In some embodiments, the anti-PD-1 antibody (e.g., anti-PD-1 monoclonal antibody) or antigen binding fragment thereof is cemiplimab.
  • the dosages for the anti-TIGIT antibody e.g., anti-TIGIT monoclonal antibody
  • the anti-PD-1 antibody e.g., anti-PD-1 monoclonal antibody
  • gemcitabine or a pharmaceutically acceptable salt thereof or cisplatin described herein can be used in various kits herein.
  • a kit can also comprise a dosage of about 400 mg pembrolizumab, 1 dosage of about 400 mg anti- TIGIT antibody, 2 dosages of about 800 mg/m 2 or about 1000 mg/m 2 gemcitabine or a pharmaceutically acceptable salt thereof, and about 20 mg/m 2 to about 25 mg/m 2 cisplatin, which are sufficient for a 6-week treatment.
  • the kit comprises (a) a TIGIT antagonist; (b) a PD-1 antagonist; (c) capecitabine represented by Formula (V) or a pharmaceutically acceptable salt thereof and (d) oxaliplatin represented by Formula (VI).
  • the kit further comprises instructions for administering to a human patient the TIGIT antagonist, the PD-1 antagonist, capecitabine or a pharmaceutically acceptable salt and oxaliplatin.
  • the kit comprises: (a) one or more dosages of an anti-TIGIT antibody (e.g., anti-TIGIT monoclonal antibody) or antigen binding fragment thereof; (b) one or more dosages of an anti-PD-1 antibody (e.g., anti-PD-1 monoclonal antibody) or antigen binding fragment thereof; (c) one or more dosages of capecitabine or a pharmaceutically acceptable salt; (d) one or more dosages of oxaliplatin; and (e) instructions for administering to a human patient the anti-human TIGIT monoclonal antibody or antigen binding fragment thereof, the anti-human PD-1 monoclonal antibody or antigen binding fragment thereof, capecitabine or a pharmaceutically acceptable salt and oxaliplatin.
  • an anti-TIGIT antibody e.g., anti-TIG
  • kits can also comprise a dosage of about 400 mg pembrolizumab, 1 dosage of about 400 mg anti- TIGIT antibody, 124 dosages of about 750 or about 1000 mg/m 2 capecitabine or a pharmaceutically acceptable salt thereof, and 2 dosages of about 100 or about 130 mg/m 2 oxaliplatin, which are sufficient for a 6-week treatment.
  • the kit comprises means for separately retaining the components, such as a container, divided bottle, or divided foil packet.
  • a kit of this disclosure can be used for administration of different dosage forms, for example, oral and parenteral, for administration of the separate compositions at different dosage intervals, or for titration of the separate compositions against one another.
  • the anti-PD-1 antibody e.g., anti-PD-1 monoclonal antibody
  • antigen binding fragment thereof is cemiplimab.
  • mTPI calls for an additional de-escalation
  • enrollment will be closed.
  • Treatment with Composition A will continue for a total of 35 administrations (approximately 2 years) or until any of the discontinuation criteria are met.
  • Treatment with the RP2D of 5-FU and cisplatin will continue until any of the discontinuation criteria are met.
  • x TNBC An mTPI design with a target DLT rate of 30% will be used to identify the preliminary RP2D of paclitaxel to use in combination with Composition A for the treatment of participants with TNBC.
  • Dose Level 0 Dose Level –1 Participants are planned at the starting doses of chemotherapeutic agents as listed in Table 10. However, depending on the accrual rate, the completion of DLT evaluation period and number of DLTs observed, fewer participants may be enrolled at the starting dose. Participants will be closely followed for DLTs for the first cycle after the first dose of study intervention (the DLT evaluation period). The dose will be evaluated on an ongoing basis as participants complete the DLT evaluation period.
  • the dose should be de-escalated, if allowed per-protocol, and the current dose will not be explored further.
  • Table 11 Dose-finding Rules per mTPI Design (Target Toxicity Rate up to 30%) Number of Participants Evaluable for DLT at Current Dose Number of participants 3 4 5 6 7 8 9 10 p p have completed enrollment at the starting dose, the enrollment at this dose level will be halted and a new set of participants will be enrolled and treated at the next lower dose level. This process will continue, with up to 10 DLT-evaluable participants enrolled at each dose explored, until 10 participants have been enrolled at any of the tested doses and a dosing decision of “S” (for staying at current dose) is made for the 10th participant evaluated.
  • Treatment with 5- FU may follow 1 to 2 days after Composition A (e.g., Day 2 or Day 3) as needed per local standard of care. Duration of 5-FU treatment will not exceed 35 cycles. Cisplatin 80 mg/m 2 will be administered as a 60- or 120-minute IV infusion (or per site’s standard practice) Q3W on Day 1 of each treatment cycle after Composition A administration according to approved prescribing information in each country/region or local institutional guidelines. Duration of cisplatin treatment will be capped at 6 doses; cisplatin dosing may occur after Cycle 6 if cisplatin was withheld for 1 or more cycles during Cycles 2 to 6.
