WO2017205801A1 - Association d'agents d'immunothérapie et d'inhibiteurs de la tyrosine kinase de la rate - Google Patents

Association d'agents d'immunothérapie et d'inhibiteurs de la tyrosine kinase de la rate Download PDF

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WO2017205801A1
WO2017205801A1 PCT/US2017/034786 US2017034786W WO2017205801A1 WO 2017205801 A1 WO2017205801 A1 WO 2017205801A1 US 2017034786 W US2017034786 W US 2017034786W WO 2017205801 A1 WO2017205801 A1 WO 2017205801A1
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cancer
compound
certain embodiments
dose
syk inhibitor
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PCT/US2017/034786
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English (en)
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Karuppiah Kannan
Robert W. KLEINFIELD
Yaping Shou
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Takeda Pharmaceutical Company Limited
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—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
    • 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
    • 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

Definitions

  • This disclosure provides new combination therapies for treating cancers.
  • this disclosure provides methods for treating a cancer, comprising administering to a subject having a cancer a therapeutically effective amount of a combination comprising an immunotherapy agent and a spleen tyrosine kinase (SYK) inhibitor.
  • SYK spleen tyrosine kinase
  • Spleen tyrosine kinase is a 72 kDa non-receptor cytoplasmic tyrosine kinase.
  • SYK has a primary amino acid sequence similar to that of zeta-associated protein-70 (ZAP-70) and is involved in receptor-mediated signal transduction.
  • ZAP-70 zeta-associated protein-70
  • the N-terminal domain of SYK contains two Src-homology 2 (SH2) domains, which bind to diphosphorylated immunoreceptor tyrosine-based activation motifs (ITAMs) found in the cytoplasmic signaling domains of many immunoreceptor complexes.
  • ITAMs diphosphorylated immunoreceptor tyrosine-based activation motifs
  • the C-terminus contains the catalytic domain, and includes several catalytic loop autophosphorylation sites that are responsible for receptor-induced SYK activation and subsequent downstream signal propagation.
  • SYK is expressed in many cell types involved in adaptive and innate immunity, including lymphocytes (B cells, T cells, and NK cells), granulocytes (basophils, neutrophils, and eosinophils), monocytes, macrophages, dendritic cells, and mast cells.
  • B cells lymphocytes
  • T cells T cells
  • NK cells granulocytes (basophils, neutrophils, and eosinophils), monocytes, macrophages, dendritic cells, and mast cells.
  • SYK is expressed in other cell types, including airway epithelium and fibroblasts in the upper respiratory system.
  • SYK's role in ITAM-dependent signaling and its expression in many cell types suggest that compounds which inhibit SYK activity may be useful for treating hematological malignancies, such as acute myeloid leukemia, B-cell chronic lymphocytic leukemia, B-cell lymphoma (e.g., mantle cell lymphoma), and T-cell lymphoma (e.g., peripheral T-cell lymphoma); as well as epithelial cancers, such as lung cancer, pancreatic cancer, and colon cancer. See, e.g., HAHN et al., Cancer Cell, 16:281-294 (2009); CHU et al., Immunol.
  • the invention relates to a method of treating a cancer comprising administering to a subject having a cancer a therapeutically effective amount of a combination comprising an immunotherapy agent and a SYK inhibitor.
  • the cancer is non-small cell lung cancer, head and neck squamous cell carcinoma, or triple negative breast cancer.
  • the SYK inhibitor is 6- ((lR,2S)-2-aminocyclohexylamino)-7-fluoro-4-(l -methyl- lH-pyrazol-4-yl)-lH-pyrrolo[3, 4- c]pyridine-3(2H)-one citrate or a crystalline form thereof.
  • the SYK inhibitor is 6- ((lR,2S)-2-aminocyclohexylamino)-7-fluoro-4-(l -methyl- lH-pyrazol-4-yl)-lH-pyrrolo[3, 4- c]pyridine-3(2H)-one citrate or a crystalline form thereof.
  • immunotherapy agent is nivolumab.
  • the invention relates to a medical kit for treating a cancer comprising a therapeutically effective amount of a combination comprising an immunotherapy agent and a SYK inhibitor.
  • Figure 1 exemplifies an effect of Compound A, anti-PD-1, and Compound-A plus anti-PD-1 combination on tumor volumes against in vivo CT26 mouse syngeneic colon cancer model.
  • Figure 2 exemplifies an effect of Compound A, anti-PD-1, and Compound-A plus anti-PD-1 combination on survival against in vivo CT26 mouse syngeneic colon cancer model.
  • Figure 3 exemplifies an effect of Compound A, anti-PD-1, and Compound-A plus anti-PD-1 combination on B-cells (B220+ cells).
  • Figure 4 exemplifies an effect of Compound A, anti-PD-1, and Compound-A plus anti-PD-1 combination on MDSCs (CD11B+ cells).
  • Figure 5 exemplifies an effect of Compound A, anti-PD-1, and Compound-A plus anti-PD-1 combination on tumor volumes against in vivo 4T1 mouse syngeneic breast cancer model.
  • Figure 6 exemplifies tumor volumes of re-challenged animals in CT-26 mouse syngeneic colon cancer model.
  • Figure 7 exemplifies % mice with tumors for re-challenged animals in CT-26 mouse syngeneic colon cancer model.
  • Figure 8 exemplifies an effect of Compound A, anti-PD-1, and Compound A plus anti-PD-1 combination on tumor B220+ cells in CT-26 mouse syngeneic colon cancer model.
  • Figure 9 exemplifies an effect of Compound A, anti-PD-1, and Compound A plus anti-PD-1 combination on tumor NK+CD3-/activation ( Kp46) in CT-26 mouse syngeneic colon cancer model.
  • Figure 10 exemplifies an effect of Compound A, anti-PD-1, and Compound A plus anti-PD-1 combination on tumor F4/80+ TAMs in CT-26 mouse syngeneic colon cancer model.
  • Figure 11 exemplifies an effect of Compound A, anti-PD-1, and Compound A plus anti-PD-1 combination on tumor CD4+ Treg in CT-26 mouse syngeneic colon cancer model.
  • Figure 12 exemplifies an effect of Compound A on the percentage of MDSCs in the tumor infiltrating leukocytes in syngeneic B16BL6 murine melanoma model.
  • Figure 13 exemplifies an effect of Compound A on MDSC (CD1 lb+) in HCC70 triple negative breast cancer xenograph model.
  • Figure 14 exemplifies individual tumor growth of each animal in vehicle treatment group in MH-22A liver syngeneic model.
  • Figure 15 exemplifies individual tumor growth of each animal in Compound A treatment group in MH-22A liver syngeneic model.
  • Figure 16 exemplifies individual tumor growth of each animal in anti-PD-1 treatment group in MH-22A liver syngeneic model.
  • Figure 17 exemplifies individual tumor growth of each animal in Compound A + anti-PD-1 treatment group in MH-22A liver syngeneic model.
  • Figure 18 exemplifies average tumor volume over time in female C3H/HeN mice bearing MH-22A syngeneic model dosed with vehicle, Compound A, anti-PD-1, or Compound-A plus anti- PD-1 combination.
  • Figure 19 exemplifies average tumor volume over time for the untreated female C3H mice or the tumor-free survivors from previous study (which were treated with Compound A and anti-PD-1 combination in the previous study) after re-challenge with MH-22A syngeneic model.
  • Figure 20 exemplifies an individual tumor volume over time of tumor-free survivors from previous study (where mice were treated with Compound A and anti-PD-1 combination) after re- challenge with MH-22A syngeneic model.
  • SYK is a 72 kDa non-receptor cytoplasmic tyrosine kinase.
  • SYK inhibitor refers to a compound having the ability to interact with Spleen tyrosine kinase and inhibit its enzymatic activity.
  • treatment is meant to include the full spectrum of intervention for the cancer from which the subject is suffering, such as administration of the combination to alleviate, slow, stop, or reverse one or more symptoms of the cancer or to delay the progression of the cancer even if the cancer is not actually eliminated.
  • Treatment can include, for example, a decrease in the severity of a symptom, the number of symptoms, or frequency of relapse, e.g., the inhibition of tumor growth, the arrest of tumor growth, or the regression of already existing tumors.
  • subject means a mammal, and “mammal” includes, but is not limited to, a human.
  • the subject has been treated with an agent, e.g., an immunotherapy agent and/or an SYK inhibitor, prior to initiation of treatment according to the method of the disclosure.
  • the subject is at risk of developing or experiencing a recurrence of a cancer.
  • the subject is a cancer patient.
  • anti-cancer agent refers to any agent useful in the treatment of a neoplastic condition.
  • anti-cancer agents comprises chemotherapeutic agents.
  • the term "effective amount” or “therapeutically effective amount” refers to that the amount of a compound, or combination of one or more compounds when administered (either sequentially or simultaneously) that elicits the desired biological or medicinal response, e.g., either destroys the target cancer cells or slows or arrests the progression of the cancer in a subject.
  • the therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one skilled in the art.
  • the term also applies to a dose that will induce a particular response in target cells, e.g., reduction of platelet adhesion and/or cell migration.
  • the "therapeutically effective amount” as used herein refers to the amount of an immunotherapy agent and the amount of a SYK inhibitor that, when administered in combination have a beneficial effect.
  • the combined effect is additive.
  • the combined effect is synergistic.
  • the amount of the immunotherapy agent and/or the amount of the SYK inhibitor may be used in a "sub-therapeutic amount", i.e., less than the therapeutically effective amount of the immunotherapy agent or SYK inhibitor alone.
  • Combination administration refers to administering of more than one pharmaceutically active ingredients (including but not limited to an immunotherapy agent and an SYK inhibitor as disclosed herein) to a subject. Combination administration may refer to simultaneous administration or may refer to sequential administration of the immunotherapy agent and the SYK inhibitor as disclosed herein.
  • the terms “simultaneous” and “simultaneously” refer to the administration of the immunotherapy agent and the SYK inhibitor as disclosed herein, to a subject at the same time, or at two different time points that are separated by no more than 2 hours.
  • the terms “sequential” and “sequentially” refer to the administration of the immunotherapy agent and the SYK inhibitor as disclosed herein, to a subject at two different time points that are separated by more than 2 hours, e.g., about 3 hours, 4 hours, 5 hours, about 8 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days or even longer.
  • the term "synergistic effect” refers to a situation where the combination of two or more agents produces a greater effect than the sum of the effects of each of the individual agents.
  • the term encompasses not only a reduction in symptoms of the disorder to be treated, but also an improved side effect profile, improved tolerability, improved patient compliance, improved efficacy, or any other improved clinical outcome.
  • a "sub-therapeutic amount" of an agent or therapy is an amount less than the effective amount for that agent or therapy as a single agent, but when combined with an effective or sub-therapeutic amount of another agent or therapy can produce a result desired by the physician, due to, for example, synergy in the resulting efficacious effects, or reduced side effects.
  • pharmaceutically acceptable salt refers to salts derived from a variety of organic and inorganic counter ions well known in the art. Pharmaceutically acceptable acid addition salts may be formed with inorganic acids and organic acids.
  • suitable salts see, e.g., BERGE et al, J. Pharm. Sci. 66: 1-19 (1977) and Remington: The Science and Practice of Pharmacy, 20th Ed., ed. A. Gennaro, Lippincott Williams & Wilkins, 2000.
  • Non-limiting examples of suitable acid salts includes: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, lactate acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • Non-limiting examples of suitable base salts includes: sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
  • carrier includes any and all solvents, diluents, and other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • Remington The Science and Practice of Pharmacy, 20th Ed., ed. A. Gennaro, Lippincott Williams & Wilkins, 2000 discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof.
  • any conventional carrier medium is incompatible with the compounds of the disclosure, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this disclosure.
  • compounds described herein include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structure except for the replacement of a hydrogen atom by a deuterium or tritium, or the replacement of a carbon atom by a 13 C- or 14 C-enriched carbon are within the scope of the disclosure.
  • the diastereomeric purity of such a compound may be at least 80%, at least 90%, at least 95%, or at least 99%.
  • the term "diastereomeric purity" refers to the amount of a compound having the depicted relative stereochemistry, expressed as a percentage of the total amount of all diastereomers present.
  • Substituted when used in connection with a chemical substituent or moiety (e.g., an alkyl group), means that one or more hydrogen atoms of the substituent or moiety have been replaced with one or more non-hydrogen atoms or groups, provided that valence requirements are met and that a chemically stable compound results from the substitution.
  • a chemical substituent or moiety e.g., an alkyl group
  • alkyl refers to straight chain and branched saturated hydrocarbon groups, generally having a specified number of carbon atoms (e.g., C 1-3 alkyl refers to an alkyl group having 1 to 3 carbon atoms, Ci -6 alkyl refers to an alkyl group having 1 to 6 carbon atoms, and so on).
