WO2011150044A1 - Combination - Google Patents

Combination Download PDF

Info

Publication number
WO2011150044A1
WO2011150044A1 PCT/US2011/037881 US2011037881W WO2011150044A1 WO 2011150044 A1 WO2011150044 A1 WO 2011150044A1 US 2011037881 W US2011037881 W US 2011037881W WO 2011150044 A1 WO2011150044 A1 WO 2011150044A1
Authority
WO
WIPO (PCT)
Prior art keywords
amino
chloro
methyl
administered
cancer
Prior art date
Application number
PCT/US2011/037881
Other languages
French (fr)
Inventor
Rakesh Kumar
Original Assignee
Glaxosmithkline Llc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Glaxosmithkline Llc filed Critical Glaxosmithkline Llc
Priority to EP11787314.1A priority Critical patent/EP2575460A4/en
Priority to JP2013512197A priority patent/JP2013526613A/en
Priority to US13/699,103 priority patent/US20130237554A1/en
Publication of WO2011150044A1 publication Critical patent/WO2011150044A1/en
Priority to US14/565,691 priority patent/US20150094283A1/en

Links

Classifications

    • 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
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
    • 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
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non 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
    • A61K31/506—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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

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 the VEGFR inhibitor: 5-[[4-[(2,3-dimethyl-2H-indazol-6- yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide, or a pharmaceutically acceptable salt thereof, and the Akt inhibitor: / ⁇ /- ⁇ (1 S)-2-amino-1 -[(3- fluorophenyl)methyl]ethyl ⁇ -5-chloro-4-(4-chloro-1 -methyl-1 H-pyrazol-5-yl)-2- thiophenecarboxamide, or a pharmaceutically acceptable salt thereof, pharmaceutical compositions comprising the same, and methods of using such combinations in the treatment of cancer.
  • cancer results from the deregulation of the normal processes that control cell division, differentiation and apoptotic cell death.
  • Apoptosis (programmed cell death) plays essential roles in embryonic development and pathogenesis of various diseases, such as degenerative neuronal diseases, cardiovascular diseases and cancer.
  • One of the most commonly studied pathways, which involves kinase regulation of apoptosis, is cellular signaling from growth factor receptors at the cell surface to the nucleus (Crews and Erikson, Cell, 74:215-17, 1993).
  • Angiogenesis is the development of new blood vessels from the pre-existing vasculature.
  • Angiogenesis is defined herein as involving: (i) activation of endothelial cells; (ii) increased vascular permeability; (iii) subsequent dissolution of the basement membrane and extravasation of plasma components leading to formation of a provisional fibrin gel extracellular matrix; (iv) proliferation and mobilization of endothelial cells; (v) reorganization of mobilized endothelial cells to form functional capillaries; (vi) capillary loop formation; and (vi) deposition of basement membrane and recruitment of perivascular cells to newly formed vessels.
  • Normal angiogenesis is active during tissue growth from embryonic development through maturity and then enters a period of relative quiescence during adulthood. Normal angiogenesis is also activated during wound healing, and at certain stages of the female reproductive cycle. Inappropriate or pathological angiogenesis has been associated with several disease states including various retinopathies, ischemic disease, atherosclerosis, chronic inflammatory disorders, and cancer. The role of angiogenesis in disease states is discussed, for instance, in Fan et al, Trends in Pharmacol Sci. 16:54-66; Shawveret al, DDT Vol. 2, No.2 February 1997; Folkmann, 1995, Nature Medicine 1 :27-31. In cancer the growth of solid tumors has been shown to be dependent on angiogenesis.
  • VEGF vascular endothelial growth factor receptor
  • VEGFRs vascular endothelial growth factor receptors
  • VEGF is a polypeptide, which has been linked to inappropriate or pathological angiogenesis (Pinedo, H. M. et al The Oncologist, Vol.5, No. 90001 , 1 -2, Apr. 2000).
  • VEGFR(s) are protein tyrosine kinases (PTKs) that catalyze the phosphorylation of specific tyrosine residues in proteins that are involved in the regulation of cell growth, differentiation, and survival.
  • PTKs protein tyrosine kinases
  • VEGFRI Flt-I
  • VEGFR2 Flk-I and KDR
  • VEGFR3 Flt-4
  • VEGF expression may be constitutive to tumor cells and can also be upregulated in response to certain stimuli.
  • One such stimulus is hypoxia, where VEGF expression is upregulated in both tumor and associated host tissues.
  • the VEGF ligand activates VEGFR2 by binding to its extracellular VEGF binding site. This leads to receptor dimerization of VEGFRs and autophosphorylation of tyrosine residues at the intracellular kinase domain of VEGFR2.
  • the kinase domain operates to transfer a phosphate from ATP to the tyrosine residues, thus providing binding sites for signaling proteins downstream of VEGFR-2 leading ultimately to angiogenesis.
  • antagonism of the VEGFR2 kinase domain would block phosphorylation of tyrosine residues and serve to disrupt initiation of angiogenesis.
  • inhibition at the ATP binding site of the VEGFR2 kinase domain would prevent binding of ATP and prevent phosphorylation of tyrosine residues.
  • Such disruption of the proangiogenesis signal transduction pathway associated with VEGFR2 should therefore inhibit tumor angiogenesis and thereby provide a potent treatment for cancer or other disorders associated with inappropriate angiogenesis.
  • Apoptosis plays essential roles in embryonic development and pathogenesis of various diseases, such as degenerative neuronal diseases, cardiovascular diseases and cancer. Recent work has led to the identification of various pro- and anti-apoptotic gene products that are involved in the regulation or execution of programmed cell death. Expression of anti-apoptotic genes, such as Bcl2 or Bcl-x L , inhibits apoptotic cell death induced by various stimuli. On the other hand, expression of pro-apoptotic genes, such as Bax or Bad, leads to programmed cell death (Adams et al. Science, 281 :1322-1326 (1998)). The execution of programmed cell death is mediated by caspase -1 related proteinases, including caspase-3, caspase- 7, caspase-8 and caspase-9 etc (Thornberry et al. Science, 281 :1312-1316 (1998)).
  • PI3K phosphatidylinositol 3'-OH kinase
  • Akt/PKB pathway appears important for regulating cell survival/cell death (Kulik et al. Mol. Cell. Biol. 17:1595- 1606 (1997); Franke et al, Cell, 88:435-437 (1997); Kauffmann-Zeh et al. Nature 385:544-548 (1997) Hemmings Science, 275:628-630 (1997); Dudek et al., Science, 275:661 -665 (1997)).
  • PI3K phosphatidylinositol 3'-OH kinase
  • PDGF platelet derived growth factor
  • NEF nerve growth factor
  • IGF-I insulin-like growth factor-1
  • Activated PI3K leads to the production of phosphatidylinositol (3,4,5)-triphosphate (Ptdlns (3,4,5)-P3), which in turn binds to, and promotes the activation of, the serine/threonine kinase Akt, which contains a pleckstrin homology (PH)-domain (Franke et al Cell, 81 :727-736 (1995); Hemmings Science, 277:534 (1997); Downward, Curr. Opin. Cell Biol. 10:262-267 (1998), Alessi et al., EMBO J. 15: 6541 -6551 (1996)).
  • PH pleckstrin homology
  • PI3K or dominant negative Akt/PKB mutants abolish survival-promoting activities of these growth factors or cytokines. It has been previously disclosed that inhibitors of PI3K (LY294002 or wortmannin) blocked the activation of Akt/PKB by upstream kinases. In addition, introduction of constitutively active PI3K or Akt/PKB mutants promotes cell survival under conditions in which cells normally undergo apoptotic cell death (Kulik et al. 1997, Dudek et al. 1997).
  • Akt2 is overexpressed in a significant number of ovarian (J. Q. Cheung et al. Proc. Natl. Acad. Sci. U.S.A. 89:9267-9271 (1992)) and pancreatic cancers (J. Q. Cheung et al. Proc. Natl. Acad. Sci. U.S.A. 93:3636-3641 (1996)).
  • Akt3 was found to be overexpressed in breast and prostate cancer cell lines (Nakatani et al. J. Biol.Chem. 274:21528-21532 (1999).
  • Akt-2 was over-expressed in 12% of ovarian carcinomas and that amplification of Akt was especially frequent in 50% of undifferentiated tumors, suggestion that Akt may also be associated with tumor aggressiveness (Bellacosa, et al., Int. J. Cancer, 64, pp. 280-285, 1995). Increased Akt1 kinase activity has been reported in breast, ovarian and prostate cancers (Sun et al. Am. J. Pathol. 159: 431-7 (2001 )).
  • the tumor suppressor PTEN a protein and lipid phosphatase that specifically removes the 3' phosphate of Ptdlns(3,4,5)-P3, is a negative regulator of the PI3K/Akt pathway (Li et al. Science 275:1943-1947 (1997), Stambolic et al. Cell 95:29-39 (1998), Sun et al. Proc. Nati. Acad. Sci. U.S.A. 96:6199-6204 (1999)).
  • Germline mutations of PTEN are responsible for human cancer syndromes such as Cowden disease (Liaw et al. Nature Genetics 16:64-67 (1997)).
  • PTEN is deleted in a large percentage of human tumors and tumor cell lines without functional PTEN show elevated levels of activated Akt (Li et al. supra, Guldberg et al. Cancer Research 57:3660-3663 (1997), Risinger et al. Cancer Research 57:4736-4738 (1997)).
  • One embodiment of this invention provides a method of treating cancer in a human in need thereof which comprises the in vivo administration of a therapeutically effective amount of a combination of 5-[[4-[(2,3-dimethyl-2H-indazol-6- yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulforiamide, or a pharmaceutically acceptable salt, suitably the monohydrochloride salt, thereof, and ⁇ /- ⁇ (1 S)-2-amino-1 -[(3-fluorophenyl)methyl]ethyl ⁇ -5-chloro-4-(4-chloro-1 -methyl-1 H- pyrazol-5-yl)-2-thiophenecarboxamide, or a pharmaceutically acceptable salt, suitably the hydrochloride salt, thereof, to such human.
  • One embodiment of this invention provides a method of treating cancer in a human in need thereof which comprises the in vivo administration of a therapeutically effective amount of a combination of 5-[[4-[(2,3-dimethyl-2H-indazol-6- yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulforiamide, or a pharmaceutically acceptable salt, suitably the monohydrochloride salt, thereof, and ⁇ /- ⁇ (1 S)-2-amino-1 -[(3-fluorophenyl)methyl]ethyl ⁇ -5-chloro-4-(4-chloro-1 -methyl-1 H- pyrazol-5-yl)-2-thiophenecarboxamide, or a pharmaceutically acceptable salt, suitably the hydrochloride salt, thereof, to such human,
  • the combination is administered within a specified period, and wherein the combination is administered for a duration of time.
  • One embodiment of this invention provides a method of treating cancer in a human in need thereof which comprises the in vivo administration of a therapeutically effective amount of a combination of 5-[[4-[(2,3-dimethyl-2H-indazol-6- yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulforiamide, or a pharmaceutically acceptable salt, suitably the monohydrochloride salt, thereof, and ⁇ /- ⁇ (1 S)-2-amino-1 -[(3-fluorophenyl)methyl]ethyl ⁇ -5-chloro-4-(4-chloro-1 -methyl-1 H- pyrazol-5-yl)-2-thiophenecarboxamide, or a pharmaceutically acceptable salt, suitably the hydrochloride salt, thereof, to such human,
  • Figure 1 depicts the dose response curves of cell growth inhibition by Compound A, Compound C or a combination of Compound A and Compound C on the growth of SKOV3 tumor xenografts in SCID mice.
  • the present invention relates to combinations that exhibit antiproliferative activity.
  • the method relates to methods of treating cancer by the coadministration of 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2- pyrimidinyl]amino]-2-methylbenzenesulfonamide, or a pharmaceutically acceptable salt, suitably the monohydrochloride salt, thereof, (hereinafter Compound A, or a pharmaceutically acceptable salt, suitably the monohydrochloride salt, thereof,
  • Compound A is disclosed and claimed, along with pharmaceutically acceptable salts thereof, as being useful as an inhibitor of VEGFR activity, particularly in treatment of cancer, in International Application No. PCT/US01/49367, having an International filing date of December 19, 2001 , International Publication Number WO02/0591 10 and an International Publication date of August 1 , 2002, the entire disclosure of which is hereby incorporated by reference, Compound A is the compound of Example 69.
  • Compound A can be prepared as described in International Application No. PCT/US01/49367.
  • Compound A is in the form of a monohydrochloride salt. This salt form can be prepared by one of skill in the art from the description in International Application No. PCT/US01/49367, having an International filing date of December 19, 2001 .
  • Compound A is sold commercially as the monohydrochloride salt.
  • Compound A is sold commercially as the monohydrochloride salt.
  • Compound B is disclosed and claimed, along with pharmaceutically acceptable salts thereof, as being useful as an inhibitor of AKT activity, particularly in treatment of cancer, in International Application No. PCT/US2008/053269, having an International filing date of February 7, 2008; International Publication Number WO 2008/098104 and an International Publication date of August 14, 2008, the entire disclosure of which is hereby incorporated by reference, Compound B is the compound of example 96. Compound B can be prepared as described in International Application No. PCT/US2008/053269.