  • Cisplatin may be administered on Day 2, if required per local guidelines; however, Day 1 is the preferred day for intervention administration.
  • Gemcitabine will be administered as an IV infusion on Days 1 and 8 of a 3 week cycle, according to local guidelines and product label procedures. Premedication with antiemetic therapy can be given prior to cisplatin and gemcitabine administration.
  • MASCC Multinational Association of Supportive Care in Cancer
  • Oxaliplatin 130 mg/m 2 will be administered as a 60- to 120 minute IV infusion or per the site’s standard practice on Day 1 of each treatment cycle.
  • Capecitabine will be administered orally as a 1000 mg/m 2 dose twice daily from Day 1 to Day 14 of each treatment cycle. The evening dose of capecitabine should be taken approximately 12 hours after the morning dose.
  • Capecitabine should be taken with food, or within 30 minutes after food/meal, with approximately 200 mL of water.
  • the medical history will collect all active conditions and any condition diagnosed within the prior 10 years that the investigator considers to be clinically important. Details regarding the disease for which the participant has enrolled in this study will be recorded separately and not listed as medical history. If a medical condition is diagnosed at the time of screening due to the physical examination, laboratory tests, radiologic assessment, other assessment, and/or a combination of these evaluations, the medical condition is to be recorded as a baseline condition along with the participant’s other medical history unless due to any protocol-specified intervention (e.g., procedure, washout or run-in treatment including placebo run-in). Comprehensive details regarding the participant’s cancer history will be recorded separately and not listed as medical history.
  • protocol-specified intervention e.g., procedure, washout or run-in treatment including placebo run-in.
  • the investigator or qualified designee will review before medication use, including any protocol-specified washout requirement, and record prior medication taken by the participant within 28 days before the first dose of study intervention.
  • the investigator or qualified designee will record medication, if any, taken by the participant during the study. All consented participants will be given a unique screening number that will be used to identify the participant for all procedures that occur before randomization/intervention allocation. Each participant will be assigned only 1 screening number. Screening numbers must not be reused for different participants.
  • Any participant who is screened multiple times will retain the original screening number assigned at the initial screening Visit. All eligible participants will be allocated, by nonrandom assignment, and will receive a treatment/randomization number.
  • the treatment/randomization number identifies the participant for all procedures occurring after treatment allocation/randomization. Once a treatment/randomization number is assigned to a participant, it can never be reassigned to another participant. A single participant cannot be assigned more than 1 treatment/randomization number. Exclusion criteria The participant must be excluded from the study if the participant: 1. Has a history of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 3 years.
  • Neoadjuvant/adjuvant therapy should have been completed at least 6 months prior to diagnosis of advanced and/or unresectable disease, and participants should not have received gemcitabine and/or cisplatin in the neoadjuvant/adjuvant setting. Participants who received prior neoadjuvant/adjuvant therapy with R2 postoperative pathology of the oncologic resection are excluded. 4.
  • Participants with known untreated, asymptomatic brain metastases may participate but will require regular imaging of the brain as a site of disease.
  • asymptomatic brain metastases i.e., no neurological symptoms, no requirement for corticosteroids, no or minimal surrounding edema, and no lesion >1.5 cm
  • Known severe hypersensitivity ( ⁇ Grade 3) to Composition A or chemotherapy for the cohort to which the participant is allocated including dihydropyrimidine dehydrogenase deficiency for 5-FU and capecitabine, respectively) and/or any of their excipients.
  • New lesions will be classified as measurable or nonmeasurable, using the same size thresholds and rules as for baseline lesion assessment in RECIST 1.1. From measurable new lesions, up to 5 lesions total (up to 2 per organ), may be selected as New Lesions – Target. The sum of diameters of these lesions will be calculated and kept distinct from the sum of diameters for target lesions at baseline. All other new lesions will be followed qualitatively as New Lesions – Nontarget.
