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WO2017066664A1 - Polythérapie comprenant un inhibiteur de raf pour le traitement du cancer colorectal - Google Patents

Polythérapie comprenant un inhibiteur de raf pour le traitement du cancer colorectal Download PDF

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WO2017066664A1
WO2017066664A1 PCT/US2016/057173 US2016057173W WO2017066664A1 WO 2017066664 A1 WO2017066664 A1 WO 2017066664A1 US 2016057173 W US2016057173 W US 2016057173W WO 2017066664 A1 WO2017066664 A1 WO 2017066664A1
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Prior art keywords
colorectal cancer
pharmaceutically acceptable
inhibitor
acceptable salt
braf
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Rachael L. BRAKE
Karuppiah Kannan
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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • 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

  • This disclosure relates to methods for the treatment of colorectal cancer.
  • the disclosure provides methods for treatment of colorectal cancer by administering a RAF inhibitor or pharmaceutically acceptable salt thereof in combination with one or more of an EGFR inhibitor or topoisomerase I inhibitor or a pharmaceutically acceptable salt thereof.
  • Anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibodies are an effective therapy for a minority of patients with metastatic colorectal cancer (mCRC).
  • An intrinsic mechanism of resistance to anti-EGFR therapy is dysregulation of the MAPK pathway which is common in mCRC.
  • Up to 55% of colon cancers harbor a mutation in KRAS or NRAS with another 8% to 10% with BRAF mutations (Karapetis CS, et al. N Engl J Med 2008;359(17): 1757-65; Douillard JY et al. N Engl. J Med 2013;369(11): 1023-34; Kalady MF, et al.
  • Combinations with a RAF inhibitor or pharmaceutically acceptable salt thereof designed to inhibit MAPK kinase signaling could be helpful for the treatment of colorectal cancer and might potentially overcome the resistance to particular anticancer agents.
  • topoisomerase I inhibitor or a pharmaceutically acceptable salt thereof may have additive or even synergistic therapeutic effects.
  • new colorectal cancer treatment regimens including combination therapies.
  • Figure 1 is a graph that shows the effect of Compound A in combination with irinotecan in COL 205 colon xenograft tumors in NU/NU mice: tumor volume.
  • Figure 2 is a line graph that shows the effect Compound A, cetuximab, and Compound A in combination with cetuximab in Balb/c nude female mice bearing primary colorectal tumor PHTX-24C xenograft models.
  • the PHTX-24C models are KRAS non-exon 2 mutation positive.
  • Figure 3 is a line graph that shows the effect Compound A, cetuximab, and Compound A in combination with cetuximab in female Balb/c nude mice bearing primary colorectal tumor CR1530 xenograft models.
  • the CR1530 models are KRAS non-exon 2 mutation positive.
  • Figure 4 is a bar graph that shows the effect of Compound A alone and in combination with cetuximab on pERK levels in the PHTX-24C colorectal cancer model.
  • Figure 5 is a bar graph that shows the effect of Compound A alone and in combination with Cetuximab on pERK levels in the CR1530 colorectal cancer model.
  • the present disclosure realates to new combination therapies for the treatment of colorectal cancer.
  • the present disclosure relates to methods and compositions for treating a subject suffering from colorectal cancer, comprising administering to the subject a RAF inhibitor or a pharmaceutically acceptable salt thereof; and one or more of: (i) an EGFR inhibitor or (ii) a
  • topoisomerase I inhibitor or a pharmaceutically acceptable salt thereof wherein the amount of said inhibitors is such that the combination thereof is therapeutically effective in the treatment of colorectal cancer.
  • RAF kinase refers to any one of a family of serine/threonine- protein kinases.
  • the family consists of three isoform members (BRAF, RCRAF (RAF-1), and ARAF).
  • 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.
  • 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” is meant to refer to any RAF kinase protein from any species, including, without limitation.
  • the RAF kinase is a human RAF kinase.
  • RAF inhibitor is used to signify a compound which is capable of interacting with one or more isoform members (BRAF, CRAF (RAF-1) and/or ARAF) of the serine/threonine-protein kinase, RAF including mutant forms.
  • RAF mutant forms include BRAF V600E, BRAF V600D, BRAF V600K, BRAF V600E + T5291 and/or BRAF V600E + G468A.
  • the RAF 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, ARAF, and CRAF kinase.
  • the RAF inhibitor or a pharmaceutically acceptable salt thereof is selective for BRAF (wild type), BRAF V600E, ARAF and CRAF.
  • the RAF inhibitor or a pharmaceutically acceptable salt thereof is selective for RBRAF (wild type), BRAF V600E, ARAF and CRAF.
  • the RAF inhibitor or a pharmaceutically acceptable salt thereof is selective for BRAF (wild type), BRAF V600D, ARAF and CRAF.
  • the RAF inhibitor or a pharmaceutically acceptable salt thereof is selective for BRAF (wild type), BRAF V600K, and CRAF. 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 CRAF kinases. In some embodiments, the RAF inhibitor or a pharmaceutically acceptable salt thereof is selective for BRAF(wild type), BRAF V600E and RCRAF. In some embodiments, the RAF inhibitor or a pharmaceutically acceptable salt thereof is selective for BRAF (wild type), BRAF V600D and CRAF. In some embodiments, the RAF inhibitor or a pharmaceutically acceptable salt thereof is selective for BRAF (wild type), BRAF V600K and CRAF. In some embodiments, the RAF inhibitor or a pharmaceutically acceptable salt thereof is selective for mutant BRAF. In some embodiments, 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.