  • Compound B is in the form of a hydrochloride salt.
  • the salt form can be prepared by one of skill in the art from the description in International Application No. PCT/US2010/022323, having an International filing date of January 28, 2010; International Publication Number WO 2010/088331 and an International Publication date of August 5, 2010, the entire disclosure of which is hereby incorporated by reference.
  • Compound B in the form of a hydrochloride salt can be prepared as described in International Application No. PCT/US2010/022323.
  • Compound C is a compound of the structure:
  • Compound C is disclosed and claimed, along with pharmaceutically acceptable salts thereof, as being useful as an inhibitor of AKT activity, particularly in treatment of cancer, in International Application No. PCT/US2008/053269, having an International filing date of February 7, 2008; International Publication Number WO 2008/098104 and an International Publication date of August 14, 2008, Compound C is the compound of example 224.
  • Compound C can be prepared as described in International Application No. PCT/US2008/053269.
  • Compound C is expected to perform reasonably similar to Compound B in the experiment depicted herein.
  • the administration of a therapeutically effective amount of the combinations of the invention are advantageous over the individual component compounds in that the combinations will provide one or more of the following improved properties when compared to the individual administration of a therapeutically effective amount of a component compound: i) a greater anticancer effect than the most active single agent, ii) synergistic or highly synergistic anticancer activity, iii) a dosing protocol that provides enhanced anticancer activity with reduced side effect profile, iv) a reduction in the toxic effect profile, v) an increase in the therapeutic window, or vi) an increase in the bioavailability of one or both of the component compounds.
  • the compounds of the invention may contain one or more chiral atoms, or may otherwise be capable of existing as two enantiomers.
  • the compounds of this invention include mixtures of enantiomers as well as purified enantiomers or enantiomerically enriched mixtures. Also, it is understood that all tautomers and mixtures of tautomers are included within the scope of Compound A, and pharmaceutically acceptable salts thereof, and Compound B, and pharmaceutically acceptable salts thereof.
  • the compounds of the invention may form a solvate which is understood to be a complex of variable stoichiometry formed by a solute (in this invention, Compound A or a salt thereof and/or Compound B or a salt thereof) and a solvent.
  • solvents for the purpose of the invention may not interfere with the biological activity of the solute.
  • suitable solvents include, but are not limited to, water, methanol, ethanol and acetic acid.
  • the solvent used is a pharmaceutically acceptable solvent.
  • the solvent used is water.
  • contemplated herein is a method of treating cancer using a combination of the invention where Compound A, or a pharmaceutically acceptable salt thereof, and/or Compound B or a pharmaceutically acceptable salt thereof are administered as pro-drugs.
  • Pharmaceutically acceptable pro-drugs of the compounds of the invention are readily prepared by those of skill in the art.
  • day refers to a time within one calendar day which begins at midnight and ends at the following midnight.
  • treating means: (1 ) to ameliorate or prevent the condition of 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 treatment thereof, or (4) to slow the progression of the condition or one or more of the biological manifestations of the condition.
  • Prophylactic therapy is also contemplated thereby.
  • prevention is not an absolute term.
  • 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.
  • 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.
  • the term "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.
  • the term "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.
  • “combination” and derivatives thereof, as used herein is meant either, simultaneous administration or any manner of separate sequential administration of a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, and Compound B or a pharmaceutically acceptable salt thereof.
  • the compounds are administered in a close time proximity to each other.
  • the compounds are administered in the same dosage form, e.g. one compound may be administered topically and the other compound may be administered orally.
  • both compounds are administered orally.
  • the combination kit as used herein is meant the pharmaceutical composition or compositions that are used to administer Compound A, or a pharmaceutically acceptable salt thereof, and Compound B, or a pharmaceutically acceptable salt thereof, according to the invention.
  • the combination kit can contain Compound A, or a pharmaceutically acceptable salt thereof, and Compound B, or a pharmaceutically acceptable salt thereof, in a single pharmaceutical composition, such as a tablet, or in separate pharmaceutical compositions.
  • the combination kit will contain Compound A, or a pharmaceutically acceptable salt thereof, and Compound B, or a pharmaceutically acceptable salt thereof, in separate pharmaceutical compositions.
  • the combination kit can comprise Compound A, or a pharmaceutically acceptable salt thereof, and Compound B, or a pharmaceutically acceptable salt thereof, in separate pharmaceutical compositions in a single package or in separate pharmaceutical compositions in separate packages.
  • a combination kit comprising the components:
  • Compound B or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.
  • Compound B or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier, wherein the components are provided in a form which is suitable for sequential, separate and/or simultaneous administration.
  • a first container comprising Compound A, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier;
  • a second container comprising Compound B, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier, and a container means for containing said first and second containers.
  • the "combination kit” can also be provided by instruction, such as dosage and administration instructions.
  • dosage and administration instructions can be of the kind that is provided to a doctor, for example by a drug product label, or they can be of the kind that is provided by a doctor, such as instructions to a patient.
  • the regimen of compounds administered does not have to commence with the start of treatment and terminate with the end of treatment, it is only required that the number of consecutive days in which both compounds are administered and the optional number of consecutive days in which only one of the component compounds is administered, or the indicated dosing protocol - including the amount of compound administered, occur at some point during the course of treatment.
  • Compound A means — Compound A, or a pharmaceutically acceptable salt thereof— .
  • Compound B means — Compound B, or a pharmaceutically acceptable salt thereof— .
  • Compound B is replaced by: 8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl[1 ,2,4]triazolo[3,4-f]-1 ,6- naphthyridin-3(2H)-one; which has the following structure (depicted as the chloride salt):
  • Compound B is replaced by: 8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl[1 ,2,4]triazolo[3,4-f]-1 ,6- naphthyridin-3(2H)-one or a pharmaceutically acceptable salt thereof.
  • the compound 8-[4-(1 -aminocyclobutyl)phenyl]-9-phenyl[1 ,2,4]triazolo[3,4-f]- 1 ,6-naphthyridin-3(2H)-one is disclosed and claimed, along with pharmaceutically acceptable salts thereof, as being useful as an inhibitor of AKT activity, particularly in treatment of cancer, in United States Patent 7,576,209 which issued on August 18, 2009.
  • 8-[4-(1 -aminocyclobutyl)phenyl]-9-phenyl[1 ,2,4]triazolo[3,4-f]-1 ,6-naphthyridin- 3(2H)-one can be prepared as described in United States Patent 7,576,209.
  • loading dose as used herein will be understood to mean a single dose or short duration regimen of Compound A or Compound B having a dosage higher than the maintenance dose administered to the subject to rapidly increase the blood concentration level of the drug.
  • a short duration regimen for use herein will be from: 1 to 14 days; suitably from 1 to 7 days; suitably from 1 to 3 days; suitably for three days; suitably for two days; suitably for one day.
  • the "loading dose” can increase the blood concentration of the drug to a therapeutically effective level.
  • the "loading dose” can increase the blood concentration of the drug to a therapeutically effective level in conjunction with a maintenance dose of the drug.
  • the "loading dose” can be administered once per day, or more than once per day (e.g., up to 4 times per day).
  • the “loading dose” will be administered once a day.
  • the loading dose will be an amount from 2 to 100 times the maintenance dose; suitably from 2 to 10 times; suitably from 2 to 5 times; suitably 2 times; suitably 3 times; suitably 4 times; suitably 5 times.
  • the loading dose will be administered for from 1 to 7 days; suitably from 1 to 5 days; suitably from 1 to 3 days; suitably for 1 day; suitably for 2 days; suitably for 3 days, followed by a maintenance dosing protocol.
  • 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 combinations of this invention are administered within a "specified period”.
  • the specified period can include simultaneous administration. When both compounds of the invention are administered once a day the specified period refers
  • the specified period is calculated based on the first administration of each compound on a specific day. All administrations of a compound of the invention that are subsequent to the first during a specific day are not considered when calculating the specific period.
  • the specified period will be about 24 hours; suitably they will both be administered within about 12 hours of each other - in this case, the specified period will be about 12 hours; suitably they will both be administered within about 1 1 hours of each other - in this case, the specified period will be about 1 1 hours; suitably they will both be administered within about 10 hours of each other - in this case, the specified period will be about 10 hours; suitably they will both be administered within about 9 hours of each other - in this case, the specified period will be about 9 hours; suitably they will both be administered within about 8 hours of each other - in this case, the specified period will be about 8 hours; suitably they will both be administered within about 7 hours of each other - in this case, the specified period will be about 7 hours; suitably they will both be administered within about 6 hours of each other - in this case, the specified period will be about 6 hours; suit
  • the compounds when the combination of the invention is administered for a "specified period", the compounds will be co-administered for a "duration of time".
  • duration of time and derivatives thereof, as used herein is meant that both compounds of the invention are administered within a “specified period” for an indicated number of consecutive days, optionally followed by a number of consecutive days where only one of the component compounds is administered.
  • both compounds will be administered within a specified period for at least 1 day - in this case, the duration of time will be at least 1 day; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 2 consecutive days - in this case, the duration of time will be at least 2 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 3 consecutive days - in this case, the duration of time will be at least 3 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 5 consecutive days - in this case, the duration of time will be at least 5 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 7 consecutive days - in this case, the duration of time will be at least 7 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 14 consecutive days - in this case, the duration of time will be at least 14 days; suitably,
  • both compounds are administered within a specified period for over 30 days, the treatment is considered chronic treatment and will continue until an altering event, such as a reassessment in cancer status or a change in the condition of the patient, warrants a modification to the protocol.
  • both compounds will be administered within a specified period for at least 1 day, followed by the administration of
  • the duration of time will be at least 2 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 1 day, followed by administration of
  • the duration of time will be at least 3 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 1 day, followed by administration of
  • the duration of time will be at least 4 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 1 day, followed by administration of
  • the duration of time will be at least 5 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 1 day, followed by administration of
  • the duration of time will be at least 7 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 1 day, followed by administration of
  • the duration of time will be at least 8 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 2 consecutive days, followed by administration of Compound A alone for at least 1 day - in this case, the duration of time will be at least 3 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 2 consecutive days, followed
  • the duration of time will be at least 4 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least
  • the duration of time will be at least 5 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 2 consecutive days, followed by administration of
  • the duration of time will be at least 7 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least
  • the duration of time will be at least 8 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 2 consecutive days, followed by administration of
  • the duration of time will be at least 4 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 3 consecutive
  • the duration of time will be at least 5 days; suitably, during the course of treatment, both compounds will be administered within a specified period
  • the duration of time will be at least 6 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 3 consecutive days, followed by administration of Compound A alone for at least 4 consecutive days - in this case, the duration of time will be at least 7 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 3 consecutive days, followed
  • the duration of time will be at least 8 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least
  • the duration of time will be at least 9 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 3 consecutive days, followed by administration of
  • the duration of time will be at least 5 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period
  • the duration of time will be at least 6 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 4 consecutive days, followed by
  • the duration of time will be at least 7 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least
  • the duration of time will be at least 8 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 4 consecutive days, followed by administration of
  • the duration of time will be at least 6 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 5 consecutive days, followed by administration of
  • the duration of time will be at least 8 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 5 consecutive days, followed by administration of
  • the duration of time will be at least 10 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 7 consecutive days, followed by administration of
  • the duration of time will be at least 21 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 30 consecutive days, followed by administration of
  • both compounds will be administered within a specified period for from 1 to 3
  • both compounds will be administered within a specified period for from 3 to 6 consecutive days, followed by
  • both compounds will be administered within a specified period for 2 consecutive days, followed by administration of Compound A alone for from 3 to 7 consecutive days.
  • both compounds will be administered within a specified period for from 1 to 3 days over a 7 day period, and during the other days
  • Compound A will be administered alone.
  • both compounds will be administered within a specified period for 2 days over a 7 day period, and during the other days of the 7 day period
  • Compound A will be administered alone.
  • both compounds will be administered within a specified period for at least 1 day, followed by the administration of
  • the duration of time will be at least 3 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 2 consecutive days, followed
  • the duration of time will be at least 4 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least
  • the duration of time will be at least 5 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 2 consecutive days, followed by administration of
  • the duration of time will be at least 7 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least
  • the duration of time will be at least 8 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 2 consecutive days, followed by administration of
  • the duration of time will be at least 4 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 3 consecutive
  • the duration of time will be at least 5 days; suitably, during the course of treatment, both compounds will be administered within a specified period
  • the duration of time will be at least 6 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 3 consecutive days, followed by administration of
  • the duration of time will be at least 8 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least
  • the duration of time will be at least 9 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 3 consecutive days, followed by administration of
  • the duration of time will be at least 5 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period
  • the duration of time will be at least 6 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 4 consecutive days, followed by
  • the duration of time will be at least 7 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least
  • the duration of time will be at least 8 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 4 consecutive days, followed by administration of
  • the duration of time will be at least 6 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 5 consecutive days, followed by administration of Compound B alone for at least 2 consecutive days - in this case, the duration of time will be at least 7 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 5 consecutive days, followed by administration of Compound B alone for at least 1 day - in this case, the duration of time will be at least 6 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 5 consecutive days, followed by administration of Compound B alone for at least 2 consecutive days - in this case, the duration of time will be at least 7 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 5 consecutive
  • the duration of time will be at least 8 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 5 consecutive days, followed by administration of
  • the duration of time will be at least 10 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 7 consecutive days, followed by administration of
  • the duration of time will be at least 21 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 30 consecutive days, followed by administration of
  • both compounds will be administered within a specified period for from 1 to 3
  • both compounds will be administered within a specified period for from 3 to 6 consecutive days, followed by
  • both compounds will be administered within a specified period for from 1 to 3 days over a 7 day period, and during the other days
  • Compound B will be administered alone.