  • the participant On the confirmatory scans, the participant will be classified as progression confirmed (with an overall response of iCPD), or as showing persistent unconfirmed progression (with an overall response of iUPD), or as showing disease stability or response (stable disease by iRECIST (iSD) / partial response by iRECIST (iPR) / complete response by iRECIST (iCR)).
  • the assessment of the subsequent confirmation scan proceeds in an identical manner, with possible outcomes of iCPD, iUPD, and iSD/iPR/iCR. Resolution of iUPD Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if: x None of the progression-confirming factors identified above occurs, AND x The target lesion sum of diameters (initial target lesions) is not above the disease progression threshold. The response is classified as iSD or iPR (depending on the sum of diameters of the target lesions), or iCR if all lesions resolve.
  • iUPD results from any significant further growth of nontarget lesions, taken as a whole.
  • New lesions o New lesions appear for the first time
  • Additional new lesions appear o Previously identified new target lesions show an increase of ⁇ 5 mm in the new lesion sum of diameters, from the nadir value of that sum o Previously identified nontarget lesions show any significant growth
  • the overall response for that visit is iUPD, and the iUPD evaluation process (see Assessment at the Confirmatory Scan above) is repeated. Progression must be confirmed before iCPD can occur.
  • the decision process on the subsequent iUPD is identical to the iUPD confirmation process for the initial disease progression, with one exception, which can occur if new lesions had occurred at a prior instance of iUPD, had not resolved, then worsened (increase in size or number) leading to the second iUPD. If new lesion worsening has not resolved at the confirmatory scan, then iUPD cannot resolve to iSD or iPR. It will remain iUPD until either a decrease in the new lesion burden allows resolution to iSD or iPR, or until new or worsening cause of progression indicates iCPD. Discontinuation Discontinuation of study intervention does not represent withdrawal from the study.
  • participant As certain data on clinical events beyond study intervention discontinuation may be important to the study, they must be collected through the participant’s last scheduled follow- up, even if the participant has discontinued study intervention. Therefore, all participants who discontinue study intervention before completion of the protocol-specified treatment period will still continue to be monitored in the study and participate in the study visits and procedures unless the participant has withdrawn from the study. Participants may discontinue study intervention at any time for any reason or be discontinued from the study intervention at the discretion of the investigator should any untoward effect occur. In addition, a participant may be discontinued from study intervention by the investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or for administrative and/or other safety reasons.
  • a participant must be discontinued from study intervention, but continue to be monitored in the study for any of the following reasons: x The participant or participant’s legally acceptable representative requests to discontinue study intervention. x Any prolonged interruption of study intervention beyond the permitted periods, for irAE or AE management or other allowed dose interruptions, require Sponsor consultation before restarting treatment. If treatment will not be restarted, the participant will continue to be monitored in the study and the reason for discontinuation of study intervention will be recorded in the medical record. x The participant has a medical condition or personal circumstance, which in the opinion of the investigator and/or Sponsor, placed the participant at unnecessary risk from continued administration of study intervention. x The participant has a confirmed positive serum pregnancy test.
  • Radiographic disease progression (after obtaining informed consent addendum and Sponsor communication, the investigator may elect to continue treatment beyond imaging CRO (iCRO)-verified disease progression).
  • iCRO CRO
  • the participant requires any of the prohibited concomitant medication listed x Recurrence of a severe or life-threatening event, or of any of the laboratory abnormalities listed above, that are presumed to be immune-related. A participant must be withdrawn from the study if the participant or participant’s legally acceptable representative withdraws consent from the study.
  • a participant is not considered lost to follow-up until the last scheduled visit for the individual participant.
  • the missing data for the participant will be managed via the prespecified statistical data handling and analysis guidelines.