  • alkyl groups include methyl, ethyl, ⁇ -propyl, / ' -propyl, «-butyl, s-butyl, / ' -butyl, t-butyl, pent-l-yl, pent-2-yl, pent-3-yl, 3-methylbut-l-yl, 3-methylbut-2-yl, 2-methylbut-2-yl, 2,2,2- trimethyleth-l-yl, «-hexyl, and the like.
  • alkenyl refers to straight chain and branched hydrocarbon groups having one or more carbon-carbon double bonds, and generally having a specified number of carbon atoms.
  • alkenyl groups include ethenyl, 1-propen-l-yl, l-propen-2-yl, 2-propen-l-yl, 1-buten-l-yl, 1-buten- 2-yl, 3-buten-l-yl, 3-buten-2-yl, 2-buten-l-yl, 2-buten-2-yl, 2-methyl- 1-propen-l-yl, 2-methyl-2- propen-l-yl, 1,3-butadien-l-yl, l,3-butadien-2-yl, and the like.
  • Alkynyl refers to straight chain or branched hydrocarbon groups having one or more triple carbon-carbon bonds, and generally having a specified number of carbon atoms. Examples of alkynyl groups include ethynyl, 1-propyn-l-yl, 2-propyn-l-yl, 1-butyn-l-yl, 3-butyn-l-yl, 3-butyn- 2-yl, 2-butyn-l-yl, and the like.
  • Halo “Halo,” “halogen” and “halogeno” may be used interchangeably and refer to fluoro, chloro, bromo, and iodo.
  • Haloalkyl refers, respectively, to alkyl, alkenyl, and alkynyl groups substituted with one or more halogen atoms, where alkyl, alkenyl, and alkynyl are defined above, and generally having a specified number of carbon atoms.
  • haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, and the like.
  • Cycloalkyl refers to saturated monocyclic and bicyclic hydrocarbon groups, generally having a specified number of carbon atoms that comprise the ring or rings (e.g., C3-8 cycloalkyl refers to a cycloalkyl group having 3 to 8 carbon atoms as ring members).
  • Bicyclic hydrocarbon groups may include isolated rings (two rings sharing no carbon atoms), spiro rings (two rings sharing one carbon atom), fused rings (two rings sharing two carbon atoms and the bond between the two common carbon atoms), and bridged rings (two rings sharing two carbon atoms, but not a common bond).
  • the cycloalkyl group may be attached to a parent group or to a substrate at any ring atom unless such attachment would violate valence requirements.
  • the cycloalkyl group may include one or more non-hydrogen substituents unless such substitution would violate valence requirements.
  • Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • Examples of fused bicyclic cycloalkyl groups include
  • bicyclo[2.1.0]pentanyl i.e., bicyclo[2.1.0]pentan-l-yl, bicyclo[2.1.0]pentan-2-yl, and
  • bridged cycloalkyl groups include bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[3.2.1]octanyl, bicyclo[4.1.1]octanyl, bicyclo[3.3.1]nonanyl, bicyclo[4.2.1]nonanyl, bicyclo[3.3.2]decanyl, bicyclo[4.2.2]decanyl, bicyclo[4.3.1]decanyl, bicyclo[3.3.3]undecanyl, bicyclo[4.3.2]undecanyl, bicyclo[4.3.3]dodecanyl, and the like.
  • spiro cycloalkyl groups include spiro[3.3]heptanyl, spiro[2.4]heptanyl, spiro[3.4]octanyl, spiro[2.5]octanyl, spiro[3.5]nonanyl, and the like.
  • isolated bicyclic cycloalkyl groups include those derived from bi(cyclobutane), cyclobutanecyclopentane, bi(cyclopentane), cyclobutanecyclohexane, cyclopentanecyclohexane, bi(cyclohexane), etc.
  • aryl refers to fully unsaturated monocyclic aromatic hydrocarbons and to polycyclic hydrocarbons having at least one aromatic ring, both monocyclic and polycyclic aryl groups generally having a specified number of carbon atoms that comprise their ring members (e.g., C 6 -i4 aryl refers to an aryl group having 6 to 14 carbon atoms as ring members).
  • the aryl group may be attached to a parent group or to a substrate at any ring atom and may include one or more non- hydrogen substituents unless such attachment or substitution would violate valence requirements.
  • aryl groups include phenyl, biphenyl, cyclobutabenzenyl, indenyl, naphthalenyl, benzocycloheptanyl, biphenylenyl, fluorenyl, groups derived from cycloheptatriene cation, and the like.
  • Heterocycle and “heterocyclyl” may be used interchangeably and refer to saturated or partially unsaturated monocyclic or bicyclic groups having ring atoms composed of carbon atoms and 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Both the monocyclic and bicyclic groups generally have a specified number of carbon atoms in their ring or rings (e.g., C2-5 heterocyclyl refers to a heterocyclyl group having 2 to 5 carbon atoms and 1 to 4 heteroatoms as ring members). As with bicyclic cycloalkyl groups, bicyclic heterocyclyl groups may include isolated rings, spiro rings, fused rings, and bridged rings.
  • the heterocyclyl group may be attached to a parent group or to a substrate at any ring atom and may include one or more non- hydrogen substituents unless such attachment or substitution would violate valence requirements or result in a chemically unstable compound.
  • monocyclic heterocyclyl groups include oxiranyl, thiaranyl, aziridinyl (e.g., aziridin-l-yl and aziridin-2-yl), oxetanyl, thiatanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiopheneyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, 1,4-dioxanyl, 1,4-oxathianyl, morpholinyl, 1,4-dithianyl, piperazinyl, 1,4-azathianyl, oxepanyl, thiepanyl
  • Heteroaryl refers to unsaturated monocyclic aromatic groups and to polycyclic groups having at least one aromatic ring, each of the groups having ring atoms composed of carbon atoms and 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Both the monocyclic and polycyclic groups generally have a specified number of carbon atoms as ring members (e.g., Ci -9 heteroaryl refers to a heteroaryl group having 1 to 9 carbon atoms and 1 to 4 heteroatoms as ring members) and may include any bicyclic group in which any of the above-listed monocyclic heterocycles are fused to a benzene ring.
  • heteroaryl group may be attached to a parent group or to a substrate at any ring atom and may include one or more non-hydrogen substituents unless such attachment or substitution would violate valence requirements or result in a chemically unstable compound.
  • heteroaryl groups include monocyclic groups such as pyrrolyl (e.g., pyrrol-l-yl, pyrrol-2-yl, and pyrrol-3-yl), furanyl, thiopheneyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl, l-oxa-2,3-diazolyl, 1- oxa-2,4-diazolyl, l-oxa-2,5-diazolyl, l-oxa-3,4-diazolyl, l-thia-2,3-diazolyl,
  • heteroaryl groups also include bicyclic groups such as benzofuranyl,
  • the SYK inhibitor is a compound of Formula I,
  • G is C(R 5 );
  • L 1 and L 2 are each independently selected from -NH- and a bond
  • R 1 and R 2 are each independently selected from hydrogen, halo, Ci -3 alkyl, and Ci -3 haloalkyl, or R 1 and R 2 , together with the atom to which they are attached, form a C 3-6 cycloalkyl;
  • R 3 is selected from C 2-6 alkyl, C 3-8 cycloalkyl, C 2-5 heterocyclyl, and Ci.g heteroaryl, each optionally substituted with from one to five substituents independently selected from halo, oxo, -N0 2 , -CN, R 6 , and R 7 ;
  • R 4 is selected from C 3-8 cycloalkyl, C 2-5 heterocyclyl, C 6 -i4 aryl, and Ci.g heteroaryl, each optionally substituted with from one to five substituents independently selected from halo, oxo, -CN, R 6 , and
  • R 5 is selected from hydrogen, halo, -CN, Ci -4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 2-5 heterocyclyl, Ci -5 heteroaryl, and R 10 , wherein the alkyl, alkenyl, alkynyl moieties are each optionally substituted with from one to five substituents independently selected from halo, -CN, oxo, and R 10 , and wherein the heterocyclyl moiety has 3 to 6 ring atoms and the heteroaryl moiety has 5 or 6 ring atoms, and the heterocyclyl and heteroaryl moieties are each optionally substituted with from one to four substituents independently selected from halo, -N0 2 , -CN, C 1-4 alkyl, C 2 -4 alkenyl, C 2 -4 alkynyl, C 1-4 haloalkyl, and R 10 ; each R 6 is independently selected from -OR 8 , -N(R
  • each R 7 is independently selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl-(CH 2 ) m -, C 6 -i4 aryl-(CH 2 ) m -, C 2-5 heterocyclyl-(CH 2 ) m -, and C1.9 heteroaryl -(CH 2 ) m -, each optionally substituted with from one to five substituents independently selected from halo, oxo, -N0 2 , -CN, Ci -6 alkyl, Ci -6 haloalkyl, and R 10 ; each R 8 and R 9 is independently selected from hydrogen or from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl-(CH 2 ) m -, C 6 .
  • each R 10 is independently selected from -OR 11 , -N(R U )R 12 , -N(R u )C(0)R 12 , -C(0)R u , -C(0)OR u , -C(0)N(R u )R 12 , -C(0)N(R u )OR 12 , -C(0)N(R u )S(0) 2 R 12 , -NR u S(0) 2 R 12 , -S(0) n R U ,
  • each R 11 and R 12 is independently selected from hydrogen and Ci -6 alkyl; each n is independently selected from 0, 1 and 2; and each m is independently selected from 0, 1, 2, 3, and 4; wherein each of the aforementioned heteroaryl moieties has one to four heteroatoms independently selected from N, O, and S, and each of the aforementioned heterocyclyl moieties is saturated or partially unsaturated and has one or two heteroatoms independently selected from N, O, and S.
  • the SYK inhibitor is a compound of Formula II, or 6-((lR,2S)-2- aminocyclohexylamino)-7-fluoro-4-(l -methyl- lH-pyrazol-4-yl)-lH-pyrrolo[3,4-c]pyridine-3(2H)- one:
  • the SYK inhibitor is a compound of Formula III, or 6-((lR,2S)-2- aminocyclohexylamino)-7-fluoro-4-(l -methyl- lH-pyrazol-4-yl)-lH-pyrrolo[3,4-c]pyridine-3(2H)- one citrate:
  • the invention relates to a method of treating a neoplastic condition, such as a cancer, comprising administering to a subject having a neoplastic condition a
  • the neoplastic condition is a solid tumor.
  • the cancer is selected from breast cancer, lung cancer, head and neck cancer, melanoma, renal cancer, liver cancer, pancreatic cancer, colorectal cancer, ovarian cancer, gastric cancer, endometrial cancer, prostate cancer, brain and spine cancer, fallopian tube cancer, uterine cancer, bladder cancer, esophageal cancer, biliary tract cancer, urothelial cancer, soft tissue cancer, rectal cancer, thyroid cancer, bone cancer, salivary gland cancer, nasal cavity and paranasal sinus cancer, testicular cancer, adrenocortical cancer, thymic cancer, eye cancer, and gallbladder cancer.
  • the cancer is selected from breast cancer, lung cancer, and head and neck cancer. In certain embodiments, the cancer is triple negative breast cancer (TNBC). In certain embodiments, the cancer is non-small cell lung cancer (NSCLC). In certain embodiments, the cancer is head and neck squamous cell carcinoma (UNSCC).
  • the immunotherapy agent is an anti-PD-1 or anti-PD-Ll agent, such as an anti-PD-1 or anti-PD-Ll antibody. In certain embodiments, the immunotherapy agent is selected from pembrolizumab and nivolumab. In certain embodiments, the immunotherapy agent is pembrolizumab. In certain embodiments, the immunotherapy agent is nivolumab.
  • the SYK inhibitor is a compound of Formula I, II, or III. In certain embodiments, the SYK inhibitor is a compound of Formula II or a pharmaceutically acceptable salt thereof. In certain embodiments, the SYK inhibitor is a compound of Formula III or a crystalline form thereof.
  • the invention relates to a method for treating a cancer selected from breast cancer, lung cancer, head and neck cancer, melanoma, renal cancer, liver cancer, pancreatic cancer, colorectal cancer, ovarian cancer, gastric cancer, endometrial cancer, prostate cancer, brain and spine cancer, fallopian tube cancer, uterine cancer, bladder cancer, esophageal cancer, biliary tract cancer, urothelial cancer, soft tissue cancer, rectal cancer, thyroid cancer, bone cancer, salivary gland cancer, nasal cavity and paranasal sinus cancer, testicular cancer, adrenocortical cancer, thymic cancer, eye cancer, and gallbladder cancer comprising administering to a subject having a cancer selected from breast cancer, lung cancer, head and neck cancer, melanoma, renal cancer, liver cancer, pancreatic cancer, colorectal cancer, ovarian cancer, gastric cancer, endometrial cancer, prostate cancer, brain and spine cancer, fallopian tube cancer, uter
  • the invention relates to a method for treating a cancer selected from breast cancer, lung cancer, and head and neck cancer, comprising administering to a subject having a cancer selected from breast cancer, lung cancer, and head and neck cancer a therapeutically effective amount of a combination comprising an immunotherapy agent and a SYK inhibitor.
