WO2013019620A2 - Méthode de traitement du cancer au moyen d'une combinaison contenant un inhibiteur de braf, un inhibiteur de mek et un anticorps anti-ctla-4 - Google Patents

Méthode de traitement du cancer au moyen d'une combinaison contenant un inhibiteur de braf, un inhibiteur de mek et un anticorps anti-ctla-4 Download PDF

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Publication number
WO2013019620A2
WO2013019620A2 PCT/US2012/048552 US2012048552W WO2013019620A2 WO 2013019620 A2 WO2013019620 A2 WO 2013019620A2 US 2012048552 W US2012048552 W US 2012048552W WO 2013019620 A2 WO2013019620 A2 WO 2013019620A2
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cancer
compound
antibody
pharmaceutically acceptable
leukemia
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PCT/US2012/048552
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English (en)
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WO2013019620A3 (fr
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Jeffrey J. Legos
Mark J. CORNFELD
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Glaxosmithkline Llc
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Publication of WO2013019620A3 publication Critical patent/WO2013019620A3/fr

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    • 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
    • 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
    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with 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
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens

Definitions

  • the present invention relates to a method of treating cancer in a mammal and to combinations useful in such treatment.
  • the method relates to a novel combination comprising an anti-CTLA-4 antibody, with a B-Raf inhibitor, particularly A/- ⁇ 3-[5-(2-Amino-4-pyhmidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-thiazol-4-yl]-2- fluorophenyl ⁇ -2,6-difluorobenzenesulfonamide or a pharmaceutically acceptable salt thereof, and optionally further with a MEK inhibitor, particularly N-(3- ⁇ 3-cyclopropyl-5- [(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydropyrido[4,3-d]pyrimidin-1 (2H)-yl ⁇ phenyl)acetamide, or a
  • cancer results from the deregulation of the normal processes that control cell division, differentiation and apoptotic cell death and is characterized by the proliferation of malignant cells which have the potential for unlimited growth, local expansion and systemic metastasis.
  • Deregulation of normal processes include abnormalities in signal transduction pathways and response to factors which differ from those found in normal cells.
  • B-Raf inhibitors have been investigated for use in treating cancer due to increased understanding of the Ras-Raf-MEK-ERK kinase pathway (known as the MAPK pathway). Particularly, the understanding that activation of Ras proteins in response to growth factors, hormones, cytokines, etc. stimulates phosphorylation and activation of Raf kinases which, in turn, phosphorylate and activate the MEK1 and MEK2 kinases which then phosphorylate and activate the ERK1 and 2 kinases.
  • MAPK pathway Ras-Raf-MEK-ERK kinase pathway
  • Mutations in the MAPK substituent kinases are believed to negatively affect the growth signal functionality of the pathway, resulting in the establishment, development, and progression of a wide range of human cancers.
  • Naturally occurring mutations in the B-Raf kinase have been observed in significant percentages of human melanomas (Davies, H., et al., Nature (2002) 9:1 -6; Garnett, M.J. & Marais, R., Cancer Cell (2004) 6:313-319) and thyroid cancers (Cohen et al J. Nat. Cancer Inst. (2003) 95(8) 625-627 and Kimura et al Cancer Res. (2003) 63(7) 1454-1457), as well as at lower, but still significant, frequencies a number of other cancers.
  • Chemoimmunotherapy the combination of chemotherapeutic and
  • immunotherapeutic agents is a novel approach for the treatment of cancer which combines the effects of agents that directly attack tumor cells producing tumor cell necrosis or apoptosis, and agents that modulate host immune responses to the tumor.
  • Chemotherapeutic agents could enhance the effect of immunotherapy by generating tumor antigens to be presented by antigen-presenting cells creating a "polyvalent" tumor cell vaccine, and by distorting the tumor architecture, thus facilitating the penetration of the immunotherapeutic agents as well as the expanded immune population.
  • the present inventors have identified a combination of therapeutic agents that provides increased activity over monotherapy.
  • Raf inhibitor A/- ⁇ 3-[5-(2-Amino-4-pyhmidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-thiazol-4-yl]-2- fluorophenyl ⁇ -2,6-difluorobenzenesulfonamide or a pharmaceutically acceptable salt thereof is described.
  • a method of treating a susceptible cancer in a human in need thereof comprising
  • a method of reating a susceptible cancer in a human in need thereof comprising administering a combination comprising
  • a method of reating a susceptible cancer in a human in need thereof comprising administering a combination comprising
  • a method of reating a susceptible cancer in a human in need thereof comprising administering a combination comprising
  • a method of treating a susceptible cancer in a human in need thereof comprising administering a combination comprising
  • a method of treating a susceptible cancer in a human in need thereof comprising administering a combination comprising
  • the above combinations may be further combined with MEK inhibitor represented by the structure of formula
  • a method of treating a susceptible cancer in a human in need thereof comprising administering a combination comprising
  • a method of treating a susceptible cancer in a human in need thereof comprising administering a combination comprising
  • a method of treating a susceptible cancer in a human in need thereof comprising administering a combination comprising
  • a method of treating a susceptible cancer in a human in need thereof comprising administering a combination comprising
  • Compound B for the treatment of a susceptible cancer in a human.
  • a method of treating cancer in a mammal in need thereof which comprises administering a therapeutically effective amount of a combination of the invention wherein the combination is administered within a specific period and for a duration of time.
  • FIG. 1 is a chart showing number of live lymphocytes in control and tumor bearing mice after no treatment or treatment with BRAF inhibitor or combination of BRAF inhibitor and MEK inhibitor.
  • FIG. 2 is a chart showing number of CD8+ T cells in control and tumor bearing mice after no treatment or treatment with BRAF inhibitor or combination of BRAF inhibitor and MEK inhibitor.