  • both compounds will be administered within a specified period for 2 days over a 7 day period, and during the other days of the 7 day period
  • Compound B will be administered alone.
  • Compound A and Compound B will be administered within a specified period for from 1 to 3 days over a 7 day period,
  • this 7 day protocol is repeated for 2 cycles or for 14 days; suitably for 4 cycles or 28 days; suitably for continuous administration.
  • Compound A and Compound B will be administered within a specified period for from 1 to 3 days over a 7 day period,
  • this 7 day protocol is repeated for 2 cycles or for 14 days; suitably for 4 cycles or 28 days; suitably for continuous administration.
  • Compound A and Compound B will be administered within a specified period for 3 days over a 7 day period, and during
  • this 7 day protocol is repeated for 2 cycles or for 14 days; suitably for 4 cycles or 28 days; suitably for continuous administration.
  • Compound A and Compound B will be administered within a specified period for 3 days over a 7 day period, and during
  • this 7 day protocol is repeated for 2 cycles or for 14 days; suitably for 4 cycles or 28 days; suitably for continuous administration.
  • Compound A and Compound B will be administered within a specified period for 2 days over a 7 day period, and during
  • Compound A will be administered alone.
  • this 7 day protocol is repeated for 2 cycles or for 14 days; suitably for 4 cycles or 28 days; suitably for continuous administration.
  • Compound A and Compound B will be administered within a specified period for 2 days over a 7 day period, and during
  • this 7 day protocol is repeated for 2 cycles or for 14 days; suitably for 4 cycles or 28 days; suitably for continuous administration.
  • Compound A and Compound B will be administered within a specified period for 1 day during a 7 day period, and during
  • this 7 day protocol is repeated for 2 cycles or for 14 days; suitably for 4 cycles or 28 days; suitably for continuous administration.
  • Compound A and Compound B will be administered within a specified period for 1 day during a 7 day period, and during
  • this 7 day protocol is repeated for 2 cycles or for 14 days; suitably for 4 cycles or 28 days; suitably for continuous administration.
  • Compound A and Compound B will be administered within a specified period for from 1 to 5 days over a 14 day period,
  • this 14 day protocol is repeated for 2 cycles or for 28 days; suitably for continuous administration.
  • Compound A and Compound B will be administered within a specified period for from 1 to 5 days over a 14 day period,
  • Compound B will be administered alone.
  • this 14 day protocol is repeated for 2 cycles or for 28 days; suitably for continuous administration.
  • Compound B is subsequently administered for one or more consecutive days.
  • a drug holiday utilized between the sequential administration of one of Compound A and Compound B and the other of
  • a drug holiday is a period of days
  • the drug holiday will be a period of days selected from: 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 1 1 days, 12 days, 13 days and 14 days.
  • one of Compound A and Compound B is administered for from 1 to 30 consecutive days, followed by an optional drug holiday, followed by
  • one of Compound A and Compound B is administered for from 1 to 21 consecutive days, followed by an optional drug holiday, followed by
  • one of Compound A and Compound B is administered for from 1 to 14 consecutive days, followed by a drug holiday of from 1 to 14 days,
  • one of Compound A and Compound B is administered for from 2 to 7 consecutive days, followed by a drug holiday of from 2 to
  • Compound B will be administered first in the sequence, followed by
  • Compound B is administered for from 1 to 21 consecutive days, followed by an
  • Compound B is administered for from 3 to 21 consecutive days, followed by a drug holiday of from 1 to 14 days, followed by
  • Compound A for from 3 to 21 consecutive days.
  • Compound B is administered for from 3 to 21 consecutive days, followed by a drug
  • Compound B is administered for 21 consecutive days, followed by an optional drug holiday, followed by administration of Compound
  • Compound B is administered for 14 consecutive days, followed by a drug holiday of from 1 to 14 days, followed by
  • Compound A for 14 consecutive days.
  • Compound B is administered for 7 consecutive days, followed by a drug holiday of from 3 to 10 days,
  • Compound B is administered for 3 consecutive days, followed by a drug holiday of
  • Compound B is administered for 3 consecutive days, followed by a
  • Compound A will be administered first in the sequence, followed by
  • Compound A is administered for from 1 to 21 consecutive days, followed by an
  • Compound A is administered for from 3 to 21 consecutive days, followed by a drug holiday of from 1 to 14 days, followed by
  • Compound A is administered for from 3 to 21 consecutive days, followed by a drug
  • Compound A is administered for 21 consecutive days, followed by an optional drug holiday, followed by administration of Compound
  • Compound A is administered for 14 consecutive days, followed by a drug holiday of from 1 to 14 days, followed by
  • Compound B 2 2 administration of Compound B for 14 consecutive days.
  • Compound A is administered for 7 consecutive days, followed by a drug holiday of from 3 to 10 days, followed by administration of Compound B for 7 consecutive days.
  • a drug holiday of from 3 to 10 days, followed by administration of Compound B for 7 consecutive days.
  • Compound A is administered for 3 consecutive days, followed by a drug holiday of
  • Compound A is administered for 3 consecutive days, followed by a
  • Compound A is administered for 7 consecutive days,
  • Compound B is administered for 1 day, followed by administration
  • Compound A for 7 consecutive days.
  • Compound B is administered for 7 consecutive days.
  • a "specified period” administration and a “sequential” administration can be followed by repeat dosing or can be followed by an alternate dosing protocol, and a drug holiday may precede the repeat dosing or alternate dosing protocol.
  • the amount of Compound A administered as part of the combination according to the present invention will be an amount selected from about 50mg to about 1 ,200mg; suitably, the amount will be selected from about 100mg to about 1 ,000mg; suitably, the amount will be selected from about 100mg to about 800mg; suitably, the amount will be selected from about 100mg to about 600mg; suitably, the amount will be 50mg, suitably, the amount will be 100mg, suitably, the amount will be 200mg, suitably, the amount will be 400mg, suitably, the amount will be 600mg; suitably, the amount will be 800mg; suitably, the amount will be 1 ,000mg; suitably, the amount will be 1 ,200mg. Accordingly, the amount of
  • Compound A administered as part of the combination according to the present invention will be an amount selected from about 50mg to about 1 ,200 mg.
  • the amount of Compound A administered as part of the combination according to the present invention is suitably selected from 50mg, 100mg, 200mg,
  • Compound A is administered from 1 to 4 times a day, in one or more tablets.
  • the selected amount of Compound A is administered twice a day, in one or
  • the selected amount of Compound A is administered once a
  • the administration of Compound A will begin as a loading dose.
  • the loading dose will be an amount from 2 to 100 times the maintenance dose; suitably from 2 to 10 times; suitably from 2 to 5 times; suitably 2 times; suitably 3 times; suitably 4 times; suitably 5 times.
  • the loading does will be administered from 1 to 7 days; suitably from 1 to 5 days; suitably from 1 to 3 days; suitably for 1 day; suitably for 2 days; suitably for 3 days, followed by a maintenance dosing protocol.
  • the amount of Compound B administered as part of the combination according to the present invention will be an amount selected from about 5mg to about 500mg; suitably, the amount will be selected from about 25mg to about 400mg; suitably, the amount will be selected from about 30mg to about 375mg; suitably, the amount will be selected from about 35mg to about 350mg; suitably, the amount will be selected from about 40mg to about 300mg; suitably, the amount will be selected from about 45mg to about 275mg; suitably, the amount will be selected from about 50mg to about 250mg; suitably, the amount will be selected from about 55mg to about 225mg; suitably, the amount will be selected from about 60mg to about 200mg; suitably, the amount will be selected from about 65mg to about 175mg; suitably, the amount will be selected from about 70mg to about 150mg; suitably, the amount will be selected from about 50mg to about 300mg; suitably, the amount of the amount
  • the amount of Compound B administered as part of the combination according to the present invention will be an amount selected from
  • the amount of Compound B administered as part of the combination according to the present invention can be 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 1 10mg, 1 15mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg or 500mg.
  • the amount of Compound B administered as part of the combination according to the present invention can be 5mg, 10mg, 15mg, 20mg, 25mg, 30mg,
  • the selected amount of Compound B is administered twice a day.
  • the selected amount of Compound B is administered twice a day.
  • the administration of Compound B will begin as a loading dose.
  • the loading dose will be an amount from 2 to 100 times the maintenance dose; suitably from 2 to 10 times; suitably from 2 to 5 times; suitably 2 times; suitably 3 times; suitably 4 times; suitably 5 times.
  • the loading does will be administered from 1 to 7 days; suitably from 1 to 5 days; suitably from 1 to 3 days; suitably for 1 day; suitably for 2 days; suitably for 3 days, followed by a maintenance dosing protocol.
  • the method of the present invention may also be employed with other therapeutic methods of cancer treatment.
  • the invention further provides
  • compositions which include Compound A and/or Compound B , and one or more pharmaceutically acceptable carriers.
  • the combinations of the present invention are as described above.
  • the carrier(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation, capable of pharmaceutical formulation, and not deleterious to the recipient thereof.
  • 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 formulations are those containing a daily dose or sub-dose, or an appropriate fraction thereof, of an active ingredient. Furthermore, such pharmaceutical formulations may be prepared by any of the methods well known in the pharmacy art. Compound A and Compound B may be administered by any appropriate route.
  • Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). It will be appreciated that the preferred route may vary with, for example, the condition of the recipient of the combination and the cancer to be treated. It will also be appreciated that each of the agents administered may be administered by the same or different routes and that
  • Compound A and Compound B may be compounded together in a pharmaceutical
  • composition/formulation Suitably, Compound A and Compound B are administered in separate pharmaceutical compositions.
  • Solid or liquid pharmaceutical carriers are employed.
  • Solid carriers include, starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • Liquid carriers include syrup, peanut oil, olive oil, saline, and water.
  • the carrier may include a prolonged release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
  • the amount of solid carrier varies widely but, suitably, may be from about 25 mg to about 1 g per dosage unit.
  • the preparation will suitably be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule, or an aqueous or nonaqueous liquid suspension.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing and coloring agent can also be present.
  • the formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • Compound A in combination with Compound B are administered to a human.
  • the therapeutically effective amount of the administered agents of the present invention will depend upon a number of factors including, for example, the age and weight of the subject, the precise condition requiring treatment, the severity of the condition, the nature of the formulation, and the route of administration. Ultimately, the therapeutically effective amount will be at the discretion of the attending physician.
  • the combinations of the invention are tested for efficacy, advantageous and synergistic properties generally according to known procedures. For example:
  • AKT inhibitor Compound B
  • SID once daily
  • the percentage of tumor growth inhibition is calculated on each day of tumor measurement using the formula: 100x[1 - (average growth of the compound-treated tumors / average growth of vehicle-treated control tumors)]. Data is plotted as mean ⁇ sem for tumor volume for each group.
  • the combinations of the present invention are tested for efficacy, advantageous and synergistic properties according to known procedures such as described below.
  • the combinations of the invention are tested for efficacy, advantageous and synergistic properties generally according to the following combination cell proliferation assays.
  • Cells are plated in 384-well plates at 500 cells/well in culture media appropriate for each cell type, supplemented with 10% FBS and 1 % penicillin/streptomycin, and incubated overnight at 37°C, 5% C0 2 .
  • the cellular response is determined for each compound and/or compound combination using a 4- or 6- parameter curve fit of cell viability against concentration using the I DBS XLfit plug-in for Microsoft Excel software and determining the concentration required for 50% inhibition of cell growth (glC 50 ). Background correction is made by subtraction of values from wells containing no cells.
  • CI Combination Index
  • EHSA Excess Over Highest Single Agent
  • EOBIiss Excess Over Bliss
  • Tumor volume in the two different vehicle treated groups increased at similar rate, suggesting minimal effect of these vehicles on the SKOV3 tumor growth.
  • Compound A treatment at 100 mg/kg, twice daily resulted in 47% inhibition of tumor growth compared to vehicle treated mice.
  • Treatment of mice with Compound C at 10 and 30 mg/kg, once daily, resulted in 67% and 86% inhibition of tumor growth, respectively, compared to vehicle treated mice.
  • Combined treatment with Compound A (100 mg/kg, twice daily) and Compound C at 10 or 30 mg/kg resulted in 75% and 95% inhibition of tumor growth, respectively, suggesting an increase in tumor growth inhibition in the combination group compared to AKT inhibitor alone.
  • Table 1 Effect of Compound C and Compound A alone and in combination on the growth of human ovarian xenografts (SKOV-3) in SCID mice
  • the present invention relates to a method for treating or lessening the severity of a cancer selected from: brain (gliomas), glioblastomas, Bannayan- Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast, inflammatory breast cancer, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, prostate, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid,
  • a cancer selected from: brain (gliomas), glioblastomas, Bannayan- Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast, inflammatory breast cancer, 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, Chronic neutrophilic leukemia, Acute lymphoblastic T cell leukemia, Plasmacytoma, Immunoblastic large cell leukemia, Mantle cell leukemia, Multiple myeloma Megakaryoblastic leukemia, multiple myeloma, acute megakaryocyte leukemia, promyelocytic leukemia, Erythroleukemia,
  • lymphoma malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma,
  • neuroblastoma bladder cancer, urothelial cancer, lung cancer, vulval cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor) and testicular cancer.