  • the invention relates to a method for treating a cancer selected from T BC, NSCLC, or UNSCC, comprising administering to a subject having a cancer selected from TNBC, NSCLC, or UNSCC a therapeutically effective amount of a combination comprising an immunotherapy agent and a SYK inhibitor.
  • the immunotherapy agent is an anti-PD-1 or anti-PD-Ll agent, such as an anti-PD-1 or anti-PD-Ll antibody.
  • the immunotherapy agent is selected from pembrolizumab and nivolumab.
  • the immunotherapy agent is pembrolizumab.
  • the immunotherapy agent is nivolumab.
  • the SYK inhibitor is a compound of Formula I, Formula II, or Formula III.
  • the SYK inhibitor is a compound of Formula II or a pharmaceutically acceptable salt thereof.
  • the SYK inhibitor is a compound of Formula III or a crystalline form thereof.
  • the cancer is breast cancer.
  • the breast cancer is hormone receptor negative.
  • the breast cancer is HER2 negative.
  • the breast cancer is triple negative breast cancer.
  • the invention relates to a method for treating breast cancer (e.g., triple negative breast cancer) comprising administering to a subject having breast cancer a therapeutically effective amount of a combination comprising an immunotherapy agent and a SYK inhibitor.
  • the immunotherapy agent is an anti-PD-1 or anti-PD-Ll agent, such as an anti-PD-1 or anti-PD-Ll antibody.
  • the immunotherapy agent is selected from pembrolizumab and nivolumab.
  • the immunotherapy agent is pembrolizumab. In certain embodiments, the immunotherapy agent is nivolumab. In certain embodiments, the SYK inhibitor is a compound of Formula I, Formula II, or Formula III. In certain embodiments, the SYK inhibitor is a compound of Formula II or a pharmaceutically acceptable salt thereof. In certain embodiments, the SYK inhibitor is a compound of Formula III or a crystalline form thereof.
  • the cancer is lung cancer. In certain embodiments, the cancer is non-small cell lung cancer. In certain embodiments, the non-small cell lung cancer is squamous non-small cell lung cancer. In certain embodiments, the non-small cell lung cancer is non-squamous non-small cell lung cancer. In certain embodiments, the cancer is small cell lung cancer. In certain embodiments, the invention relates to a method for treating lung cancer (e.g., non-small cell lung cancer or small cell lung cancer) comprising administering to a subject having lung cancer a therapeutically effective amount of a combination comprising an immunotherapy agent and a SYK inhibitor.
  • lung cancer e.g., non-small cell lung cancer or small cell lung cancer
  • the immunotherapy agent is an anti-PD-1 or anti-PD-Ll agent, such as an anti-PD-1 or anti-PD-Ll antibody.
  • the immunotherapy agent is selected from pembrolizumab and nivolumab.
  • the immunotherapy agent is pembrolizumab.
  • the immunotherapy agent is nivolumab.
  • the SYK inhibitor is a compound of Formula I, Formula II, or Formula III.
  • the SYK inhibitor is a compound of Formula II or a pharmaceutically acceptable salt thereof.
  • the SYK inhibitor is a compound of Formula III or a crystalline form thereof.
  • the cancer is head and neck cancer.
  • the head and neck cancer is head and neck squamous cell carcinoma (UNSCC).
  • UNSCC head and neck squamous cell carcinoma
  • the invention relates to a method for treating head and neck cancer (e.g., UNSCC) comprising administering to a subject having head and neck cancer a therapeutically effective amount of a combination comprising an immunotherapy agent and a SYK inhibitor.
  • the immunotherapy agent is an anti-PD-1 or anti-PD-Ll agent, such as an anti-PD-1 or anti-PD-Ll antibody.
  • the immunotherapy agent is selected from pembrolizumab and nivolumab.
  • the immunotherapy agent is
  • the immunotherapy agent is nivolumab.
  • the SYK inhibitor is a compound of Formula I, Formula II, or Formula III.
  • the SYK inhibitor is a compound of Formula II or a pharmaceutically acceptable salt thereof.
  • the SYK inhibitor is a compound of Formula III or a crystalline form thereof.
  • the cancer is melanoma.
  • the invention relates to a method for treating melanoma comprising administering to a subject having melanoma a therapeutically effective amount of a combination comprising an immunotherapy agent and a SYK inhibitor.
  • the immunotherapy agent is an anti-PD-1 or anti-PD-Ll agent, such as an anti-PD-1 or anti-PD-Ll antibody.
  • the immunotherapy agent is selected from pembrolizumab and nivolumab.
  • the immunotherapy agent is pembrolizumab.
  • the immunotherapy agent is nivolumab.
  • the SYK inhibitor is a compound of Formula I, Formula II, or Formula III. In certain embodiments, the SYK inhibitor is a compound of Formula II or a pharmaceutically acceptable salt thereof. In certain embodiments, the SYK inhibitor is a compound of Formula III a crystalline form thereof.
  • the cancer is renal cancer.
  • the renal cancer is renal cell carcinoma (RCC).
  • the invention relates to a method for renal cancer (e.g., RCC) comprising administering to a subject having renal cancer a therapeutically effective amount of a combination comprising an immunotherapy agent and a SYK inhibitor.
  • the immunotherapy agent is an anti-PD-1 or anti-PD-Ll agent, such as an anti- PD-1 or anti-PD-Ll antibody.
  • the immunotherapy agent is selected from pembrolizumab and nivolumab.
  • the immunotherapy agent is
  • the immunotherapy agent is nivolumab.
  • the SYK inhibitor is a compound of Formula I, Formula II, or Formula III.
  • the SYK inhibitor is a compound of Formula II or a pharmaceutically acceptable salt thereof.
  • the SYK inhibitor is a compound of Formula III or a crystalline form thereof.
  • the cancer is liver cancer.
  • the liver cancer is hepatocellular carcinoma (HCC).
  • the invention relates to a method for treating liver cancer (e.g., HCC) comprising administering to a subject having liver cancer a therapeutically effective amount of a combination comprising an immunotherapy agent and a SYK inhibitor.
  • the immunotherapy agent is an anti-PD-1 or anti-PD-Ll agent, such as an anti-PD-1 or anti-PD-Ll antibody.
  • the immunotherapy agent is selected from pembrolizumab and nivolumab.
  • the immunotherapy agent is pembrolizumab.
  • the immunotherapy agent is nivolumab.
  • the SYK inhibitor is a compound of Formula I, Formula II, or Formula III.
  • the SYK inhibitor is a compound of Formula II or a pharmaceutically acceptable salt thereof.
  • the SYK inhibitor is a compound of Formula III or a crystalline form thereof.
  • the cancer is pancreatic cancer.
  • the invention relates to a method for treating pancreatic cancer comprising administering to a subject having pancreatic cancer a therapeutically effective amount of a combination comprising an immunotherapy agent and a SYK inhibitor.
  • the immunotherapy agent is an anti-PD-1 or anti-PD-Ll agent, such as an anti-PD-1 or anti-PD-Ll antibody.
  • the immunotherapy agent is selected from pembrolizumab and nivolumab. In certain embodiments, the immunotherapy agent is pembrolizumab. In certain embodiments, the
  • the immunotherapy agent is nivolumab.
  • the SYK inhibitor is a compound of Formula I, Formula II, or Formula III.
  • the SYK inhibitor is a compound of Formula II or a pharmaceutically acceptable salt thereof.
  • the SYK inhibitor is a compound of Formula III or a crystalline form thereof.
  • the cancer is colorectal cancer.
  • the invention relates to a method for treating colorectal cancer comprising administering to a subject having colorectal cancer a therapeutically effective amount of a combination comprising an immunotherapy agent and a SYK inhibitor.
  • the immunotherapy agent is an anti-PD-1 or anti-PD-Ll agent, such as an anti-PD-1 or anti-PD-Ll antibody.
  • the immunotherapy agent is selected from pembrolizumab and nivolumab. In certain embodiments, the immunotherapy agent is pembrolizumab. In certain embodiments, the
  • the immunotherapy agent is nivolumab.
  • the SYK inhibitor is a compound of Formula I, Formula II, or Formula III.
  • the SYK inhibitor is a compound of Formula II or a pharmaceutically acceptable salt thereof.
  • the SYK inhibitor is a compound of Formula III or a crystalline form thereof.
  • the cancer is ovarian cancer.
  • the invention relates to a method for treating ovarian cancer comprising administering to a subject having ovarian cancer a therapeutically effective amount of a combination comprising an immunotherapy agent and a SYK inhibitor.
  • the immunotherapy agent is an anti-PD-1 or anti-PD-Ll agent, such as an anti-PD-1 or anti-PD-Ll antibody.
  • the immunotherapy agent is selected from pembrolizumab and nivolumab.
  • the immunotherapy agent is pembrolizumab.
  • the immunotherapy agent is nivolumab.
  • the SYK inhibitor is a compound of Formula I, Formula II, or Formula III. In certain embodiments, the SYK inhibitor is a compound of Formula II or a pharmaceutically acceptable salt thereof. In certain embodiments, the SYK inhibitor is a compound of Formula III or a crystalline form thereof.
  • the cancer is gastric cancer.
  • the gastric cancer is gastroesophageal adenocarcinoma.
  • the invention relates to a method for treating gastric cancer (e.g., gastroesophageal adenocarcinoma) comprising
  • the method comprising administering to a subject having gastric cancer a therapeutically effective amount of a combination comprising an immunotherapy agent and a SYK inhibitor.
  • a combination comprising an immunotherapy agent and a SYK inhibitor.
  • the immunotherapy agent is an anti-PD-1 or anti-PD-Ll agent, such as an anti-PD-1 or anti-PD-Ll antibody.
  • the immunotherapy agent is selected from pembrolizumab and nivolumab.
  • the immunotherapy agent is pembrolizumab.
  • the immunotherapy agent is nivolumab.
  • the SYK inhibitor is a compound of Formula I, Formula II, or Formula III.
  • the SYK inhibitor is a compound of Formula II or a pharmaceutically acceptable salt thereof.
  • the SYK inhibitor is a compound of Formula III or a crystalline form thereof.
  • the cancer is endometrial cancer.
  • the invention relates to a method for treating endometrial cancer comprising administering to a subject having endometrial cancer a therapeutically effective amount of a combination comprising an immunotherapy agent and a SYK inhibitor.
  • the immunotherapy agent is an anti-PD-1 or anti-PD-Ll agent, such as an anti-PD-1 or anti-PD-Ll antibody.
  • the immunotherapy agent is selected from pembrolizumab and nivolumab. In certain embodiments, the immunotherapy agent is pembrolizumab. In certain embodiments, the
  • the immunotherapy agent is nivolumab.
  • the SYK inhibitor is a compound of Formula I, Formula II, or Formula III.
  • the SYK inhibitor is a compound of Formula II or a pharmaceutically acceptable salt thereof.
  • the SYK inhibitor is a compound of Formula III or a crystalline form thereof.
  • the cancer is prostate cancer.
  • the invention relates to a method for treating prostate cancer comprising administering to a subject having prostate cancer a therapeutically effective amount of a combination comprising an immunotherapy agent and a SYK inhibitor.
  • the immunotherapy agent is an anti-PD-1 or anti-PD-Ll agent, such as an anti-PD-1 or anti-PD-Ll antibody.
  • the immunotherapy agent is selected from pembrolizumab and nivolumab.
  • the immunotherapy agent is pembrolizumab.
  • the immunotherapy agent is nivolumab.
  • the SYK inhibitor is a compound of Formula I, Formula II, or Formula III. In certain embodiments, the SYK inhibitor is a compound of Formula II or a pharmaceutically acceptable salt thereof. In certain embodiments, the SYK inhibitor is a compound of Formula III or a crystalline form thereof.
  • the cancer is selected from brain and spine cancer, fallopian tube cancer, uterine cancer, bladder cancer, esophageal cancer, biliary tract cancer, urothelial cancer, soft tissue cancer, rectal cancer, thyroid cancer, bone cancer, salivary gland cancer, nasal cavity and paranasal sinus cancer, testicular cancer, adrenocortical cancer, thymic cancer, eye cancer, and gallbladder cancer.