  • FIG. 3 is a chart showing number of CD4 effector T cells in control and tumor bearing mice after no treatment or treatment with BRAF inhibitor or combination of BRAF inhibitor and MEK inhibitor.
  • FIG. 4 is a chart showing number of CD4+Foxp3+ regulatory T cells in control and tumor bearing mice after no treatment or treatment with BRAF inhibitor or combination of BRAF inhibitor and MEK inhibitor.
  • Suitable anti-CTLA4 antagonist agents for use in the methods of the invention include, without limitation, anti-CTLA4 antibodies, human anti-CTLA4 antibodies, mouse anti-CTLA4 antibodies, mammalian anti-CTLA4 antibodies, humanized anti-CTLA4 antibodies, monoclonal anti-CTLA4 antibodies, polyclonal anti-CTLA4 antibodies, chimeric anti-CTLA4 antibodies, MDX-010 (ipilimumab), tremelimumab, anti-CD28 antibodies, anti-CTLA4 adnectins, anti-CTLA4 domain antibodies, single chain anti-CTLA4 fragments, heavy chain anti-CTLA4 fragments, light chain anti-CTLA4 fragments, inhibitors of CTLA4 that agonize the costimulatory pathway, the antibodies disclosed in PCT Publication No.
  • Additional anti-CTLA4 antagonists include, but are not limited to, the following: any inhibitor that is capable of disrupting the ability of CD28 antigen to bind to its cognate ligand, to inhibit the ability of CTLA4 to bind to its cognate ligand, to augment T cell responses via the co-stimulatory pathway, to disrupt the ability of B7 to bind to CD28 and/or CTLA4, to disrupt the ability of B7 to activate the co- stimulatory pathway, to disrupt the ability of CD80 to bind to CD28 and/or CTLA4, to disrupt the ability of CD80 to activate the co-stimulatory pathway, to disrupt the ability of CD86 to bind to CD28 and/or CTLA4, to disrupt the ability of CD86 to activate the co-stimulatory pathway, and to disrupt the co-stimulatory pathway, in general from being activated.
  • CTLA-4 antibodies A preferred clinical CTLA-4 antibody is human monoclonal antibody 10DI (also referred to as MDX-OI0 and ipilimumab and available from Medarex, Inc., Bloomsbury, NJ) is disclosed in WO 01 /14424.
  • Each of the anti-CTLA4 antagonist agents referenced herein may be administered either alone or in combination with a peptide antigen (e.g., gplOO), either alone or in addition to an anti-proliferative agent disclosed herein.
  • a peptide antigen e.g., gplOO
  • a non- limiting example of a peptide antigen would be a gplOO peptide comprising, or alternatively consisting of, the sequence selected from the group consisting of: IMDQVPFSV (SEQ ID NO:3), and YLEPGPVTV (SEQ ID NO:4).
  • Such a peptide may be administered orally, or preferably by injection s.c. at 1 mg emulsified in incomplete Freund's adjuvant (IFA) injected s.c. in one extremity, and 1 mg of either the same or a different peptide emulsified in IFA may be injected in another extremity.
  • IFA incomplete Freund's adj
  • Ipilimumab refers to an anti-CTLA-4 antibody, and is a fully human lgG1 -kappa antibody derived from transgenic mice having human genes encoding heavy and light chains to generate a functional human repertoire.
  • Ipilimumab can also be referred to by its CAS Registry No. 477202-00-9, and is disclosed as antibody 10DI in PCT Publication No. WO 01 /14424, incorporated herein by reference in its entirety and for all purposes.
  • Ipilimumab describes a human monoclonal antibody or antigen-binding portion thereof that specifically binds to CTLA4, comprising a light chain variable region and a heavy chain variable region having a light chain variable region comprised of SEQ ID NO:1 , and comprising a heavy chain region comprised of SEQ ID NO:2.
  • Pharmaceutical compositions of Ipilimumab include all pharmaceutically acceptable compositions comprising Ipilimumab and one or more diluents, vehicles and/or excipients.
  • Ipilimumab examples of a pharmaceutical composition comprising Ipilimumab are provided in PCT Publication No. W02007/67959. Ipilimumab may be administered by I.V.
  • the anti-CTLA4 antibody may preferably be administered at about 0.3 -
  • a dosage of CTLA-4 antibody is administered about every three weeks.
  • the CTLA-4 antibody may be administered by an escalating dosage regimen including administering a first dosage of CTLA-4 antibody at about 3 mg/kg, a second dosage of CTLA-4 antibody at about 5 mg/kg, and a third dosage of CTLA-4 antibody at about 9 mg/kg.
  • the escalating dosage regimen includes administering a first dosage of CTLA-4 antibody at about 5 mg/kg and a second dosage ofCTLA-4 antibody at about 9 mg/kg.
  • the present invention provides an escalating dosage regimen, which includes administering an increasing dosage of CTLA-4 antibody about every six weeks.
  • a stepwise escalating dosage regimen which includes administering a first CTLA-4 antibody dosage of about 3 mg/kg, a second CTLA-4 antibody dosage of about 3 mg/kg, a third CTLA-4 antibody dosage of about 5 mg/kg, a fourth CTLA-4 antibody dosage of about 5 mg/kg, and a fifth CTLA-4 antibody dosage of about 9 mg/kg.
  • a stepwise escalating dosage regimen is provided, which includes administering a first dosage of 5 mg/kg, a second dosage of 5 mg/kg, and a third dosage of 9 mg/kg.
  • the BRaf inhibitor A/- ⁇ 3-[5-(2-Amino-4-pyrimidinyl)-2-(1 ,1 - dimethylethyl)-1 ,3-thiazol-4-yl]-2-fluorophenyl ⁇ -2,6-difluorobenzenesulfonamide or pharmaceutically acceptable salt thereof is represented by a compound formula (I):
  • Compound A the group of possible compound and salts is collectively referred to as Compound A, meaning that reference to Compound A will refer to any of the compound or pharmaceutically acceptable salt thereof in the alternative.
