WO2017165491A1 - Utilisation d'un antagoniste de pd-1 et d'un inhibiteur de raf dans le traitement du cancer - Google Patents

Utilisation d'un antagoniste de pd-1 et d'un inhibiteur de raf dans le traitement du cancer Download PDF

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WO2017165491A1
WO2017165491A1 PCT/US2017/023539 US2017023539W WO2017165491A1 WO 2017165491 A1 WO2017165491 A1 WO 2017165491A1 US 2017023539 W US2017023539 W US 2017023539W WO 2017165491 A1 WO2017165491 A1 WO 2017165491A1
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cancer
pan
antagonist
raf
raf inhibitor
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Rachael L. BRAKE
Patrick Kelly
Qunli Xu
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Millennium Pharmaceuticals Inc
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Millennium Pharmaceuticals Inc
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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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • 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 [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IG], 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 [IG], 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • the present disclosure relates to combination therapies useful for the treatment of cancer.
  • the disclosure relates to a combination therapy which comprises an antagonist of a Programmed Death 1 protein (PD-1) and a pan-RAF inhibitor.
  • PD-1 Programmed Death 1 protein
  • pan-RAF inhibitor an antagonist of a Programmed Death 1 protein
  • PD-1 Programmed cell death 1
  • PD-1 when engaged by the ligand PD-Ll, triggers inhibitory signaling in T-cells.
  • PD-Ll can be constitutively expressed on the surface of cancer cells or can be expressed in response to T cells producing immune-stimulating cytokines such as interferons.
  • PDL-1 can also be expressed on antigen presenting cells (APC) and may have an indirect effect on tumor cells via the T cell.
  • APC antigen presenting cells
  • Nivolumab is an anti-PD-1 monoclonal antibody (mAb) that disrupts the PD-1 / PD-Ll interaction with resultant tumor recognition by cytotoxic T cells.
  • Nivolumab has demonstrated long term benefit to a clinically significant but infrequent number of patients with treatment naive and relapsed/refractory metastatic melanoma. While tumor PD-Ll expression is associated with improved outcomes, benefit was also observed in a subset of patients whose disease was PD-Ll negative/indeterminate.
  • Compound A is a potent, small molecule MAPK pathway inhibitor currently being developed for the treatment of solid tumors, both as a single agent and in combination with other agents.
  • As a pan-RAF inhibitor Compound A has the ability to inhibit both RAF monomer- and dimer-mediated signaling, which is a key feature that distinguishes it from approved BRAF inhibitors (vemurafenib and dabrafenib).
  • Figure 1 is a bar graph that shows tumor immunophenotyping results from a
  • Figure 2 is a bar graph that shows MDSC (myeloid-derived suppressor cells) and TAM (tumor associated macrophages) immunophenotyping results of CD1 lb+Lin cells from a CT26 syngeneic mouse model (Example 1).
  • MDSC myeloid-derived suppressor cells
  • TAM tumor associated macrophages
  • the present disclosure relates to new combination therapies for the treatment of cancer.
  • the present disclosure relates to methods and compositions for treating a subject suffering from a cancer, comprising administering to the subject a pan-RAF inhibitor or a pharmaceutically acceptable salt thereof; and a Programmed Death 1 Protein (PD-1) antagonist; wherein the amount of the pan-RAF inhibitor and PD-1 antagonist is such that the combination thereof is therapeutically effective in the treatment of a cancer.
  • a pan-RAF inhibitor such as Compound A, having a beneficial effect on the tumor microenvironment by increasing cytotoxic T cell infiltration into the tumor, such effect enhances the efficacy of PD-1 checkpoint blockade in RAF and RAS mutant cancers.
  • pan-RAF inhibitor has advantages over each therapeutic agent administered alone and other combinations involving PD-1 antagonists and other MAPK pathway inhibitors, such as BRAF and MEK inhibitors. Combinations with other MAPK pathway inhibitors, such as BRAF and MEK inhibitors, can suffer from overlapping/additive toxicities as well as drug-mediated CRAF re-activation of the MAPK pathway, which may lead to reduced therapeutic benefit.
  • a pan-RAF inhibitor such as Compound A with its long half-life, may overcome the biological and pharmacological limitations of these other combinations.
  • a pan-RAF inhibitor, such as Compound A in combination with a PD-1 antagonist can provide a superior clinical benefit with a better safety profile.
  • subject includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, rabbit) and most preferably a human.
  • a mammal e.g., rat, mouse, dog, cat, rabbit
  • antibody refers to any form of antibody that exhibits the desired biological or binding activity. Thus, it is used in the broadest sense and specifically covers, but is not limited to, monoclonal antibodies (including full length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), humanized, fully human antibodies, chimeric antibodies and camelized single domain antibodies.
  • Monoclonal antibodies including full length monoclonal antibodies
  • polyclonal antibodies include multispecific antibodies (e.g., bispecific antibodies), humanized, fully human antibodies, chimeric antibodies and camelized single domain antibodies.
  • Parental antibodies are antibodies obtained by exposure of an immune system to an antigen prior to modification of the antibodies for an intended use, such as humanization of an antibody for use as a human therapeutic.
  • the basic antibody structural unit comprises a tetramer.
  • Each tetramer includes two identical pairs of polypeptide chains, each pair having one "light” (about 25 kDa) and one "heavy” chain (about 50-70 kDa).
  • the amino-terminal portion of each chain includes a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition.
  • the carboxy -terminal portion of the heavy chain may define a constant region primarily responsible for effector function.
  • human light chains are classified as kappa and lambda light chains.
  • human heavy chains are typically classified as mu, delta, gamma, alpha, or epsilon, and define the antibody's isotype as IgM, IgD, IgG, IgA, and IgE, respectively.
  • the variable and constant regions are joined by a "J" region of about 12 or more amino acids, with the heavy chain also including a "D” region of about 10 more amino acids. See generally, Fundamental Immunology Ch. 7 (Paul, W., ed., 2nd ed. Raven Press, N.Y. (1989).
  • variable regions of each light/heavy chain pair form the antibody binding site.
  • an intact antibody has two binding sites.
  • the two binding sites are, in general, the same.
  • variable domains of both the heavy and light chains comprise three hypervariable regions, also called complementarity determining regions (CDRs), which are located within relatively conserved framework regions (FR).
  • CDRs complementarity determining regions
  • FR framework regions
  • the CDRs are usually aligned by the framework regions, enabling binding to a specific epitope.
  • both light and heavy chains variable domains comprise FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4.
  • the assignment of amino acids to each domain is, generally, in accordance with the definitions of Sequences of Proteins of Immunological Interest, Kabat, et al; National Institutes of Health, Bethesda, Md. ; 5th ed.; NIH Publ. No.
  • hypervariable region refers to the amino acid residues of an antibody that are responsible for antigen-binding.
  • the hypervariable region comprises amino acid residues from a "complementarity determining region” or "CDR” (i.e. CDRLl, CDRL2 and CDRL3 in the light chain variable domain and CDRH1, CDRH2 and CDRH3 in the heavy chain variable domain).
  • CDR complementarity determining region
  • antibody fragment or “antigen binding fragment” refers to antigen binding fragments of antibodies, i.e. antibody fragments that retain the ability to bind specifically to the antigen bound by the full-length antibody, e.g. fragments that retain one or more CDR regions.
  • antibody binding fragments include, but are not limited to, Fab, Fab', F(ab') 2 , and Fv fragments; diabodies; linear antibodies; single-chain antibody molecules, e.g., sc-Fv; nanobodies and multispecific antibodies formed from antibody fragments.
  • An antibody that "specifically binds to" a specified target protein is an antibody that exhibits preferential binding to that target as compared to other proteins, but this specificity does not require absolute binding specificity.
  • An antibody is considered “specific” for its intended target if its binding is determinative of the presence of the target protein in a sample, e.g. without producing undesired results such as false positives.
  • Antibodies, or binding fragments thereof, useful in the present disclosure will bind to the target protein with an affinity that is at least two fold greater, preferably at least ten times greater, more preferably at least 20- times greater, and most preferably at least 100-times greater than the affinity with non-target proteins.
  • an antibody is said to bind specifically to a polypeptide comprising a given amino acid sequence, e.g. the amino acid sequence of a mature human PD- 1, or human PD- LI, if it binds to polypeptides comprising that sequence but does not bind to proteins lacking that sequence.
  • Chimeric antibody refers to an antibody in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in an antibody derived from a particular species (e.g., human) or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in an antibody derived from another species (e.g., mouse) or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity.
  • a particular species e.g., human
  • another species e.g., mouse
  • Human antibody refers to an antibody that comprises human immunoglobulin protein sequences only.
  • a human antibody may contain murine carbohydrate chains if produced in a mouse, in a mouse cell, or in a hybridoma derived from a mouse cell.
  • mouse antibody or rat antibody refer to an antibody that comprises only mouse or rat immunoglobulin sequences, respectively.
  • Humanized antibody refers to forms of antibodies that contain sequences from non-human (e.g., murine) antibodies as well as human antibodies. Such antibodies contain minimal sequence derived from non-human immunoglobulin.
  • the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human
  • the humanized antibody optionally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin.
  • Fc immunoglobulin constant region
  • the prefix "hum”, “hu” or “h” is added to antibody clone designations when necessary to distinguish humanized antibodies from parental rodent antibodies.
  • the humanized forms of rodent antibodies will generally comprise the same CDR sequences of the parental rodent antibodies, although certain amino acid substitutions may be included to increase affinity, increase stability of the humanized antibody, or for other reasons.