  • the present invention relates to a method for treating or lessening the severity of a cancer selected from: brain (gliomas), glioblastomas, Bannayan- Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, prostate, sarcoma and thyroid.
  • a cancer selected from: brain (gliomas), glioblastomas, Bannayan- Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, prostate, sarcoma and thyroid.
  • the present invention relates to a method for treating or lessening the severity of a cancer selected from ovarian, breast, pancreatic and prostate.
  • the present invention relates to a method of treating or lessening the severity of a cancer that is either wild type or mutant for Ras/Raf and either wild type or mutant for PIK3CA/PTEN.
  • the present invention also relates to a method of treating or lessening the severity of a cancer that has activated AKT, e.g., by mutation or amplification of AKT1 , AKT2 or AKT3 genes.
  • the present invention also relates to a method of treating or lessening the severity of a cancer that has activated EGFR or ErbB-2, e.g., by mutation, amplification of the gene or overexpression of the protein.
  • 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
  • Cancers that are either wild type or mutant for Ras/Raf, PIK3CA/PTEN, AKT, EGFR or ErbB-2 or have amplification of PIK3CA, AKT, EGFR or ErbB-2 genes or have overexpression of EGFR or ErbB2 protein are identified by known methods.
  • wild type or mutant Ras/Raf, PIK3CA/PTEN, AKT EGFR or ErbB-2 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 or in-situ hybridization. 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 immunocytochemistry.
  • This invention provides a combination comprising 5-[[4-[(2,3- dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2- methylbenzenesulfonamide, or a pharmaceutically acceptable salt, suitably the monohydrochloride salt, thereof, and / ⁇ /- ⁇ (1 S)-2-amino-1 -[(3- fluorophenyl)methyl]ethyl ⁇ -5-chloro-4-(4-chloro-1 -methyl-1 H-pyrazol-5-yl)-2- thiophenecarboxamide, or a pharmaceutically acceptable salt, suitably the hydrochloride salt, thereof.
  • This invention also provides for a combination comprising 5-[[4-[(2,3- dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2- methylbenzenesulfonamide, or a pharmaceutically acceptable salt, suitably the monohydrochloride salt, thereof, and / ⁇ /- ⁇ (1 S)-2-amino-1 -[(3- fluorophenyl)methyl]ethyl ⁇ -5-chloro-4-(4-chloro-1 -methyl-1 H-pyrazol-5-yl)-2- thiophenecarboxamide, or a pharmaceutically acceptable salt, suitably the hydrochloride salt, thereof.
  • This invention also provides for a combination comprising 5-[[4-[(2,3- dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2- methylbenzenesulfonamide, or a pharmaceutically acceptable salt, suitably the monohydrochloride salt, thereof, and / ⁇ /- ⁇ (1 S)-2-amino-1 -[(3- fluorophenyl)methyl]ethyl ⁇ -5-chloro-4-(4-chloro-1 -methyl-1 H-pyrazol-5-yl)-2- thiophenecarboxamide, or a pharmaceutically acceptable salt, suitably the hydrochloride salt, thereof, for use in treating cancer.
  • This invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a combination of 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2- pyrimidinyl]amino]-2-methylbenzenesulfonamide, or a pharmaceutically acceptable salt, suitably the monohydrochloride salt, thereof, and / ⁇ /- ⁇ (1 S)-2-amino-1 -[(3- fluorophenyl)methyl]ethyl ⁇ -5-chloro-4-(4-chloro-1 -methyl-1 H-pyrazol-5-yl)-2- thiophenecarboxamide, or a pharmaceutically acceptable salt, suitably the hydrochloride salt, thereof.
  • This invention also provides a combination kit comprising 5-[[4-[(2,3- dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2- methylbenzenesulfonamide, or a pharmaceutically acceptable salt, suitably the monohydrochloride salt, thereof, and / ⁇ /- ⁇ (1 S)-2-amino-1 -[(3- fluorophenyl)methyl]ethyl ⁇ -5-chloro-4-(4-chloro-1 -methyl-1 H-pyrazol-5-yl)-2- thiophenecarboxamide, or a pharmaceutically acceptable salt, suitably the hydrochloride salt, thereof.
  • This invention also provides for the use of a combination comprising 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2- methylbenzenesulfonamide, or a pharmaceutically acceptable salt, suitably the monohydrochloride salt, thereof, and / ⁇ /- ⁇ (1 S)-2-amino-1 -[(3- fluorophenyl)methyl]ethyl ⁇ -5-chloro-4-(4-chloro-1 -methyl-1 H-pyrazol-5-yl)-2- thiophenecarboxamide, or a pharmaceutically acceptable salt, suitably the hydrochloride salt, thereof, in the manufacture of a medicament.
  • This invention also provides for the use of a combination comprising 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2- methylbenzenesulfonamide, or a pharmaceutically acceptable salt, suitably the monohydrochloride salt, thereof, and / ⁇ /- ⁇ (1 S)-2-amino-1 -[(3- fluorophenyl)methyl]ethyl ⁇ -5-chloro-4-(4-chloro-1 -methyl-1 H-pyrazol-5-yl)-2- thiophenecarboxamide, or a pharmaceutically acceptable salt, suitably the hydrochloride salt, thereof, in the manufacture of a medicament to treat cancer.
  • This invention also provides a method of treating cancer which comprises administering a combination of 5-[[4-[(2,3-dimethyl-2H-indazol-6- yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulforiamide, or a pharmaceutically acceptable salt, suitably the monohydrochloride salt, thereof, and ⁇ /- ⁇ (1 S)-2-amino-1 -[(3-fluorophenyl)methyl]ethyl ⁇ -5-chloro-4-(4-chloro-1 -methyl-1 H- pyrazol-5-yl)-2-thiophenecarboxamide, or a pharmaceutically acceptable salt, suitably the hydrochloride salt, thereof, to a subject in need thereof.
  • the following examples are intended for illustration only and are not intended to limit the scope of the invention in any way.
  • An oral dosage form for administering a combination of the present invention is produced by filing a standard two piece hard gelatin capsule with the ingredients in the proportions shown in Table I, below.
  • An oral dosage form for administering one of the compounds of the present invention is produced by filing a standard two piece hard gelatin capsule with the ingredients in the proportions shown in Table II, below.
  • An oral dosage form for administering one of the compounds of the present invention is produced by filing a standard two piece hard gelatin capsule with the ingredients in the proportions shown in Table III, below. Table III
  • sucrose, microcrystalline cellulose and the compounds of the invented combination are mixed and granulated in the proportions shown with a 10% gelatin solution.
  • the wet granules are screened, dried, mixed with the starch, talc and stearic acid, then screened and compressed into a tablet.
  • Example 5 Tablet Composition
  • sucrose, microcrystalline cellulose and one of the compounds of the invented combination as shown in Table V below, are mixed and granulated in the proportions shown with a 10% gelatin solution.
  • the wet granules are screened, dried, mixed with the starch, talc and stearic acid, then screened and compressed into a tablet.
  • sucrose, microcrystalline cellulose and one of the compounds of the invented combination are mixed and granulated in the proportions shown with a 10% gelatin solution.
  • the wet granules are screened, dried, mixed with the starch, talc and stearic acid, then screened and compressed into a tablet.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Oncology (AREA)
  • Hematology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

The present invention relates to a method of treating cancer in a human and to pharmaceutical combinations useful in such treatment. In particular, the method relates to a cancer treatment method that includes administering 5-[[4-[(2,3- dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2- methylbenzenesulfonamide, or a pharmaceutically acceptable salt thereof, and Λ/- {(1 S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1 H- pyrazol-5-yl)-2-thiophenecarboxamide, or a pharmaceutically acceptable salt thereof, to a human in need thereof.

Description

COMBINATION
FIELD OF THE INVENTION
The present invention relates to a method of treating cancer in a mammal and to combinations useful in such treatment. In particular, the method relates to a novel combination comprising the VEGFR inhibitor: 5-[[4-[(2,3-dimethyl-2H-indazol-6- yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide, or a pharmaceutically acceptable salt thereof, and the Akt inhibitor: /\/-{(1 S)-2-amino-1 -[(3- fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1 -methyl-1 H-pyrazol-5-yl)-2- thiophenecarboxamide, or a pharmaceutically acceptable salt thereof, pharmaceutical compositions comprising the same, and methods of using such combinations in the treatment of cancer.
BACKGROUND OF THE INVENTION
Generally, cancer results from the deregulation of the normal processes that control cell division, differentiation and apoptotic cell death. Apoptosis (programmed cell death) plays essential roles in embryonic development and pathogenesis of various diseases, such as degenerative neuronal diseases, cardiovascular diseases and cancer. One of the most commonly studied pathways, which involves kinase regulation of apoptosis, is cellular signaling from growth factor receptors at the cell surface to the nucleus (Crews and Erikson, Cell, 74:215-17, 1993).
The process of angiogenesis is the development of new blood vessels from the pre-existing vasculature. Angiogenesis is defined herein as involving: (i) activation of endothelial cells; (ii) increased vascular permeability; (iii) subsequent dissolution of the basement membrane and extravasation of plasma components leading to formation of a provisional fibrin gel extracellular matrix; (iv) proliferation and mobilization of endothelial cells; (v) reorganization of mobilized endothelial cells to form functional capillaries; (vi) capillary loop formation; and (vi) deposition of basement membrane and recruitment of perivascular cells to newly formed vessels. Normal angiogenesis is active during tissue growth from embryonic development through maturity and then enters a period of relative quiescence during adulthood. Normal angiogenesis is also activated during wound healing, and at certain stages of the female reproductive cycle. Inappropriate or pathological angiogenesis has been associated with several disease states including various retinopathies, ischemic disease, atherosclerosis, chronic inflammatory disorders, and cancer. The role of angiogenesis in disease states is discussed, for instance, in Fan et al, Trends in Pharmacol Sci. 16:54-66; Shawveret al, DDT Vol. 2, No.2 February 1997; Folkmann, 1995, Nature Medicine 1 :27-31. In cancer the growth of solid tumors has been shown to be dependent on angiogenesis. The progression of leukemias as well as the accumulation of fluid associated with malignant ascites and pleural effusions also involve pro-angiogenic factors. (See Folkmann, J., J. Nat'1. Cancer Inst, 1990, 82, 4-6). Central to the process of angiogenesis are vascular endothelial growth factor
(VEGF) and its receptors, termed vascular endothelial growth factor receptor(s) (VEGFRs), The roles VEGF and VEGFRs play in the vascularization of solid tumors, progression of hematopoietic cancers and modulation ofvascular permeability have drawn great interest in the scientific community. VEGF is a polypeptide, which has been linked to inappropriate or pathological angiogenesis (Pinedo, H. M. et al The Oncologist, Vol.5, No. 90001 , 1 -2, Apr. 2000). VEGFR(s) are protein tyrosine kinases (PTKs) that catalyze the phosphorylation of specific tyrosine residues in proteins that are involved in the regulation of cell growth, differentiation, and survival. (A. F. Wilks, Progress in Growth Factor Research, 1990, 2, 97-1 1 1 ; S. A. Courtneidge, Dev. Supp.1 , 1993, 57-64; J. A. Cooper, Semin. Cell Biol., 1994,5(6),377-387; R. F. Paulson, Semin. Immunol.1995, 7(4), 267-277; A. C. Chan, Curro Opin. Immunol.1996, 8(3), 394-401 ).
Three PTK receptors for VEGF have been identified: VEGFRI (Flt-I); VEGFR2 (Flk-I and KDR) and VEGFR3 (Flt-4). These receptors are involved in angiogenesis and participate in signal transduction. (Mustonen, T. et al J. Cell. Biol. 1995: 129:895-898; Ferrara and Davis-Smyth, Endocrine Reviews, 18(1 ):4-25, 1997; McMahon, G., The Oncologist, Vol. 5, No 90001 , 3-10, Apr. 2000). Of particular interest is VEGFR2, which is a transmembrane receptor PTK expressed primarily in endothelial cells. Activation of VEGFR-2 by VEGF is a critical step in the signal transduction pathway that initiates tumor angiogenesis. VEGF expression may be constitutive to tumor cells and can also be upregulated in response to certain stimuli. One such stimulus is hypoxia, where VEGF expression is upregulated in both tumor and associated host tissues. The VEGF ligand activates VEGFR2 by binding to its extracellular VEGF binding site. This leads to receptor dimerization of VEGFRs and autophosphorylation of tyrosine residues at the intracellular kinase domain of VEGFR2. The kinase domain operates to transfer a phosphate from ATP to the tyrosine residues, thus providing binding sites for signaling proteins downstream of VEGFR-2 leading ultimately to angiogenesis. (Ferrara and Davis-Smyth, Endocrine Reviews, 18(1 ):4-25, 1997; McMahon, G. The Oncologist, Vol. 5, No.9000l, 3-10, Apr. 2000.)