  • pan-RAF inhibitor refers to a RAF inhibitor that inhibits more than the BRAF V600 isoform of RAF proteins.
  • topoisomerase I inhibitor refers to agents designed to interfere with the action of the enzyme topoisomerase I.
  • Irinotecan is an example of a small molecule
  • EGFR inhibitor refers to agents that inhibit the tyrosine kinase epidermal growth factor receptor (EGFR).
  • Cetuximab, panitumumab, zalutumumab, nimotuzumab, and matuzumab are examples of monoclonal antibody EGFR inhibitors.
  • Gefitinib and erlotinib are examples of small molecule EGFR inhibitors.
  • treatment is meant to include the full spectrum of intervention for the colorectal cancer from which the subject is suffering, such as administration of the combination to alleviate, slow, stop, or reverse one or more symptoms of the colorectal cancer and to delay the progression of the cancer even if the cancer is not actually eliminated.
  • Treatment can include, for example, a decrease in the severity of a symptom, the number of symptoms, or frequency of relapse, e.g., the inhibition of tumor growth, the arrest of tumor growth, or the regression of already existing tumors.
  • the term "therapeutically effective amount” as used herein to refer to combination therapy means the amount of the combination of agents taken together so that the combined effect elicits the desired biological or medicinal response, i.e., either destroys the target colorectal cancer cells or slows or arrests the progression of the colorectal cancer in a subject.
  • the "therapeutically effective amount” as used herein to refer to combination therapy would be the amount of the RAF inhibitor or the pharmaceutically acceptable salt thereof and the amount of one or more of: (i) an EGFR inhibitor or (ii) a topoisomerase I inhibitor or a pharmaceutically acceptable salt thereof that when administered together, either sequentially or simultaneously, on the same or different days during a treatment cycle, has a combined effect that is beneficial.
  • the combined effect is additive. In some embodiments, the combined effect is synergistic. Further, it will be recognized by one skilled in the art that in the case of combination therapy with a therapeutically effective amount, as in the example above, the amount of the RAF inhibitor or the pharmaceutically acceptable salt thereof and/or the amount of the one or more of: (i) an EGFR inhibitor or (ii) a topoisomerase I inhibitor or a pharmaceutically acceptable salt thereof individually may or may not be therapeutically effective.
  • Cytotoxic effect in reference to the effect of an agent on a cell, means killing of the cell.
  • Cytostatic effect means an inhibition of cell proliferation.
  • a “cytotoxic agent” means an agent that has a cytotoxic or cytostatic effect on a cell, thereby depleting or inhibiting the growth of, respectively, cells within a cell population.
  • the growth of cells contacted with a combination described herein is inhibited by at least about 50% as compared to growth of non-contacted cells.
  • cell proliferation of contacted cells is inhibited by at least about 75%, at least about 90%, or at least about 95% as compared to non-contacted cells.
  • the phrase "inhibiting cell proliferation" includes a reduction in the number of contacted cells, as compare to non-contacted cells.
  • subject means a mammal, and “mammal” includes, but is not limited to a human.
  • structures depicted herein are meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure except for the replacement of a hydrogen atom by a deuterium or tritium, or the replacement of a carbon atom by a 13 C- or 14 C -enriched carbon are within the scope of the disclosure.
  • RAF inhibitor or a pharmaceutically acceptable salt thereof inhibits more isoforms of RAF kinase proteins than BRAF V600. In some embodiment, the or a pharmaceutically acceptable salt thereof inhibits more isoforms of RAF kinase proteins than BRAF V600E. In some embodiments, the RAF inhibitor or a pharmaceutically acceptable salt thereof inhibits BRAF, mutant BRAF, ARAF, and CRAF. In some embodiments, the RAF inhibitor or a
  • the RAF inhibitor or a pharmaceutically acceptable salt thereof is selective for BRAF, BRAF V600E, ARAF and CRAF. In some embodiments, the RAF inhibitor or a pharmaceutically acceptable salt thereof is selective for BRAF, BRAF V600E, ARAF and CRAF. In some embodiments, the RAF inhibitor or a pharmaceutically acceptable salt thereof is selective for BRAF, BRAF V600D, ARAF and CRAF. In some embodiments, the RAF inhibitor or a pharmaceutically acceptable salt thereof is selective for BRAF, BRAF V600K, and CRAF. In some embodiments, the RAF inhibitor or a pharmaceutically acceptable salt thereof is selective for BRAF, BRAF V600E and CRAF. In some embodiments, the RAF inhibitor or a pharmaceutically acceptable salt thereof is selective for BRAF, BRAF V600E and CRAF. In some embodiments, the RAF inhibitor or a
  • the pharmaceutically acceptable salt thereof is selective for BRAF, BRAF V600D and CRAF. In some embodiments, the RAF inhibitor or a pharmaceutically acceptable salt thereof is selective for BRAF, BRAF V600K and CRAF. In some embodiments, the RAF inhibitor or a pharmaceutically acceptable salt thereof is selective for mutant BRAF. In some embodiments, the RAF inhibitor or a
  • 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.