  • Compound A is disclosed and claimed, along with pharmaceutically acceptable salts thereof, as being useful as an inhibitor of BRaf activity, particularly in the treatment of cancer, in PCT patent application PCT/US09/42682.
  • Compound A is embodied by Examples 58a through 58e of the application.
  • the PCT application was published on 12 November 2009 as publication WO2009/137391 , and is hereby incorporated by reference.
  • the salts of the present invention are pharmaceutically acceptable salts.
  • Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention.
  • Salts of the compounds of the present invention may comprise acid addition salts derived from a nitrogen on a substituent in a compound of the present invention.
  • Representative salts include the following salts: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, monopotassium maleate, mucate, napsylate, nitrate, N- methylglucamine, ox
  • phosphate/diphosphate polygalacturonate
  • potassium salicylate
  • sodium stearate
  • subacetate succinate
  • tannate tartrate
  • teoclate tosylate
  • triethiodide triethiodide
  • solvent refers to a complex of variable stoichiometry formed by a solute (in this invention, compound of formula (I) or a salt thereof, and a solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, methanol, dimethylsulforide. ethanol and acetic acid. In one embodiment, the solvent used is a pharmaceutically acceptable solvent.
  • compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. As is known to those skilled in the art, the amount of active ingredient per dose will depend on the condition being treated, the route of administration and the age, weight and condition of the patient. Preferred unit dosage compositions are those containing a daily dose or sub-dose, or an appropriate fraction thereof, of an active ingredient. Furthermore, such pharmaceutical compositions may be prepared by any of the methods well known in the pharmacy art. More particular methods of administration are described in PCT publication WO2009/137391 .
  • the amount of Compound A (based on weight of unsalted/unsolvated amount) administered as part of the combination according to the present invention will be an amount selected from about 10mg to about 600mg.
  • the amount will be selected from about 30mg to about 300mg; suitably, the amount will be selected from about 30mg to about 280mg; suitably, the amount will be selected from about 40mg to about 260mg; suitably, the amount will be selected from about 60mg to about 240mg; suitably, the amount will be selected from about 80mg to about 220mg; suitably, the amount will be selected from about 90mg to about 210mg; suitably, the amount will be selected from about 100mg to about 200mg, suitably, the amount will be selected from about 1 10mg to about 190mg, suitably, the amount will be selected from about 120mg to about 180mg, suitably, the amount will be selected from about 130mg to about 170mg, suitably, the amount
  • the amount of Compound A administered as part of the combination according to the present invention will be an amount selected from about 10mg to about 300 mg.
  • the amount of Compound A administered as part of the combination according to the present invention is suitably selected from 10mg, 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 1 10mg, 1 15mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230mg, 235mg, 240mg, 245mg, 250mg, 255mg,
  • Compound A is administered at an amount of 150mg twice a day.
  • the selected amount of Compound A is administered once a day.
  • Compound B is disclosed and claimed, along with pharmaceutically acceptable salts thereof, and also as solvates thereof, as being useful as an inhibitor of MEK activity, particularly in treatment of cancer, in WO 2005/121 142.
  • Compound B is the compound of Example 4-1 .
  • Compound B can be prepared as described in WO 2005/121 142.
  • Compound B is in the form of a dimethyl sulfoxide solvate.
  • Compound B is in the form of a sodium salt.
  • Compound B is in the form of a solvate selected from: hydrate, acetic acid, ethanol, nitromethane, chlorobenzene, 1 -pentancol, isopropyl alcohol, ethylene glycol and 3-methyl-1 -butanol.
  • solvates and salt forms can be prepared by one of skill in the art from the description in WO 2005/121 142.
  • Compound B may be alternatively described as N-(3- ⁇ 3- cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydropyrido[4,3-d]pyrimidin-1 (2H)-yl ⁇ phenyl)acetamide.
  • the combinations of the invention are believed to have utility in disorders wherein the inhibition of B-Raf activity and the raising of a specific immune response to an anti-CTLA-4 antibody is beneficial.
  • the present invention thus also provides a combination of the invention, for use in therapy, particularly in the treatment of disorders wherein the inhibition of B-Raf activity and the raising of a specific immune response to an anti-CTLA-4 antibody is beneficial, particularly cancer.
  • a further aspect of the invention provides a method of treatment of a disorder wherein inhibition of B-Raf activity and the raising of a specific immune response to an anti-CTLA-4 antibody is beneficial, comprising administering a combination of the invention.
  • a further aspect of the invention provides a method of treatment of a disorder associated with a BRAF V600E mutation wherein inhibition of B-Raf activity and the raising of a specific immune response to an anti-CTLA-4 antibody is beneficial, comprising administering a combination of the invention.
  • a further aspect of the present invention provides the use of a combination of the invention in the manufacture of a medicament for the treatment of a disorder wherein the inhibition of B-Raf activity and the raising of a specific immune response to an anti-CTLA-4 antibody is beneficial.
  • a further aspect of the present invention provides the use of a combination of the invention in the manufacture of a medicament for the treatment of a disorder associated with a BRAF V600E mutation wherein the inhibition of B-Raf activity and the raising of a specific immune response to an anti-CTLA-4 antibody is beneficial.
  • concomitant administration refers to administration of two (or more) therapies such that the therapeutic moieties are introduced into the body at the same time, or close enough in time that either a) the first administered therapy is still in the subject's system (has not been metabolised, excreted or the like) at the time subsequent therapy(ies) are administered, or b) wherein the first administered therapy has caused up-regulation of one or more antigens within the subject, and where the second therapy is administered while said antigens are still up-regulated. Administration may be by different routes. As used herein the terms concurrently and concomitantly are substitutable.