  • cancer refers to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.
  • examples of cancer include but are not limited to, skin cancer, ocular cancer, gastrointestinal cancer, thyroid cancer, breast cancer, ovarian cancer, central nervous system cancer, laryngeal cancer, cervical cancer, lymphatic system cancer, genitourinary tract cancer, bone cancer, biliary tract cancer, endometrial cancer, liver cancer, lung cancer, prostate cancer, pancreatic cancer, and colon cancer.
  • lung cancer includes non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). In some embodiments, the cancer is not NSCLC.
  • the cancer is selected from skin cancer, ocular cancer, gastrointestinal cancer, thyroid cancer, breast cancer, ovarian cancer, brain cancer, laryngeal cancer, cervical cancer, lymphatic system cancer, genitourinary tract cancer, bone cancer, biliary tract cancer, endometrial cancer, uterine cancer, liver cancer, lung cancer, prostate cancer and colon cancer.
  • the cancer is a hematological malignancy.
  • the hematological malignancy is selected from acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), chronic lymphoblastic leukemia (CLL), myelodysplastic syndrome, B-cell lymphoma, non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma.
  • the cancer is NHL.
  • the NHL is selected from diffused large B cell lymphoma, follicular lymphoma, and multiple myeloma.
  • the cancer is skin cancer.
  • the skin cancer is melanoma.
  • the cancer is lung cancer.
  • the cancer is non-small cell lung cancer (NSCLC).
  • the cancer is squamous NSCLC.
  • the cancer is non-squamous NSCLC.
  • the cancer is gastrointestinal cancer.
  • gastrointestinal cancer As used herein,
  • gastrointestinal cancer includes cancer of the esophagus, stomach (also known as gastric cancer), biliary system, pancreas, small intestine, large intestine, rectum and anus).
  • the gastrointestinal cancer is adenocarcinoma of the esophagus, adenocarcinoma of the gastroesophageal junction or adenocarcinoma of the stomach.
  • the gastrointestinal cancer is stomach cancer.
  • the cancer is colon cancer.
  • Colon cancer is also known as colorectal (CRC), bowel, or rectum cancer.
  • the cancer is a central nervous system cancer.
  • the central nervous system cancer is brain cancer.
  • thyroid cancer is thyroid carcinoma.
  • genitourinary tract cancer is bladder cancer.
  • the hematogical malignancy is selected from acute myelogenous leukemia (AML) and chronic lymphocytic leukemia (CLL).
  • AML acute myelogenous leukemia
  • CLL chronic lymphocytic leukemia
  • the combinations described herein are used to treat a genetically defined subset of one or more of the cancers described above.
  • the cancer is BRAF, NRAS, or KRAS mutation positive cancer.
  • BRAF B-Raf proto-oncogene, serine/threonine kinase, the gene associated with the niRNA sequence assigned as GenBank Accession No. NM 004333, SEQ ID NO:l (open reading frame is SEQ ID NO:2, nucleotides 62 to 2362 of SEQ ID NO:l), encoding GenPept Accession No. NP_004324, SEQ ID NO:3).
  • Other names for BRAF include rafBl and Noonan Syndrome 7 (NS7).
  • BRAF functions as a serine/threonine kinase, has a role in regulating the MAP kinase/ERKs signaling pathway and can be found on chromosome 7q.
  • KRAS or “K-Ras” refers to v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog, the gene associated with the mRNA sequence assigned as GenBank Accession No. NM 004985, SEQ ID NO:4 (open reading frame is SEQ ID NO:5, nucleotides 193 to 759 of SEQ ID NO:4), encoding GenPept Accession No. NP_004976, SEQ ID NO:6, the predominant transcript variant of K-Ras gene on chromosome 12.
  • Other names for K-Ras include KRAS2, and Noonan Syndrome 3 (NS3).
  • K-Ras functions as an oncogene with GTPase activity and can be found on chromosome 12. K-Ras interacts with the cell membrane and various effector proteins, such as Akt and Cdc42, which carry out its signaling function through the cytoskeleton and effects on cell motility (Fotiadou et al. (2007) Mol. Cel. Biol. 27:6742-6755).
  • NRAS neuroblastoma RAS viral (v-ras) oncogene homolog, the gene associated with the mRNA sequence assigned as GenBank Accession No. NM_002524, SEQ ID NO:7 (open reading frame is SEQ ID NO:8, nucleotides 255 to 824 of SEQ ID NO:7), encoding GenPept Accession No. NP 002515, SEQ ID NO:9).
  • Other names for N-Ras include Autoimmune Lymphoproliferative Syndrome type IV (ALPS4), NRAS1, and Noonan Syndrome 6 (NS6).
  • N-Ras functions as an oncogene with GTPase activity and can be found on chromosome lp.
  • NRAS interacts with the cell membrane and various effector proteins, such as RAF and RhoA, which carry out its signaling function through the cytoskeleton and effects on cell adhesion (Fotiadou et al. (2007) Mol. Cel. Biol. 27:6742-6755).
  • the cancer is a RAS mutation positive cancer.
  • RAS mutations include NRAS and KRAS.
  • the RAS mutation positive cancer is pancreatic cancer, colorectal cancer, non-small cell lung cancer, AML/myeloma or melanoma.
  • the RAS mutation positive cancer is pancreatic cancer.
  • the RAS mutation positive cancer is colorectal cancer.
  • the RAS mutation positive cancer is non-small cell lung cancer. In some embodiments, the RAS mutation positive cancer is AML/myeloma. In some embodiments, the RAS mutation positive cancer is melanoma.
  • the cancer is KRAS mutation positive cancer.
  • the KRAS mutation positive cancer is pancreatic cancer, colorectal cancer, non- small cell lung cancer, AML/myeloma or melanoma.
  • the KRAS mutation positive cancer is pancreatic cancer.
  • the KRAS mutation positive cancer is colorectal cancer.
  • the KRAS mutation positive cancer is non-small cell lung cancer.
  • the KRAS mutation positive cancer is AML/myeloma.
  • the KRAS mutation positive cancer is melanoma.
  • the cancer is a KRAS exon 2 mutation positive cancer.
  • one or more of the KRAS exon 2 mutation is in codon 12 or codon 13. In some embodiments, the KRAS exon 2 mutation is in codon 12. In some embodiments, the KRAS exon 2 mutation is in codon 13.
  • the cancer is a KRAS non-exon 2 mutation positive cancer. In some embodiments, the cancer is a KRAS exon 3 or exon 4 mutation positive cancer. In some embodiments, the cancer is a KRAS exon 3 mutation positive cancer. In some embodiments, the KRAS exon 3 mutation is in codon 61. In some embodiments, the cancer is a KRAS exon 4 mutation positive cancer. In some embodiments, the KRAS exon 4 mutation is in codon 117 or codon 146. In some embodiments, the KRAS exon 4 mutation is in codon 117. In some embodiments, the KRAS exon 4 mutation is in codon 146.
  • the cancer is a BRAF mutation positive cancer.
  • the BRAF mutation positive cancer is melanoma, colorectal cancer, non-small cell lung cancer, or AML/myeloma.
  • the BRAF mutation positive cancer is melanoma.
  • the BRAF mutation positive cancer is colorectal.
  • the BRAF mutation positive cancer is non-small cell lung cancer.
  • the BRAF mutation positive cancer is AML/myeloma.
  • the cancer is a BRAF V-600 mutation positive cancer.
  • the BRAF mutation is V600E.
  • the BRAF mutation is V600G.
  • the BRAF mutation is V600A.
  • the BRAF mutation is V600K.
  • the BRAF mutation is V600M.
  • the BRAF mutation is V600R.
  • the BRAF mutation is V600 K.
  • the cancer is an NRAS mutation positive cancer.
  • the NRAS mutation positive cancer is pancreatic cancer, colorectal cancer, non-small cell lung cancer, AML/myeloma or melanoma.
  • the NRAS mutation positive cancer is pancreatic cancer.
  • the NRAS mutation positive cancer is colorectal cancer.
  • the NRAS mutation positive cancer is non-small cell lung cancer.
  • the NRAS mutation positive cancer is AML/myeloma.
  • the NRAS mutation positive cancer is melanoma.
  • the cancer is an NRAS exon 2, exon 3, or exon 4 mutation positive cancer.
  • the cancer is an NRAS non-exon 2 mutation positive cancer. In some embodiments, the cancer is an NRAS exon 3 mutation positive cancer. In some embodiments, one or more of the NRAS exon 3 mutations is in codon 59 or codon 61. In some embodiments, the NRAS exon 3 mutation is in codon 59. In some embodiments, the NRAS mutation is in codon 61. In some embodiments, the colorectal cancer is an NRAS exon 4 mutation positive colorectal cancer. In some embodiments, the one or more of the NRAS exon 4 mutations is in codon 117 or codon 146. In some embodiments, the NRAS exon 4 mutation is in codon 117. In some embodiments, the NRAS exon 4 mutation is in codon 146.
  • the cancer is an NRAS exon 2 mutation positive cancer.
  • the one or more of the NRAS exon 2 mutations is in codon 12 or codon 13. In some embodiments, the NRAS exon 2 mutation is in codon 12. In some embodiments, that NRAS exon 13.
  • the cancer is relapsed, refractory, or advanced cancer.
  • the cancer is refractory.
  • refractory cancer does not respond to treatment; it is also known as resistant cancer.
  • the tumor is unresectable.
  • an unresectable tumor is unable to be removed by surgery.
  • the cancer has not been previously treated.
  • the cancer is locally advanced.