Consequently, antagonism of the VEGFR2 kinase domain would block phosphorylation of tyrosine residues and serve to disrupt initiation of angiogenesis. Specifically, inhibition at the ATP binding site of the VEGFR2 kinase domain would prevent binding of ATP and prevent phosphorylation of tyrosine residues. Such disruption of the proangiogenesis signal transduction pathway associated with VEGFR2 should therefore inhibit tumor angiogenesis and thereby provide a potent treatment for cancer or other disorders associated with inappropriate angiogenesis.
Apoptosis (programmed cell death) plays essential roles in embryonic development and pathogenesis of various diseases, such as degenerative neuronal diseases, cardiovascular diseases and cancer. Recent work has led to the identification of various pro- and anti-apoptotic gene products that are involved in the regulation or execution of programmed cell death. Expression of anti-apoptotic genes, such as Bcl2 or Bcl-xL, inhibits apoptotic cell death induced by various stimuli. On the other hand, expression of pro-apoptotic genes, such as Bax or Bad, leads to programmed cell death (Adams et al. Science, 281 :1322-1326 (1998)). The execution of programmed cell death is mediated by caspase -1 related proteinases, including caspase-3, caspase- 7, caspase-8 and caspase-9 etc (Thornberry et al. Science, 281 :1312-1316 (1998)).
The phosphatidylinositol 3'-OH kinase (PI3K)/Akt/PKB pathway appears important for regulating cell survival/cell death (Kulik et al. Mol. Cell. Biol. 17:1595- 1606 (1997); Franke et al, Cell, 88:435-437 (1997); Kauffmann-Zeh et al. Nature 385:544-548 (1997) Hemmings Science, 275:628-630 (1997); Dudek et al., Science, 275:661 -665 (1997)). Survival factors, such as platelet derived growth factor (PDGF), nerve growth factor (NGF) and insulin-like growth factor-1 (IGF-I), promote cell survival under various conditions by inducing the activity of PI3K (Kulik et al. 1997, Hemmings 1997). Activated PI3K leads to the production of phosphatidylinositol (3,4,5)-triphosphate (Ptdlns (3,4,5)-P3), which in turn binds to, and promotes the activation of, the serine/threonine kinase Akt, which contains a pleckstrin homology (PH)-domain (Franke et al Cell, 81 :727-736 (1995); Hemmings Science, 277:534 (1997); Downward, Curr. Opin. Cell Biol. 10:262-267 (1998), Alessi et al., EMBO J. 15: 6541 -6551 (1996)). Specific inhibitors of PI3K or dominant negative Akt/PKB mutants abolish survival-promoting activities of these growth factors or cytokines. It has been previously disclosed that inhibitors of PI3K (LY294002 or wortmannin) blocked the activation of Akt/PKB by upstream kinases. In addition, introduction of constitutively active PI3K or Akt/PKB mutants promotes cell survival under conditions in which cells normally undergo apoptotic cell death (Kulik et al. 1997, Dudek et al. 1997).
Analysis of Akt levels in human tumors showed that Akt2 is overexpressed in a significant number of ovarian (J. Q. Cheung et al. Proc. Natl. Acad. Sci. U.S.A. 89:9267-9271 (1992)) and pancreatic cancers (J. Q. Cheung et al. Proc. Natl. Acad. Sci. U.S.A. 93:3636-3641 (1996)). Similarly, Akt3 was found to be overexpressed in breast and prostate cancer cell lines (Nakatani et al. J. Biol.Chem. 274:21528-21532 (1999). It was demonstrated that Akt-2 was over-expressed in 12% of ovarian carcinomas and that amplification of Akt was especially frequent in 50% of undifferentiated tumors, suggestion that Akt may also be associated with tumor aggressiveness (Bellacosa, et al., Int. J. Cancer, 64, pp. 280-285, 1995). Increased Akt1 kinase activity has been reported in breast, ovarian and prostate cancers (Sun et al. Am. J. Pathol. 159: 431-7 (2001 )).
The tumor suppressor PTEN, a protein and lipid phosphatase that specifically removes the 3' phosphate of Ptdlns(3,4,5)-P3, is a negative regulator of the PI3K/Akt pathway (Li et al. Science 275:1943-1947 (1997), Stambolic et al. Cell 95:29-39 (1998), Sun et al. Proc. Nati. Acad. Sci. U.S.A. 96:6199-6204 (1999)). Germline mutations of PTEN are responsible for human cancer syndromes such as Cowden disease (Liaw et al. Nature Genetics 16:64-67 (1997)). PTEN is deleted in a large percentage of human tumors and tumor cell lines without functional PTEN show elevated levels of activated Akt (Li et al. supra, Guldberg et al. Cancer Research 57:3660-3663 (1997), Risinger et al. Cancer Research 57:4736-4738 (1997)).
These observations demonstrate that the PI3K/Akt pathway plays important roles for regulating cell survival or apoptosis in tumorigenesis and/or cancer. It would be useful to provide a novel therapy which provides more effective and/or enhanced treatment of an individual suffering the effects of cancer.
SUMMARY OF THE INVENTION
One embodiment of this invention provides a combination comprising:
(i) a compound of Structure (I):
Figure imgf000006_0001
or a pharmaceutically acceptable salt thereof; and (ii) a compound of Structure (II):
Figure imgf000006_0002
or a pharmaceutically acceptable salt thereof.
One embodiment of this invention provides a method of treating cancer in a human in need thereof which comprises the in vivo administration of a therapeutically effective amount of a combination of 5-[[4-[(2,3-dimethyl-2H-indazol-6- yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulforiamide, or a pharmaceutically acceptable salt, suitably the monohydrochloride salt, thereof, and Λ/-{(1 S)-2-amino-1 -[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1 -methyl-1 H- pyrazol-5-yl)-2-thiophenecarboxamide, or a pharmaceutically acceptable salt, suitably the hydrochloride salt, thereof, to such human. One embodiment of this invention provides a method of treating cancer in a human in need thereof which comprises the in vivo administration of a therapeutically effective amount of a combination of 5-[[4-[(2,3-dimethyl-2H-indazol-6- yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulforiamide, or a pharmaceutically acceptable salt, suitably the monohydrochloride salt, thereof, and Λ/-{(1 S)-2-amino-1 -[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1 -methyl-1 H- pyrazol-5-yl)-2-thiophenecarboxamide, or a pharmaceutically acceptable salt, suitably the hydrochloride salt, thereof, to such human,
wherein the combination is administered within a specified period, and wherein the combination is administered for a duration of time.
One embodiment of this invention provides a method of treating cancer in a human in need thereof which comprises the in vivo administration of a therapeutically effective amount of a combination of 5-[[4-[(2,3-dimethyl-2H-indazol-6- yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulforiamide, or a pharmaceutically acceptable salt, suitably the monohydrochloride salt, thereof, and Λ/-{(1 S)-2-amino-1 -[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1 -methyl-1 H- pyrazol-5-yl)-2-thiophenecarboxamide, or a pharmaceutically acceptable salt, suitably the hydrochloride salt, thereof, to such human,
wherein the compounds of the combination are administered sequentially.
BRIEF DESCRIPTION OF THE DRAWINGS Figure - 1 Figure 1 depicts the dose response curves of cell growth inhibition by Compound A, Compound C or a combination of Compound A and Compound C on the growth of SKOV3 tumor xenografts in SCID mice.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to combinations that exhibit antiproliferative activity. Suitably, the method relates to methods of treating cancer by the coadministration of 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2- pyrimidinyl]amino]-2-methylbenzenesulfonamide, or a pharmaceutically acceptable salt, suitably the monohydrochloride salt, thereof, (hereinafter Compound A, or a pharmaceutically acceptable salt, suitably the monohydrochloride salt, thereof,
which compound is represented by Structure I:
Figure imgf000008_0001
and /\/-{(1 S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1 - methyl-1 H-pyrazol-5-yl)-2-thiophenecarboxamide, or a pharmaceutically acceptable salt, suitably the hydrochloride salt, thereof, (hereinafter Compound B or a pharmaceutically acceptable salt, suitably the hydrochloride salt, thereof,
which compound is represented by Structure II:
Figure imgf000008_0002
Compound A is disclosed and claimed, along with pharmaceutically acceptable salts thereof, as being useful as an inhibitor of VEGFR activity, particularly in treatment of cancer, in International Application No. PCT/US01/49367, having an International filing date of December 19, 2001 , International Publication Number WO02/0591 10 and an International Publication date of August 1 , 2002, the entire disclosure of which is hereby incorporated by reference, Compound A is the compound of Example 69. Compound A can be prepared as described in International Application No. PCT/US01/49367. Suitably, Compound A is in the form of a monohydrochloride salt. This salt form can be prepared by one of skill in the art from the description in International Application No. PCT/US01/49367, having an International filing date of December 19, 2001 . Compound A is sold commercially as the monohydrochloride salt. Compound
®
A is known by the generic name pazopanib and the trade name Votrient . Compound B is disclosed and claimed, along with pharmaceutically acceptable salts thereof, as being useful as an inhibitor of AKT activity, particularly in treatment of cancer, in International Application No. PCT/US2008/053269, having an International filing date of February 7, 2008; International Publication Number WO 2008/098104 and an International Publication date of August 14, 2008, the entire disclosure of which is hereby incorporated by reference, Compound B is the compound of example 96. Compound B can be prepared as described in International Application No. PCT/US2008/053269.
Suitably, Compound B is in the form of a hydrochloride salt. The salt form can be prepared by one of skill in the art from the description in International Application No. PCT/US2010/022323, having an International filing date of January 28, 2010; International Publication Number WO 2010/088331 and an International Publication date of August 5, 2010, the entire disclosure of which is hereby incorporated by reference. Compound B in the form of a hydrochloride salt can be prepared as described in International Application No. PCT/US2010/022323.
For use in the experiment and data depicted herein the AKT inhibitor used was /\/-{(1 S)-2-amino-1 -[(3,4-difluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1- methyl-1 H-pyrazol-5-yl)-2-furancarboxamide (hereinafter Compound C). Compound C is a compound of the structure:
Figure imgf000009_0001
Compound C is disclosed and claimed, along with pharmaceutically acceptable salts thereof, as being useful as an inhibitor of AKT activity, particularly in treatment of cancer, in International Application No. PCT/US2008/053269, having an International filing date of February 7, 2008; International Publication Number WO 2008/098104 and an International Publication date of August 14, 2008, Compound C is the compound of example 224. Compound C can be prepared as described in International Application No. PCT/US2008/053269. Compound C is expected to perform reasonably similar to Compound B in the experiment depicted herein. The administration of a therapeutically effective amount of the combinations of the invention are advantageous over the individual component compounds in that the combinations will provide one or more of the following improved properties when compared to the individual administration of a therapeutically effective amount of a component compound: i) a greater anticancer effect than the most active single agent, ii) synergistic or highly synergistic anticancer activity, iii) a dosing protocol that provides enhanced anticancer activity with reduced side effect profile, iv) a reduction in the toxic effect profile, v) an increase in the therapeutic window, or vi) an increase in the bioavailability of one or both of the component compounds. The compounds of the invention may contain one or more chiral atoms, or may otherwise be capable of existing as two enantiomers. Accordingly, the compounds of this invention include mixtures of enantiomers as well as purified enantiomers or enantiomerically enriched mixtures. Also, it is understood that all tautomers and mixtures of tautomers are included within the scope of Compound A, and pharmaceutically acceptable salts thereof, and Compound B, and pharmaceutically acceptable salts thereof.
The compounds of the invention may form a solvate which is understood to be a complex of variable stoichiometry formed by a solute (in this invention, Compound A or a salt thereof and/or Compound B 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, ethanol and acetic acid. Suitably the solvent used is a pharmaceutically acceptable solvent. Suitably the solvent used is water.
The pharmaceutically acceptable salts of the compounds of the invention are readily prepared by those of skill in the art.
Also, contemplated herein is a method of treating cancer using a combination of the invention where Compound A, or a pharmaceutically acceptable salt thereof, and/or Compound B or a pharmaceutically acceptable salt thereof are administered as pro-drugs. Pharmaceutically acceptable pro-drugs of the compounds of the invention are readily prepared by those of skill in the art.
When referring to a dosing protocol, the term "day", "per day" and the like, refer to a time within one calendar day which begins at midnight and ends at the following midnight.
By the term "treating" and derivatives thereof as used herein, is meant therapeutic therapy. In reference to a particular condition, treating means: (1 ) to ameliorate or prevent the condition of 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 treatment thereof, or (4) to slow the progression of the condition or one or more of the biological manifestations of the condition. Prophylactic therapy is also contemplated thereby. The skilled artisan will appreciate that "prevention" is not an absolute term. In medicine, "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. 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. As used herein, the term "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. Furthermore, the term "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. By the term "combination" and derivatives thereof, as used herein is meant either, simultaneous administration or any manner of separate sequential administration of a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, and Compound B or a pharmaceutically acceptable salt thereof. Preferably, if the administration is not simultaneous, the compounds are administered in a close time proximity to each other. Furthermore, it does not matter if the compounds are administered in the same dosage form, e.g. one compound may be administered topically and the other compound may be administered orally. Suitably, both compounds are administered orally.