  • the invention relates to a method for treating cancer selected from brain and spine cancer, fallopian tube cancer, uterine cancer, bladder cancer, esophageal cancer, biliary tract cancer, urothelial cancer, soft tissue cancer, rectal cancer, thyroid cancer, bone cancer, salivary gland cancer, nasal cavity and paranasal sinus cancer, testicular cancer, adrenocortical cancer, thymic cancer, eye cancer, and gallbladder cancer comprising administering to a subject having cancer selected from brain and spine cancer, fallopian tube cancer, uterine cancer, bladder cancer, esophageal cancer, biliary tract cancer, urothelial cancer, soft tissue cancer, rectal cancer, thyroid cancer, bone cancer, salivary gland cancer, nasal cavity and paranasal sinus cancer, testicular cancer, adrenocortical cancer, thymic cancer, eye cancer, and gallbladder cancer a therapeutically effective amount of a combination comprising an immunotherapy agent and a SYK inhibitor
  • the immunotherapy agent is an anti-PD-1 or anti-PD-Ll agent, such as an anti-PD-1 or anti-PD-Ll antibody.
  • the immunotherapy agent is selected from pembrolizumab and nivolumab.
  • the immunotherapy agent is pembrolizumab.
  • the immunotherapy agent is nivolumab.
  • the SYK inhibitor is a compound of Formula I, Formula II, or Formula III.
  • the SYK inhibitor is a compound of Formula II or a pharmaceutically acceptable salt thereof.
  • the SYK inhibitor is a compound of Formula III or a crystalline form thereof.
  • the invention relates to a method of suppressing tumor regrowth, comprising administering a therapeutically effective amount of a combination comprising an immunotherapy agent and a SYK inhibitor.
  • the immunotherapy agent is an anti-PD-1 or anti-PD-Ll agent, such as an anti-PD-1 or anti-PD-Ll antibody.
  • the immunotherapy agent is selected from pembrolizumab and nivolumab. In certain embodiments, the immunotherapy agent is pembrolizumab. In certain embodiments, the
  • the immunotherapy agent is nivolumab.
  • the SYK inhibitor is a compound of Formula I, Formula II, or Formula III.
  • the SYK inhibitor is a compound of Formula II or a pharmaceutically acceptable salt thereof.
  • the SYK inhibitor is a compound of Formula III or a crystalline form thereof.
  • the growth of cells contacted with an immunotherapy agent and a SYK inhibitor is retarded by at least about 50% as compared to growth of non-contacted cells.
  • cell proliferation of contacted cells is inhibited by at least about 75%, at least about 90%), or at least about 95%> as compared to non-contacted cells.
  • the phrase "inhibiting cell proliferation" includes a reduction in the number of contacted cells, as compare to non-contacted cells.
  • an immunotherapy agent and an inhibitor of SYK that inhibits cell proliferation in a contacted cell may induce the contacted cell to undergo growth retardation, to undergo growth arrest, to undergo programmed cell death (i.e., apoptosis), or to undergo necrotic cell death.
  • the immunotherapy agent and SYK inhibitor are administered such that they provide a synergistic effect in the treatment of a neoplastic disease.
  • the immunotherapy agent and/or the SYK inhibitor may be administered in a subtherapeutic amount.
  • the immunotherapy agent and SYK inhibitor are administered such that they provide an additive effect in the treatment of a neoplastic disease.
  • the immunotherapy agent and the SYK inhibitor are administered simultaneously, wherein simultaneous administration may comprise the two agents in a single formulation or may comprise the two agents in separate formulations.
  • the immunotherapy agent and the SYK inhibitor are administered sequentially.
  • the immunotherapy agent is administered prior to the SYK inhibitor.
  • the SYK inhibitor is administered prior to the immunotherapy agent.
  • the SYK inhibitor is administered orally and the immunotherapy agent is administered intravenously. In certain embodiments, the SYK inhibitor is administered intravenously and the immunotherapy agent is administered orally. In certain embodiments, the SYK inhibitor and the immunotherapy agent are both administered orally. In certain embodiments, the SYK inhibitor and the immunotherapy agent are both administered intravenously.
  • the amounts or suitable doses of the selective inhibitor of SYK depends upon a number of factors, including the nature of the severity of the condition to be treated, the particular inhibitor, the route of administration and the age, weight, general health, and response of the individual subject.
  • the suitable dose level is one that achieves an effective exposure as measured by increased skin mitotic index, or decreased chromosome alignment and spindle bipolarity in tumor mitotic cells, or other standard measures of effective exposure in cancer patients.
  • the suitable dose level is one that achieves a therapeutic response as measured by tumor regression, or other standard measures of disease progression, progression free survival or overall survival.
  • the suitable dose level is one that achieves this therapeutic response and also minimizes any side effects associated with the administration of the therapeutic agent.
  • the SYK inhibitor is administered daily.
  • Suitable daily dosages of a SYK inhibitor of Formula I, II, or III can generally range, in single or divided or multiple doses, from about 20 mg to about 150 mg per day or about 40 mg to about 120 mg.
  • suitable daily doses are about 20 mg, 30 mg, about 30 mg, about 40 mg, 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, or about 140 mg or about 150 mg per day.
  • the suitable dose may be given once daily or may be divided such that the compound is given twice or three times daily.
  • the daily dose of the SYK inhibitor is about 20 mg. In certain embodiments, the daily dose of the SYK inhibitor is about 30 mg. In certain embodiments, the daily dose of the SYK inhibitor is about 40 mg. In certain embodiments, the daily dose of the SYK inhibitor is about 60 mg.
  • the daily dose of the SYK inhibitor is about 80 mg. In certain embodiments, the daily dose of the SYK inhibitor is about 100 mg. In certain embodiments, the daily dose of the SYK inhibitor is about 120 mg. In certain embodiments, the daily dose of the SYK inhibitor is about 150 mg. In certain embodiments, the SYK inhibitor is administered once daily. In certain embodiments, the SYK inhibitor is administered orally, once daily.
  • the immunotherapy agent is administered once every two weeks or once every three weeks. In certain embodiments, the immunotherapy agent is administered once every two weeks. In certain embodiments, the immunotherapy agent is administered once every three weeks. In certain embodiments, the immunotherapy agent is administered once every four weeks. In another embodiment, the immunotherapy agent is dosed according to a weight-based dosing, e.g., mg/kg. In another embodiment, the immunotherapy agent is administered as a fixed dose, e.g., mg per dose. Suitable doses of an immunotherapy agent can generally range from about 1 mg/kg to about 4 mg/kg or about 2 mg/kg to about 3 mg/kg. In certain embodiments a suitable dose of the immunotherapy agent is 2 mg/kg. In certain embodiments, a suitable dose of the
  • immunotherapy agent is 3 mg/kg. In certain embodiments, a suitable dose of the immunotherapy agent is from about 200 mg to about 300 mg. In certain embodiments, a suitable dose of the immunotherapy agent is 240 mg. In certain embodiments, the immunotherapy agent is nivolumab administered at a dose of 3 mg/kg every 2 weeks, such as on days 1 and 15 of a 28 day cycle. In certain embodiments, the immunotherapy agent is nivolumab administered at a dose of 240 mg every two weeks, such as on day 1 and 15 of a 28-day cycle. In certain embodiments, nivolumab is administered once every two weeks at about 240 mg dose.
  • nivolumab is administered once every two weeks on day 1 and 15 of a 28-day cycle at about 240 mg dose.
  • the immunotherapy agent is pembrolizumab administered at a dose of 2 mg/kg every 3 weeks, such as on days 1 and 22 of a 28 day cycle.
  • the tumor necrosis factor is administered once every two weeks on day 1 and 15 of a 28-day cycle at about 240 mg dose.
  • the immunotherapy agent is pembrolizumab administered at a dose of 2 mg/kg every 3 weeks, such as on days 1 and 22 of a 28 day cycle.
  • the immunotherapy agent is pembrolizumab administered at a dose of 2 mg/kg every 3 weeks, such as on days 1 and 22 of a 28 day cycle.
  • immunotherapy agent is administered intravenously. In certain embodiments, the immunotherapy agent is administered according to local guidelines. In certain embodiments, the immunotherapy agent is administered according to the product insert or the summary of product characteristic for the immunotherapy agent. In certain embodiments, nivolumab is administered according to its U.S. product insert or summary of product characteristics. See, e.g., OPDIVO (nivolumab) [prescribing information], Princeton, NJ: Bristol-Myers Squibb, 2016, available at
  • the therapeutically effective amount of the subject combination of compounds may vary depending upon the intended application ⁇ in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like.
  • the term also applies to a dose that will induce a particular response in target cells, e.g., reduction of proliferation or downregulation of activity of a target protein.
  • the specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.
  • the amounts or suitable doses of the methods of this disclosure depends upon a number of factors, including the nature of the severity of the condition to be treated, the particular inhibitor, the route of administration and the age, weight, general health, and response of the individual subject.
  • the suitable dose level is one that achieves a therapeutic response as measured by tumor regression, or other standard measures of disease progression, progression free survival or overall survival.
  • the suitable dose level is one that achieves this therapeutic response and also minimizes any side effects associated with the administration of the therapeutic agent.
  • the suitable dose levels may be ones that prolong the therapeutic response and/or prolong life.
  • a suitable dose of the immunotherapy agent and the SYK inhibitor may be taken at any time of the day or night.
  • a suitable dose of each therapeutic agent is taken in the morning.
  • a suitable dose of each therapeutic agent is taken in the evening.
  • a suitable dose of each of the therapeutic agents is taken both in the morning and the evening.
  • a suitable dose of each inhibitor may be taken with or without food.
  • a suitable dose of a therapeutic agent is taken with a meal.
  • a suitable dose of a therapeutic agent is taken while fasting.
  • the SYK inhibitor and the immunotherapy agent are both N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoe-N-(N-N-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoe
  • the immunotherapy agent inhibitor is administered as a solid dosage form. In certain embodiments, the immunotherapy agent is administered as a liquid dosage form. In certain embodiments, the SYK inhibitor is administered as a solid dosage form. In certain embodiments, the SYK inhibitor is administered as a liquid dosage form.
  • solid dosage forms for oral administration are capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as, for example, glycerol, (d) disintegrating agents such as, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as, for example
  • solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also optionally be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • solid dosage forms may be embedding compositions that may comprise polymeric substances and waxes.
  • liquid dosage forms for oral administration are pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, cyclodextrins, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents,
  • kits comprise an immunotherapy agent and an SYK inhibitor as described herein.
  • the kits comprise an immunotherapy agent and an SYK inhibitor as described herein, in suitable packaging, and written materials that can comprise instructions for use, discussion of clinical studies, listing of side effects, and the like.
  • such kits may also comprise information, such as, for example, scientific literature references, package insert materials, clinical trial results, and/or summaries of these and the like, which indicate or establish the activities and/or advantages of the composition, and/or which describe dosing, administration, side effects, drug interactions, or other information useful to the health care provider.
  • kits may further comprise another agent.
  • the SYK inhibitor of the present disclosure and the immunotherapy agent are provided as separate compositions in separate containers within the kit.
  • the SYK inhibitor of the present disclosure and the immunotherapy agent are provided as a single composition within a container in the kit.
  • Suitable packaging and additional articles for use e.g., measuring cup for liquid preparations, foil wrapping to minimize exposure to air, and the like are known in the art and may be included in the kit. Kits described herein can be provided, marketed and/or promoted to health providers, including physicians, nurses, pharmacists, formulary officials, and the like. Kits may also, in some embodiments, be marketed directly to the consumer.
  • the present invention also provides methods for further combination therapies in which, in addition to an immunotherapy agent and an SYK inhibitor, one or more agents known to modulate other pathways, or the same pathway, may be used.
  • such therapy includes but is not limited to the combination of the composition comprising at least one immunotherapy agent and at least one SYK inhibitor, as described herein, with one or more additional therapeutic agents such as anticancer agents, chemotherapeutic agents, therapeutic antibodies, and radiation treatment, to provide, where desired, a synergistic or additive therapeutic effect.
  • pathways that may be targeted by administering another agent include, but are not limited to, spleen tyrosine kinase (SYK), MAP kinase, Raf kinases, Akt, NFkB, WNT, RAS/ RAF/MEK/ERK, JNK/SAPK, p38 MAPK, Src Family Kinases, JAK/STAT and/or PKC signaling pathways.
  • SYK spleen tyrosine kinase
  • MAP kinase Raf kinases
  • Akt Akt
  • NFkB NFkB
  • WNT WNT
  • RAS/ RAF/MEK/ERK JNK/SAPK
  • p38 MAPK Src Family Kinases
  • JAK/STAT PKC signaling pathways.
  • other agents may target one or more members of one or more signaling pathways.