  • RAF inhibitors include the compounds and pharmaceutically acceptable salts described herein, as well as compounds and pharmaceutically acceptable salts disclosed in, for example, WO 2006/065703, WO 2010/064722, WO 2011/117381, WO 2011/090738, WO 2011/161216, WO 2011/097526, WO 2011/025927, WO 2011/023773, WO 2011/147764, WO 2011/079133, and WO 2011/063159.
  • BRAF specific inhibitors include vemurafinib (Roche), dabrafenib (GSK), and encoratinib (Novatis). Also suitable for use in the methods of the disclosure are solvated and hydrated forms of any of these compounds.
  • RAF inhibitors or pharmaceutically acceptable salts thereof can be prepared in a number of ways well known to one skilled in the art of organic synthesis, including, but not limited to, the methods of synthesis described in detail in the above references.
  • the RAF inhibitor or pharmaceutically acceptable salt thereof is a compound that inhibits more isoforms of RAF kinase proteins than BRAF V600.
  • inhibitors of RAF kinase or pharmaceutically acceptable salts thereof that inhibit more isoforms of RAF kinase proteins than BRAF V600 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, HM95573, and REDX-04988
  • 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.
  • the 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 RAF inhibitor is N- ⁇ 7-cyano-6-[4-fluoro-3-( ⁇ [3-(trifluoromethyl)- phenyl]acetyl ⁇ amino)phenoxy]-l,3-benzothiazol-2-yl ⁇ cyclopropanecarboxamide (Compound B) or a pharmaceutically acceptable salt thereof;
  • RAF inhibitors such as Compound A and Compound B, that can inhibit more isoforms of RAF kinase proteins that BRAF V600 have the ability to inhibit both RAF monomer and dimer-mediated signaling, which is a key feature that distinguishes these RAF inhibitors from recently approved BRAF specific inhibitors (vemurafenib and dabrafenib).
  • 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 are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
  • 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, ethane sulfonate, 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 + (Ci_ 4 alkyl) 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.
  • the RAF kinase inhibitor inhibits more than the BRAF V600 isoform of RAF proteins.
  • the combination comprises both an EGFR inhibitor and a
  • topoisomerase I inhibitor or a pharmaceutically acceptable salt thereof.
  • the combination comprises a RAF kinase inhibitor and an EGFR inhibitor.
  • the EGFR inhibitor is cetuximab or panitumab.
  • the EGFR inhibitor is cetuximab.
  • the EGFR inhibitor is panitumab.
  • the combination comprises a RAF kinase inhibitor and a RAF kinase inhibitor
  • topoisomerase I inhibitor or a pharmaceutically acceptable salt thereof.
  • the topoisomerase I inhibitor is irinotecan or a pharmaceutically acceptable salt thereof.
  • the topoisomerase I inhibitor is irinotecan.
  • the RAF kinase inhibitor is Compound A or Compound B. In some embodiments, the RAF kinase inhibitor is Compound A. In some embodiments, the RAF kinase inhibitor is Compound B.
  • compositions comprising a combination of a RAF kinase inhibitor or a pharmaceutically acceptable salt thereof, and one or more of: (i) an EGFR inhibitor or (ii) a topoisomerase I inhibitor or a pharmaceutically acceptable salt thereof.
  • the combinations described herein may be used to treat a high unmet medical need colorectal cancer.
  • the combinations described herein are used to treat a genetically defined subset of colorectal cancer.
  • Genes such as BRAF, NRAS, and KRAS are mutated in colorectal cancer.
  • Examples of public databases which include information about mutations associated with colorectal cancers are the Database of Genotypes and Phenotypes (dbGaP) maintained by the National Center for Biotechnology Information (Bethesda, MD) and Catalogue of Somatic Mutations in Cancer (COSMIC) database maintained by the Wellcome Trust Sanger Institute (Cambridge, UK).
  • GenBank or GenPept accession numbers and useful nucleic acid and peptide sequences can be found at the website maintained by the National Center for Biotechnology Information, Bethesda, MD.
  • the content of all database accession records e.g., from Affymetrix HG133 annotation files, Entrez, GenBank, RefSeq, COSMIC) cited throughout this application (including the Tables) are hereby incorporated by reference.
  • the colorectal cancer is BRAF, NRAS, and/or KRAS mutation postitive colorectal cancer.
  • BRAF BRAF proto-oncogene, serine/threonine kinase, the gene associated with the mRNA sequence assigned as GenBank Accession No. NM_004333, SEQ ID NO: 1 (open reading frame is SEQ ID NO: 2, nucleotides 62 to 2362 of SEQ ID NO: 1), encoding GenPept Accession No. NP_004324, SEQ ID NO:3).
  • Other names for BRAF include RAFB 1 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.
  • the exons in BRAF are found in SEQ ID NO: l at nucleotide bases 1.
  • 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.
  • KRAS functions as an oncogene with GTPase activity and can be found on chromosome 12.
  • KRAS 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.
  • NRAS neuroblastoma RAS viral (v-ras) oncogene homolog, the gene associated with the mRNA sequence assigned as GenBank Accession No.
  • NRAS 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 exons in NRAS are found in SEQ ID NO: 7 at nucleotide bases 1..237 (exon 1), 238..365 (exon 2), 366..544 (exon 3), 545..704 (exon 4), 705..828 (exon 5), 829..867 (exon 6), and 868..4454 (exon 7).
  • the colorectal cancer is KRAS mutation positive colorectal cancer. In some embodiments, the colorectal cancer is a KRAS exon 2 mutation positive colorectal cancer. In some embodiments, 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.