  • "locally advanced” refers to a cancer that is somewhat extensive but still confined to one area. In some instances, "locally advanced” can refer to a small tumor that hasn't spread but has invaded nearby organs or tissues that make it difficult to remove with surgery alone.
  • the cancer is metastatic.
  • metastatic cancer is a cancer that has spread from the part of the body where it started (the primary site) to other parts of the body.
  • the cancer that may be treated in accordance with the disclosed combination includes one or more cancers characterized by elevated expression of PD-1, PD-L1, and/or PD-L2 in tested tissue samples. In some embodiments, the cancer that may be treated in accordance with the disclosed combination includes one or more cancers characterized by decreased expression of PD-1, PD-L1, and/or PD-L2 in tested tissue samples. In some embodiments, the cancer that may be treated in accordance with the disclosed combination is PD-L1 positive. In some embodiments, the cancer that may be treated in accordance with the disclosed combination is PD-L1 negative.
  • Biotherapeutic agent means a biological molecule, such as an antibody or fusion protein, that blocks ligand / receptor signaling in any biological pathway that supports tumor maintenance and/or growth or suppresses the anti-tumor immune response.
  • CDR or “CDRs” as used herein means complementarity determining region(s) in a immunoglobulin variable region, defined using the Kabat numbering system, unless otherwise indicated.
  • “Chemotherapeutic agent” is a chemical compound useful in the treatment of cancer.
  • Classes of chemotherapeutic agents include, but are not limited to: alkylating agents, antimetabolites, kinase inhibitors, spindle poison plant alkaloids, cytoxic/antitumor antibiotics, topisomerase inhibitors, photosensitizers, anti-estrogens and selective estrogen receptor modulators (SERMs), anti-progesterones,estrogen receptor down-regulators (ERDs), estrogen receptor antagonists, leutinizing hormone-releasing hormone agonists, anti-androgens, aromatase inhibitors, EGFR inhibitors, VEGF inhibitors, anti-sense oligonucleotides that that inhibit expression of genes implicated in abnormal cell proliferation or tumor growth.
  • SERMs selective estrogen receptor modulators
  • ESDs estrogen receptor down-regulators
  • estrogen receptor antagonists leutinizing hormone-releasing hormone agonists, anti-androgens, aromata
  • Chemotherapeutic agents useful in the treatment methods of the present disclosure include cytostatic and/or cytotoxic agents.
  • Consists essentially of and variations such as “consist essentially of or
  • a PD-1 antagonist that consists essentially of a recited amino acid sequence may also include one or more amino acids, including substitutions of one or more amino acid residues, which do not materially affect the properties of the binding compound.
  • Raf kinase refers to any one of a family of serine/threonine-protein kinases.
  • the family consists of three isoform members (BRAF, C-Raf (Raf-1), and A-Raf).
  • Raf protein kinases are involved in the MAPK signaling pathway consisting of a kinase cascade that relays extracellular signals to the nucleus to regulate gene expression and key cellular functions.
  • the term “Raf kinase” or “RAF kinase” is meant to refer to any Raf kinase protein from any species, including, without limitation.
  • the Raf kinase is a human Raf kinase.
  • RAF RAF kinase inhibitor
  • Raf kinase inhibitor is used to signify a compound which is capable of interacting with one or more isoform members (BRAF, C-Raf (Raf-1) and/or A-Raf) of the serine/threonine-protein kinase, Raf including mutant forms.
  • BRAF mutant forms include BRAF V600E, BRAF V600D, and BRAF V600K.
  • the one or more isoforms of RAF protein kinase is at least about 50% inhibited, at least about 75% inhibited, at least about 90% inhibited, at least about 95% inhibited, at least about 98% inhibited, or at least about 99% inhibited.
  • the concentration of RAF kinase inhibitor required to reduce RAF kinase activity by 50% is less than about 1 ⁇ , less than about 500 nM, less than about 100 nM, less than about 50 nM, less than about 25 nM, less than about 10 nM, less than about 5 nM, or less than about 1 nM.
  • such inhibition is selective for one or more Raf isoforms, i.e., the Raf inhibitor or a pharmaceutically acceptable salt thereof is selective for one or more of BRAF (wild type), mutant BRAF, A-Raf, and C-Raf kinase.
  • the Raf inhibitor or a pharmaceutically acceptable salt thereof is selective for BRAF (wild type), BRAF V600E, A-Raf and C-Raf.
  • the Raf inhibitor or a pharmaceutically acceptable salt thereof is selective for BRAF (wild type), BRAF V600E, A-Raf and C-Raf.
  • the Raf inhibitor or a pharmaceutically acceptable salt thereof is selective for BRAF (wild type), BRAF V600D, A-Raf and C-Raf. In some embodiments, the Raf inhibitor or a pharmaceutically acceptable salt thereof is selective for BRAF (wild type), BRAF V600K, and C-Raf. In some embodiments, the Raf inhibitor or a pharmaceutically acceptable salt thereof is selective for more than BRAF V600. In some embodiments, the Raf inhibitor or a pharmaceutically acceptable salt thereof is selective for more than BRAF V600E.
  • the Raf inhibitor or a pharmaceutically acceptable salt thereof is selective for BRAF and C-Raf kinases. In some embodiments, the Raf inhibitor or a pharmaceutically acceptable salt thereof is selective for BRAF (wild type), BRAF V600E and C-Raf. In some embodiments, the Raf inhibitor or a pharmaceutically acceptable salt thereof is selective for BRAF (wild type), BRAF V600D and C-Raf. In some embodiments, the Raf inhibitor or a pharmaceutically acceptable salt thereof is selective for BRAF (wild type), BRAF V600K and C-Raf. In some embodiments, the Raf inhibitor or a pharmaceutically acceptable salt thereof is selective for mutant BRAF.
  • the Raf inhibitor or a pharmaceutically acceptable salt thereof is selective for mutant BRAF V600E. In some embodiments, the Raf inhibitor or a pharmaceutically acceptable salt thereof is selective for mutant BRAF V600D. In some embodiments, the Raf inhibitor or a pharmaceutically acceptable salt thereof is selective for mutant BRAF V600K.
  • wild type refers to a polypeptide or polynucleotide sequence that occurs in a native population without genetic modification.
  • a mutant includes a polypeptide or polynucleotide having at least one modification to an amino acid or nucleic acid compared to the corresponding amino acid or nucleic acid found in a wild type polypeptide or polynucleotide. Included in the term mutant is Single Nucleotide Polymorphism (SNP) where a single base pair distinction exists in the sequence of a nucleic acid strand compared to the most prevalently found (wild type) nucleic acid strand.
  • SNP Single Nucleotide Polymorphism
  • pan-RAF inhibitor refers to a Raf inhibitor that inhibits more Raf kinases than BRAF (wild type) and/or the mutant isoform BRAF V600.
  • the pan-RAF inhibitor is selected from (R)-2-(l-(6-amino-5-chloropyrimidine-4- carboxamide)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide (Compound A) , N- ⁇ 7-cyano-6-[4-fluoro-3-( ⁇ [3-(trifluoromethyl)-phenyl] -acetyl ⁇ -amino) - phenoxy]-l,3-benzothiazol-2-yl ⁇ cyclopropanecarboxamide (Compound B) or a
  • the pan-RAF inhibitor is (R)-2-(l-(6-amino-5- chloropyrimidine-4-carboxamide)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole- 5-carboxamide (Compound A) or a pharmaceutically acceptable salt thereof:
  • the pan-RAF inhibitor is N- ⁇ 7-cyano-6- [4-fluoro-3 -( ⁇ [3 -
  • Pan-RAF inhibitors such as Compound A and Compound B, that can inhibit more isoforms of Raf kinase proteins than BRAF V600 have the ability to inhibit both Raf monomer and dimer-mediated signaling, which is a key feature that
  • pan-Raf inhibitors from recently approved BRAF specific inhibitors
  • the term "pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • a “pharmaceutically acceptable salt” means any non-toxic salt of a compound disclosed herein that, upon
  • administration to a recipient is capable of providing, either directly or indirectly, the compound or an active metabolite or residue thereof.
  • Pharmaceutically acceptable salts of compounds described herein include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(Cl-4alkyl)4 salts. This disclosure also provides the quaternization of any basic nitrogen-containing groups. Water or oil-soluble or dispersable products may be obtained by such quaternization.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
  • pan-RAF inhibitors may be used in the methods of the instant disclosure.
  • these pan-RAF inhibitors include for example, Compound A, Compound B, compounds disclosed in WO 2009/006389, and US 2013/0252977 (DP-4978/ LY3009120), and including but not limited to compounds RAF-265, ARQ-736, CEP-32496, CCT 196969, CCT 241161, and REDX-04988.
  • Pan-RAF inhibitors or a pharmaceutically acceptable salts thereof can be assayed in vitro or in vivo for their ability to bind to and/or inhibit Raf kinases.
  • In vitro assays include biochemical FRET assays to measure the phophorylation of MEK by Raf kinases as a method for quantifying the ability of compounds to inhibit the enzymatic activity of Raf kinases.
  • the compounds also can be assayed for their ability to affect cellular or physiological functions mediated by Raf kinase activity. For example in vitro assays quantitate the amount of phosphor-ERK in colorectal cancer cells. Assays for each of these activities are known in the art.
  • Framework region or "FR” as used herein means the immunoglobulin variable regions excluding the CDR regions.
  • Homology refers to sequence similarity between two polypeptide sequences when they are optimally aligned.
  • a position in both of the two compared sequences is occupied by the same amino acid monomer subunit, e.g., if a position in a light chain CDR of two different Abs is occupied by alanine, then the two Abs are homologous at that position.