By the term "combination kit" as used herein is meant the pharmaceutical composition or compositions that are used to administer Compound A, or a pharmaceutically acceptable salt thereof, and Compound B, or a pharmaceutically acceptable salt thereof, according to the invention. When both compounds are administered simultaneously, the combination kit can contain Compound A, or a pharmaceutically acceptable salt thereof, and Compound B, or a pharmaceutically acceptable salt thereof, in a single pharmaceutical composition, such as a tablet, or in separate pharmaceutical compositions. When the compounds are not administered simultaneously, the combination kit will contain Compound A, or a pharmaceutically acceptable salt thereof, and Compound B, or a pharmaceutically acceptable salt thereof, in separate pharmaceutical compositions. The combination kit can comprise Compound A, or a pharmaceutically acceptable salt thereof, and Compound B, or a pharmaceutically acceptable salt thereof, in separate pharmaceutical compositions in a single package or in separate pharmaceutical compositions in separate packages. In one aspect there is provided a combination kit comprising the components:
Compound A, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier; and
Compound B, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.
In one embodiment of the invention the combination kit comprises the following components:
Compound A, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier; and
Compound B, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier, wherein the components are provided in a form which is suitable for sequential, separate and/or simultaneous administration.
In one embodiment the combination kit comprises:
a first container comprising Compound A, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier; and
a second container comprising Compound B, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier, and a container means for containing said first and second containers.
The "combination kit" can also be provided by instruction, such as dosage and administration instructions. Such dosage and administration instructions can be of the kind that is provided to a doctor, for example by a drug product label, or they can be of the kind that is provided by a doctor, such as instructions to a patient.
Unless otherwise defined, in all dosing protocols described herein, the regimen of compounds administered does not have to commence with the start of treatment and terminate with the end of treatment, it is only required that the number of consecutive days in which both compounds are administered and the optional number of consecutive days in which only one of the component compounds is administered, or the indicated dosing protocol - including the amount of compound administered, occur at some point during the course of treatment.
2
As used herein the term "Compound A " means — Compound A, or a pharmaceutically acceptable salt thereof— .
2
As used herein the term "Compound B " means — Compound B, or a pharmaceutically acceptable salt thereof— .
In one embodiment of the present invention Compound B is replaced by: 8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl[1 ,2,4]triazolo[3,4-f]-1 ,6- naphthyridin-3(2H)-one; which has the following structure (depicted as the chloride salt):
Figure imgf000014_0001
ci
2
In one embodiment of the present invention Compound B is replaced by: 8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl[1 ,2,4]triazolo[3,4-f]-1 ,6- naphthyridin-3(2H)-one or a pharmaceutically acceptable salt thereof.
The compound 8-[4-(1 -aminocyclobutyl)phenyl]-9-phenyl[1 ,2,4]triazolo[3,4-f]- 1 ,6-naphthyridin-3(2H)-one is disclosed and claimed, along with pharmaceutically acceptable salts thereof, as being useful as an inhibitor of AKT activity, particularly in treatment of cancer, in United States Patent 7,576,209 which issued on August 18, 2009. 8-[4-(1 -aminocyclobutyl)phenyl]-9-phenyl[1 ,2,4]triazolo[3,4-f]-1 ,6-naphthyridin- 3(2H)-one can be prepared as described in United States Patent 7,576,209.
The term "loading dose" as used herein will be understood to mean a single dose or short duration regimen of Compound A or Compound B having a dosage higher than the maintenance dose administered to the subject to rapidly increase the blood concentration level of the drug. Suitably, a short duration regimen for use herein will be from: 1 to 14 days; suitably from 1 to 7 days; suitably from 1 to 3 days; suitably for three days; suitably for two days; suitably for one day. In some embodiments, the "loading dose" can increase the blood concentration of the drug to a therapeutically effective level. In some embodiments, the "loading dose" can increase the blood concentration of the drug to a therapeutically effective level in conjunction with a maintenance dose of the drug. The "loading dose" can be administered once per day, or more than once per day (e.g., up to 4 times per day). Suitably the "loading dose" will be administered once a day. Suitably, the loading dose will be an amount from 2 to 100 times the maintenance dose; suitably from 2 to 10 times; suitably from 2 to 5 times; suitably 2 times; suitably 3 times; suitably 4 times; suitably 5 times. Suitably, the loading dose will be administered for from 1 to 7 days; suitably from 1 to 5 days; suitably from 1 to 3 days; suitably for 1 day; suitably for 2 days; suitably for 3 days, followed by a maintenance dosing protocol.
The term "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.
Suitably the combinations of this invention are administered within a "specified period".
By the term "specified period" and derivatives thereof, as used herein is
2 meant the interval of time between the administration of one of Compound A and
2 2 2
Compound B and the other of Compound A and Compound B . Unless otherwise defined, the specified period can include simultaneous administration. When both compounds of the invention are administered once a day the specified period refers
2 2
to timing of the administration of Compound A and Compound B during a single day. When one or both compounds of the invention are administered more than once a day, the specified period is calculated based on the first administration of each compound on a specific day. All administrations of a compound of the invention that are subsequent to the first during a specific day are not considered when calculating the specific period.
Suitably, if the compounds are administered within a "specified period" and not administered simultaneously, they are both administered within about 24 hours of each other - in this case, the specified period will be about 24 hours; suitably they will both be administered within about 12 hours of each other - in this case, the specified period will be about 12 hours; suitably they will both be administered within about 1 1 hours of each other - in this case, the specified period will be about 1 1 hours; suitably they will both be administered within about 10 hours of each other - in this case, the specified period will be about 10 hours; suitably they will both be administered within about 9 hours of each other - in this case, the specified period will be about 9 hours; suitably they will both be administered within about 8 hours of each other - in this case, the specified period will be about 8 hours; suitably they will both be administered within about 7 hours of each other - in this case, the specified period will be about 7 hours; suitably they will both be administered within about 6 hours of each other - in this case, the specified period will be about 6 hours; suitably they will both be administered within about 5 hours of each other - in this case, the specified period will be about 5 hours; suitably they will both be administered within about 4 hours of each other - in this case, the specified period will be about 4 hours; suitably they will both be administered within about 3 hours of each other - in this case, the specified period will be about 3 hours; suitably they will be administered within about 2 hours of each other - in this case, the specified period will be about 2 hours; suitably they will both be administered within about 1 hour of each other - in this case, the specified period will be about 1 hour. As used herein, the
2 2
administration of Compound A and Compound B in less than about 45 minutes apart is considered simultaneous administration.
Suitably, when the combination of the invention is administered for a "specified period", the compounds will be co-administered for a "duration of time".
By the term "duration of time" and derivatives thereof, as used herein is meant that both compounds of the invention are administered within a "specified period" for an indicated number of consecutive days, optionally followed by a number of consecutive days where only one of the component compounds is administered.
Regarding "specified period" administration:
Suitably, during the course of treatment, both compounds will be administered within a specified period for at least 1 day - in this case, the duration of time will be at least 1 day; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 2 consecutive days - in this case, the duration of time will be at least 2 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 3 consecutive days - in this case, the duration of time will be at least 3 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 5 consecutive days - in this case, the duration of time will be at least 5 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 7 consecutive days - in this case, the duration of time will be at least 7 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 14 consecutive days - in this case, the duration of time will be at least 14 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 30 consecutive days - in this case, the duration of time will be at least 30 days. When, during the course of treatment, both compounds are administered within a specified period for over 30 days, the treatment is considered chronic treatment and will continue until an altering event, such as a reassessment in cancer status or a change in the condition of the patient, warrants a modification to the protocol.
Further regarding "specified period" administration:
Suitably, during the course of treatment, both compounds will be administered within a specified period for at least 1 day, followed by the administration of
2
Compound A alone for at least 1 day - in this case, the duration of time will be at least 2 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 1 day, followed by administration of
2
Compound A alone for at least 2 days - in this case, the duration of time will be at least 3 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 1 day, followed by administration of
2
Compound A alone for at least 3 days - in this case, the duration of time will be at least 4 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 1 day, followed by administration of
2
Compound A alone for at least 4 days - in this case, the duration of time will be at least 5 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 1 day, followed by administration of
2
Compound A alone for at least 5 days - in this case, the duration of time will be at least 6 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 1 day, followed by administration of
2
Compound A alone for at least 6 days - in this case, the duration of time will be at least 7 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 1 day, followed by administration of
2
Compound A alone for at least 7 days - in this case, the duration of time will be at least 8 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 2 consecutive days, followed by administration of Compound A alone for at least 1 day - in this case, the duration of time will be at least 3 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 2 consecutive days, followed
2
by administration of Compound A alone for at least 2 consecutive days - in this case, the duration of time will be at least 4 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least
2
2 consecutive days, followed by administration of Compound A alone for at least 3 consecutive days - in this case, the duration of time will be at least 5 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 2 consecutive days, followed by administration of
2
Compound A alone for at least 4 consecutive days - in this case, the duration of time will be at least 6 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 2 consecutive days, followed
2
by administration of Compound A alone for at least 5 consecutive days - in this case, the duration of time will be at least 7 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least
2
2 consecutive days, followed by administration of Compound A alone for at least 6 consecutive days - in this case, the duration of time will be at least 8 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 2 consecutive days, followed by administration of
2
Compound A alone for at least 7 consecutive days - in this case, the duration of time will be at least 9 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 3 consecutive days, followed
2
by administration of Compound A alone for at least 1 day - in this case, the duration of time will be at least 4 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 3 consecutive
2
days, followed by administration of Compound A alone for at least 2 consecutive days - in this case, the duration of time will be at least 5 days; suitably, during the course of treatment, both compounds will be administered within a specified period
2 for at least 3 consecutive days, followed by administration of Compound A alone for at least 3 consecutive days - in this case, the duration of time will be at least 6 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 3 consecutive days, followed by administration of Compound A alone for at least 4 consecutive days - in this case, the duration of time will be at least 7 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 3 consecutive days, followed
2
by administration of Compound A alone for at least 5 consecutive days - in this case, the duration of time will be at least 8 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least
2
3 consecutive days, followed by administration of Compound A alone for at least 6 consecutive days - in this case, the duration of time will be at least 9 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 3 consecutive days, followed by administration of
2
Compound A alone for at least 7 consecutive days - in this case, the duration of time will be at least 10 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 4 consecutive
2
days, followed by administration of Compound A alone for at least 1 day - in this case, the duration of time will be at least 5 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period
2 for at least 4 consecutive days, followed by administration of Compound A alone for at least 2 consecutive days - in this case, the duration of time will be at least 6 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 4 consecutive days, followed by
2
administration of Compound A alone for at least 3 consecutive days - in this case, the duration of time will be at least 7 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least
2
4 consecutive days, followed by administration of Compound A alone for at least 4 consecutive days - in this case, the duration of time will be at least 8 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 4 consecutive days, followed by administration of
2
Compound A alone for at least 7 consecutive days - in this case, the duration of time will be at least 1 1 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 5
2
consecutive days, followed by administration of Compound A alone for at least 1 day - in this case, the duration of time will be at least 6 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 5 consecutive days, followed by administration of
2
Compound A alone for at least 2 consecutive days - in this case, the duration of time will be at least 7 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 5 consecutive
2
days, followed by administration of Compound A alone for at least 3 consecutive days - in this case, the duration of time will be at least 8 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 5 consecutive days, followed by administration of
2
Compound A alone for at least 4 consecutive days - in this case, the duration of time will be at least 9 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 5 consecutive
2
days, followed by administration of Compound A alone for at least 5 consecutive days - in this case, the duration of time will be at least 10 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 7 consecutive days, followed by administration of
2
Compound A alone for at least 2 consecutive days - in this case, the duration of time will be at least 9 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 14 consecutive
2
days, followed by administration of Compound A alone for at least 7 consecutive days - in this case, the duration of time will be at least 21 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 30 consecutive days, followed by administration of
2
Compound A alone for at least 7 consecutive days - in this case, the duration of time will be at least 37 consecutive days. Suitably, during the course of treatment, both compounds will be administered within a specified period for from 1 to 3
2
consecutive days, followed by administration of Compound A alone for from 3 to 7 consecutive days. Suitably, during the course of treatment, both compounds will be administered within a specified period for from 3 to 6 consecutive days, followed by
2
administration of Compound A alone for from 1 to 4 consecutive days. Suitably, during the course of treatment, both compounds will be administered within a
2 specified period for 5 consecutive days, followed by administration of Compound A alone for 2 consecutive days. Suitably, during the course of treatment, both compounds will be administered within a specified period for 2 consecutive days, followed by administration of Compound A alone for from 3 to 7 consecutive days. Suitably, during the course of treatment, both compounds will be administered within a specified period for from 1 to 3 days over a 7 day period, and during the other days
2
of the 7 day period Compound A will be administered alone. Suitably, during the course of treatment, both compounds will be administered within a specified period for 2 days over a 7 day period, and during the other days of the 7 day period
2
Compound A will be administered alone.