  • the KRAS exon 2 mutation is in codon 13 Examples include, but are not limited to KRAS protein (SEQ ID NO: 6) mutations G12S, G12R, G12C, G12D, G12A, G12V, G12C, G12F, G13S, G13R, G13C, G13D, G13A, G13V, G13G, V14I, V14G, L19F, and Q22K.
  • the KRAS has a G12 mutation.
  • the KRAS has G13 mutation.
  • the colorectal cancer is a KRAS non-exon 2 mutation positive colorectal cancer. In some some embodiments, the colorectal cancer is a KRAS exon 3 or exon 4 mutation positive colorectal cancer. In some embodiments, the colorectal cancer is a KRAS exon 3 mutation positive colorectal cancer. In some embodiments, the KRAS exon 3 mutation is in codon 61. Examples include, but are not limited to KRAS protein (SEQ ID NO: 6) mutations A59T, A59E, A59G, A59T, G60G, Q61K, Q61E, Q61R, Q61L, Q61H, E63K.
  • the KRAS mutation is Q61. In some embodiments, the KRAS mutation is Q61R, Q61L, or Q61H. In some embodiments, the KRAS mutation is Q61R. In some embodiments, the KRAS mutation is Q61L. In some embodiments, the KRAS mutation is Q61H. In some embodiments, the colorectal cancer is a KRAS exon 4 mutation positive colorectal cancer. In some embodiments, the KRAS exon 4 mutation is in codon 1 17 or codon 146. In some embodiments, the KRAS exon 4 mutation is in codon 1 17. In some embodiments, the KRAS exon 4 mutation is in codon 146.
  • KRAS protein SEQ ID NO: 6 mutations Kl 17R, Kl 17N, Kl 17N, C I 18S, P121H, P 121 S, T127I, A130fs* 14, A130V, A134T, A134V, R135K, R135T, S 136N, Y137Y, G138R, G138E, G138G, P 140S, E143K, A146T, A 146P, A146V, K147K, K147N, T148fs*6, R149G, Q 150* .
  • the KRAS has a Kl 17 mutation or A146 mutation.
  • the KRAS mutation is Kl 17N.
  • the KRAS mutation is A 146T or A146V.
  • the KRAS mutation is A146T.
  • the KRAS mutation is A146V.
  • the colorectal cancer is a BRAF mutation positive colorectal cancer. In some embodiments, the colorectal cancer is a BRAF V600 mutation positive colorectal cancer.
  • Examples include, but are not limited to BRAF protein (SEQ ID NO: 3) mutations V600R,
  • the BRAF mutation is V600E. In some embodiments, the BRAF mutation is V600G. In some embodiments, the BRAF mutation is V600A. In some embodiments, the BRAF mutation is V600K. In some embodiments, the BRAF mutation is V600M. In some embodiments, the BRAF mutation is V600R. In some embodiments, the BRAF mutation is V600 K. In some embodiments, the BRAF has a V600 mutation.
  • the colorectal cancer is an NRAS mutation positive colorectal cancer. In some embodiments, the colorectal cancer is an NRAS exon 2, exon 3, or exon 4 mutation positive colorectal cancer.
  • the colorectal cancer is an NRAS non-exon 2 mutation positive colorectal cancer. In some embodiments, the colorectal cancer is an NRAS exon 3 mutation positive colorectal 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.
  • NRAS protein SEQ ID NO: 9 mutations A59T, A59S, G60E, Q61K, Q61E, Q61R, Q61P, Q61H, Q61L, Q61H, and R68T.
  • the NRAS has a Q61 mutation.
  • the colorectal cancer is an NRAS exon 4 mutation positive colorectal cancer.
  • the one or more of the NRAS exon 4 mutations is in codon 117 or codon 146.
  • the NRAS exon 4 mutation is in codon 117.
  • the NRAS exon 4 mutation is in codon 146. Examples include, but are not limited to NRAS protein (SEQ ID NO: 9) mutations A130D, H131R, E132K, G138R, P140P, A146T, A146V, A146P, A146T, and T148S.
  • the NRAS mutation is A146T.
  • the NRAS has a A 146 mutation.
  • the colorectal cancer is an NRAS exon 2 mutation positive colorectal cancer.
  • the one or more of the NRAS exon 2 mutations is in codon 12 or codon 13.
  • the NRAS exon 2 mutation is in codon 12.
  • that NRAS codon 13. Examples include, but are not limited to NRAS protein (SEQ ID NO: 9) mutations G12S, G12C, G13S, G13R, G13C, G13D, G13A, G13V, and A18T.
  • the NRAS has a G12 mutation.
  • the NRAS has a G13 mutation.
  • the colorectal cancer is relapsed, refractory, or advanced colorectal cancer. In some embodiments, the colorectal cancer is refractory. In one aspect, the colorectal cancer is primary colorectal cancer. In one aspect, refractory colorectal cancer does not respond to treatment; it is also known as resistant colorectal cancer. In some embodiments, the tumor is unresectable. In one aspect, an unresectable tumor is unable to be removed by surgery. In some embodiments, the colorectal cancer has not been previously treated. In some embodiments, the colorectal cancer is locally advanced.