  • the percent of homology is the number of homologous positions shared by the two sequences divided by the total number of positions compared x 100. For example, if 8 of 10 of the positions in two sequences are matched or homologous when the sequences are optimally aligned then the two sequences are 80% homologous.
  • the comparison is made when two sequences are aligned to give maximum percent homology.
  • the comparison can be performed by a BLAST algorithm wherein the parameters of the algorithm are selected to give the largest match between the respective sequences over the entire length of the respective reference sequences.
  • BLAST ALGORITHMS Altschul, S.F., et al, (1990) J. Mol. Biol. 215:403-410; Gish, W., et al, (1993) Nature Genet. 3:266-272; Madden, T.L., et al, (1996) Meth. Enzymol. 266:131-141 ; Altschul, S.F., et al, (1997) Nucleic Acids Res. 25:3389-3402; Zhang, J., et al, (1997) Genome Res. 7:649-656; Wootton, J.C., et al, (1993) Comput. Chem.
  • isolated antibody and “isolated antibody fragment” refers to the purification status and in such context means the named molecule is substantially free of other biological molecules such as nucleic acids, proteins, lipids, carbohydrates, or other material such as cellular debris and growth media. Generally, the term “isolated” is not intended to refer to a complete absence of such material or to an absence of water, buffers, or salts, unless they are present in amounts that substantially interfere with experimental or therapeutic use of the binding compound as described herein.
  • Kabat as used herein means an immunoglobulin alignment and numbering system pioneered by Elvin A. Kabat ((1991) Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md.).
  • conventional (polyclonal) antibody preparations typically include a multitude of different antibodies having different amino acid sequences in their variable domains, particularly their CDRs, which are often specific for different epitopes.
  • the modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method.
  • the monoclonal antibodies to be used in accordance with the present disclosure may be made by the hybridoma method first described by Kohler et al. (1975) Nature 256: 495, or may be made by recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567).
  • the hybridoma method first described by Kohler et al. (1975) Nature 256: 495 or may be made by recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567).
  • “monoclonal antibodies” may also be isolated from phage antibody libraries using the techniques described in Clackson et al. (1991) Nature 352: 624-628 and Marks et al. (1991) J. Mol. Biol. 222: 581-597, for example. See also Presta (2005) J. Allergy Clin. Immunol. 1 16:731.
  • PD-1 antagonist means any chemical compound or biological molecule that blocks binding of PD-Ll expressed on a cancer cell or an antigen presenting cell (APC) to PD-1 expressed on an immune cell (T cell, B cell or NKT cell) and could also apply to inhibitors that block binding of PD-L2 expressed on a cancer cell to the immune-cell expressed PD-1.
  • APC antigen presenting cell
  • PD-1 and its ligands include: PDCD1, PD1, CD279 and SLEB2 for PD-1; PDCDILI, PDLl, B7H1, B7-4, CD274 and B7-H for PD-Ll; and PDCD1L2, PDL2, B7-DC, Btdc and CD273 for PD-L2.
  • the PD-1 antagonist blocks binding of human PD-Ll to human PD-1, and may block binding of both human PD-Ll and PD-L2 to human PD-1.
  • Human PD-1 amino acid sequences can be found in NCBI Locus No.: NP 005009.
  • Human PD-Ll and PD-L2 amino acid sequences can be found in NCBI Locus No.: NP 054862 and NP_079515, respectively.
  • PD-1 antagonists useful in any of the treatment methods, pharmaceutical compositions and uses of the present disclosure include a monoclonal antibody (mAb), or antigen binding fragment thereof, which specifically binds to PD-1 or PD-Ll, and preferably specifically binds to human PD-1 or human PD-Ll.
  • the mAb may be a human antibody, a humanized antibody or a chimeric antibody, and may include a human constant region.
  • the human constant region is selected from the group consisting of IgGl, IgG2, IgG3 and IgG4 constant regions, and in embodiments, the human constant region is an IgGl or IgG4 constant region.
  • the antigen binding fragment is selected from the group consisting of Fab, Fab'-SH, F(ab')2, scFv and Fv fragments.
  • Examples of mAbs that bind to human PD- 1 are described in US7521051, US8779105, US8008449, US8900587, US8952136, US8354509, US8735553, US9102728, US8993731, US9102727, US9181342, US8927697, US8945561, US748802, US7322582, US7524498 and US9205148.
  • Specific anti-human PD-1 mAbs useful as the PD-1 antagonist in the treatment methods, pharmaceutical compositions and uses of the present disclosure include, but are not limited to: pembrolizumab (formerly MK-3475 and
  • lambrolizumab marketed in the USA under the tradename KEYTRUDA ® , a humanized IgG4 niAb with the structure described in WHO Drug Information, Vol. 27, No. 2, pages 161-162 (2013); nivolumab (formerly ONO-4538, MDX1106 or BMS-936558), marketed in the USA under the tradename OPDIVO ® , a human IgG4 mAb with the structure described in WHO Drug Information, Vol. 27, No. 1, pages 68-69 (2013); and the humanized antibodies h409Al 1, h409A16 and h409A17, which are described in WO2008/156712; PDR-100; SHR-1210;
  • mAbs that bind to human PD-L1 are described in WO2013/019906, W02010/077634 Al and US8383796.
  • Specific anti-human PD-L1 mAbs useful as the PD-1 antagonist in the treatment methods, pharmaceutical compositions and uses of the present disclosure include, but are not limited to atezolizumab (MPDL3280A), BMS- 936559, durvalumab (MEDI4736), and avelumab (MSB0010718C).
  • compositions and uses of the present disclosure include an immunoadhesion that specifically binds to PD-1 or PD-L1, and preferably specifically binds to human PD-1 or human PD-L1, e.g., a fusion protein containing the extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region such as an Fc region of an immunoglobulin molecule.
  • immunoadhesion molecules that specifically bind to PD-1 are described in WO2010/027827 and WO2011/066342.
  • AMP-224 also known as B7- DCIg
  • B7- DCIg B7- DCIg
  • the PD-1 antagonist is selected from nivolumab, pembrolizumab, PDR-001, SHR-1210, AMP-224, REGN-2810, MEDI-0680, BGB-108, PF- 06801591, atezolizumab, durvalumab, and BMS-936559, and AMP-224.
  • the PD-1 antagonist is selected from nivolumab, pembrolizumab, PDR-001, SHR-1210, AMP-224, REGN-2810, MEDI-0680, BGB-108, and PF-06801591, and AMP-224.
  • the PD-1 antagonist is selected from pembrolizumab and nivolumab.
  • the PD-1 antagonist is nivolumab.
  • the PD-1 antagonist is pembrolizumab.
  • the PD-1 antagonist is selected from atezolizumab, durvalumab, avelumab and BMS-936559.
  • the PD-1 antagonist is a monoclonal antibody, or antigen binding fragment thereof, which comprises nivolumab.
  • the PD-1 antagonist is a monoclonal antibody, or antigen binding fragment thereof, which comprises pembrolizumab.
  • the PD-1 antagonist is a monoclonal antibody, or antigen binding fragment thereof, which specifically binds to human PD-1 and comprises (a) a heavy chain variable region of an antibody described herein or a variant thereof, and (b) a light chain variable region of an antibody described herein or a variant thereof.
  • a variant of a heavy chain variable region sequence is identical to the reference sequence except having up to seventeen conservative amino acid substitutions in the framework region (i.e., outside of the CDRs), and preferably has less than ten, nine, eight, seven, six or five conservative amino acid substitutions in the framework region.
  • a variant of a light chain variable region sequence is identical to the reference sequence except having up to five conservative amino acid substitutions in the framework region (i.e., outside of the CDRs), and preferably has less than four, three or two conservative amino acid substitution in the framework region.
  • PD-L1 or "PD-L2" expression as used herein means any detectable level of expression of the designated PD-L protein on the cell surface or of the designated PD-L mR A within a cell or tissue.
  • PD-L protein expression may be detected with a diagnostic PD-L antibody in an IHC assay of a tumor tissue section or by flow cytometry.
  • PD-L protein expression by tumor cells may be detected by PET imaging, using a binding agent (e.g., antibody fragment, affibody and the like) that specifically binds to the desired PD-L target, e.g., PD-L1 or PD-L2.
  • a binding agent e.g., antibody fragment, affibody and the like
  • Techniques for detecting and measuring PD-L mRNA expression include RT- PCR and realtime quantitative RT-PCR.
  • tissue Section refers to a single part or piece of a tissue sample, e.g., a thin slice of tissue cut from a sample of a normal tissue or of a tumor.
  • Treating" or “treating” a cancer as used herein means to administer a combination therapy comprising a PD-1 antagonist and a pan-RAF inhibitor to a subject having a cancer, or diagnosed with a cancer, to achieve at least one positive therapeutic effect, such as for example, reduced number of cancer cells, reduced tumor size, reduced rate of cancer cell infiltration into peripheral organs, or reduced rate of tumor metastasis or tumor growth.
  • Positive therapeutic effects in cancer can be measured in a number of ways (See, W. A. Weber, J. Nucl. Med. 50: IS- 10S (2009)).
  • a T/C ⁇ 42% is the minimum level of anti-tumor activity.
  • the treatment achieved by a therapeutically effective amount is any of progression free survival (PFS), disease free survival (DFS) or overall survival (OS).
  • PFS also referred to as "Time to Tumor Progression” indicates the length of time during and after treatment that the cancer does not grow, and includes the amount of time patients have experienced a complete response or a partial response, as well as the amount of time patients have experienced stable disease.