Further regarding "specified period" administration:
Suitably, during the course of treatment, both compounds will be administered within a specified period for at least 1 day, followed by the administration of
2
Compound B alone for at least 1 day - in this case, the duration of time will be at least 2 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 1 day, followed by administration of
2
Compound B alone for at least 2 days - in this case, the duration of time will be at least 3 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 1 day, followed by administration of
2
Compound B alone for at least 3 days - in this case, the duration of time will be at least 4 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 1 day, followed by administration of
2
Compound B alone for at least 4 days - in this case, the duration of time will be at least 5 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 1 day, followed by administration of
2
Compound B alone for at least 5 days - in this case, the duration of time will be at least 6 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 1 day, followed by administration of
2
Compound B alone for at least 6 days - in this case, the duration of time will be at least 7 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 1 day, followed by administration of
2
Compound B alone for at least 7 days - in this case, the duration of time will be at least 8 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 2 consecutive days, followed by
2
administration of Compound B alone for at least 1 day - in this case, the duration of time will be at least 3 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 2 consecutive days, followed
2
by administration of Compound B alone for at least 2 consecutive days - in this case, the duration of time will be at least 4 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least
2
2 consecutive days, followed by administration of Compound B alone for at least 3 consecutive days - in this case, the duration of time will be at least 5 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 2 consecutive days, followed by administration of
2
Compound B alone for at least 4 consecutive days - in this case, the duration of time will be at least 6 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 2 consecutive days, followed
2
by administration of Compound B alone for at least 5 consecutive days - in this case, the duration of time will be at least 7 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least
2
2 consecutive days, followed by administration of Compound B alone for at least 6 consecutive days - in this case, the duration of time will be at least 8 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 2 consecutive days, followed by administration of
2
Compound B alone for at least 7 consecutive days - in this case, the duration of time will be at least 9 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 3 consecutive days, followed
2
by administration of Compound B alone for at least 1 day - in this case, the duration of time will be at least 4 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 3 consecutive
2
days, followed by administration of Compound B alone for at least 2 consecutive days - in this case, the duration of time will be at least 5 days; suitably, during the course of treatment, both compounds will be administered within a specified period
2 for at least 3 consecutive days, followed by administration of Compound B alone for at least 3 consecutive days - in this case, the duration of time will be at least 6 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 3 consecutive days, followed by administration of
2
Compound B alone for at least 4 consecutive days - in this case, the duration of time will be at least 7 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 3 consecutive days, followed
2
by administration of Compound B alone for at least 5 consecutive days - in this case, the duration of time will be at least 8 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least
2
3 consecutive days, followed by administration of Compound B alone for at least 6 consecutive days - in this case, the duration of time will be at least 9 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 3 consecutive days, followed by administration of
2
Compound B alone for at least 7 consecutive days - in this case, the duration of time will be at least 10 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 4 consecutive
2
days, followed by administration of Compound B alone for at least 1 day - in this case, the duration of time will be at least 5 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period
2 for at least 4 consecutive days, followed by administration of Compound B alone for at least 2 consecutive days - in this case, the duration of time will be at least 6 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 4 consecutive days, followed by
2
administration of Compound B alone for at least 3 consecutive days - in this case, the duration of time will be at least 7 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least
2
4 consecutive days, followed by administration of Compound B alone for at least 4 consecutive days - in this case, the duration of time will be at least 8 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 4 consecutive days, followed by administration of
2
Compound B alone for at least 7 consecutive days - in this case, the duration of time will be at least 1 1 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 5
2
consecutive days, followed by administration of Compound B alone for at least 1 day - in this case, the duration of time will be at least 6 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 5 consecutive days, followed by administration of Compound B alone for at least 2 consecutive days - in this case, the duration of time will be at least 7 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 5 consecutive
2
days, followed by administration of Compound B alone for at least 3 consecutive days - in this case, the duration of time will be at least 8 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 5 consecutive days, followed by administration of
2
Compound B alone for at least 4 consecutive days - in this case, the duration of time will be at least 9 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 5 consecutive
2
days, followed by administration of Compound B alone for at least 5 consecutive days - in this case, the duration of time will be at least 10 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 7 consecutive days, followed by administration of
2
Compound B alone for at least 2 consecutive days - in this case, the duration of time will be at least 9 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 14 consecutive
2
days, followed by administration of Compound B alone for at least 7 consecutive days - in this case, the duration of time will be at least 21 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 30 consecutive days, followed by administration of
2
Compound B alone for at least 7 consecutive days - in this case, the duration of time will be at least 37 consecutive days. Suitably, during the course of treatment, both compounds will be administered within a specified period for from 1 to 3
2
consecutive days, followed by administration of Compound B alone for from 3 to 7 consecutive days. Suitably, during the course of treatment, both compounds will be administered within a specified period for from 3 to 6 consecutive days, followed by
2
administration of Compound B alone for from 1 to 4 consecutive days. Suitably, during the course of treatment, both compounds will be administered within a
2 specified period for 5 consecutive days, followed by administration of Compound B alone for 2 consecutive days. Suitably, during the course of treatment, both compounds will be administered within a specified period for 2 consecutive days,
2
followed by administration of Compound B alone for from 3 to 7 consecutive days. Suitably, during the course of treatment, both compounds will be administered within a specified period for from 1 to 3 days over a 7 day period, and during the other days
2
of the 7 day period Compound B will be administered alone. Suitably, during the course of treatment, both compounds will be administered within a specified period for 2 days over a 7 day period, and during the other days of the 7 day period
2
Compound B will be administered alone.
Further regarding "specified period" administration:
2 2
Suitably, during the course of treatment, Compound A and Compound B will be administered within a specified period for from 1 to 3 days over a 7 day period,
2
and during the other days of the 7 day period Compound A will be administered alone. Suitably, this 7 day protocol is repeated for 2 cycles or for 14 days; suitably for 4 cycles or 28 days; suitably for continuous administration.
2 2
Suitably, during the course of treatment, Compound A and Compound B will be administered within a specified period for from 1 to 3 days over a 7 day period,
2
and during the other days of the 7 day period Compound B will be administered alone. Suitably, this 7 day protocol is repeated for 2 cycles or for 14 days; suitably for 4 cycles or 28 days; suitably for continuous administration.
2 2
Suitably, during the course of treatment, Compound A and Compound B will be administered within a specified period for 3 days over a 7 day period, and during
2
the other days of the 7 day period Compound A will be administered alone. Suitably, this 7 day protocol is repeated for 2 cycles or for 14 days; suitably for 4 cycles or 28 days; suitably for continuous administration.
2 2
Suitably, during the course of treatment, Compound A and Compound B will be administered within a specified period for 3 days over a 7 day period, and during
2
the other days of the 7 day period Compound B will be administered alone. Suitably, this 7 day protocol is repeated for 2 cycles or for 14 days; suitably for 4 cycles or 28 days; suitably for continuous administration.
2 2
Suitably, during the course of treatment, Compound A and Compound B will be administered within a specified period for 2 days over a 7 day period, and during
2
the other days of the 7 day period Compound A will be administered alone. Suitably, this 7 day protocol is repeated for 2 cycles or for 14 days; suitably for 4 cycles or 28 days; suitably for continuous administration. Suitably, during the course of treatment, Compound A and Compound B will be administered within a specified period for 2 days over a 7 day period, and during
2
the other days of the 7 day period Compound B will be administered alone. Suitably, this 7 day protocol is repeated for 2 cycles or for 14 days; suitably for 4 cycles or 28 days; suitably for continuous administration.
2 2
Suitably, during the course of treatment, Compound A and Compound B will be administered within a specified period for 1 day during a 7 day period, and during
2
the other days of the 7 day period Compound A will be administered alone. Suitably, this 7 day protocol is repeated for 2 cycles or for 14 days; suitably for 4 cycles or 28 days; suitably for continuous administration.
2 2
Suitably, during the course of treatment, Compound A and Compound B will be administered within a specified period for 1 day during a 7 day period, and during
2
the other days of the 7 day period Compound B will be administered alone. Suitably, this 7 day protocol is repeated for 2 cycles or for 14 days; suitably for 4 cycles or 28 days; suitably for continuous administration.
2 2
Suitably, during the course of treatment, Compound A and Compound B will be administered within a specified period for from 1 to 5 days over a 14 day period,
2
and during the other days of the 14 day period Compound A will be administered alone. Suitably, this 14 day protocol is repeated for 2 cycles or for 28 days; suitably for continuous administration.
2 2 Suitably, during the course of treatment, Compound A and Compound B will be administered within a specified period for from 1 to 5 days over a 14 day period,
2
and during the other days of the 14 day period Compound B will be administered alone. Suitably, this 14 day protocol is repeated for 2 cycles or for 28 days; suitably for continuous administration.
Suitably, if the compounds are not administered during a "specified period", they are administered sequentially. By the term "sequential administration", and
2
derivates thereof, as used herein is meant that one of Compound A and Compound
2 2 B is administered for one or more consecutive days and the other of Compound A
2
and Compound B is subsequently administered for one or more consecutive days. Also, contemplated herein is a drug holiday utilized between the sequential administration of one of Compound A and Compound B and the other of
2 2
Compound A and Compound B . As used herein, a drug holiday is a period of days
2 2 after the sequential administration of one of Compound A and Compound B and
2 2 before the administration of the other of Compound A and Compound B where
2 2
neither Compound A nor Compound B is administered. Suitably the drug holiday will be a period of days selected from: 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 1 1 days, 12 days, 13 days and 14 days.
Regarding sequential administration:
2 2
Suitably, one of Compound A and Compound B is administered for from 1 to 30 consecutive days, followed by an optional drug holiday, followed by
2 2
administration of the other of Compound A and Compound B for from 1 to 30
2 2
consecutive days. Suitably, one of Compound A and Compound B is administered for from 1 to 21 consecutive days, followed by an optional drug holiday, followed by
2 2
administration of the other of Compound A and Compound B for from 1 to 21
2 2
consecutive days. Suitably, one of Compound A and Compound B is administered for from 1 to 14 consecutive days, followed by a drug holiday of from 1 to 14 days,
2 2 followed by administration of the other of Compound A and Compound B for from 1
2 2 to 14 consecutive days. Suitably, one of Compound A and Compound B is administered for from 2 to 7 consecutive days, followed by a drug holiday of from 2 to
2 2
10 days, followed by administration of the other of Compound A and Compound B for from 2 to 7 consecutive days.
2
Suitably, Compound B will be administered first in the sequence, followed by
2
an optional drug holiday, followed by administration of Compound A . Suitably,
2
Compound B is administered for from 1 to 21 consecutive days, followed by an
2
optional drug holiday, followed by administration of Compound A for from 1 to 21
2
consecutive days. Suitably, Compound B is administered for from 3 to 21 consecutive days, followed by a drug holiday of from 1 to 14 days, followed by
2
administration of Compound A for from 3 to 21 consecutive days. Suitably, Compound B is administered for from 3 to 21 consecutive days, followed by a drug
2
holiday of from 3 to 14 days, followed by administration of Compound A for from 3 to
2
21 consecutive days. Suitably, Compound B is administered for 21 consecutive days, followed by an optional drug holiday, followed by administration of Compound
2 2
A for 14 consecutive days. Suitably, Compound B is administered for 14 consecutive days, followed by a drug holiday of from 1 to 14 days, followed by
2 2 administration of Compound A for 14 consecutive days. Suitably, Compound B is administered for 7 consecutive days, followed by a drug holiday of from 3 to 10 days,
2
followed by administration of Compound A for 7 consecutive days. Suitably,
2
Compound B is administered for 3 consecutive days, followed by a drug holiday of
2
from 3 to 14 days, followed by administration of Compound A for 7 consecutive
2
days. Suitably, Compound B is administered for 3 consecutive days, followed by a
2 drug holiday of from 3 to 10 days, followed by administration of Compound A for 3 consecutive days.
2
Suitably, Compound A will be administered first in the sequence, followed by
2
an optional drug holiday, followed by administration of Compound B . Suitably,
2
Compound A is administered for from 1 to 21 consecutive days, followed by an
2
optional drug holiday, followed by administration of Compound B for from 1 to 21
2
consecutive days. Suitably, Compound A is administered for from 3 to 21 consecutive days, followed by a drug holiday of from 1 to 14 days, followed by
2
administration of Compound B for from 3 to 21 consecutive days. Suitably,
2
Compound A is administered for from 3 to 21 consecutive days, followed by a drug
2
holiday of from 3 to 14 days, followed by administration of Compound B for from 3 to
2
21 consecutive days. Suitably, Compound A is administered for 21 consecutive days, followed by an optional drug holiday, followed by administration of Compound
2 2
B for 14 consecutive days. Suitably, Compound A is administered for 14 consecutive days, followed by a drug holiday of from 1 to 14 days, followed by
2 2 administration of Compound B for 14 consecutive days. Suitably, Compound A is administered for 7 consecutive days, followed by a drug holiday of from 3 to 10 days, followed by administration of Compound B for 7 consecutive days. Suitably,
2
Compound A is administered for 3 consecutive days, followed by a drug holiday of
2
from 3 to 14 days, followed by administration of Compound B for 7 consecutive
2
days. Suitably, Compound A is administered for 3 consecutive days, followed by a
2 drug holiday of from 3 to 10 days, followed by administration of Compound B for 3
2
consecutive days. Suitably, Compound A is administered for 7 consecutive days,
2 2 followed by administration of Compound B for 1 day. Suitably, Compound A is
2 administered for 6 consecutive days, followed by administration of Compound B for
2
1 day. Suitably, Compound B is administered for 1 day, followed by administration
2 2
of Compound A for 7 consecutive days. Suitably, Compound B is administered for
2
1 day, followed by administration of Compound A for 6 consecutive days.
It is understood that a "specified period" administration and a "sequential" administration can be followed by repeat dosing or can be followed by an alternate dosing protocol, and a drug holiday may precede the repeat dosing or alternate dosing protocol.