  • “locally advanced” refers to a colorectal 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 colorectal cancer is metastatic. In one aspect, metastatic colorectal 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 RAF inhibitor or a pharmaceutically acceptable salt thereof and one or more of: (i) an EGFR inhibitor or (ii) a topoisomerase I inhibitor or a pharmaceutically acceptable salt thereof are administered in such a way that they provide a beneficial effect in the treatment of a colorectal cancer.
  • Administration can be by any suitable means provided that the administration provides the desired therapeutic effect, i.e., additivity or synergism.
  • the amounts or suitable dosages of the RAF inhibitor or a pharmaceutically acceptable salt thereof 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 inhibition of more isoforms of BRAF kinase proteins than BRAF V600.
  • the suitable dose level is one that achieves inhibition of BRAF, CRAF, ARAF and/or BRAFV600E.
  • the suitable dose level is one that achieves inhibition of BRAF, CRAF, and/or
  • 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. In some embodiments, the suitable dose level is one that achieves this therapeutic response and also minimizes any side effects associated with the administration of the therapeutic agent.
  • the present disclosure relates to a method of treating a subject suffering from colorectal cancer, comprising administering to the subject Compound A or a pharmaceutically acceptable salt thereof; and one or more of: (i) an EGFR inhibitor or (ii) a topoisomerase I inhibitor or a
  • Compound A or a pharmaceutically acceptable salt thereof is administered in an amount of about 400 mg to about 600 mg per dose. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered in an amount of about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg per dose. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof, is administered in an amount of about 400 mg per dose. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof, is administered in an amount of about 600 mg per dose.
  • Compound A or a pharmaceutically acceptable salt thereof is administered in an amount of about 400 mg to about 600 mg per dose on days 2, 9, 16 and 23 of a 28-day cycle. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof, is administered in an amount of about 400 mg per dose on days 2, 9, 16 and 23 of a 28-day cycle. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof, is administered in an amount of about 600 mg per dose on days 2, 9, 16 and 23 of a 28-day cycle.
  • the present disclosure relates to a method of treating a subject suffering from colorectal cancer, comprising administering to the subject Compound A or a pharmaceutically acceptable salt thereof; and one or more of: (i) an EGFR inhibitor or (ii) a topoisomerase I inhibitor or a
  • Compound A or a pharmaceutically acceptable salt thereof is administered every other day (qod) in an amount of from about 100 mg to about 200 mg per dose.
  • Compound A or a pharmaceutically acceptable salt thereof is administered in an amount of about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg per dose.
  • Compound A or a pharmaceutically acceptable salt thereof is administered in an amount of about 100 mg per dose. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof, is administered in an amount of about 160 mg per dose. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof, is administered in an amount of about 200 mg per dose.
  • Compound A or a pharmaceutically acceptable salt thereof is administered in an amount of from about 100 mg to about 200 mg on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26 of a 28-day cycle. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof, is administered in an amount of 100 mg per dose on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26 of a 28-day cycle. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof, is administered in an amount of 160 mg per dose on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26 of a 28-day cycle. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof, is administered in an amount of 200 mg per dose on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26 of a 28 -day cycle.
  • the EGFR inhibitor is cetuximab.
  • the cetuximab is administered once weekly (QW) with a rest period of 6 days between each administration in an amount of up to 400 mg/m 2 per the first dose and up to 250 mg/m 2 per dose after the first dose.
  • the cetuximab is administered once weekly with a rest period of 6 days between each administration in an amount of about 400 mg/m 2 per the first dose and in an amount of about 250 mg/m 2 per dose after the first dose.
  • the cetuximab is administered in an amount of about 400 mg/m 2 per dose on day 1 (cycle 1) and in an amount of about 250 mg/m 2 per dose on days 1, 8, 15 and 22 (all cycles thereafter) of a 28-day cycle. In some embodiments, the cetuximab is administered over about 1-hour by IV infusion.
  • the EGFR inhibitor is panitumumab.
  • the panitumab is administered in an amount of about 6 mg/kg every 14 days as an intravenous infusion over 60 minutes ( ⁇ 1000 mg) or 90 minutes (>1000 mg).
  • the irinotecan is administered in an amount of up to 180 mg/m 2 dose. In some embodiments, the irinotecan is administered in an amount of about 180 mg/m 2 dose. In some embodiments, the irinotecan is administered in an amount of about 180 mg/m 2 on days 1 and 15 of a 28- day cycle. In some embodiments, the irinotecan is administered over 90 min by IV infusion.
  • the method further comprises administering one or more antiemetics selected from dexamethasone, 5HT 3 blocker (ondanestron, granisetron) and prochlorperazine.
  • one or more antiemetics selected from dexamethasone, 5HT 3 blocker (ondanestron, granisetron) and prochlorperazine.
  • the disclosure provides a method for extending duration of response to treatment in subject suffering from colorectal cancer comprising administering to the subject a RAF inhibitor or a pharmaceutically acceptable salt thereof; and one or more of: (i) an EGFR inhibitor or (ii) a
  • topoisomerase I inhibitor or a pharmaceutically acceptable salt thereof; the amount of said inhibitors being such that the combination thereof is effective for extending the duration of response.
  • the RAF inhibitor or a pharmaceutically acceptable salt thereof can be administered by any method known to one skilled in the art.
  • the RAF inhibitor or a pharmaceutically acceptable salt thereof can be administered in some embodiments as a pharmaceutical composition of a RAF inhibitor and a pharmaceutically acceptable carrier, such as those described herein.