  • NFkB nuclear factor-kappaB
  • Representative members of the nuclear factor-kappaB (NFkB) pathway include but are not limited to RelA (p65), RelB, c-Rel, p50/pl05 (NF- ⁇ 1), p52/p 100 (NF-KB2), IkB, and IkB kinase.
  • RelA p65
  • RelB c-Rel
  • p50/pl05 NF- ⁇ 1
  • p52/p 100 NF-KB2
  • IkB nuclear factor-kappaB
  • IkB IkB
  • IkB kinase IkB kinase
  • PI3K phosphatidylinositol 3 -kinase
  • agents include FLT3 LIGAND, EGFR, IGF-IR, HER2/neu, VEGFR, and PDGFR.
  • Downstream members of the PI3K/AKT pathway that may be targeted by agents according to the methods of the invention include, but are not limited to, forkhead box O transcription factors, Bad, GSK-3P, ⁇ - ⁇ , mTOR, MDM-2, and S6 ribosomal subunit.
  • Example 1 In vivo CT26 mouse syngeneic colon cancer model.
  • mice Balb/c mice from JAX (approximately 20 grams body weight, female) were used. They were group-housed and provided food and water ad libitum prior to the experiment. Mice were maintained on a 12-hour light and dark cycle and maintained in the vivarium for at least 7 days after receipt prior to investigations.
  • Drugs used in this study Compound A (10, 30, and 60 mg/kg, formulated in 0.5% Methocel at 1, 3, and 6 mg/mL, dosed at 10 mL/kg, oral administration (PO)).
  • Anti-PD-1 monoclonal antibody (Anti-PD-1) BioXcell, RMP1-14, formulated in 0.9% saline at 2 mg/ml, dosed at 5 mL/kg, intraperitoneal administration (IP) for final dose of 10 mg/kg.
  • CT26 cells (ATCC CRL-2638) were cultured in RPMI-1640 containing 10% FBS and pen/strep. Media was changed every 2-3 days and cells were split at -80% confluence. A maximum of 20 passages were allowed prior to re-initiating the culture from the original cell stock.
  • CT26 syngeneic model Day -2 prior to tumor injection, the fur of each animal was shaved from the rump up to the middle of the back and extends to the flank on each side. At day 0, CT26 cells were suspended in cold RPMI1640 media and Matrigel (1 : 1) to final cell concentration of 2xl0 6 /ml and injected O. lmL (0.2 x 10 6 cells/mouse) subcutaneously in the flank. At Day 7 after inoculation, animals were sorted and randomized into 8 groups and treatment was initiated as illustrated in Table 1. Tumor size was measured by caliper (width x length) and body weights were recorded twice a week until day 21.
  • Results are expressed as mean ⁇ standard error of the mean (SEM). A probability level of p ⁇ 0.05 was considered statistically significant. Results are shown in Figure 1 and Table 2 below. Briefly, Compound A monotherapy demonstrated TGI of 13, 17.3, and 38.3% at 10, 30, and 60 mg/kg, respectively and Compound A combination therapy demonstrated TGI of 3.6, 58.5, 70.1% at 10, 30, and 60 mg/kg, respectively. Compound A showed a protective effect on body weight loss at 60 mg/kg monotherapy and at doses of 30 and 60 mg/kg in combination therapy. Compound A at 60 mg/kg monotherapy produced survival of 30% at Day 35 and Compound A in combination therapy produced survival of 60 and 80% at Day 35 for 30 and 60 mg/kg, respectively. Table 2.
  • FIG. 3 and Figure 4 show that Compound A, either alone or in combination with anti PD-1 antibody resulted in decrease in percentage of B-cells (B220 +cells) and myeloid-derived suppressor cells (MDSCs) (CD1 lb+ cells). This suggests that Compound A impacts B-cells and MDSCs in the tumor milieu.
  • Example 2 In vivo 4T1 mouse syngeneic breast cancer model.
  • the objective of the study was to evaluate the antitumor activity of Compound A alone or Compound A in combination with the mouse Anti-PD-1 antibody in a syngeneic mouse model of 4T1 breast cancer.
  • Compound A at 60 mg/kg was administered daily (QD) PO for 21 consecutive days.
  • Anti- PD-1 at 10 mg/kg was administered every 4 days (Q4D) IP for 3 doses in total.
  • Compound A at 60 mg/kg combined with Anti-PD-1 at 10 mg/kg was administered following the same dosing regimen as the single agents. Administration route, schedule, and duration for this study are summarized in Table 3.
  • Tumor growth and body weight were measured twice per week. Tumor growth inhibition and body weight change were calculated on Day 19 of treatment.
  • AAUCs tumor volume versus time curves
  • Example 3 Clinical solid tumor study design— a study of Compound A in combination with nivolumab in subjects with advanced solid tumors.
  • MDSCs myeloid-derived suppressor cells
  • Fms-like tyrosine kinase 3 (FLT3) and its ligand have been shown to induce MDSCs in vitro.
  • Fms-like tyrosine kinase 3 (FLT3) and its ligand have been shown to induce MDSCs in vitro.
  • Fms-like tyrosine kinase 3 (FLT3) and its ligand have been shown to induce MDSCs in vitro.
  • Fms-like tyrosine kinase 3 (FLT3) and its ligand have been shown to induce MDSCs in vitro.
  • LCHNER et al. J. Transl. Med. 9:90 (2011).
  • MDSC-mediated immune suppression has been reported in many solid tumors, including, but not limited to breast cancer, head and neck, and NSCLC. COTECHINI et al., Cancer. J., 21(4): 343- 50 (2015).
  • SYK inhibition results in the loss of MDSCs and activation of T-cell response, both in vitro and in vivo. See, e.g., LUGER et al., PLoS One, 8(10):e76115 (2013).
  • LUGER et al. PLoS One, 8(10):e76115 (2013).
  • synergistic activity may be observed when a PD-1 receptor inhibitor that promotes T-cell function is administered in combination with a SYK inhibitor.
  • a SYK inhibitor such as Compound A
  • an anti-PD-1 agent may improve tumor regression via modulation of the tumor-infiltrating immune cells and other immune cells in the tumor microenvironment.
  • the make-up of the tumor microenvironment which differs among different tumor types, informs the choice of diseases to be evaluated in this study.
  • Tumors in which there is MDSC or B-cell suppression are of particular interest: nonclinical assessment suggests that tumors such as T BC, NSCLC, and HNSCC show MDSC-mediated tumor immunosuppression.
  • the study intends to clinically evaluate the combination effect of Compound A and nivolumab in 3 advanced solid tumor types (TNBC, NSCLC, and HNSCC).
  • TNBC 3 advanced solid tumor types
  • NSCLC 3 advanced solid tumor types
  • HNSCC 3 advanced solid tumor types
  • ORR overall response rate
  • DOR duration of response
  • a 2-week, single-agent Compound A treatment period before combination therapy is planned in 10 response-evaluable subjects in each of the expansion cohorts.
  • Correlative science studies are planned in pretreatment and post-treatment tumor biopsies and peripheral blood samples taken from these subjects with the intent of having more mechanistic understanding of the role of SYK in the tumor immunity and direct tumor effect, if any.
  • the purpose of this study is to evaluate the maximum tolerated dose (MTD) or recommended Part 2 dose (RP2D), safety and efficacy of Compound A in combination with nivolumab in subjects with advanced solid tumors.
  • MTD maximum tolerated dose
  • R2D recommended Part 2 dose
  • the drug being tested is Compound A.
  • This study will look at the determination of MTD/ RP2D and efficacy measured by overall response rate (ORR) in subjects who take Compound A in combination with nivolumab.
  • ORR overall response rate
  • the study will include a dose escalation phase (Part 1) and a dose expansion phase (Part 2).
  • the study will include a dose escalation phase (Part 1) and a dose expansion phase (Part 2).
  • Part 1 the subject population will consist of all-comer subjects with advanced solid tumors for whom 1 or more prior lines of therapy have failed and who have no effective therapeutic options available based on investigator assessment.
  • the dose expansion phase will include 3 cohorts: (1) subjects with metastatic triple-negative breast cancer (T BC) who have had >1 prior line of chemotherapy; (2) subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) that has progressed on or after a prior platinum-based chemotherapy; and (3) subjects with locally advanced or metastatic head and neck squamous cell carcinoma (HNSCC) that has progressed or recurred within 6 months of the last platinum-based chemotherapy.
  • T BC metastatic triple-negative breast cancer
  • NSCLC locally advanced or metastatic non-small cell lung cancer
  • HNSCC head and neck squamous cell carcinoma
  • subjects will be administered Compound A orally once daily during each 28-day treatment cycle.
  • Subjects receiving the combination therapy will also receive nivolumab once every 2 weeks intravenously (IV) over 60 minutes on Day 1 and Day 15 of each 28- day treatment cycle (for subjects who receive 2 weeks of Compound A monotherapy before starting combination treatment, the first nivolumab infusion will be administered on Cycle 1 Day 15).
  • the Compound A dose will be administered first followed by the nivolumab infusion (infusion to begin within 30 minutes after the Compound A dose).
  • Subjects, including those who achieve a complete response may receive study treatment until they experience disease progression (PD) or unacceptable toxicities.
  • PD disease progression
  • nivolumab The dose of nivolumab will be 3 mg/kg IV.
  • the starting dose of Compound A will be 60 mg QD.
  • Dose escalation will follow a standard 3+3 escalation scheme, and dosing will increase to 100 mg QD, provided that the safety and tolerability of the 60 mg dose has been demonstrated.
  • Dose escalation will continue until the maximum tolerated dose (MTD) is reached, or until 100 mg QD of Compound A (the maximally administered dose, (MAD)) is determined to be safe and tolerable, or until a recommended phase 2 dose (RP2D), if different from the MTD or MAD, has been identified on the basis of the safety, tolerability, and preliminary pharmacokinetic (PK) and efficacy data (if available) observed in Cycle 1 and beyond. At least 6 subjects will be evaluated at the RP2D (the MTD, MAD, or a lower dose as determined) before making a decision to advance to further dose expansion.
  • MTD maximum tolerated dose
  • MAD maximally administered dose
  • expansion cohorts are planned in subjects with TNBC, NSCLC, and HNSCC. Thirty response-evaluable subjects will be enrolled in each expansion cohort, including approximately 10 subjects in each cohort who are able to provide evaluable serial biopsies. Additionally, each expansion cohort will include 24 response-evaluable subjects who are naive to anti- PD-l/anti-PD-Ll therapy and 6 response-evaluable subjects who are relapsed/refractory to prior anti-PD-l/anti-PD-Ll therapy.
  • Ten response-evaluable subjects in each expansion cohort will first receive single-agent treatment with Compound A for 2 weeks at the RP2D previously determined in combination with nivolumab. Following the 2-week, single-agent treatment, Compound A treatment will continue (at the same dose) in combination with nivolumab during Week 3 and beyond.
  • the subset of expansion subjects who will be treated with single-agent Compound A at its combination RP2D during Weeks 1 and 2 should have accessible tumors for core or excisional biopsy and provide permission for the biopsies to be taken. These subjects will undergo mandatory biopsies before single-agent Compound A treatment begins, at the end of the 2-week treatment window, and after 6 weeks of treatment with Compound A in combination with nivolumab; an optional biopsy will also be taken at the time of PD.
  • the biopsies will be used for biomarker analysis evaluating the effect of Compound A on tumor cells and on immune/stromal cells supporting tumor tissue.
  • Dose escalation Subjects aged 18 years or older with advanced solid tumors for whom 1 or more prior lines of therapy have failed and who have no effective therapeutic options available based on investigator assessment.
  • Dose expansion Subjects aged 18 years or older with: (1) metastatic T BC with >1 prior line of chemotherapy; (2) locally advanced or metastatic NSCLC that has progressed on or after a prior platinum-based chemotherapy; or (3) locally advanced or metastatic HNSCC that has progressed or recurred within 6 months of the last platinum-based chemotherapy.
  • Compound A oral daily dosing with 3+3 dose escalation planned at 60 and 100 mg.
  • the RP2D determined in combination with nivolumab during dose escalation will be used for dose expansion cohorts.
  • Nivolumab 3 mg/kg IV dosing over 60 minutes every 2 weeks (Day 1 and Day 15 of each 28-day cycle). For subjects participating in the 2-week monotherapy run-in with
  • Compound A the first dose will be on Cycle 1 Day 15.
  • Treatment will continue until disease progression (PD), unacceptable toxicities, or withdrawal due to other reasons.
  • the estimated treatment duration is 12 months.
  • Part 1 Compound A + Nivolumab Compound A 60 mg, tablets, orally, once daily in each 28-day treatment cycles in combination with nivolumab 3 milligram per kilogram (mg/kg), infusion, intravenously over 60 minutes, on Days 1 and 15 in each 28 days treatment cycles until PD or unacceptable toxicity.