  • the anti-CTLA-4 antibody is a) administered subsequent to completion of administration of the BRAF inhibitor, or b) administered subsequent to initial administration of the BRAF inhibitor, wherein treatment may overlap in time.
  • treatment of BRAF V600E mutant tumor cells with a specific BRAF V600E inhibitor may lead to up-regulation and therefore increased expression of melanocyte differentiation antigens (MDAs), and it is further recognized that up-regulation of MDAs may be associated with improved recognition of the tumor cells by antigen- specific T lymphocytes.
  • MDAs melanocyte differentiation antigens
  • response to treatment means a response to anti-cancer treatment may be measured in any way as is known and accepted in the art, including by following the response of the tumor (complete regression of the tumor(s) (complete response), reduction in size or volume of the tumor(s) (partial response); no apparent growth or progression of tumor(s) (stable disease), or mixed response (regression or stabilization of some tumors but not others)).
  • the effect of anti-cancer treatment may be assessed by following the patient, e.g., by
  • Any assessment of response may be compared to individuals who did not receive the treatment, or to individuals who received an alternative treatment.
  • the combination of the invention is suitable for use in treatment of a cancer such that inhibition of B-Raf activity and the raising of a specific immune response to an anti-CTLA-4 antibody has a beneficial effect.
  • "Susceptible cancers” include, but are limited to, both primary and metastatic forms of head and neck, breast cancer, inflammatory breast cancer, lung cancer, non-small cell lung cancer (NSCLC), colon cancer, prostate cancers, primary CNS tumors such as gliomas, glioblastomas, astrocytomas and ependymomas, and secondary CNS tumors (i.e., metastases to the central nervous system of tumors originating outside of the central nervous system), Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma,
  • lymphoblastic T cell leukemia Chronic myelogenous leukemia, Chronic lymphocytic leukemia, Hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia (AML), Chronic neutrophilic leukemia, plasmacytoma,
  • Immunoblastic large cell leukemia Mantle cell leukemia, megakaryoblastic leukemia, multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, hodgkins lymphoma, non-hodgkins
  • lymphoma lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, vulval cancer, cervical cancer, endometrial cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor), Barret's adenocarcinoma; billiary tract carcinomas; cholangiocarcinoma; myelodysplastic syndromes, pituitary adenoma, and testicular cancer.
  • GIST gastrointestinal stromal tumor
  • "susceptible cancer” refers to a cancer exhibiting a BRAF V600E mutation.
  • the V600E amino acid substitution in B-Raf is described, for example, in Kumar et al. (2004) J Invest Dermatol. 122(2):342-8. This mutation commonly results from a T1799A mutation in the coding sequence for human B-Raf.
  • the step of analyzing a sample from said neoplasm to determine whether a mutation encoding a V600E amino acid substitution is present in the coding sequence for B-Raf is performed by determining whether the coding sequence for B-Raf in cells of the neoplasm contains the T1799A mutation.
  • the present invention relates to a method for treating or lessening the severity of melanoma.
  • the present invention relates to a method for treating or lessening the severity of V600E-mutant melanoma.
  • the present invention relates to a method for treating or lessening the severity of V600E-mutant metastatic melanoma.
  • the regimen of combined B-Raf inhibitor compound and immunotherapeutic does not have to commence at the start of treatment and terminate with the end of treatment. It is only required that at some point during treatment both the B-Raf inhibitor and the immunotherapeutic be administered on the same days.
  • neoplasm refers to an abnormal growth of cells or tissue and is understood to include benign, i.e., non-cancerous growths, and malignant, i.e., cancerous growths.
  • neoplastic means of or related to a neoplasm.
  • the term "agent” is understood to mean a substance that produces a desired effect in a tissue, system, animal, mammal, human, or other subject. Accordingly, the term “anti-neoplastic agent” is understood to mean a substance producing an anti-neoplastic effect in a tissue, system, animal, mammal, human, or other subject. It is also to be understood that an “agent” may be a single compound, single antigen, or a combination or composition of two or more compounds or antigens.
  • treating means: (1 ) to ameliorate the condition or one or more of the biological manifestations of the condition, (2) to interfere with (a) one or more points in the biological cascade that leads to or is responsible for the condition or (b) one or more of the biological manifestations of the condition (3) to alleviate one or more of the symptoms, effects or side effects associated with the condition or one or more of the symptoms, effects or side effects associated with the condition or treatment thereof, or (4) to slow the progression of the condition or one or more of the biological manifestations of the condition.
  • prevention is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof.
  • prevention is not an absolute term. Prophylactic therapy is appropriate, for example, when a subject is considered at high risk for developing cancer, such as when a subject has a strong family history of cancer or when a subject has been exposed to a carcinogen.
  • effective amount means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.
  • therapeutically effective amount means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.
  • Compound A and the anti-CTLA-4 antibodyimmunotherapeutic may be employed in either concurrent or concomitant administration.
  • concurrent or concomitant administration may be employed in either concurrent or concomitant administration.
  • one or more doses of Compound A are administered simultaneously or separately with one or more doses of the anti-CTLA-4 antibody.
  • loading dose as used herein will be understood to mean a single dose or short duration regimen of Compound A and/or the anti-CTLA-4 antibody having a dosage higher than the maintenance dose administered to the subject to, for example, rapidly increase the blood concentration level of the drug.
  • maintenance dose as used herein will be understood to mean a dose that is serially administered (for example; at least twice), and which is intended to either slowly raise blood concentration levels of the compound to a therapeutically effective level, or to maintain such a therapeutically effective level.
  • the maintenance dose is generally administered once per day and the daily dose of the maintenance dose is lower than the total daily dose of the loading dose.
  • the mammal in the methods and uses of the present invention is a human.
  • the present invention relates to a method of treating or lessening the severity of a cancer that is either wild type or mutant for each of Raf, Ras, MEK, and PI3K/Pten.