  • a pharmaceutically acceptable carrier such as those described herein.
  • the pharmaceutical composition of a RAF inhibitor or a pharmaceutically acceptable salt thereof is a solid dispersion extrudate as described in WO2015148828A1.
  • the pharmaceutical composition of a RAF inhibitor or a pharmaceutically acceptable salt thereof is a solid dispersion extrudate comprising a vinylpyrrolidinone-vinyl acetate copolymer and one or more pharmaceutical acceptable excipients.
  • the copolymer is copovidone e.g, Kollidon® VA64.
  • the pharmaceutical composition of a RAF inhibitor or a pharmaceutically acceptable salt thereof is amorphous.
  • the one or more of: (i) an EGFR inhibitor ir (ii) a topoisomerase I inhibitor or a pharmaceutically acceptable salt thereof can be administered by any method known to one skilled in the art.
  • a pharmaceutically acceptable salt of the RAF inhibitor or the one or more of: (i) an EGFR inhibitor or (ii) a topoisomerase I inhibitor or a pharmaceutically acceptable salt thereof is utilized, the salt preferably is derived from an inorganic or organic acid or base.
  • suitable salts see, e.g., Berge et al, J. Pharm. Sci. 66: 1-19 (1977) and Remington: The Science and Practice of Pharmacy, 20th Ed. , ed. A. Gennaro, Lippincott Williams & Wilkins, 2000.
  • Nonlimiting examples of suitable acid addition salts include the following: acetate, adipate, alginate, aspartate, benzoate, benzene sulfonate, bisulfate, butyrate, citrate, camphorate, camphor sulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate,
  • lucoheptanoate glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3 -phenyl -propionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate.
  • Suitable base addition salts include, without limitation, ammonium salts, alkali metal salts, such as sodium and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts, salts with organic bases, such as dicyclohexylamine, N-methyl-D-glucamine, t-butylamine, ethylene diamine, ethanolamine, and choline, and salts with amino acids such as arginine, lysine, and so forth.
  • alkali metal salts such as sodium and potassium salts
  • alkaline earth metal salts such as calcium and magnesium salts
  • salts with organic bases such as dicyclohexylamine, N-methyl-D-glucamine, t-butylamine, ethylene diamine, ethanolamine, and choline
  • amino acids such as arginine, lysine, and so forth.
  • basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides, such as benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates
  • long chain halides such as
  • 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 an active 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 active 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.
  • Remington The Science and Practice of Pharmacy, 20th Ed. , ed. A. Gennaro, Lippincott Williams & Wilkins, 2000 discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof.
  • any conventional carrier medium is incompatible with the compounds of the disclosure, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this disclosure.
  • 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.
  • compositions of this disclosure are formulated for pharmaceutical administration to a mammal.
  • 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 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.
  • the formulations of the disclosure may be designed to be short-acting, fast-releasing, or long-acting.
  • compounds 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, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as,
  • 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 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. [081] In order to prolong the effect of a compound of the present disclosure, it may be desirable to slow the absorption of the compound from subcutaneous or intramuscular injection.
  • Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or
  • microemulsions that are compatible with body tissues.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this disclosure with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert,
  • 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 example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate
  • 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.
  • the active agents can also be in micro-encapsulated 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 pharmaceutical formulating art.
  • 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 a compound of this disclosure include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component 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 a compound to the body.
  • Such dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • 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 compounds and compositions of the present disclosure 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.
  • the disclosure includes a kit, comprising (i) a RAF inhibitor or a pharmaceutically salt thereof; and one or more of: (i) an EGFR inhibitor or (ii) a topoisomerase I inhibitor or a
  • RAF inhibitor or a pharmaceutically salt thereof in combination with the one or more of: (i) an EGFR inhibitor or a pharmaceutically salt thereof or (ii) a topoisomerase I inhibitor or a pharmaceutically salt thereof.
  • the present disclosure relates to a kit, comprising (i) a RAF inhibitor or a pharmaceutically salt thereof; and one or more of: (i) an EGFR inhibitor or a pharmaceutically salt thereof or (ii) a topoisomerase I inhibitor or a pharmaceutically salt thereof when used to treat colorectal cancer in a subject; and instructions for administering the RAF inhibitor or a pharmaceutically salt thereof, in combination with the one or more of: (i) an EGFR inhibitor or a pharmaceutically salt thereof or (ii) a topoisomerase I inhibitor or a pharmaceutically acceptable salt thereof.
  • the present disclosure relates to methods for treating a subject suffering from colorectal 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 colorectal cancer by administering to the subject a pharmaceutical composition described herein, said method comprising: subjecting a nucleic acid sample from a colorectal cancer (tumor) sample from the subject to BRAF, NRAS, or KRAS mutational testing or PCR, wherein the presence of at least one mutation in 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 colorectal cancer, said method comprising: i) obtaining a nucleic acid sample from a colorectal 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 pharmaceutical composition 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.
  • a probe e.g., a nucleic acid probe, e.g., a hybridization probe
  • 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 (Bethesda, MD) and Catalogue of Somatic Mutations in Cancer (COSMIC) database maintained by the Wellcome Trust Sanger Institute (Cambridge, UK).
  • dbGaP Database of Genotypes and Phenotypes
  • COSMIC Catalogue of Somatic Mutations in Cancer
  • 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. (201 1) J. Genet. Genomics 38:95-109 and Shendure and Hanlee (2008) Nature Biotech. 26: 1 135-1 145).