  • DFS refers to the length of time during and after treatment that the patient remains free of disease.
  • OS refers to a prolongation in life expectancy as compared to naive or untreated subjects or patients.
  • the dosage regimen of a combination therapy described herein that is effective to treat a cancer patient may vary according to factors such as the disease state, age, and weight of the patient, and the ability of the therapy to elicit an anti-cancer response in the subject.
  • While an embodiment of the treatment method, pharmaceutical compositions and uses of the present disclosure may not be effective in achieving a positive therapeutic effect in every subject, it should do so in a statistically significant number of subjects as determined by any statistical test known in the art such as the Student's t-test, the chi2-test, the U-test according to Mann and Whitney, the Kruskal-Wallis test (H-test), Jonckheere-Terpstra- test and the Wilcoxon-test.
  • any statistical test known in the art such as the Student's t-test, the chi2-test, the U-test according to Mann and Whitney, the Kruskal-Wallis test (H-test), Jonckheere-Terpstra- test and the Wilcoxon-test.
  • Tumor as it applies to a subject diagnosed with, or suspected of having, a cancer refers to a malignant or potentially malignant neoplasm or tissue mass of any size, and includes primary tumors and secondary neoplasms.
  • a solid tumor is an abnormal growth or mass of tissue that usually does not contain cysts or liquid areas. Different types of solid tumors are named for the type of cells that form them. Examples of solid tumors are sarcomas, carcinomas, and lymphomas. Leukemias (cancers of the blood) generally do not form solid tumors (National Cancer Institute, Dictionary of Cancer Terms).
  • Tumor burden also referred to as “tumor load” refers to the total amount of tumor material distributed throughout the body. Tumor burden refers to the total number of cancer cells or the total size of tumor(s), throughout the body, including lymph nodes and bone narrow. Tumor burden can be determined by a variety of methods known in the art, such as, e.g. by measuring the dimensions of tumor(s) upon removal from the subject, e.g., using calipers, or while in the body using imaging techniques, e.g., ultrasound, bone scan, computed tomography (CT) or magnetic resonance imaging (MRI) scans.
  • CT computed tomography
  • MRI magnetic resonance imaging
  • tumor size refers to the total size of the tumor which can be measured as the length and width of a tumor. Tumor size may be determined by a variety of methods known in the art, such as, e.g. by measuring the dimensions of tumor(s) upon removal from the subject, e.g., using calipers, or while in the body using imaging techniques, e.g., bone scan, ultrasound, CT or MRI scans.
  • imaging techniques e.g., bone scan, ultrasound, CT or MRI scans.
  • Variable regions or "V region” as used herein means the segment of IgG chains which is variable in sequence between different antibodies. It extends to Kabat residue 109 in the light chain and 1 13 in the heavy chain.
  • the disclosure provides a method for treating a cancer in a subject comprising administering to the subject a combination therapy which comprises a PD-1 antagonist and a pan-RAF inhibitor.
  • the combination therapy may also comprise one or more additional therapeutic agents.
  • the combination therapy comprises the additional therapeutic agents is vedolizumab and ipilimumab.
  • Each therapeutic agent in a combination therapy of the disclosure may be administered either alone or in a pharmaceutical composition which comprises the therapeutic agent and one or more pharmaceutically acceptable carriers, excipients and diluents, according to standard pharmaceutical practice.
  • Each therapeutic agent in a combination therapy of the disclosure may be administered simultaneously (i.e., in the same pharmaceutical composition), concurrently (i.e., in separate pharmaceutical compositions administered one right after the other in any order) or sequentially in any order.
  • Sequential administration is particularly useful when the therapeutic agents in the combination therapy are in different dosage forms (one agent is a tablet or capsule and another agent is a sterile liquid) and/or are administered on different dosing schedules.
  • the PD-1 antagonist is administered before
  • the PD-1 antagonist is administered after administration of the pan-RAF inhibitor.
  • the PD-1 antagonist is administered at least 1 hour after administration of the pan-RAF inhibitor.
  • nivolumab is administered at least 1 hour after Compound A oral dosing.
  • the PD-1 antagonist and pan-RAF inhibitor are administered concomitantly.
  • At least one of the therapeutic agents in the combination therapy is administered using the same dosage regimen (dose, frequency and duration of treatment) that is typically employed when the agent is used as monotherapy for treating the same cancer.
  • the subject receives a lower total amount of at least one of the therapeutic agents in the combination therapy than when the agent is used as monotherapy, e.g., smaller doses, less frequent doses, and/or shorter treatment duration.
  • Each therapeutic agent in a combination therapy of the disclosure can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal, topical, and transdermal routes of administration.
  • a combination therapy of the disclosure may be used prior to or following surgery to remove a tumor and may be used prior to, during or after radiation therapy.
  • a combination therapy of the disclosure is administered to a subject who has not been previously treated with a biotherapeutic or chemotherapeutic agent, i.e., is treatment-naive.
  • the combination therapy is administered to a subject who failed to achieve a sustained response after prior therapy with a biotherapeutic or chemotherapeutic agent, i.e., is treatment-experienced.
  • a combination therapy of the disclosure is typically used to treat a tumor that is large enough to be found by palpation or by imaging techniques well known in the art, such as MRJ, ultrasound, or CAT scan.
  • a combination therapy of the disclosure is used to treat an advanced stage tumor having dimensions of at least about 200 mm 3 300 mm 3 , 400 mm 3 , 500 mm 3 , 750 mm 3 , or up to 1000 mm 3 .
  • a dosage regimen for a combination therapy of the disclosure depends on several factors, including the serum or tissue turnover rate of the entity, the level of symptoms, the immunogenicity of the entity, and the accessibility of the target cells, tissue or organ in the subject being treated.
  • a dosage regimen maximizes the amount of each therapeutic agent delivered to the subject consistent with an acceptable level of side effects. Accordingly, the dose amount and dosing frequency of each agent in the combination depends in part on the particular therapeutic agent, the severity of the cancer being treated, and subject characteristics.
  • Determination of the appropriate dosage regimen may be made by the clinician, e.g., using parameters or factors known or suspected in the art to affect treatment or predicted to affect treatment, and will depend, for example, on the subject's clinical history (e.g., previous therapy), the type and stage of the cancer to be treated and biomarkers of response to one or more of the therapeutic agents in the combination therapy.
  • Biotherapeutic agents in a combination therapy of described in the disclosure may be administered by continuous infusion, or by doses at intervals of, e.g., daily, every other day, three times per week, or one time each week, two weeks, three weeks, monthly, bimonthly, etc.
  • a total weekly dose is generally at least 0.05 ⁇ g/kg, 0.2 ⁇ g/kg, 0.5 ⁇ g/kg, 1 ⁇ g/kg, 10 ⁇ g/kg, 100 ⁇ g/kg, 0.2 mg/kg, 1.0 mg/kg, 2.0 mg/kg, 10 mg/kg, 25 mg/kg, 50 mg/kg body weight or more. See, e.g., Yang et al. (2003) New Engl. J. Med.
  • the dosing regimen will comprise administering the anti-human PD-1 mAb at a dose of 1, 2, 3, 5 or lOmg/kg at intervals of about 14 days ( ⁇ 2 days) or about 21 days ( ⁇ 2 days) or about 30 days ( ⁇ 2 days) throughout the course of treatment.
  • a subject will be administered an intravenous (IV) infusion of a pharmaceutical composition comprising any of the PD-1 antagonists described herein.
  • the PD-1 antagonist in the combination therapy is nivolumab, which is administered intravenously at a dose selected from the group consisting of: 1 mg/kg Q2W, 2 mg/kg Q2W, 3 mg/kg Q2W, 5 mg/kg Q2W, 10 mg Q2W, 1 mg/kg Q3W, 2 mg/kg Q3W, 3 mg/kg Q3W, 5 mg/kg Q3W, and 10 mg Q3W.
  • the PD-1 antagonist in the combination therapy is pembrolizumab, which is administered intravenously at a dose selected from the group consisting of 1 mg/kg Q2W, 2 mg/kg Q2W, 3 mg/kg Q2W, 5 mg/kg Q2W, 10 mg Q2W, 1 mg/kg Q3W, 2 mg/kg Q3W, 3 mg/kg Q3W, 5 mg/kg Q3W, and 10 mg Q3W.
  • pembrolizumab is administered intravenously which comprises 25 mg/ml pembrolizumab, 7% (w/v) sucrose, 0.02% (w/v) polysorbate 80 in 10 mM histidine buffer pH 5.5, and the selected dose of the pharmaceutical composition is administered by IV infusion over a time period of 30 minutes.
  • the optimal dose for pembrolizumab in combination with a pan-RAF inhibitor may be identified by dose escalation starting with 2 mg/kg and going up to 10 mg/kg with the frequency of administration matched to that selected for the pan-RAF inhibitor, e.g., Compound A.
  • a pharmaceutical composition comprising an anti-PD-1 antibody as the PD-1 antagonist may be provided as a liquid formulation or prepared by reconstituting a lyophilized powder with sterile water for injection prior to use.
  • a pharmaceutical composition comprising pembrolizumab is provided in a glass vial which contains about 50 mg of pembrolizumab. In some embodiments, a
  • composition comprising nivolumab is provided in a glass vial which contains about 40 mg/4mL or 100 mg/lOniL of nivolumab.
  • Formulation of an antibody or fragment to be administered will vary according to the route of administration and formulation (e.g., solution, emulsion, capsule) selected.