  • This includes but is not limited to patients having cancers that are mutant for RAF, wild type for RAS, wild type for MEK, and wild type for PI3K/PTEN; mutant for RAF, mutant for RAS, wild type for MEK, and wild type for PI3K/PTEN; mutant for RAF, mutant for RAS, mutant for MEK, and wild type for PI3K/PTEN; and mutant for RAF, wild type for RAS, mutant for MEK, and wild type PI3K/PTEN .
  • 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 sequence 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, respectively. 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
  • wild type or mutant tumor cells can be identified by DNA amplification and sequencing techniques, DNA and RNA detection techniques, including, but not limited to Northern and Southern blot, respectively, and/or various biochip and array technologies. Wild type and mutant polypeptides can be detected by a variety of techniques including, but not limited to immunodiagnostic techniques such as ELISA, Western blot or immunocyto
  • PAP Pyrophosphorolysis-activated polymerization
  • PCR methods may be used. Liu, Q et al; Human Mutation 23:426-436 (2004).
  • therapeutically effective amounts of Compound A is discussed above.
  • the therapeutically effective amount of the further therapeutic agents of the present invention will depend upon a number of factors including, for example, the age and weight of the mammal, the precise condition requiring treatment, the severity of the condition, the nature of the formulation, and the route of
  • the therapeutically effective amount will be at the discretion of the attendant physician or veterinarian.
  • the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • the invented method of treatment includes administration of the disclosed BRaf inhibitor, anti-CTLA-4 antibody, and at least one additional anti-neoplastic agent.
  • any anti-neoplastic agent that has activity versus a susceptible tumor being treated may be co-administered in the treatment of cancer in the present invention.
  • examples of such agents can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S. Hellman (editors), 6 th edition (February 15, 2001 ), Lippincott Williams & Wilkins Publishers.
  • anti-neoplastic agents useful for combination with the BRaf, MEK, and PI3K inhibitors discussed above include, but are not limited to, anti-microtubule agents such as diterpenoids and vinca alkaloids; platinum coordination complexes; alkylating agents such as nitrogen mustards, oxazaphosphorines, alkylsulfonates, nitrosoureas, and triazenes; antibiotic agents such as anthracydins, actinomycins and bleomycins; topoisomerase II inhibitors such as epipodophyllotoxins; antimetabolites such as purine and pyrimidine analogues and anti-folate compounds; topoisomerase I inhibitors such as
  • camptothecins hormones and hormonal analogues; signal transduction pathway inhibitors; receptor tyrosine kinase inhibitors; serine-threonine kinase inhibitors; non- receptor tyrosine kinase inhibitors; angiogenesis inhibitors, immunotherapeutic agents; proapoptotic agents; and cell cycle signalling inhibitors.
  • Anti-microtubule or anti-mitotic agents such as diterpenoids and vinca alkaloids (such as vinblastine, vincristine, and vinorelbine); diterpenoids, such as paclitaxel (TAXOL®)and its analog docetaxel; platinum coordination complexes, such as cisplatin and carboplatin; alkylating agents, such as cyclophosphamide, melphalan, and chlorambucil; alkyl sulfonates such as busulfan; nitrosoureas such as carmustine; and triazenes such as dacarbazine.
  • diterpenoids and vinca alkaloids such as vinblastine, vincristine, and vinorelbine
  • diterpenoids such as paclitaxel (TAXOL®)and its analog docetaxel
  • platinum coordination complexes such as cisplatin and carboplatin
  • alkylating agents such as cyclophosphamide, mel
  • antibiotic anti-neoplastics such as actinomycins such as dactinomycin, anthracydins such as daunorubicin and doxorubicin; and bleomycins; topoisomerase II inhibitors, such as epipodophyllotoxins, such as etoposide and teniposide.
  • anti-neoplastic agents that may be used in combination with the invention include antimetabolite neoplastic agents, such as fluorouracil (5-fluoro-2,4- (1 H,3H) pyrimidinedione, 5-fluoro deoxyuridine (floxuridine) and 5- fluorodeoxyuridine monophosphate), methotrexate, cytarabine, mecaptopurine (PURINETHOL®), thioguanine (TABLOID®), and gemcitabine (GEMZAR®).
  • antimetabolite neoplastic agents such as fluorouracil (5-fluoro-2,4- (1 H,3H) pyrimidinedione, 5-fluoro deoxyuridine (floxuridine) and 5- fluorodeoxyuridine monophosphate
  • methotrexate such as methotrexate, cytarabine, mecaptopurine (PURINETHOL®), thioguanine (TABLOID®), and gemcita
  • Additional anti-neoplastic agents that may be used in combination with the invention include camptothecins, including, camptothecin and camptothecin derivatives available or under development as Topoisomerase I inhibitors, such as irinotecan, topotecan, and the various optical forms of 7-(4-methylpiperazino- methylene)-10,1 1 -ethylenedioxy-20-camptothecin; Irinotecan HCI (CAMPTOSAR®); Irinotecan; and Topotecan HCI (HYCAMTIN®).
  • Further anti-neoplastic agents that may be used in combination with the invention include rituximab (RITUXAN® and MABTHERA®); ofatumumab
  • mTOR inhibitors include but are not limited to rapamycin and rapalogs, RAD001 or everolimus (Afinitor), CCI-779 or temsirolimus, AP23573, AZD8055, WYE-354, WYE-600, WYE-687 and Pp121 ; bexarotene (Targretin®); and sorafenib (Nexavar®).
  • the invented combination may be used in combination with hormones useful in treating cancer.