  • nivolumab 3 milligram per kilogram (mg/kg) milligram per kilogram (mg/kg)
  • infusion intravenously over 60 minutes, on Days 1 and 15 in each 28 days treatment cycles until PD or unacceptable toxicity.
  • the first nivolumab infusion will be administered on Cycle 1 Day 15.
  • Dose escalation of Compound A to 100 mg may be done using a 3 + 3 dose escalation design to determine a maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D).
  • MTD maximum tolerated dose
  • R2D recommended Phase 2 dose
  • Part 2 Metastatic TNBC Subjects with metastatic triple-negative breast cancer (TNBC) will receive Compound A at RP2D as determined in Part 1, tablets, orally, once daily in each 28-day treatment cycles in combination with nivolumab 3 mg/kg, infusion over 60 minutes, intravenously, once only on Day 15 of Cycle 1 (following first 2 week monotherapy of Compound A) and thereafter Days 1 and 15 in each 28 days treatment cycles until progressive disease or unacceptable toxicity.
  • TNBC metastatic triple-negative breast cancer
  • Part 2 Metastatic NSCLC Subjects with metastatic NSCLC will receive Compound A at RP2D as determined in Part 1, tablets, orally, once daily in each 28-day treatment cycles in combination with nivolumab 3 mg/kg, infusion over 60 minutes, intravenously, once only on Day 15 of Cycle 1 (following first 2 week monotherapy of Compound A) and thereafter Days 1 and 15 in each 28 days treatment cycles until progressive disease or unacceptable toxicity.
  • Part 2 Metastatic HNSCC Subjects with metastatic HNSCC will receive Compound A at RP2D as determined in Part 1, tablets, orally, once daily in each 28-day treatment cycles in combination with nivolumab 3 mg/kg, infusion over 60 minutes, intravenously, once only on Day 15 of Cycle 1 (following first 2 week monotherapy of Compound A and thereafter Days 1 and 15 in each 28 days treatment cycles until progressive disease or unacceptable toxicity.
  • Suitable venous access for the study-required blood sampling including PK and pharmacodynamic sampling.
  • Mandatory biopsies will be taken before Compound A monotherapy, after the 2 weeks of Compound A monotherapy, and after 6 weeks of Compound A plus nivolumab combination therapy.
  • An optional biopsy may be taken at PD with additional consent from the subject, (d) One, two, or three line(s) of chemotherapy for metastatic disease and with progression of disease on last treatment regimen.
  • neoadjuvant and/or adjuvant chemotherapy regimens do not count as a prior line of therapy.
  • Prior treatment must include an anthracycline and/or a taxane in the neoadjuvant, adjuvant, or metastatic setting with the exception for subjects who are clinically contraindicated for these chemotherapies.
  • subjects must have: (a) Locally advanced or metastatic (stage IIIB, stage IV, or recurrent) NSCLC with measurable lesions per RECIST verion 1.1. (b) PD during or following at least 1 prior treatment.
  • Subjects should have received a prior platinum-containing, 2-drug regimen for locally advanced, unresectable/inoperable or metastatic NSCLC had or disease recurrence within 6 months of treatment with a platinum-based adjuvant/neoadjuvant regimen or combined modality (e.g., chemoradiation) regimen with curative intent, (c) Subjects with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic alternations should have PD on prior therapy for these aberrations, (d) Safely accessible tumor lesions (based on investigator's assessment) for serial pretreatment and
  • EGFR epidermal growth factor receptor
  • ALK anaplastic lymphoma kinase
  • posttreatment biopsies are required for subjects receiving Compound A monotherapy run-in treatment for 2 weeks followed by Compound A plus nivolumab combination treatment
  • any T-cell co-stimulation agents or inhibitors of checkpoint pathways such as anti- programmed cell death protein 1 (PD-1), anti- programmed cell death 1 ligand 1 (PD-L1), anti- programmed cell death 1 ligand 2 (PD-L2), anti- CD137, or anti-CTLA-4 antibody; or other agents specifically targeting T cells are prohibited.
  • PD-1 programmed cell death protein 1
  • PD-L1 anti- programmed cell death 1 ligand 1
  • PD-L2 anti- programmed cell death 1 ligand 2
  • anti-CTLA-4 antibody anti-CTLA-4 antibody
  • HIV human immunodeficiency virus
  • any clinically significant co-morbidities such as uncontrolled pulmonary disease, known impaired cardiac function or clinically significant cardiac disease (specified below), active central nervous system disease, active infection, or any other condition that could compromise the subject's participation in the study.
  • Subjects with any of the following cardiovascular conditions are excluded: (a) Acute myocardial infarction within 6 months before starting study drug, (b) Current or history of New York Heart Association Class III or IV heart failure, (c) Evidence of current uncontrolled cardiovascular conditions including cardiac arrhythmias, angina, pulmonary
  • the MTD/MAD will be estimated by a standard 3+3 method using data collected in the dose escalation phase. AEs will be summarized by treatment group and overall. Categorical variables such as ORR, disease control rate, and rate of PD at 6 months will be tabulated by treatment group and overall. Time to event variables such as DOR, PFS, and OS will be analyzed using Kaplan-Meier survival curves, and Kaplan-Meier medians (if estimable) will be provided. PK parameters will be summarized as appropriate.
  • Sample size justification During the dose escalation phase, dose escalation will be conducted according to a standard 3+3 dose escalation schema, and approximately 9 to 12 dose- limiting toxicity-evaluable subjects will be enrolled.
  • the MTD/RP2D cohort will have at least 6 subjects.
  • Each cohort uses a null hypothesis of response rate ⁇ 20%, versus an alternative hypothesis of response rate >40% for subjects who are naive to anti-PD/PD-Ll and any other immune-directed antitumor therapies. Therefore,
  • response-evaluable subjects for each cohort will be needed.
  • 6 response-evaluable subjects with prior exposure to a PD-1 or PD-L1 inhibitor will be enrolled in each expansion cohort.
  • 30 response-evaluable subjects for each cohort and 90 response- evaluable subjects in total will be needed for all expansion cohorts.
  • Part 1, RP2D (baseline up to 6 months): the RP2D of Compound A will be determined in Part 1 (dose escalation) on the basis of the safety, tolerability, preliminary pharmacokinetics (PK), and efficacy data observed in Cycle 1 and beyond.
  • ORR is defined as the percentage of subjects with complete response (CR), or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
  • CR is defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis ⁇ 10 mm). No new lesions.
  • TEAEs treatment-emergent adverse events
  • DOR Duration of Response
  • Subjects without documentation of PD at the time of analysis will be censored at the date of their last response assessment that is SD or better.
  • PD percentage of subjects with progression of disease (PD) at Month 6.
  • PFS progression free survival
  • serum/urine M-component difference between involved, uninvolved FLC levels; bone marrow plasma cell percent; development of new bone lesions or soft tissue plasmacytomas development or increase in the size of existing bone lesions or soft tissue plasmacytomas; hypercalcaemia development.
  • Part 2 overall survival (OS) (baseline up to 6 months after the last dose of study treatment (approximately 18 months)). Overall survival is defined as the time from study entry to the time of death.
  • OS overall survival
  • Part 1 maximum observed plasma concentration (Cmax) for Compound A (Cycle 1 : Days 1 and 15: predose and at multiple time points (up to 8 hours)). [0194] (13) Part 1 : time to reach the Cmax (Tmax) for Compound A (Cycle 1 : Days 1 and 15:
  • Part 1 area under the plasma concentration-time curve from time 0 to time tau (AUC tau)(Cycle 1 : Days 1 and 15: predose and at multiple time points (up to 8 hours)).
  • Example 4 In vivo CT26 mouse syngeneic colon cancer model - re-challenge.
  • mice were all previously treated with Compound A (60 mpk) plus anti-PDl monoclonal antibody (Anti-PD-1) - in that previous study, female Balb/C mice (J AX) were inoculated with 0.2 x 10e6 cells in left hind flank 7 days prior to randomization and treatment start.
  • Compound (A) was administered orally (PO) on a once daily (QD) schedule for 14 days, while anti- PD-1 was administered at 10 mg/kg intraperitoneally (IP) for a total of 5 doses on days 0, 2, 6, 8, 11.
  • IP intraperitoneally
  • CT26 colon carcinoma cell line is commonly used for syngeneic tumor model growth in the Balb/c mouse.
  • CT26 colon carcinoma cells originate from Mus musculus, and subcutaneous inoculations develop to lethal tumors.
  • mice Balb/c mice from JAX (approximately 20 grams body weight) wereused. They were group-housed and provided food and water ad libitum prior to the experiment. Mice were maintained on a 12-hour light and dark cycle and maintained in the vivarium for at least 7 days after receipt prior to investigations.
  • Animal preparation Day -2 prior to tumor injection, the animals fur was shaved from the rump up to the middle of back and extended to the flank of each side. Caution was taken not to abrade the skin with the razor.
  • Tumor Injection Day 0: the following procedure was followed: (a) aspirate media, wash cells with cold PBS, trypsinize to release, wash with PBS and collect cells; (b) spin, aspirate and resuspend in PBS, strain, spin again; (c) aspirate and resuspend in plain RPMI; (d) adjust cell concentration to 4xl0e6/ml. Cells were kept cold. Matrigel stock was prepared. Cell stock and matrigel were mixed (1 : 1) to final cell concentration of 2xl0e6/ml. The injection of 0.1 ml resulted in 0.2xl0e6 cells/mouse. Animals were restrained and inoculated with 0.1ml of the cells plus matrigel subcutaneously in the flank. Bevel of needle was pointed up and rotated upon exit.
  • Tumor Growth Day 7-21: Day 7 after inoculation, animals were sorted and randomized. Animals with abnormally small, large, or misshapen tumors were excluded prior to randomization. Prior to following randomization, animals were implanted subcutaneously with a micro tracker chip readable by the TMS system for identification. Tumors were measured by caliper (width x length) and body weight was recorded.
  • Endpoints tumor volume; body weight; FACS - Day 7, 14, 20: pentamer staining of blood, spleen, and bone marrow to try and identify CT26 specific T-cells.
  • Figure 6 exemplifies tumor volumes of re-challenged animals in CT-26 mouse syngeneic colon cancer model.
  • Figure 7 exemplifies % mice with tumors for re-challenged animals in CT-26 mouse syngeneic colon cancer model.
  • Example 5 In vivo CT26 mouse syngeneic colon cancer model - immunosuppressive immune cells.
  • Compound A is a dual inhibitor of Spleen Tyrosine Kinase (SYK) and FLT3 that is being evaluated as a treatment for hematological malignancies in multiple clinical trials.
  • SYK is a nonreceptor cytoplasmic tyrosine kinase that is a common member of various signal transduction cascades in cells of the hematopoietic lineage including those involved in B-cell receptor (BCR) activation.
  • BCR B-cell receptor
  • Compound A + anti-PD-1 treatment significantly affected the immunosuppressive immune cells in the CT-26 model.
  • Spleens and tumors were removed and dissociated into single cell suspensions using the gentle MACS dissociator (Miltenyl Biotec). Spleens were processed in autoMACS buffer with 0.5% BSA and tumors in RPMI 1640 media with enzymes A, D and R provided in the MACS tumor dissociation kit. After red blood cell removal (eBioscience lysis buffer), cells were washed and suspended at 20xl0e6 viable cells/ml. Single cell suspension was distributed into 96 well U bottom plate in PBS for viability staining (Zombie Aqua, Biolegend).
  • Example 6 In vivo subcutaneous B16BL16 murine melanoma model.
  • C57BL6 mice bearing syngeneic B16BL6 melanoma tumors were treated with Compound A 60 mg/kg QD PO for 7 days, and tumors were then collected and processed for flow cytometry.
  • the percentage of MDSCs in the tumor infiltrating lymphocytes decreased following treatment with Compound A.
  • mice Each mouse (Mus musculus, female C57BL/6 mice; average weight 18.1 g at inoculation and 19.3 g at dosing initiation; 7-8 weeks age at inoculation; acclimation period 6 days) was inoculated subcutaneously at the right lower flank with B16BL6 tumor cells (2 x 10e5) in 0.1 ml of PBS for tumor development. Tumor growth was monitored with vernier calipers and the mean tumor volume (MTV) was calculated using the formula (0.5 x [length x width 2 ]). When the MTV reached 100 mm 3 , animals were randomized into treatment groups and dosed according to study design; dosing was initiated on Day 0 of the study. Mice were dosed PO with Compound A.