  • An appropriate pharmaceutical composition comprising an antibody or functional fragment thereof to be administered can be prepared in a physiologically acceptable vehicle or carrier.
  • suitable carriers include, for example, aqueous or alcoholic/aqueous solutions, emulsions or
  • Parenteral vehicles can include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's or fixed oils.
  • aqueous carriers include water, buffered water, buffered saline, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol), dextrose solution and glycine.
  • Intravenous vehicles can include various additives, preservatives, or fluid, nutrient or electrolyte replenishes (See, generally, Remington's
  • compositions can optionally contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents and toxicity adjusting agents, for example, sodium acetate, sodium chloride, potassium chloride, calcium chloride and sodium lactate.
  • auxiliary substances for example, sodium acetate, sodium chloride, potassium chloride, calcium chloride and sodium lactate.
  • the antibodies and fragments described in this disclosure can be lyophilized for storage and reconstituted in a suitable carrier prior to use according to art-known
  • the antibody or fragment can be solubilized and loaded into a suitable dispenser for administration (e.g., an atomizer, nebulizer or pressurized aerosol dispenser).
  • a suitable dispenser for administration e.g., an atomizer, nebulizer or pressurized aerosol dispenser.
  • the antibody or fragment can be administered in a single dose or multiple doses.
  • the dosage can be determined by methods known in the art and is dependent, for example, upon the antibody or fragment chosen, the subject's age, sensitivity and tolerance to drugs, and overall well-being.
  • Antibodies and antigen-binding fragments thereof such as human, humanized and chimeric antibodies and antigen-binding fragments can often be administered with less frequency than other types of therapeutics.
  • an effective amount of an antibody can range from about 0.01 mg/kg to about 5 or 10 mg/kg administered daily, weekly, biweekly or monthly.
  • compositions for use in the method of the disclosure may be formulated in unit dosage form for ease of administration and uniformity of dosage.
  • unit dosage form refers to a physically discrete unit of agent appropriate for the subject to be treated. It will be understood, however, that the total daily usage of the therapeutic agents of the combination will be decided by the attending physician within the scope of sound medical judgment.
  • a unit dosage form for parenteral administration may be in ampoules or in multi- dose containers.
  • pan-RAF inhibitor and PD-1 antagonist are administered in such a way that they provide a beneficial effect in the treatment of a cancer. Administration can be by any suitable means provided that the administration provides the desired therapeutic effect, i.e., additivity or synergism.
  • the pan-RAF inhibitor and PD-1 antagonist are administered during the same cycle of therapy, e.g., during one cycle of therapy, both the RAF kinse inhibitor and PD-1 antagonist are administered to the subject.
  • the pan-RAF inhibitor and PD-1 antagonist are cyclically administered to a subject. Cycling therapy involves the administration of a first agent (e.g., a first prophylactic or therapeutic agent) for a period of time, followed by the administration of a second agent and/or third agent (e.g., a second and/or third prophylactic or therapeutic agent) for a period of time and repeating this sequential administration. Cycling therapy can reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one of the therapies, and/or improve the efficacy of the treatment.
  • a first agent e.g., a first prophylactic or therapeutic agent
  • a second agent and/or third agent e.g., a second and/or third prophylactic or therapeutic agent
  • non-treatment period of particular time duration is then followed by a non-treatment period of particular time duration, during which the therapeutic agents are not administered to the subject.
  • This non-treatment period can then be followed by a series of subsequent treatment and non-treatment periods of the same or different frequencies for the same or different lengths of time.
  • the treatment and non-treatment periods are alternated. It will be understood that the period of treatment in cycling therapy may continue until the subject has achieved a complete response or a partial response, at which point the treatment may be stopped. Alternatively, the period of treatment in cycling therapy may continue until the subject has achieved a complete response or a partial response, at which point the period of treatment may continue for a particular number of cycles. In some embodiments, the length of the period of treatment may be a particular number of cycles, regardless of subject response. In some other embodiments, the length of the period of treatment may continue until the subject relapses.
  • the amounts or suitable dosages of the pan-RAF inhibitor 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.
  • Suitable daily dosages of inhibitors of Raf kinases can generally range, in single or divided or multiple doses, from about 10% to about 100% of the maximum tolerated dose as a single agent. In some embodiments, the suitable dosages are from about 15% to about 100% of the maximum tolerated dose as a single agent. In some some embodiments, the suitable dosages are from about 25% to about 90% of the maximum tolerated dose as a single agent. In some other embodiments, the suitable dosages are from about 30% to about 80% of the maximum tolerated dose as a single agent. In some other embodiments, the suitable dosages are from about 40% to about 75% of the maximum tolerated dose as a single agent.
  • the suitable dosages are from about 45% to about 60% of the maximum tolerated dose as a single agent. In some embodiments, suitable dosages are about 10%, about 15%), about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 105%, or about 110% of the maximum tolerated dose as a single agent.
  • a suitable dosage of a pan-RAF inhibitor may be taken at any time of the day or night. In some embodiments, a suitable dosage of a selective inhibitor of pan-RAF inhibitor is taken in the morning. In some other embodiments, a suitable dosage of a pan-RAF inhibitor is taken in the evening. In some other embodiments, a suitable dosage of a pan-RAF inhibitor is taken both in the morning and the evening. It will be understood that a suitable dosage of a pan-RAF inhibitor may be taken with or without food. In some embodiments a suitable dosage of a pan-RAF inhibitor is taken with a meal. In some embodiments a suitable dosage of a pan-RAF inhibitor is taken while fasting. In some embodiments a suitable dosage of a pan-RAF inhibitor is taken on an empty stomach with subjects remaining nothing by mouth except for water for 2 hours before and 1 hour after each dose.
  • the present disclosure provides a method of treating a subject suffering from a cancer, comprising administering to the subject: (i) Compound A or a pharmaceutically acceptable salt thereof; and (ii) a PD-1 antagonist; the amount of (i) and (ii) being such that the combination thereof is therapeutically effective in the treatment of a cancer.
  • Compound A is a pan-RAF inhibitor with a long half life which can support once weekly dosing (QW).
  • QW dosing
  • Compound A is administered once weekly with a rest period of 6 days between each administration. Suitable weekly dosages of Compound A can generally range, in single or divided or multiple doses, from about 300 mg to about 600 mg once weekly (QW).
  • Compound A can generally range, in single or divided or multiple doses, from 300 mg to 600 mg once weekly (QW). In some embodiments, Compound A is administered from about 300 to about 600 mg once weekly. In some embodiments, Compound A is administered from up to 300 to 600 mg once weekly. Once weekly means with a rest period of 6 days between each administration. In some embodiments, Compound A is administered as a single dose. In some embodiments, Compound A is administered QW in an amount of 300 mg to 600 mg per dose. In some embodiments, Compound A is administered in an amount of 300 mg to 600 mg per dose on starting on day 1 , week 1 and is administered once weekly with a rest period of 6 days between each administration.
  • Compound A is administered as a divided dose. In some embodiments, Compound A is administered as a divided dose on the same day. In some embodiments, Compound A is administered in multiple doses. In some other embodiments, the suitable weekly dosage is from about 400 mg to about 600 mg per dose once a week. In some other embodiments, the suitable weekly dosage is from about 200 mg to about 500 mg per dose once a week. In some other embodiments, the suitable weekly dosage is from about 200 mg to about 300 mg per dose once a week. In some embodiments, suitable weekly dosages are about 200 mg, 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, or about 900 mg per dose once a week.
  • the QW dosing schedule differentiates the combination of Compound A and PD-1 antagonist based on superior safety from other available therapies. In some embodiments, the QW dosing schedule differentiates the combination of Compound A and PD-1 antagonist based on superior efficacy from other available therapies.
  • the dosage of the pan-RAF inhibitor administered to a subject will also depend on frequency of administration.
  • Compound A is administered once weekly (QW) in an amount of 300 mg to 600 mg per dose with a rest period of 6 days between each administration.
  • Compound A is in an amount of 300 mg to 600 mg per dose administered starting on day 1, week 1.
  • Compound A is administered every other day. In some embodiments, Compound A is administered every other day (QOD) in an amount of from about 100 mg to about 200 mg per dose. In some some embodiments, Compound A is administered QOD in an amount of about 100 mg per dose. In some embodiments, Compound A is administered QOD in an amount of about 200 mg per dose.
  • QOD QOD
  • Compound A is administered from up to about 200 mg per dose. In some embodiments, Compound A is administered from up to 200 mg per dose. Suitable QOD dosages of a pan-RAF inhibitor e.g., Compound A can generally range, in single or divided or multiple doses, from up to about 200 mg per dose. In some embodiments, Compound A is administered as a single dose. In some embodiments, Compound A is administered as a divided dose. In some embodiments, Compound A is administered in multiple doses. Other suitable dosages of Compound A can generally range, in single or divided or multiple doses, from about 50 mg to about 200 mg per dose.
  • suitable dosages of Compound A can generally range, in single or divided or multiple doses, from about 75 mg to about 200 mg per dose. In some embodiments, the suitable dosages are from about 100 mg to about 200 mg per dose. In some other embodiments, the suitable dosages are from about 150 mg to about 200 mg twice daily.
  • suitable dosages are about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, or about 200 mg per dose.
  • the suitable dosage of Compound A is from about 100 mg to about 200 mg per dose.
  • the term "pharmaceutically acceptable carrier” is used herein to refer to a material that is compatible with a recipient subject.
  • the subject is a mammal.
  • the subject is a human.
  • the material is suitable for delivering active therapeutic agent to the target site without terminating the activity of the agent.