  • hormones and hormonal analogues useful in cancer treatment include, but are not limited to, adrenocorticosteroids such as prednisone and prednisolone; aminoglutethimide and other aromatase inhibitors such as anastrozole, letrazole, vorazole, and exemestane; progestrins such as megestrol acetate; estrogens, androgens, and anti-androgens such as flutamide, nilutamide, bicalutamide, cyproterone acetate and 5a-reductases such as finasteride and dutasteride; anti-estrogens such as tamoxifen, toremifene, raloxifene, droloxifene, iodoxyfene, as well as selective estrogen receptor modulators (SERMS) such those described in U.S. Patent Nos. 5,681
  • gonadotropin-releasing hormone GnRH
  • analogues thereof which stimulate the release of leutinizing hormone (LH) and/or follicle stimulating hormone (FSH) for the treatment prostatic carcinoma, for instance, LHRH agonists and antagagonists such as goserelin acetate and luprolide.
  • the invented combination may be used in further combination with signal transduction pathway inhibitors, such as inhibitors of receptor tyrosine kinases, nonreceptor tyrosine kinases, SH2/SH3domain blockers, serine/threonine kinases, phosphotidyl inositol-3 kinases, myo-inositol signaling, and Ras oncogenes
  • signal transduction pathway inhibitors such as inhibitors of receptor tyrosine kinases, nonreceptor tyrosine kinases, SH2/SH3domain blockers, serine/threonine kinases, phosphotidyl inositol-3 kinases, myo-inositol signaling, and Ras oncogenes
  • inculding growth factor receptors include, for example, epidermal growth factor receptor (EGFr), platelet derived growth factor receptor (PDGFr), erbB2, erbB4, ret, vascular end
  • TIE-2 immunoglobulin-like and epidermal growth factor homology domains
  • IGFI insulin growth factor -I
  • cfms macrophage colony stimulating factor
  • BTK BTK
  • ckit cmet
  • FGF fibroblast growth factor
  • Trk receptors TrkA, TrkB, and TrkC
  • ephrin eph receptors
  • RET protooncogene eph receptors
  • An exemplary signal transduction pathway inhibitor is lapatinib (Tykerb/Tyverb®), a dual EGFR/ErbB2 inhibitor.
  • Tyrosine kinases which are not growth factor receptor kinases are termed non-receptor tyrosine kinases.
  • Non-receptor tyrosine kinases useful in the present invention which are targets or potential targets of anti-cancer drugs, include cSrc, Lck, Fyn, Yes, Jak, cAbl, FAK (Focal adhesion kinase), Brutons tyrosine kinase, and Bcr-Abl.
  • Such non-receptor kinases and agents which inhibit non-receptor tyrosine kinase function are described in Sinh, S. and Corey, S.J., (1999) Journal of
  • SH2/SH3 domain blockers are agents that disrupt SH2 or SH3 domain binding in a variety of enzymes or adaptor proteins including, PI3-K p85 subunit, Src family kinases, adaptor molecules (She, Crk, Nek, Grb2) and Ras-GAP.
  • SH2/SH3 domains as targets for anti-cancer drugs are discussed in Smithgall, T.E. (1995), Journal of Pharmacological and Toxicological Methods. 34(3) 125-32.
  • Inhibitors of Serine/Threonine Kinases including MAP kinase cascade blockers which include blockers of Raf kinases (rafk), Mitogen or Extracellular
  • MEKs Regulated Kinase
  • ERKs Extracellular Regulated Kinases
  • Protein kinase C family member blockers including blockers of PKCs (alpha, beta, gamma, epsilon, mu, lambda, iota, zeta).
  • IkB kinase family IKKa, IKKb
  • PKB family kinases PKB family kinases
  • akt kinase family members akt kinase family members
  • TGF beta receptor kinases Such Serine/Threonine kinases and inhibitors thereof are described in Yamamoto, T., Taya, S., Kaibuchi, K., (1999), Journal of Biochemistry.
  • Inhibitors of Phosphotidyl inositol-3 Kinase family members including blockers of PI3-kinase, ATM, DNA-PK, and Ku are also useful in the present invention.
  • Such kinases are discussed in Abraham, R.T. (1996), Current Opinion in Immunology. 8 (3) 412-8; Canman, C.E., Lim, D.S. (1998), Oncogene 17 (25) 3301 -3308; Jackson, S.P. (1997), International Journal of Biochemistry and Cell Biology. 29 (7):935-8; and Zhong, H. et al, Cancer res, (2000) 60(6), 1541 -1545.
  • Myo-inositol signaling inhibitors such as phospholipase C blockers and Myoinositol analogues.
  • signal inhibitors are described in Powis, G., and Kozikowski A., (1994) New Molecular Targets for Cancer Chemotherapy ed., Paul Workman and David Kerr, CRC press 1994, London.
  • Ras Oncogene Another group of signal transduction pathway inhibitors are inhibitors of Ras Oncogene.
  • Such inhibitors include inhibitors of farnesyltransferase, geranyl-geranyl transferase, and CAAX proteases as well as anti-sense oligonucleotides, ribozymes and immunotherapy.
  • Such inhibitors have been shown to block ras activation in cells containing wild type mutant ras , thereby acting as antiproliferation agents.
  • Ras oncogene inhibition is discussed in Scharovsky, O.G., Rozados, V.R., Gervasoni, S.I. Matar, P. (2000), Journal of Biomedical Science. 7(4) 292-8; Ashby, M.N . (1998), Current Opinion in Lipidology. 9 (2) 99 - 102; and BioChim. Biophys. Acta, (19899) 1423(3):19-30.
  • antibody antagonists to receptor kinase ligand binding may also serve as signal transduction inhibitors.
  • This group of signal transduction pathway inhibitors includes the use of humanized antibodies to the extracellular ligand binding domain of receptor tyrosine kinases.
  • Imclone C225 EGFR specific antibody see Green, M.C. et al, Monoclonal Antibody Therapy for Solid Tumors, Cancer Treat.