  • Informed Consent The investigator or medically qualified designee (consistent with local requirements) must obtain documented informed consent from each potential participant (or their legally acceptable representative) prior to participating in this clinical study If there are changes to the participant’s status during the study (e.g., health or age of majority requirements), the investigator or medically qualified designee must ensure the appropriate documented informed consent is in place.
  • Tumor Imaging and Assessment of Disease The term “scan” refers to any medical imaging data used to assess tumor burden and may include cross-sectional imaging (such as CT or MRI), medical photography, or other methods as specified in this protocol.
  • Initial Tumor Imaging Initial tumor scans at screening must be performed within 28 days before the date of randomization/allocation. Any scans obtained after Cycle 1 Day 1 cannot be included in the screening assessment. The site must review screening scans to confirm the participant has measurable disease per RECIST 1.1.
  • Tumor scans performed as part of routine clinical management are acceptable for screening if they are of acceptable diagnostic quality and performed within 28 days of randomization and can be assessed by the iCRO. If brain scans are required to document the stability of existing metastases, the brain MRI should be acquired during screening. Bone scans are required at screening for participants with a history of bone metastases and/or for those participants with indicative clinical signs/symptoms such as bone pain or elevated alkaline phosphatase levels.
  • Tumor Imaging During the Study The first on study scan should be performed at 9 weeks (63 days +7 days) from the date of randomization/allocation. Subsequent tumor scans should be performed every 9 weeks (63 days ⁇ 7 days) or more frequently if clinically indicated.
  • Adverse Event An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.
  • x New conditions detected or diagnosed after study intervention administration even though it may have been present before the start of the study.
  • x Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
  • x Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention or a concomitant medication.
  • x For all reports of overdose (whether accidental or intentional) with an associated AE, the AE term should reflect the clinical symptoms or abnormal test result. An overdose without any associated clinical symptoms or abnormal laboratory results is reported using the terminology “accidental or intentional overdose without adverse effect.”
  • x Any new cancer that is not a condition of the study). Progression of the cancer under study is not a reportable event.
  • x Medical or surgical procedure e.g., endoscopy, appendectomy: the condition that leads to the procedure is the AE.
  • x Situations in which an untoward medical occurrence did not occur social and/or convenience admission to a hospital).
  • Serious Adverse Event SAE If an event is not an AE per the above, then it cannot be an SAE even if serious conditions are met.
  • An SAE is defined as any untoward medical occurrence that, at any dose: x Results in death.
  • x Is life-threatening.
  • life-threatening in the definition of “serious” refers to an event in which the participant was at risk of death at the time of the event. It does not refer to an event, which hypothetically might have caused death, if it were more severe.
  • x Requires inpatient hospitalization or prolongation of existing hospitalization. Hospitalization is defined as an inpatient admission, regardless of length of stay, even if the hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not worsened is not an SAE.
  • g y Second Course – TNBC Post-treatment Visits Notes E Survi Second Course – TNBC Post-treatment Visits Notes E Survi s
  • the amino acid sequences of antibody reagents are listed in Table 24.
  • Treatment groups consisted of: 1) Isotype mIgG1 antibody + Isotype mIgG2a antibody + 0.9% saline; 2) Anti-PD-1 mIgG1 antibody + Isotype mIgG2a antibody + 0.9% saline; 3) Anti-TIGIT mIgG2a antibody + Isotype mIgG1 antibody + 0.9% saline; 4) Anti-PD-1 mIgG1 antibody + anti-TIGIT mIgG2a antibody + 0.9% saline; 5) Gemcitabine + cisplatin + Isotype mIgG1 antibody + Isotype mIgG2a antibody; and 6) Anti-PD-1 mIgG1 antibody + anti-TIGIT mIgG2a antibody + gemcitabine + cisplatin.
  • Isotype mIgG1 and anti-PD-1 antibodies were dosed intraperitoneally every 5 days at 5 mg/kg body weight.
  • Isotype mIgG2a and anti-TIGIT antibodies were dosed intraperitoneally every 5 days at 10 mg/kg body weight.
  • Gemcitabine was dosed intraperitoneally once weekly at 100 mg/kg body weight for four total doses.
  • Cisplatin was dosed intraperitoneally once weekly at 4 mg/kg body weight for four total doses. Start of treatments was considered Day 0 and dosing based on schedules continued as described until Day 55. Caliper measurements of tumors and body weights were captured twice weekly.