  • the toxicity or adverse effects, if any, associated with the carrier preferably are commensurate with a reasonable risk/benefit ratio for the intended use of the therapeutic agent.
  • 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.
  • Williams & Wilkins, 2000 discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as 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.
  • materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as disodium hydrogen phosphate, potassium hydrogen phosphate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium hydroxide and aluminum hydroxide, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, pyrogen-free water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose, sucrose, starches such as corn starch and potato starch, cellulose and
  • compositions of the disclosure can be manufactured by methods well known in the art such as conventional granulating, mixing, dissolving, encapsulating, lyophilizing, or emulsifying processes, among others.
  • Compositions may be produced in various forms, including granules, precipitates, or particulates, powders, including freeze dried, rotary dried or spray dried powders, amorphous powders, tablets, capsules, syrup, suppositories, injections, emulsions, elixirs, suspensions or solutions.
  • Formulations may optionally contain solvents, diluents, and other liquid vehicles, dispersion or suspension aids, surface active agents, pH modifiers, isotonic agents, thickening or emulsifying agents, stabilizers and preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • compositions of this disclosure are formulated for pharmaceutical administration to a subject.
  • Compound A is formulated as described in WO 2010/064722.
  • Such pharmaceutical compositions of the present disclosure may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the compositions are administered orally, intravenously, or subcutaneously.
  • compositions of the disclosure may be designed to be short-acting, fast-releasing, or long- acting. Still further, the agents of the combination can be administered in a local rather than systemic means, such as administration (e.g., by injection) at a tumor site.
  • Liquid dosage forms for oral administration include, but are not limited to, 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,
  • 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,
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or
  • injectables diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • Compositions formulated for parenteral administration may be injected by bolus injection or by timed push, or may be administered by continuous infusion.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • at least one therapeutic agent of the combination 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 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 glycerol, d) disintegrating agents such as 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 quaternary ammonium compounds, g) wetting agents such as, for
  • 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 can 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 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. Examples of embedding compositions that can be used include polymeric substances and waxes. 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.
  • One or more of the therapeutic agents of the combination can also be in microencapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also 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. Examples of embedding compositions that can be used include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of one or more therapeutic agents of the combination include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the therapeutic agent is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this disclosure.
  • the present disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of one or more of the therapeutic agents of the combination to the body.
  • Such dosage forms can be made by dissolving or dispensing the therapeutic agent in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the therapeutic agent across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the therapeutic agent in a polymer matrix or gel.
  • the combination described herein may be provided as a kit which comprises a first container and a second container and a package insert.
  • the first container contains at least one dose of a pharmaceutical composition comprising an anti-PD-1 antagonist
  • the second container contains at least one dose of a pharmaceutical composition comprising a pan-RAF inhibitor
  • the package insert, or label which comprises instructions for treating a subject for a cancer using the pharmaceutical compositions.
  • the first and second containers may be comprised of the same or different shape (e.g., vials, syringes and bottles) and/or material (e.g., plastic or glass).
  • the kit may further comprise other materials that may be useful in
  • the anti-PD-1 antagonist is an anti-PD-1 antibody.
  • the anti-PD-1 antibody is nivolumab.
  • the anti-PD-1 antibody is pembrolizumab.
  • the pan-RAF inhibitor is Compound A or a pharmaceutically acceptable salt thereof.
  • the present disclosure relates to methods for treating a subject suffering from a cancer by administering to the subject a pharmaceutical composition described herein, said method comprising: a) measuring at least one characteristic of at least one or more BRAF, NRAS and/or KRAS markers associated with gene mutation in a subject sample comprising tumor cells; b) identifying whether the at least one characteristic measured in step a) is informative for outcome upon treatment with the pharmaceutical composition; and c) determining to treat the subject with the pharmaceutical composition if the informative characteristic indicates that the tumor cells comprise at least one marker gene with a BRAF, NRAS and/or KRAS mutational status that indicates a favorable outcome to treatment with the pharmaceutical composition.
  • the present disclosure relates to methods for treating a subject suffering from a cancer by administering to the subject a pharmaceutical composition described herein, said method comprising: subjecting a nucleic acid sample from a cancer (tumor) sample from the subject to BRAF, NRAS, or KRAS mutational testing or PCR, wherein the presence of a mutation in either BRAF, NRAS, or KRAS gene indicates an increased likelihood of pharmacological effectiveness of the treatment.
  • the present disclosure relates to methods of treating a subject suffering from a cancer, said method comprising: i) obtaining a nucleic acid sample from a cancer sample from said subject; ii) subjecting the sample to BRAF, NRAS, or KRAS mutational testing or PCR and identifying the presence of at least one mutation in BRAF, NRAS, or KRAS gene; and iii) administering an effective amount of a combination described herein to the subject in whose sample the presence of at least one mutation in BRAF or KRAS gene is identified.
  • a mutation in a marker can be identified by sequencing a nucleic acid, e.g., a DNA, RNA, cDNA or a protein correlated with the marker gene, e.g., a genotype marker gene, e.g., BRAF or NRAS.
  • a nucleic acid primer can be designed to bind to a region comprising a potential mutation site or can be designed to complement the mutated sequence rather than the wild type sequence.
  • Primer pairs can be designed to bracket a region comprising a potential mutation in a marker gene.
  • a primer or primer pair can be used for sequencing one or both strands of DNA corresponding to the marker gene.
  • a primer can be used in conjunction with a probe, e.g., a nucleic acid probe, e.g., a hybridization probe, to amplify a region of interest prior to sequencing to boost sequence amounts for detection of a mutation in a marker gene.
  • regions which can be sequenced include an entire gene, transcripts of the gene and a fragment of the gene or the transcript, e.g., one or more of exons or untranslated regions or a portion of a marker comprising a mutation site.
  • mutations to target for primer selection and sequence or composition analysis can be found in public databases which collect mutation information, such as Database of Genotypes and Phenotypes (dbGaP) maintained by the National Center for Biotechnology Information
  • Sequencing methods are known to one skilled in the art. Examples of methods include the Sanger method, the SEQUENOMTM method and Next Generation Sequencing (NGS) methods.
  • the Sanger method comprising using electrophoresis, e.g., capillary electrophoresis to separate primer-elongated labeled DNA fragments, can be automated for high-throughput applications.
  • the primer extension sequencing can be performed after PCR amplification of regions of interest.
  • Software can assist with sequence base calling and with mutation identification.
  • SEQUENOMTM MASSARRAY® sequencing analysis (San Diego, CA) is a mass-spectrometry method which compares actual mass to expected mass of particular fragments of interest to identify mutations.
  • NGS technology also called “massively parallel sequencing” and “second generation sequencing” in general provides for much higher throughput than previous methods and uses a variety of approaches (reviewed in Zhang et al. (2011) J. Genet. Genomics 38:95-109 and Shendure and Hanlee (2008) Nature Biotech.
  • NGS methods can identify low frequency mutations in a marker in a sample.
  • Some NGS methods see, e.g., GS-FLX Genome Sequencer (Roche Applied Science, Branford, CT), Genome analyzer (Illumina, Inc. San Diego, CA) SOLIDTM analyzer (Applied
  • Biosystems, Carlsbad, CA), Polonator G.007 (Dover Systems, Salem, NH), HELISCOPETM (Helicos Biosciences Corp., Cambridge, MA)) use cyclic array sequencing, with or without clonal amplification of PCR products spatially separated in a flow cell and various schemes to detect the labeled modified nucleotide that is incorporated by the sequencing enzyme (e.g., polymerase or ligase).
  • the sequencing enzyme e.g., polymerase or ligase.
  • primer pairs can be used in PCR reactions to amplify regions of interest. Amplified regions can be ligated into a concatenated product.
  • Clonal libraries are generated in the flow cell from the PCR or ligated products and further amplified ("bridge” or “cluster” PCR) for single-end sequencing as the polymerase adds a labeled, reversibly terminated base that is imaged in one of four channels, depending on the identity of the labeled base and then removed for the next cycle.
  • Software can aid in the comparison to genomic sequences to identify mutations.
  • Another NGS method is exome sequencing, which focuses on sequencing exons of all genes in the genome. As with other NGS methods, exons can be enriched by capture methods or amplification methods.
  • DNA e.g., genomic DNA corresponding to the wild type or mutated marker can be analyzed both by in situ and by in vitro formats in a biological sample using methods known in the art.
  • DNA can be directly isolated from the sample or isolated after isolating another cellular component, e.g., RNA or protein. Kits are available for DNA isolation, e.g., QIAAMP® DNA Micro Kit (Qiagen, Valencia, CA). DNA also can be amplified using such kits.
  • mRNA corresponding to the marker can be analyzed both by in situ and by in vitro formats in a biological sample using methods known in the art.
  • Many expression detection methods use isolated RNA.
  • any RNA isolation technique that does not select against the isolation of mRNA can be utilized for the purification of RNA from tumor cells (see, e.g., Ausubel et al., ed., Current Protocols in Molecular Biology, John Wiley & Sons, New York 1987-1999).
  • large numbers of tissue samples can readily be processed using techniques well known to those of skill in the art, such as, for example, the single-step RNA isolation process of Chomczynski (1989, U.S. Patent No. 4,843,155).
  • RNA can be isolated using standard procedures (see e.g., Chomczynski and Sacchi (1987) Anal. Biochem.l62:156-159), solutions (e.g., trizol, TRI REAGENT® (Molecular Research Center, Inc., Cincinnati, OH; see U.S. Patent No. 5,346,994) or kits (e.g., a QIAGEN® Group RNEASY® isolation kit (Valencia, CA) or LEUKOLOCKTM Total RNA Isolation System, Ambion division of Applied Biosystems, Austin, TX).