  • Herceptin ® erbB2 antibody see Tyrosine Kinase Signalling in Breast cancer:erbB Family Receptor Tyrosine Kinases, Breast cancer Res., 2000, 2(3), 176-183
  • 2CB VEGFR2 specific antibody see Brekken, R.A. et al, Selective Inhibition of VEGFR2 Activity by a monoclonal Anti-VEGF antibody blocks tumor growth in mice, Cancer Res. (2000) 60, 51 17-5124).
  • Anti-angiogenic agents including non-receptorMEKngiogenesis inhibitors may alo be useful .
  • Anti-angiogenic agents such as those which inhibit the effects of vascular edothelial growth factor, (for example the anti-vascular endothelial cell growth factor antibody bevacizumab [AvastinTM], and compounds that work by other mechanisms (for example linomide, inhibitors of integrin ⁇ 3 function, endostatin and angiostatin);
  • Agents used in immunotherapeutic regimens may also be useful in immunotherapeutic regimens.
  • Immunotherapy approaches including for example ex-vivo and in-vivo approaches to increase the
  • immunogenecity of patient tumour cells such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies
  • Agents used in proapoptotic regimens may also be used in the combination of the present invention.
  • CDK2, CDK4, and CDK6 are described in, for instance, Rosania et al, Exp. Opin. Ther. Patents (2000) 10(2):215-230.
  • adjuvant when used in this specification to refer to a component of the immunotherapy, it refers to a substance that is administered in conjunction with the immunotherapy to boost the patient's immune response to the
  • an immunotherapy may be an adjuvant treatment; the immunotherapeutic composition may comprise an adjuvant compound, such as those discussed below.
  • adjuvants are well known in the art and can be administered in a separate
  • the immunotherapeutics as described herein may further comprise a vaccine adjuvant, and/or an immunostimulatory cytokine or chemokine.
  • Suitable vaccine adjuvants for use in the present invention are commercially available such as, for example, Freund's Incomplete Adjuvant and Complete
  • Adjuvant (Difco Laboratories, Detroit, Ml); Merck Adjuvant 65 (Merck and Company, Inc., Rahway, NJ); AS02 (an Adjuvant System containing MPL and QS21 in an oil- in-water emulsion ; SmithKline Beecham, Philadelphia, PA); AS15 (an Adjuvant System containing MPL, QS21 , CpG and liposome); aluminium salts such as aluminium hydroxide gel (alum) or aluminium phosphate; salts of calcium, iron or zinc; an insoluble suspension of acylated tyrosine; acylated sugars; cationically or anionically derivatised polysaccharides; polyphosphazenes; biodegradable microspheres; monophosphoryl lipid A and quil A.
  • aluminium salts such as aluminium hydroxide gel (alum) or aluminium phosphate
  • salts of calcium, iron or zinc an insoluble suspension of acylated tyrosine
  • Cytokines such as GM-CSF or interleukin-2, -7, or -12, and chemokines may also be used as adjuvants.
  • the adjuvant composition induces an immune response predominantly of the Th1 type.
  • High levels of Th1 -type cytokines e.g., IFN- ⁇ , TNFa, IL-2 and IL-12
  • the level of Th1 - type cytokines will increase to a greater extent than the level of Th2-type cytokines.
  • the levels of these cytokines may be readily assessed using standard assays. For a review of the families of cytokines, see Mosmann and Coffman, Ann. Rev. Immunol. 7:145-173, 1989.
  • Th1 -type response include, for example a combination of monophosphoryl lipid A (MPL), such as 3-0-desacyl-4'- monophosphoryl lipid A together with an aluminium salt.
  • MPL monophosphoryl lipid A
  • TLR4 toll like receptor 4
  • glucosaminide phosphates as disclosed in WO9850399, WO0134617 and WO03065806 may also be used alone to generate a predominantly Th1 -type response.
  • TLR9 antagonists such as synthetic oligodeoxynucleotides
  • ODNs unmethylated CpG motifs
  • oligodeoxynucleotides Such oligonucleotides are well known and are described in, for example WO 96/02555.
  • CpG-containing oligodeoxynucleotides may also be used alone or in combination with other adjuvants.
  • an enhanced system involves the combination of a CpG-containing oligodeoxynucleotide and a saponin derivative particularly the combination of CpG and QS21 (Quillaja Saponaria Molina, fraction 21 ; Antigenics, New York, NY, USA) as disclosed in WOOO/09159 and WOOO/62800.
  • the formulation may additionally comprise an oil in water emulsion and/or tocopherol.
  • Another suitable adjuvant is a saponin, for example QS21 , that may be used alone or in combination with other adjuvants.
  • an enhanced system involves the combination of a monophosphoryl lipid A and saponin derivative, such as the combination of QS21 and MPL as described in WO 94/00153, or a less reactogenic composition where the QS21 is quenched with cholesterol, as described in WO 96/33739.
  • Other suitable formulations comprise an oil-in-water emulsion and ⁇ -tocopherol .
  • a particularly potent adjuvant formulation involving QS21 , MPL and a- tocopherol in an oil-in-water emulsion is described in WO 95/17210.
  • the adjuvants may be formulated in a liposomal composition.
  • the amount of MPL used is generally small, but depending on the
  • Immunotherapeutic formulation may be in the region of 1 -1000 g per dose, 1 -500 g per dose, or between 1 to 100 g per dose.
  • the adjuvant system comprises three immunostimulants: a CpG-containing oligonucleotide, MPL, & QS21 either presented in a liposomal formulation or an oil in water emulsion such as described in WO 95/17210.
  • the amount of CpG-containing oligodeoxynucleotide or immunostimulatory oligonucleotides in the adjuvants or immunotherapeutics of the present invention is generally small, but depending on the immunotherapeutic formulation may be in the region of 1 -1000 g per dose, between 1 -500 g per dose, or between 1 to 100 g per dose.