  • 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.
  • SOLIDTM analyzer (Applied Biosystems, Carlsbad, CA), Polonator G.007 (Dover Systems, Salem, NH), HELISCOPETM (Helicos Biosciences Corp., Cambridge, MA)
  • SOLIDTM analyzer Applied Biosystems, Carlsbad, CA
  • Polonator G.007 Denssion Inhibition of PCR products
  • HELISCOPETM Helicos Biosciences Corp., Cambridge, MA
  • 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
  • RNA can be isolated using standard procedures (see e.g., Chomczynski and Sacchi (1987) Anal. Biochem. 162: 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 Biosy stems, Austin, TX).
  • kits ⁇ e.g., a QIAGEN® Group RNEASY® isolation kit (Valencia, CA) or LEUKOLOCKTM Total RNA Isolation System, Ambion division of Applied Biosy stems, Austin, TX).
  • RNAse inhibitors may be added to the lysis buffer.
  • tRNA transfer RNA
  • rRNA ribosomal RNA
  • 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, immunohistochemistry,
  • FISH fluorescence in situ hybridization
  • FACS analyses northern blot, southern blot, INFINIUM® DNA analysis Bead Chips (Illumina, Inc., San Diego, CA), quantitative PCR, bacterial artificial chromosome arrays, single nucleotide polymorphism (SNP) arrays (Affymetrix, Santa Clara, CA) or cytogenetic analyses.
  • SNP single nucleotide polymorphism
  • Examples of techniques for detecting differences of at least one nucleotide between two nucleic acids include, but are not limited to, selective oligonucleotide hybridization, selective
  • 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.
  • kinase activity of Compound A was determined using a biochemical fluorescence resonance energy transfer (FRET) assay as described in WO 2009/006389.
  • FRET fluorescence resonance energy transfer
  • IC50 concentration (IC50) values of Compound A for mutant BRAF V600E, wild-type BRAF, and wild-type CRAF kinases is shown below in Table 1.
  • Compound A binds to the inactive, DFG-out conformation of BRAF kinase.
  • Example 2 In vivo tumor efficacy of Compound A in colon xenograft model
  • a xenograft study was performed using the subcutaneous (SC) human colon xenograft model, COLO205 (harboring BRAF V600E mutation).
  • COLO205 tumor-bearing female CRL NU/NU mice were treated orally with Compound A in combination with irinotecan (Pharmacia & Upjohn).
  • the purpose of the study was to evaluate efficacy of Compound A in combination with irinotecan in the BRAF mutant COLO 205 colon xenograft model (Table 2).
  • COLO 205 tumor-bearing NU/NU mice were dosed orally with Compound A (25 mg/kg, PO, QD) plus irinotecan (10 mg/kg, IP, Monday through Friday for 2 weeks). Cohorts of mice were also administered with irinotecan or Compound A as a single agent treatment.
  • NU/NU and female mice 6-8 weeks of age with an average weight of 25 grams were purchased from Charles River Laboratories. Vehicle for the test article was Polyethylene Glycol 400 (PEG400).
  • Compound A Prep was as follows: 25g of Compound A /vehicle was added to a tarred glass amber vialthat contains 16.67mL of PEG400, capped tightly and the mixture was sonicated until no drug particles remain and a solution is achieved. The result was 6 mg/mL Compound A in PEG400.
  • COLO 205 cell lines were obtained from NCI (Bethesda, Maryland). Cells were grown in RPMI 1640 + 10% fetal bovine serum + 1% L-glutamine. All cells were maintained at 37°C in humidified atmosphere equilibrated with 10% CO 2 and 90% air.
  • Percent Tumor Growth Inhibition is calculated by the change in mean treated tumor volume divided by the change in mean control tumor volume, multiplied by 100 and subtracted from 100%.
  • Compound A was administered orally at 25 mg/kg to COLO 205 tumor-bearing mice once daily either as a single agent or in combination with irinotecan (10 mg/kg, IP, Monday through Friday for 2 weeks).
  • Irinotecan demonstrated statistically significant efficacy compared to the combination vehicle controls (P ⁇ 0.05 from days 18-36) in these COLO 205 tumor-bearing mice following the second cycle of dosing (Figure 1; Data are Mean ⁇ SEM of 9-10 mice per treatment group. *** P ⁇ 0.001 or *P ⁇ 0.05 compared to combination vehicle control from Days 18 to 36. C*** P ⁇ 0.001 comparing Compound A versus irinotecan combination from days 31-56.).
  • Example 3 Prophetic Example of Methods for Measuring Markers
  • the BRAF RGQ PCR Kit v2 combines two technologies, ARMS® and Scorpions®, to detect mutations in real-time PCR assays.
  • This assay detects BRAF V600 mutations V600E (GAG) and V600E complex (GAA), V600D (GAT), V600K (A AG), V600R (AGG).
  • the kit detects the presence of the V600E (GAG) and V600E complex (GAA) but does not distinguish between them.
  • Scorpions are PCR primer covalently linked to a fluorescently labeled probe (i.e. FAMTM or HEXTM) and a quencher. During PCR when the probe is bound to the amplicon, the fluorophore and quencher become separated resulting in an increase in fluorescence signal.