  • Study objective To evaluate changes in immune cell population in tumors obtained at necropsy. Treatment was performed according to the schedule shown in Table 5. Cells were isolated from tumors. K and MDSC cells were analyzed by FACS using specific antibodies. Antibody information and panel setting are described in Tables 6 and 7, respectively. Table 5.
  • Example 7 In vivo HCC70 triple negative breast cancer xenograph model.
  • RNAscope ISH of CDl lb (Green) and CD79a (Red) carried out by ACD. Images: Scanscope XT. Analysis: Definiens Tissue Studio; first analyzed as marker area/number of nuclei as in dual IHC; second analyzed CDl lb only (real Area spot/number of nuclei) as in ISH. Data plots: Spotfire.
  • FIG. 13 illustrates an effect of Compound A on MDSC (CD1 lb+) in HCC70 xenograph model.
  • Example 8 In vivo subcutaneous MH-22A murine liver cancer model in C3H/HeN mice.
  • the objective of the study is to evaluate the in vivo anti -tumor efficacy of Compound A in the treatment of the subcutaneous MH-22A murine liver cancer model in C3H/HeN mice as a single agent or in combination with anti-PD-1 therapy.
  • Test article - Compound A it was formulated in 0.5% methyl cellulose (MC).
  • Test Article - WX-mPD-1 (WuXi AppTech, Ltd., Shanghai China): it was formulated in WX-mPDl buffer.
  • Vehicle control article - methyl cellulose (Aladdin Biochemical Technology, Shanghai, China): it was formulated as 0.5% in water solution.
  • Test system - cell line MH-22A (ECACC (96121721), Salisbury, England, UK); passage # (user stock) - P7; passage # (inoculated) - PI 1.
  • Preparation media DMEM + 2mM Glutamine + 10%) FBS.
  • Adherent or suspension adherent.
  • Initial viable cell cone. (cells/mL) in millions: 23. Volume of initial viable cell cone, used (mL): 22.
  • Final cone. (cells/mL) in millions: 25.
  • Matrigel No. Volume of Final Cell Cone. (mL): 20.24. Cell number injected (millions): 5. Volume injected (mL): 0.2.
  • Implant route subcutaneous. Implant site: right flank.
  • Test system - animal species -mouse. Strain: C3H/HeN. Source: Vital River. Beijing, China. Number of animals per group: 10. Total number of study animals: 40. Age: approximately 9 weeks at start of dosing. Sex: female. Weight: 21.6 grams at start of dosing. Acclimation period: at least 3 days.
  • AAUC change in the area under the tumor volume-time curve
  • BIW twice weekly
  • BWL body weight loss
  • MC methyl cellulose
  • PO per oral
  • QD once daily
  • TGI tumor growth inhibition.
  • MTV mean tumor volume
  • the Compound A single agent group had 2/10 animals with no tumor, the anti-PD-1 group had no complete or partial responders, while the combination treatment led to CRs in 6 animals (6/10) and SDs (a stable disease (SD) was defined as a decrease or a less than 25% increase in tumor mass from that at first treatment) in 2 animals (2/10).
  • SDs stable disease (SD) was defined as a decrease or a less than 25% increase in tumor mass from that at first treatment) in 2 animals (2/10).
  • the other 2 animals (2/10) in the combination group were sacrificed due to the development of re-challenged tumor, but still with the primary tumors
  • Table 11 shows study design and certain findings for the study.
  • AAUC change in the area under the tumor volume-time curve
  • BIW twice weekly
  • BWL body weight loss
  • MC methyl cellulose
  • PO per oral
  • QD once daily
  • TGI tumor growth inhibition.
  • Antitumor activity was determined by statistical comparisons of tumor growth between treatment groups and vehicle, conducted using a linear mixed effects regression analysis on the AAUC.
  • antitumor efficacy was evaluated by TGD, which was calculated as the difference in the median time (Days) between the treated and the vehicle control group to attain the evaluation size of 1000 mm 3 .
  • the accumulative numbers of animal loss in each group at different time-points were: (1) Vehicle: 3/10 at day 7, 7/10 at day 9, 8/10 at day 11, 9/10 at day 14 and 10/10 at day 21; (2) Compound A single agent: 2/10 at day 14, 3/10 at day 21, 4/10 at day 29, 5/10 at day 39, 6/10 at day 53, 7/10 at day 64, 8/10 at day 73 till the termination of study; (3) WX-mPD-1 single agent: 1/10 at day 7, 2/10 at day 9, 4/10 at day 11, 7/10 at day 14, 9/10 at day 23 and 10/10 at day 73; (4) Compound A and WX-mPD-1 combination: 1/10 at day 70 and 2/10 at day 84 till the end.
  • FIG. 14- Figure 17 show the individual tumor growth of each animal in each treatment group for the duration of the study.
  • Figure 18 shows average tumor volume over time in female C3H/HeN mice bearing MH-22A syngeneic model dosed with vehicle, Compound A, anti-PD-1, or Compound-A plus anti-PD-1 combination.
  • Compound A as a single agent had 2/10 animals with no tumor at the end of study. In comparison, combination treatment resulted in durable anti-tumor activity, with 6/10 tumors having complete response on Day 51.
  • TGI 83.76%
  • Combination treatment (Compound A and WX-mPD-1) resulted in therapeutic advantage over single-agent therapy in the MH-22A model of murine liver cancer, with durable inhibition of tumor growth out to Day 94 of the study.
  • the combination treatment resulted in a tumor growth delay greater than 88 days, compared to 13.8 days in the Compound A single agent treatment, and 7.1 days in the anti-PD-1 treated group.
  • Compound A as a single agent had 2/10 animals with no tumor at the end of study.
  • the combination treatment resulted in durable anti-tumor activity, with 6/10 tumors having a complete response on Day 51.
  • the anti-PD-1 group had no complete or partial responders, while the combination treatment led to CRs in 6 animals (6/10) and SDs in 2 animals (2/10).
  • the other 2 animals (2/10) in the combination group were sacrificed due to the development of re-challenged tumor, but still with the primary tumors undetectable.
  • Example 9 In vivo MH-22A liver tumor syngeneic model in C3H/HeN mice - re-challenge.
  • the objective of the study is to evaluate the tumor re-challenge of MH-22A liver tumor syngeneic model in the complete responders of female C3H mice which were treated by Compound A and WX-mPD-1 combination, and survived from the previous study (see Example 8).
  • Test System - cell line Tumor cell line: MH-22A.
  • Source ECACC (96121721), Salisbury, England, UK.
  • Passage # (user stock): P5.
  • Passage # (inoculated): P8.
  • Preparation media DMEM + 2mM Glutamine + 10% FBS.
  • Adherent or suspension adherent.
  • Initial viable cell cone. (cells/mL) in millions: 8.76. Volume of initial viable cell cone, used (mL): 20.
  • Final cone. (cells/mL) in millions: 25.
  • Matrigel No. Volume of Final Cell Cone. (mL): 7.01. Cell number injected
  • Implant route subcutaneous. Implant site: left flank.
  • Test system - animal Species: Mouse. Strain: C3H.
  • Source Treated mice: Vital River, Beijing, China. Untreated mice: Sippr-BK, Shanghai, China. Number of animals per group: 6. Total number of study animals: 12.
  • Age treated mice - approximately 17 weeks at re-challenge; untreated mice - approximately 8 weeks at re-challenge.
  • Sex female.
  • Weight treated mice - 25.6 grams at re- challenge; untreated mice - 21.8 grams at re-challenge.
  • Acclimation period at least 3 days.
  • Endpoints untreated mice (6 animals) - % BWL (body weight loss); treated mice from prior study (6 animals) - CR (a complete response was defined as a decrease in tumor mass to an undetectable size ( ⁇ 50 mm 3 ) at the study termination at day 43, % BWL (mean maximum percent BWL).
  • Tumor volume and body weight measurements The mean maximum BWL was determined for each group using the mean body weight data from the measurement period (versus inoculation body weights), and the mean maximum percent body weight change was also calculated on the basis of inoculation body weights.
  • CR was defined as a decrease in tumor mass to an undetectable size ( ⁇ 50 mm 3 ).
  • mice with tumor volume exceeding 2,000 mm 3 were sacrificed, and no additional animal death occurred with other cause.
  • the accumulative numbers of animal loss in each group at different time-points were: (1) untreated mice - 4/6 at day 12, and 6/6 at day 14; (2) treated mice - 1/6 at day 19, and 2/6 at day 33 till the termination of study.
  • Figure 19 shows average tumor volume over time for the untreated female C3H mice or the tumor-free survivors from previous study (which were treated with Compound A and anti-PD-1 combination in the previous study) after re-challenge with MH-22A syngeneic model.
  • Figure 20 shows an individual tumor volume over time of tumor-free survivors from previous study (where mice were treated with Compound A and anti-PD-1 combination) after re-challenge with MH-22A syngeneic model.
  • Compound A as a single agent or in combination with anti-PD-1 antibody treatment reduced the population of immunosuppressive immune cells (e.g. T reg cells, MDSCs, M2 macrophages, and K cells) in multiple syngeneic or xenograft models.
  • immunosuppressive immune cells e.g. T reg cells, MDSCs, M2 macrophages, and K cells
  • Compound A administered daily, orally, in combination with anti-PD-1 therapy in the CT-26 model resulted in complete tumor regressions and the animals were tumor free for 90 days post-treatment. When these animals were rechallenged with CT-26 tumor cells, they failed to form tumors suggesting a memory T-cell effect was established from the initial treatment period. Similar combination efficacy was observed in the A20 and MH- 22A models.
  • Compound A treatment in combination with anti-PD-1 resulted in complete tumor growth suppression, prolonged tumor free survival and potential immune memory against tumor cells supporting the rationale for examining the addition of Compound A to anti-PD-1 therapy in the
  • Example 10 Clinical solid tumor study design— a study of Compound A in combination with nivolumab in subjects with advanced solid tumors.
  • MDSCs myeloid-derived suppressor cells
  • Fms-like tyrosine kinase 3 (FLT3) and its ligand have been shown to induce MDSCs in vitro. LECHNER et al., J. Transl. Med. 9:90 (2011).
  • MDSC-mediated immune suppression has been reported in many solid tumors, including, but not limited to breast cancer, head and neck, and NSCLC.
  • COTECHINI et al. Cancer. J., 21(4): 343- 50 (2015).
  • a role of B cells in tumor immunity has been studied, and the requirement of B cells for tumor growth and metastasis has been documented.
  • DILILLO et al. J. Immunol., 184(7):4006-4016 (2010).
  • SYK is known to be essential for development, growth, and maintenance of B cells.
  • SYK inhibition results in the loss of MDSCs and activation of T-cell response, both in vitro and in vivo. See, e.g., LUGER et al., PLoS One, 8(10):e76115 (2013).
  • LUGER et al. PLoS One, 8(10):e76115 (2013).
  • synergistic activity may be observed when a PD-1 receptor inhibitor that promotes T-cell function is administered in combination with a SYK inhibitor.
  • a SYK inhibitor such as Compound A
  • an anti-PD-1 agent may improve tumor regression via modulation of the tumor-infiltrating immune cells and other immune cells in the tumor microenvironment.
  • the make-up of the tumor microenvironment which differs among different tumor types, informs the choice of diseases to be evaluated in this study.
  • Tumors in which there is MDSC or B-cell suppression are of particular interest: nonclinical assessment suggests that tumors such as T BC, NSCLC, and HNSCC show MDSC-mediated tumor immunosuppression.
  • the study intends to clinically evaluate the combination effect of Compound A and nivolumab in 3 advanced solid tumor types (TNBC, NSCLC, and HNSCC).
  • TNBC 3 advanced solid tumor types
  • NSCLC 3 advanced solid tumor types
  • HNSCC 3 advanced solid tumor types
  • ORR overall response rate
  • DOR duration of response
  • a 2-week, single-agent Compound A treatment period before combination therapy is planned in 10 response-evaluable subjects in each of the expansion cohorts.
  • Correlative science studies are planned in pretreatment and post-treatment tumor biopsies and peripheral blood samples taken from these subjects with the intent of having more mechanistic understanding of the role of SYK in the tumor immunity and direct tumor effect, if any.
  • the purpose of this study is to evaluate the maximum tolerated dose (MTD) or recommended Part 2 dose (RP2D), safety and efficacy of Compound A in combination with nivolumab in subjects with advanced solid tumors.
  • MTD maximum tolerated dose
  • R2D recommended Part 2 dose
  • the drug being tested is Compound A.
  • This study will look at the determination of MTD/ RP2D and efficacy measured by overall response rate (ORR) in subjects who take Compound A in combination with nivolumab.
  • ORR overall response rate
  • the study will include a dose escalation phase (Part 1) and a dose expansion phase (Part 2).
  • the study will include a dose escalation phase (Part 1) and a dose expansion phase (Part 2).