  • solutions e.g., trizol, TRI REAGENT® (Molecular Research Center, Inc., Cincinnati, OH; see U.S. Patent No. 5,346,994)
  • kits e.g., a QIAGEN® Group RNEASY® isolation kit (Valencia, CA) or LEUKOLOCKTM Total RNA Isolation System, Ambion division of Applied Biosystems, Austin, TX).
  • Poly(A)+RNA is selected by selection with oligo-dT cellulose (see Sambrook et al. (1989) Molecular Cloning—A Laboratory Manual (2nd ed.), Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y.). Alternatively, separation of RNA from DNA can be accomplished by organic extraction, for example, with hot phenol or phenol/chloroform/isoamyl alcohol. If desired, RNAse inhibitors may be added to the lysis buffer. Likewise, for certain cell types, it may be desirable to add a protein denaturation/digestion step to the protocol. For many applications, it is desirable to enrich mRNA with respect to other cellular RNAs, such as transfer RNA (tRNA) and ribosomal RNA (rRNA).
  • tRNA transfer RNA
  • rRNA ribosomal RNA
  • mRNAs contain a poly(A) tail at their 3' end. This allows them to be enriched by affinity chromatography, for example, using oligo(dT) or poly(U) coupled to a solid support, such as cellulose or SEPHADEX.RTM. medium (see Ausubel et al. (1994) Current Protocols In Molecular Biology, vol. 2, Current Protocols Publishing, New York). Once bound, poly(A)+mRNA is eluted from the affinity column using 2 mM EDTA/0.1% SDS.
  • a characteristic of a marker found in a sample can be assessed by any of a wide variety of well known methods for detecting or measuring the characteristic, e.g., of a marker or plurality of markers, e.g., of a nucleic acid (e.g., RNA, mRNA, genomic DNA, or cDNA) and/or translated protein.
  • a sample e.g., a tumor biopsy
  • a nucleic acid e.g., RNA, mRNA, genomic DNA, or cDNA
  • Non-limiting examples of such methods include immunological methods for detection of secreted, cell-surface, cytoplasmic, or nuclear proteins, protein purification methods, protein function or activity assays, nucleic acid hybridization methods, optionally including "mismatch cleavage" steps (Myers, et al. (1985) Science 230:1242) to digest mismatched, i.e. mutant or variant, regions and separation and identification of the mutant or variant from the resulting digested fragments, nucleic acid reverse transcription methods, and nucleic acid amplification methods and analysis of amplified products.
  • These methods include gene array/chip technology, RT-PCR, TAQMAN® gene expression assays (Applied Biosystems, Foster City, CA), e.g., under GLP approved laboratory conditions, in situ hybridization,
  • Examples of techniques for detecting differences of at least one nucleotide between two nucleic acids include, but are not limited to, selective oligonucleotide
  • oligonucleotide probes can be prepared in which the known polymorphic nucleotide is placed centrally (allele- or mutant-specific probes) and then hybridized to target DNA under conditions which permit hybridization only if a perfect match is found (Saiki et al. (1986) Nature 324:163); Saiki et al (1989) Proc. Natl Acad. Sci USA 86:6230; and Wallace et al. (1979) Nucl. Acids Res. 6:3543).
  • Allele specific oligonucleotide hybridization techniques can be used for the simultaneous detection of several nucleotide changes in different polymorphic or mutated regions of NRAS.
  • oligonucleotides having nucleotide sequences of specific allelic variants or mutants are attached to a solid support, e.g., a hybridizing membrane and this support, e.g., membrane, is then hybridized with labeled sample nucleic acid. Analysis of the hybridization signal thus can reveal the identity of the nucleotides of the sample nucleic acid.
  • Example 1 Tumor immunophenotype: NK-, T-, B- and Myeloid Cells in CT26
  • mice Balb/c mice from JAX (approximately 20 grams body weight, female) were used. The animals 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 (12.5 mg/kg, Formulated in 0.05% Tween/0.5% Methocel at 1.25 mg/mL, dosed at 10 mL/kg, p.o.).
  • Anti-PD-1 monoclonal antibody 200 ug/mouse, BioXcell, RMP1-14, dosed at 5 mL/kg, i.p.).
  • 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 was allowed prior to re-initiating the culture from the original cell stock [00151]
  • In vivo CT26 syngeneic model Day-2 prior to tumor injection, the animal's fur was shaved from the rump up to the middle of back and extending to the flank of each side. At day 0, CT26 cells were suspended in RPMI medium and Matrigel (1 :1) to final cell
  • mice from each group were sacrificed and spleens and tumors were collected for FACS analysis.
  • Flow cytometry was used to identify and enumerate different cell types in spleen and tumor.
  • Spleens and tumors were removed and dissociated into single cell suspensions using the gentle MACS dissociator (Miltenyl Biotec).
  • Spleens were processed in autoMACS buffer containing 0.5% BS A and tumors in RPMI-1640 media containing 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 20x10e6 viable cells/ml. Single cell suspension was distributed into 96 well U bottom plate in PBS for viability staining (Zombie Aqua, Biolegend).
  • Example 2 A Phase lb Clinical Study
  • a phase lb study to evaluate the safety, tolerability, and pharmacodynamics of an investigational treatment of Compound A in combination with standard of care immune checkpoint inhibitors in patients with advanced melanoma is undertaken. Up to about 52 subjects are enrolled. Approximately 12 subjects are assigned in dose-escalation treatments, with up to 46 subjects in expansion cohorts.
  • the subjects are adults, either male or female, with histologically confirmed, unresectable stage III or IV melanoma, according to the AJCC staging system, and with a ECOG performance status of 0-1.
  • Subjects are BRAF V600 mutation-positive or NRAS- mutation positive disease previously untreated with RAF, MEK or other inhibitors of the MAPK pathway.
  • Subjects have adequate bone marrow reserve and renal and hepatic function.
  • Compound A is administered orally at 300 mg, 400 mg, or 600 mg once weekly. Intermediate doses can be tested. Nivolumab is administered IV at a dose of 3 mg/kg Q2W. Duration of treatment is up to 50 weeks and the period of evaluation is 12 months.
  • the primary objective in the dose escalation phase plus Part 1 limited cohort expansion is to determine the recommended Part 2 dose based on the initial safety profile of the combination treatments in each arm when administered to patients with advanced melanoma.
  • the primary objective in Part 2 is to determine the initial antitumor activity of each
  • the primary endpoint is the frequency of dose limiting toxicities (DLT)(part 1) and overall response rate as measured by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (part 2).
  • Secondary safety endpoints for this study are the frequency and severity of treatment emergent adverse events (TEAEs) including serious TEAEs, and TEAEs leading to treatment dioscontinuation.
  • Secondary efficacy endpoints are duration of response (DOR), progression-free survival (PFS) and overall survival (OS).
  • Serial tumor biopsies are used to assess immune cell infiltration in the tumor microenvironment at baseline,

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Abstract

La présente invention concerne des méthodes et des kits pour le traitement du cancer. En particulier, l'invention concerne des méthodes de traitement de cancers par l'administration d'un antagoniste de PD-1 tel que le pembrolimumab, le nivolumab, l'atezolizumab, le durvalumab et l'avelumab en association avec un inhibiteur universel de RAF tel que le (R)-2-(1-(6-amino-5-chloropyrimidine-4- carboxamide)éthyl)-N-(5-chloro-4-(trifluorométhyl)pyridine-2-yl)thiazole-5-carboxamide et le N-{7-cyano-6-[4-fluoro-3-({[3- (trifluorométhyl)-phényl]acétyl}amino)phénoxy]-1,3-benzothiazol-2-yl}cyclopropanecarboxamide.
PCT/US2017/023539 2016-03-24 2017-03-22 Utilisation d'un antagoniste de pd-1 et d'un inhibiteur de raf dans le traitement du cancer Ceased WO2017165491A1 (fr)

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US11338014B2 (en) 2015-08-03 2022-05-24 Enb Therapeutics, Inc. Methods and compositions for treatment of endothelin B receptor expressing tumors
US12533390B2 (en) 2015-08-03 2026-01-27 Enb Therapeutics, Inc. Methods and compositions for treatment of Endothelin B receptor expressing tumors
US11534431B2 (en) * 2016-07-05 2022-12-27 Beigene Switzerland Gmbh Combination of a PD-1 antagonist and a RAF inhibitor for treating cancer
WO2019140324A1 (fr) * 2018-01-12 2019-07-18 Enb Therapeutics, Inc. Composés deutérés, compositions et méthodes de traitement de cancers associés à l'activation d'etbr
US10435434B2 (en) 2018-01-12 2019-10-08 Enb Therapeutics, Inc. Deuterated compounds, compositions, and methods for treating cancers associated with ETBR activation
US11066442B2 (en) 2018-01-12 2021-07-20 Enb Therapeutics, Inc. Deuterated compounds, compositions, and methods for treating cancers associated with ETBR activation
US12077604B2 (en) 2018-01-12 2024-09-03 Enb Therapeutics, Inc. Deuterated compounds, compositions, and methods for treating cancers associated with ETBR activation
JP2024514112A (ja) * 2021-04-06 2024-03-28 ジェネンテック， インコーポレイテッド ベルバラフェニブおよびコビメチニブを用いた併用療法、またはベルバラフェニブ、コビメチニブおよびアテゾリズマブを用いた併用療法

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