  • FAMTM or HEXTM fluorescently labeled probe
  • the BRAF RGQ PCR Kit v2 comprises a two-step procedure.
  • the control assay is performed to assess the total amplifiable BRAF DNA in a sample.
  • both the mutation and control assays are performed to determine the presence or absence of mutant DNA.
  • the control assay labeled with FAM, is used to assess the total amplifiable BRAF DNA in a sample.
  • the control assay amplifies a region of exon 3 of the BRAF gene.
  • the primers and Scorpion probe are designed to amplify independently of any known BRAF polymorphisms.
  • Each mutation assay contains a FAM-labeled Scorpion probe and an ARMS primer for discrimination between the wild-type DNA and a specific mutant DNA.
  • Scorpions real-time assays uses the number of PCR cycles necessary to detect a fluorescent signal above a background signal as a measure of the target molecules present at the beginning of the reaction.
  • the point at which the signal is detected above background fluorescence is called the 'cycle threshold' (Ct).
  • Sample ACt values are calculated as the difference between the mutation assay Ct and control assay Ct from the same sample. Samples are classed as mutation positive if they give a ACt less than the Cut-Off ACt value for that assay. Above this value, the sample either contains less than the percentage of mutation able to be detected by the kit (beyond the limit of the assays), or the sample is mutation negative.
  • the ACt values are calculated as follows, ensuring that the mutation and control Ct values are from the same sample:
  • Sample control Ct can range between 27-33
  • Sample mutation Ct can range between 15-40
  • Acceptable ACt for the mutant call is ⁇ 6 or 7
  • Qiagen NRAS assay for the detection of NRAS Q61 mutations includes:
  • Tumors were removed four hours after dosing and pERK (T202/Y204) levels were determined by RPPA (reverse phase protein array).
  • RPPA reverse phase protein array
  • the results for the PHTX-24C xenogRAFt model are provided in Figure 4.
  • the results for the CR-1530 xenograft model are provided in Figure 5.
  • In vivo tumor efficacy was then performed in these two KRAS non-exon 2 mutation positive colorectal cancer xenograft models as described in examples 5 and 6.
  • Example 5 In vivo tumor efficacy of in the PHTX-24C xenograft model (KRAS non-exon 2 mutation positive primary colorectal cancer)
  • PHTX-24C xenografts The PHTX-24C xenograft is a KRAS exon 4 positive mutation model with mutation at A146T. Tumor bearing mice were treated with:
  • TGI tumor growth inhibition
  • Compound A was formulated in 100% PEG400 as a solution, prepared weekly, and stored at room temperature (18 to 25°C).
  • Cetuximab (ERBITUX ® , 2 mg/mL, Batch Number IMD251, ImClone LLC, Branchburg, NJ, USA) was stored at 4°C and warmed to room temperature (18 to 25°C) just before dosing. Animals in the vehicle group were given 100% PEG400 plus 0.5% HPMC + 0.2% TWEEN 80.
  • the dose volume for vehicle and Compound A administration was 5 mL/kg body weight. Cetuximab was dosed at 0.5 mL/animal (1 mg/animal).
  • Balb/c nude female mice 10 weeks of age with a weight of 22.2 to 23.0 g were purchased from Shanghai SINO-British SIPPR/BK Lab Animal Ltd. Shanghai China Mouse body weight was measured after randomization.
  • mice bearing the proper size xenografts were randomly assigned into a group and treated with: vehicle (100% PEG400 plus 0.5% HPMC + 0.2% TWEEN 80), Compound A, cetuximab, or the combination of Compound A and cetuximab.
  • Percent TGI (MTV Vehicle group - MTV Treatment group) ⁇ MTV Vehicle group 100.
  • Example 5 In vivo tumor efficacy in the CR1530 xenograft model (KRAS non-exon 2 mutation positive primary colorectal cancer).
  • the CR1530 xenograft is a KRAS exon 3 positive mutation model with mutation at Q61H. Tumor bearing mice were treated with:
  • TGI tumor growth inhibition
  • Compound A was formulated in 100% PEG400 as a solution, prepared weekly, and stored at 4°C). Cetuximab (Merck KGaA, Lot number 203605) was stored at 4°C and was warmed to room temperature (18 to 25°C) just before dosing. Animals in the vehicle group were given 100% PEG400 plus 0.5% HPMC + 0.2% TWEEN 80. Balb/c nude female mice 10-12 weeks of age with a weight of 19.7 to 23.1 g were purchased from HFK Bio-Technology Co. Ltd. (Beijing, China). Mouse body weight was measured after randomization.

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Abstract

La présente invention concerne des méthodes de traitement du cancer colorectal. En particulier, l'invention concerne des méthodes de traitement du cancer colorectal par l'administration d'un inhibiteur de RAF ou d'un sel pharmaceutiquement acceptable de celui-ci, en combinaison avec un inhibiteur d'EGFR et/ou un inhibiteur de la topoisomérase I et/ou un sel pharmaceutiquement acceptable de ceux-ci.
PCT/US2016/057173 2015-10-16 2016-10-14 Polythérapie comprenant un inhibiteur de raf pour le traitement du cancer colorectal Ceased WO2017066664A1 (fr)

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CN113862364A (zh) * 2021-10-25 2021-12-31 天津市肿瘤医院（天津医科大学肿瘤医院） 结直肠癌诊断标志物、pap检测探针以及结直肠癌的检测试剂盒

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