  • Part 1 the subject population will consist of all-comer subjects with advanced solid tumors for whom 1 or more prior lines of therapy have failed and who have no effective therapeutic options available based on investigator assessment.
  • the dose expansion phase will include 3 cohorts: (1) subjects with metastatic triple-negative breast cancer (T BC) who have had >1 prior line of chemotherapy; (2) subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) that has progressed on or after a prior platinum-based chemotherapy; and (3) subjects with locally advanced or metastatic head and neck squamous cell carcinoma (HNSCC) that has progressed or recurred within 6 months of the last platinum-based chemotherapy.
  • T BC metastatic triple-negative breast cancer
  • NSCLC locally advanced or metastatic non-small cell lung cancer
  • HNSCC head and neck squamous cell carcinoma
  • subjects will be administered Compound A orally once daily during each 28-day treatment cycle.
  • Subjects receiving the combination therapy will also receive nivolumab once every 2 weeks intravenously (IV) over 60 minutes on Day 1 and Day 15 of each 28- day treatment cycle (for subjects who receive 2 weeks of Compound A monotherapy before starting combination treatment, the first nivolumab infusion will be administered on Cycle 1 Day 15).
  • the Compound A dose will be administered first followed by the nivolumab infusion (infusion to begin within 30 minutes after the Compound A dose).
  • Subjects, including those who achieve a complete response may receive study treatment until they experience disease progression (PD) or unacceptable toxicities.
  • PD disease progression
  • the starting dose of nivolumab will be 3 mg/kg IV.
  • the starting dose of Compound A will be 60 mg QD.
  • Dose escalation will follow a standard 3+3 escalation scheme, and dosing will increase to 100 mg QD, provided that the safety and tolerability of the 60 mg dose has been demonstrated.
  • Intermediate dose levels between 60 and 100 mg (e.g., 80 mg) or dose levels below the starting dose of 60 mg (e.g., 40 mg) may be also evaluated if appropriate.
  • Dose escalation will continue until the maximum tolerated dose (MTD) is reached, or until 100 mg QD of Compound A (the maximally administered dose, (MAD)) is determined to be safe and tolerable, or until a recommended phase 2 dose (RP2D), if different from the MTD or MAD, has been identified on the basis of the safety, tolerability, and preliminary pharmacokinetic (PK) and efficacy data (if available) observed in Cycle 1 and beyond. At least 6 subjects will be evaluated at the RP2D (the MTD, MAD, or a lower dose as determined) before making a decision to advance to further dose expansion.
  • MTD maximum tolerated dose
  • MAD maximally administered dose
  • this RP2D of Compound A may be evaluated in combination with a fixed dose of 240 mg IV nivolumab following discussion between the investigator and sponsor.
  • the fixed dose is expected to have equivalent exposure, safety and efficacy as the weight-based (3 mg/kg) dose. If the nivolumab fixed dose is evaluated, 3 subjects will be initially enrolled into the cohort.
  • nivolumab may be switched from the 3 mg/kg weight-based dose to a fixed dose of 240 mg for all subjects ongoing in the study at the time of the switch and those to be enrolled after the switch. This decision will be made on the basis of an assessment of the change in clinical practice in different regions and upon discussion and agreement between the investigators and sponsor.
  • the dose of nivolumab for all subjects in the dose expansion phase will be 3 mg/kg, unless the direct conversion to a fixed dose of nivolumab is justified by other available data.
  • expansion cohorts are planned in subjects with T BC, NSCLC, and HNSCC. Thirty response-evaluable subjects will be enrolled in each expansion cohort, including approximately 10 subjects in each cohort who are able to provide evaluable serial biopsies. Additionally, each expansion cohort will include 24 response-evaluable subjects who are naive to anti- PD-l/anti-PD-Ll therapy and 6 response-evaluable subjects who are relapsed/refractory to prior anti-PD-l/anti-PD-Ll therapy.
  • Ten response-evaluable subjects in each expansion cohort will first receive single-agent treatment with Compound A for 2 weeks at the RP2D previously determined in combination with nivolumab. Following the 2-week, single-agent treatment, Compound A treatment will continue (at the same dose) in combination with nivolumab during Week 3 and beyond.
  • the subset of expansion subjects who will be treated with single-agent Compound A at its combination RP2D during Weeks 1 and 2 should have accessible tumors for core or excisional biopsy and provide permission for the biopsies to be taken. These subjects will undergo mandatory biopsies before single-agent Compound A treatment begins, at the end of the 2-week treatment window, and after 6 weeks of treatment with Compound A in combination with nivolumab; an optional biopsy will also be taken at the time of PD.
  • the biopsies will be used for biomarker analysis evaluating the effect of Compound A on tumor cells and on immune/stromal cells supporting tumor tissue.
  • Dose escalation Subjects aged 18 years or older with advanced solid tumors for whom 1 or more prior lines of therapy have failed and who have no effective therapeutic options available based on investigator assessment.
  • Dose expansion Subjects aged 18 years or older with: (1) metastatic T BC with >1 prior line of chemotherapy; (2) locally advanced or metastatic NSCLC that has progressed on or after a prior platinum-based chemotherapy; or (3) locally advanced or metastatic HNSCC that has progressed or recurred within 6 months of the last platinum-based chemotherapy.
  • Compound A oral daily dosing with 3+3 dose escalation planned at 60 and 100 mg.
  • the RP2D determined in combination with nivolumab during dose escalation will be used for the possible fixed-dose evaluation cohort and dose expansion cohorts.
  • Nivolumab 3 mg/kg IV dosing over 60 minutes every 2 weeks (Day 1 and Day 15 of each 28-day cycle). If the 240 mg fixed-dose cohort is evaluated and deemed safe and tolerable, the dosing regimen may switch to 240 mg, on the basis of change in clinical practice and discussion between the investigator and sponsor. For subjects participating in the 2-week monotherapy run-in with Compound A, the first dose will be on Cycle 1 Day 15.
  • Treatment will continue until disease progression (PD), unacceptable toxicities, completion of the study, or withdrawal due to other reasons.
  • the estimated treatment duration is 12 months.
  • posttreatment biopsies are required for subjects receiving Compound A monotherapy run-in treatment for 2 weeks followed by Compound A plus nivolumab combination treatment (similar approximately 10/30 response-evaluable subjects); adequate, newly obtained, core or excisional biopsy of a metastatic tumor lesion not previously irradiated is required.
  • Mandatory biopsies will be taken before Compound A monotherapy, after the 2 weeks of Compound A monotherapy, and after 6 weeks of Compound A plus nivolumab combination therapy.
  • An optional biopsy may be taken at PD with additional consent from the subject, (d) One, two, or three line(s) of chemotherapy for metastatic disease and with progression of disease on last treatment regimen.
  • neoadjuvant and/or adjuvant chemotherapy regimens do not count as a prior line of therapy.
  • Prior treatment must include an anthracycline and/or a taxane in the neoadjuvant, adjuvant, or metastatic setting with the exception for subjects who are clinically contraindicated for these chemotherapies.
  • subjects must have: (a) Locally advanced or metastatic (stage IIIB, stage IV, or recurrent) NSCLC with measurable lesions per RECIST verion 1.1. (b) PD during or following at least 1 prior treatment.
  • Subjects should have received a prior platinum-containing, 2-drug regimen for locally advanced, unresectable/inoperable or metastatic NSCLC had or disease recurrence within 6 months of treatment with a platinum-based adjuvant/neoadjuvant regimen or combined modality (e.g., chemoradiation) regimen with curative intent, (c) Subjects with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic alternations should have PD on prior United States Food and Drug Administration- approved therapy for these aberrations, (d) Safely accessible tumor lesions (based on investigator's assessment) for serial pretreatment and posttreatment biopsies are required for subjects receiving Compound A monotherapy run-in treatment for 2 weeks followed by Compound A plus nivolumab combination treatment (approximately 10/30 response-evaluable subjects); adequate, newly obtained, core or excisional biopsy of a metastatic tumor lesion not previously irradiated is required.
  • prednisone equivalents or other immunosuppressive medications within 14 days before first dose of study drug.
  • Corticosteroids for topical use or in nasal spray are allowed, as are inhaled steroids and adrenal replacement steroid doses >10 mg daily in the absence of active autoimmune disease.
  • any T-cell co-stimulation agents or inhibitors of checkpoint pathways such as anti- programmed cell death protein 1 (PD-1), anti- programmed cell death 1 ligand 1 (PD-L1), anti- programmed cell death 1 ligand 2 (PD-L2), anti- CD137, or anti-CTLA-4 antibody; or other agents specifically targeting T cells are prohibited.
  • PD-1 programmed cell death protein 1
  • PD-L1 anti- programmed cell death 1 ligand 1
  • PD-L2 anti- programmed cell death 1 ligand 2
  • anti-CTLA-4 antibody anti-CTLA-4 antibody
  • Subjects with another malignancy within 2 years of study start Subjects with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection and are considered disease-free at the time of study entry.
  • inhibitors of P-glycoprotein (P-gp) and/or strong reversible inhibitors of cytochrome P450 (CYP)3A such as amiodarone, azithromycin, captopril, carvedilol, cyclosporine, diltiazem, dronedarone, erythromycin, felodipine, itraconazole, ketoconazole, nefazodone, posaconazole, quercetin, quinidine, ranolazine, ticagrelor, verapamil, and voriconazole is not permitted during the study.
  • CYP3A cytochrome P450
  • CYP 3 A reversible inhibitors and/or P-gp inhibitors are not exhaustive and is based on the US FDA draft DDI guidance, (b) Medications or supplements that are known to be strong CYP3 A mechanism-based inhibitors, such as clarithromycin,
  • conivaptan, mibefradil, telithromycin, or strong CYP3 A inducers and/or P-gp inducers such as avasimibe, carbamazepine, phenobarbital, phenytoin, primidone, rifabutin, rifapentine, rifampin, St John's wort, within 7 days, or within 5 times the inhibitor or inducer half-life (whichever is longer), before the first dose of study drug.
  • the use of these agents is not permitted during the study.
  • the list of prohibited strong CYP3 A inducers and/or P-gp inducers is not exhaustive and is based on the US FDA draft DDI guidance.
  • Non-oncology vaccine therapies for prevention of infectious diseases e.g., human papillomavirus [HPV] vaccine
  • infectious diseases e.g., human papillomavirus [HPV] vaccine
  • the inactivated seasonal influenza vaccine can be given to subjects before treatment and while on therapy without restriction.
  • Influenza vaccines containing live virus or other clinically indicated vaccinations for infectious diseases e.g., pneumovax, varicella
  • Grapefruit-containing food or beverages within 5 days before the first dose of study drug. Note that grapefruit-containing food and beverages are prohibited during the study.
  • the MTD/MAD (in combination with 3 mg/kg IV nivolumab) will be estimated by a standard 3+3 method using data collected in the dose escalation phase. AEs will be summarized by treatment group and overall. Categorical variables such as ORR, disease control rate, and rate of PD at 6 months will be tabulated by treatment group and overall. Time to event variables such as DOR, PFS, and OS will be analyzed using Kaplan-Meier survival curves, and Kaplan-Meier medians (if estimable) will be provided. PK parameters will be summarized as appropriate.
  • Sample size justification During the dose escalation phase, dose escalation will be conducted according to a standard 3+3 dose escalation schema, and approximately 12 to 18 dose- limiting toxicity-evaluable subjects will be enrolled (including 3 to 6 subjects in the possible nivolumab fixed-dose evaluation cohort).
  • the MTD/RP2D cohort will have at least 6 subjects.
  • Each cohort uses a null hypothesis of response rate ⁇ 20%, versus an alternative hypothesis of response rate >40% for subjects who are naive to anti- PD/PD-L1 and any other immune-directed antitumor therapies. Therefore, approximately 24 response-evaluable subjects for each cohort will be needed. In addition, 6 response-evaluable subjects with prior exposure to a PD-1 or PD-L1 inhibitor will be enrolled in each expansion cohort. In total, 30 response-evaluable subjects for each cohort and 90 response-evaluable subjects in total (-108 subjects based on a 15% drop-out rate) will be needed for all expansion cohorts.

Abstract

L'invention concerne de nouveaux traitements d'association pour le traitement des cancers. En particulier, l'invention concerne des méthodes de traitement de cancers comprenant l'administration à un patient atteint d'un cancer d'une quantité thérapeutiquement efficace d'un agent d'immunothérapie et d'un inhibiteur de la tyrosine kinase de la rate (SYK).
PCT/US2017/034786 2016-05-27 2017-05-26 Association d'agents d'immunothérapie et d'inhibiteurs de la tyrosine kinase de la rate WO2017205801A1 (fr)

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