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Abstract

La présente invention concerne des méthodes de cancérothérapie, qui comprennent l'administration, à un patient humain dont l'état le nécessite, : (A) d'un antagoniste de TIGIT; (b) d'un antagoniste de PD-1; et (c) d'un ou de plusieurs agents chimiothérapeutiques. L'invention concerne également des kits contenant de tels agents et des utilisations de combinaisons thérapeutiques desdits agents pour la cancérothérapie.
PCT/US2022/039767 2021-08-10 2022-08-09 Combinaison thérapeutique constituée d'un antagoniste de tigit, d'un antagoniste de pd-1 et d'un ou plusieurs agent(s) chimiothérapeutique(s) WO2023018677A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
CN202280066297.4A CN118055761A (zh) 2021-08-10 2022-08-09 包含tigit拮抗剂、pd-1拮抗剂和化学治疗剂的治疗组合
KR1020247007568A KR20240047393A (ko) 2021-08-10 2022-08-09 Tigit 길항제, pd-1 길항제 및 화학요법제(들)를 포함하는 치료 조합물
EP22856484.5A EP4384152A1 (fr) 2021-08-10 2022-08-09 Combinaison thérapeutique constituée d'un antagoniste de tigit, d'un antagoniste de pd-1 et d'un ou plusieurs agent(s) chimiothérapeutique(s)
JP2024508015A JP2024532744A (ja) 2021-08-10 2022-08-09 Ｔ１ｇｉｔアンタゴニスト、ｐｄ－１アンタゴニスト、及び（１又は複数の）化学療法剤を含む治療的組合せ
MX2024001892A MX2024001892A (es) 2021-08-10 2022-08-09 Una combinacion terapeutica que comprende un antagonista de tigit, un antagonista de pd-1 y uno o varios agentes quimioterapeuticos.

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US202163231525P 2021-08-10 2021-08-10
US63/231,525 2021-08-10
US202263327070P 2022-04-04 2022-04-04
US63/327,070 2022-04-04

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210017276A1 (en) * 2015-08-14 2021-01-21 Merck Sharp & Dohme Corp. Anti-tigit antibodies

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020096915A1 (fr) * 2018-11-05 2020-05-14 Merck Sharp & Dohme Corp. Schéma posologique d'anticorps anti-tigit pour le traitement du cancer
WO2021154761A1 (fr) * 2020-01-27 2021-08-05 Genentech, Inc. Méthodes de traitement du cancer au moyen d'un anticorps antagoniste anti-tigit

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020096915A1 (fr) * 2018-11-05 2020-05-14 Merck Sharp & Dohme Corp. Schéma posologique d'anticorps anti-tigit pour le traitement du cancer
WO2021154761A1 (fr) * 2020-01-27 2021-08-05 Genentech, Inc. Méthodes de traitement du cancer au moyen d'un anticorps antagoniste anti-tigit

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210017276A1 (en) * 2015-08-14 2021-01-21 Merck Sharp & Dohme Corp. Anti-tigit antibodies
US11958902B2 (en) * 2015-08-14 2024-04-16 Merck Sharp & Dohme Llc Anti-TIGIT antibodies

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EP4384152A1 (fr) 2024-06-19
KR20240047393A (ko) 2024-04-12
JP2024532744A (ja) 2024-09-10
MX2024001892A (es) 2024-02-29

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