  • the amount of saponin for use in the adjuvants of the present invention may be in the region of 1 -1000 g per dose, between 1 -500 g per dose, between 1 -250 g per dose, or between 1 to 100 g per dose.
  • each human dose may comprise from 1 to 1000 g of protein antigen. In one embodiment, the dose may comprise 30 - 300 g of protein antigen.
  • Useful dosages for a particular immunotherapeutic, and/or for treating a particular tumor type can be ascertained by standard studies involving observation of appropriate immune responses in vaccinated subjects. Following an initial vaccination, subjects may receive one or several booster immunisation adequately spaced.
  • the adjuvant may comprise one or more of MPL, QS21 and an immunostimulatory CpG-containing oligodeoxynucleotide. In an embodiment all three immunostimulants are present. In another embodiment MPL and Qs21 are presented in an oil in water emulsion, and in the absence of a CpG-containing oligodeoxynucleotide.
  • BRAF inhibitor and anti-CTLA-4 antibody employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small amounts until the optimum effect under the
  • the total daily dosage may be divided and administered in portions during the day if desired. Intermittent therapy (e.g., one week out of three weeks or three out of four weeks) may also be used.
  • mice To measure the effect of BRAF inhibitor and the combination of BRAF inhibitor-i- MEK inhibitor on murine immune system, four cohorts of mice were utilized: control na ' fve non-tumor bearing, topical tamoxifen induced melanoma tumor bearing untreated, topical tamoxifen induced melanoma tumor bearing treated with BRAF inhibitor, and topical tamoxifen induced melanoma tumor bearing treated with BRAF and MEK inhibitors.
  • the BRAF inhibitor used was the mesylate salt of Compound A.
  • the MEK inhibitor used was the dimethyl sulfoxide solvate of
  • CD8+ T cells CD8+ T cells
  • CD4 effector T cells CD4+Foxp3+ regulatory T cells
  • the number of live lymphocytes measured in the lymph nodes was generally reduced in tumor bearing mice, perhaps representing a general immune suppression due to metastases, which were observed in all tumor bearing mice.
  • the BRAFi treated mice exhibited slightly elevated lymphocytes in comparison to the untreated (vehicle) tumor bearing mice.
  • the BRAFi and MEKi treated mice exhibited significantly elevated lymphocyte count compared to either the untreated (vehicle) mice or mice treated with BRAFi only.
  • the number of CD8+ T cells was generally reduced in tumor bearing mice compared to control (non-tumor bearing).
  • the BRAFi treated mice exhibited slightly elevated CD8+ in comparison to the untreated (vehicle) tumor bearing mice.
  • the BRAFi and MEKi treated mice exhibited significantly elevated CD8+ compared to either the untreated (vehicle) mice or mice treated with BRAFi only.
  • the number of CD4 effector cells was generally reduced in tumor bearing mice compared to control (non-tumor bearing).
  • the BRAFi treated mice exhibited slightly elevated CD4 e ff in comparison to the untreated (vehicle) tumor bearing mice.
  • the BRAFi and MEKi treated mice exhibited significantly elevated CD4 e ff compared to either the untreated (vehicle) mice or mice treated with BRAFi only.
  • the number of CD4+Foxp3+ regulatory T cells was generally reduced in tumor bearing mice compared to control (non-tumor bearing).
  • the BRAFi treated mice exhibited slightly elevated CD4 e ff in comparison to the untreated (vehicle) tumor bearing mice.
  • the BRAFi and MEKi treated mice exhibited significantly elevated CD4 e ff compared to either the untreated (vehicle) mice or mice treated with BRAFi only.

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Abstract

La présente invention concerne une combinaison contenant des agents antinéoplasiques, qui est bien plus active qu'une monothérapie. En particulier, l'invention concerne une combinaison médicamenteuse contenant un anticorps anti-CTLA-4, un inhibiteur de B-Raf (à savoir le N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-diméthyléthyl)-1,3-thiazol-4-yl]-2-fluorophényl}-2,6-difluorobenzènesulfonamide ou un sel de qualité pharmaceutique de celui-ci) et un inhibiteur de MEK (à savoir le N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophényl)amino]-6,8-diméthyl-2,4,7-trioxo-3,4,6,7-tétrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phényl)acétamide ou un sel ou solvate de qualité pharmaceutique de celui-ci).
PCT/US2012/048552 2011-07-29 2012-07-27 Méthode de traitement du cancer au moyen d'une combinaison contenant un inhibiteur de braf, un inhibiteur de mek et un anticorps anti-ctla-4 WO2013019620A2 (fr)

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WO2014158467A1 (fr) * 2013-03-12 2014-10-02 Glaxosmithkline Llc Combinaison
CN104109159A (zh) * 2013-04-17 2014-10-22 杭州普晒医药科技有限公司 苯磺酰胺噻唑化合物的新晶型及其制备方法
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CN104379581B (zh) * 2013-04-17 2017-04-12 杭州普晒医药科技有限公司 达拉菲尼的晶型及其制备方法和用途
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WO2016130917A1 (fr) * 2015-02-12 2016-08-18 Memorial Sloan Kettering Cancer Center Traitement contre le cancer à action synergique
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WO2017165778A1 (fr) 2016-03-24 2017-09-28 Millennium Pharmaceuticals, Inc. Procédés pour traiter des événements indésirables gastro-intestinaux d'origine immunitaire dans des traitements oncologiques immunitaires
WO2017165742A1 (fr) 2016-03-24 2017-09-28 Millennium Pharmaceuticals, Inc. Procédés de traitement d'événements indésirables liés à l'immunité gastro-intestinale dans des polythérapies anti-ctla4 et anti-pd-1
WO2018098352A2 (fr) 2016-11-22 2018-05-31 Jun Oishi Ciblage d'expression du point de contrôle immunitaire induit par kras

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