2
Suitably, the amount of Compound A administered as part of the combination according to the present invention will be an amount selected from about 50mg to about 1 ,200mg; suitably, the amount will be selected from about 100mg to about 1 ,000mg; suitably, the amount will be selected from about 100mg to about 800mg; suitably, the amount will be selected from about 100mg to about 600mg; suitably, the amount will be 50mg, suitably, the amount will be 100mg, suitably, the amount will be 200mg, suitably, the amount will be 400mg, suitably, the amount will be 600mg; suitably, the amount will be 800mg; suitably, the amount will be 1 ,000mg; suitably, the amount will be 1 ,200mg. Accordingly, the amount of
2
Compound A administered as part of the combination according to the present invention will be an amount selected from about 50mg to about 1 ,200 mg. For
2
example, the amount of Compound A administered as part of the combination according to the present invention is suitably selected from 50mg, 100mg, 200mg,
400mg, 600mg, 800mg, 1 ,000mg and 1 ,200mg. Suitably, the selected amount of
2
Compound A is administered from 1 to 4 times a day, in one or more tablets. Suitably, the selected amount of Compound A is administered twice a day, in one or
2
more tablets. Suitably, the selected amount of Compound A is administered once a
2 day, in one or more tablets. Suitably, the administration of Compound A will begin as a loading dose. Suitably, the loading dose will be an amount from 2 to 100 times the maintenance dose; suitably from 2 to 10 times; suitably from 2 to 5 times; suitably 2 times; suitably 3 times; suitably 4 times; suitably 5 times. Suitably, the loading does will be administered from 1 to 7 days; suitably from 1 to 5 days; suitably from 1 to 3 days; suitably for 1 day; suitably for 2 days; suitably for 3 days, followed by a maintenance dosing protocol.
2
Suitably, the amount of Compound B administered as part of the combination according to the present invention will be an amount selected from about 5mg to about 500mg; suitably, the amount will be selected from about 25mg to about 400mg; suitably, the amount will be selected from about 30mg to about 375mg; suitably, the amount will be selected from about 35mg to about 350mg; suitably, the amount will be selected from about 40mg to about 300mg; suitably, the amount will be selected from about 45mg to about 275mg; suitably, the amount will be selected from about 50mg to about 250mg; suitably, the amount will be selected from about 55mg to about 225mg; suitably, the amount will be selected from about 60mg to about 200mg; suitably, the amount will be selected from about 65mg to about 175mg; suitably, the amount will be selected from about 70mg to about 150mg; suitably, the amount will be selected from about 50mg to about 300mg; suitably, the amount will be selected from about 75mg to about 150mg; suitably, the amount will be about
2
100mg. Accordingly, the amount of Compound B administered as part of the combination according to the present invention will be an amount selected from
2
about 5mg to about 500mg. For example, the amount of Compound B administered as part of the combination according to the present invention can be 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 1 10mg, 1 15mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg or 500mg. Suitably,
2
the selected amount of Compound B is administered twice a day. Suitably, the
2
selected amount of Compound B is administered once a day. Suitably, the administration of Compound B will begin as a loading dose. Suitably, the loading dose will be an amount from 2 to 100 times the maintenance dose; suitably from 2 to 10 times; suitably from 2 to 5 times; suitably 2 times; suitably 3 times; suitably 4 times; suitably 5 times. Suitably, the loading does will be administered from 1 to 7 days; suitably from 1 to 5 days; suitably from 1 to 3 days; suitably for 1 day; suitably for 2 days; suitably for 3 days, followed by a maintenance dosing protocol.
2 2
As used herein, all amounts specified for Compound A and Compound B are indicated as the administered amount of free or unsalted compound per dose.
The method of the present invention may also be employed with other therapeutic methods of cancer treatment.
While it is possible that, for use in therapy, therapeutically effective amounts of the combinations of the present invention may be administered as the raw chemical, it is preferable to present the combinations as a pharmaceutical composition or compositions. Accordingly, the invention further provides
2 2 pharmaceutical compositions, which include Compound A and/or Compound B , and one or more pharmaceutically acceptable carriers. The combinations of the present invention are as described above. The carrier(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation, capable of pharmaceutical formulation, and not deleterious to the recipient thereof. In accordance with another aspect of the invention there is also provided a process for
2 the preparation of a pharmaceutical formulation including admixing Compound A
2
and/or Compound B with one or more pharmaceutically acceptable carriers. As indicated above, such elements of the pharmaceutical combination utilized may be presented in separate pharmaceutical compositions or formulated together in one pharmaceutical formulation. Pharmaceutical formulations 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 formulations are those containing a daily dose or sub-dose, or an appropriate fraction thereof, of an active ingredient. Furthermore, such pharmaceutical formulations may be prepared by any of the methods well known in the pharmacy art. Compound A and Compound B may be administered by any appropriate route. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). It will be appreciated that the preferred route may vary with, for example, the condition of the recipient of the combination and the cancer to be treated. It will also be appreciated that each of the agents administered may be administered by the same or different routes and that
2 2
Compound A and Compound B may be compounded together in a pharmaceutical
2 2 composition/formulation. Suitably, Compound A and Compound B are administered in separate pharmaceutical compositions.
The compounds or combinations of the current invention are incorporated into convenient dosage forms such as capsules, tablets, or injectable preparations. Solid or liquid pharmaceutical carriers are employed. Solid carriers include, starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Liquid carriers include syrup, peanut oil, olive oil, saline, and water. Similarly, the carrier may include a prolonged release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier varies widely but, suitably, may be from about 25 mg to about 1 g per dosage unit. When a liquid carrier is used, the preparation will suitably be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule, or an aqueous or nonaqueous liquid suspension.
For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing and coloring agent can also be present. It should be understood that in addition to the ingredients mentioned above, the formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
As indicated, therapeutically effective amounts of the combinations of the
2 2
invention (Compound A in combination with Compound B ) are administered to a human. Typically, the therapeutically effective amount of the administered agents of the present invention will depend upon a number of factors including, for example, the age and weight of the subject, the precise condition requiring treatment, the severity of the condition, the nature of the formulation, and the route of administration. Ultimately, the therapeutically effective amount will be at the discretion of the attending physician. The combinations of the invention are tested for efficacy, advantageous and synergistic properties generally according to known procedures. For example:
General Method:
Female SCID mice are implanted subcutaneously with 5 x 106 SKOV3 cells (human ovarian carcinoma). When the tumor volume reaches 300-400 mm3, mice are block randomized to different treatment groups (n=8 mice/group). Mice receive AKT inhibitor, Compound B (in this assay, Compound B, is used in the form of the hydrochloride salt), at 10 or 30 mg/kg, once daily (SID) for 21 days in 20% PEG-400, 1 % DMSO in water. Compound A (in this assay, Compound A, is used in the form of monohydrochloride salt) is administered at 100 mg/kg, twice/day (BID) for 21 days either alone or in combination with Compound B. Mice are weighed and tumors measured by calipers twice weekly. Tumor volumes are calculated using the formula: tumor volume = (Length x Width2)/2. The percentage of tumor growth inhibition is calculated on each day of tumor measurement using the formula: 100x[1 - (average growth of the compound-treated tumors / average growth of vehicle-treated control tumors)]. Data is plotted as mean ± sem for tumor volume for each group.
The combinations of the present invention are tested for efficacy, advantageous and synergistic properties according to known procedures such as described below. Suitably, the combinations of the invention are tested for efficacy, advantageous and synergistic properties generally according to the following combination cell proliferation assays. Cells are plated in 384-well plates at 500 cells/well in culture media appropriate for each cell type, supplemented with 10% FBS and 1 % penicillin/streptomycin, and incubated overnight at 37°C, 5% C02. Cells
2
are treated in a grid manner with dilution of Compound A (20 dilutions, including no compound, of 2-fold dilutions starting from 1 -20 μΜ depending on combination) from
2
left to right on 384-well plate and also treated with Compound B (20 dilutions, including no compound, of 2-fold dilutions starting from 1-20 μΜ depending on combination) from top to bottom on 384-well plate and incubated as above for a further 72 hours. In some instances compounds are added in a staggered manner and incubation time can be extended up to 7days. Cell growth is measured using CellTiter-Glo® reagent according to the manufacturer's protocol and signals are read on a PerkinElmer EnVision™ reader set for luminescence mode with a 0.5-second read. Data are analyzed as described below.
Results are expressed as a percentage of the t=0 value and plotted against compound(s) concentration. The t=0 value is normalized to 100% and represents the number of cells present at the time of compound addition. The cellular response is determined for each compound and/or compound combination using a 4- or 6- parameter curve fit of cell viability against concentration using the I DBS XLfit plug-in for Microsoft Excel software and determining the concentration required for 50% inhibition of cell growth (glC50). Background correction is made by subtraction of values from wells containing no cells. For each drug combination a Combination Index (CI), Excess Over Highest Single Agent (EOHSA) and Excess Over Bliss (EOBIiss) are calculated according to known methods such as described in Chou and Talalay (1984) Advances in Enzyme Regulation, 22, 37 to 55; and Berenbaum, MC (1981 ) Adv. Cancer Research, 35, 269-335. Effect of Compound A in Combination with Compound C on the growth of SKOV3 tumor xenografts in SCID mice.
Method:
Female SCID mice were implanted subcutaneously with 5 x 106 SKOV3 cells (human ovarian carcinoma). When the tumor volume reached 300-400 mm3, mice were block randomized to different treatment groups (n=8 mice/group). Mice received the AKT inhibitor, Compound C as the free base, at 10 or 30 mg/kg, once daily (SID) for 21 days in 20% PEG-400, 1 % DMSO in water. The VEGFR inhibitor, Compound A as the monohydrochloride salt, was administered at 100 mg/kg, twice/day (BID) for 21 days either alone or in combination with the AKT inhibitor. Mice were weighed and tumors measured by calipers twice weekly. Tumor volumes were calculated using the formula: tumor volume = (Length x Width2)/2. The percentage of tumor growth inhibition was calculated on each day of tumor measurement using the formula: 100x[1 -(average growth of the compound-treated tumors / average growth of vehicle-treated control tumors)]. Data is plotted as mean ± sem for tumor volume for each group.
Results:
Tumor volume in the two different vehicle treated groups increased at similar rate, suggesting minimal effect of these vehicles on the SKOV3 tumor growth. Compound A treatment at 100 mg/kg, twice daily, resulted in 47% inhibition of tumor growth compared to vehicle treated mice. Treatment of mice with Compound C at 10 and 30 mg/kg, once daily, resulted in 67% and 86% inhibition of tumor growth, respectively, compared to vehicle treated mice. Combined treatment with Compound A (100 mg/kg, twice daily) and Compound C at 10 or 30 mg/kg resulted in 75% and 95% inhibition of tumor growth, respectively, suggesting an increase in tumor growth inhibition in the combination group compared to AKT inhibitor alone.
Table 1 : Effect of Compound C and Compound A alone and in combination on the growth of human ovarian xenografts (SKOV-3) in SCID mice
Figure imgf000035_0001
It is expected that Compound B would perform reasonably similar to Compound C in this experiment. Because the combinations of the present invention are active in the above assays they exhibit advantageous therapeutic utility in treating cancer. Suitably, the present invention relates to a method for treating or lessening the severity of a cancer selected from: brain (gliomas), glioblastomas, Bannayan- Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast, inflammatory breast cancer, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, prostate, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid,
Lymphoblastic T cell leukemia, Chronic myelogenous leukemia, Chronic lymphocytic leukemia, Hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, Chronic neutrophilic leukemia, Acute lymphoblastic T cell leukemia, Plasmacytoma, Immunoblastic large cell leukemia, Mantle cell leukemia, Multiple myeloma Megakaryoblastic leukemia, multiple myeloma, acute megakaryocyte 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, lung cancer, vulval cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor) and testicular cancer. Suitably, the present invention relates to a method for treating or lessening the severity of a cancer selected from: brain (gliomas), glioblastomas, Bannayan- Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, prostate, sarcoma and thyroid.
Suitably, the present invention relates to a method for treating or lessening the severity of a cancer selected from ovarian, breast, pancreatic and prostate.
Suitably, the present invention relates to a method of treating or lessening the severity of a cancer that is either wild type or mutant for Ras/Raf and either wild type or mutant for PIK3CA/PTEN. This includes patients who are wild type for both Ras/Raf and PIK3CA/PTEN, mutant for both Ras/Raf and PIK3CA/PTEN, mutant for Ras/Raf and wild type for PIK3CA/PTEN and wild type for Ras/Raf and mutant for PIK3CA/PTEN. The present invention also relates to a method of treating or lessening the severity of a cancer that has activated AKT, e.g., by mutation or amplification of AKT1 , AKT2 or AKT3 genes. The present invention also relates to a method of treating or lessening the severity of a cancer that has activated EGFR or ErbB-2, e.g., by mutation, amplification of the gene or overexpression of the protein.
The term "wild type" as is understood in the art refers to a polypeptide or polynucleotide sequence that occurs in a native population without genetic modification. As is also understood in the art, 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.
Cancers that are either wild type or mutant for Ras/Raf, PIK3CA/PTEN, AKT, EGFR or ErbB-2 or have amplification of PIK3CA, AKT, EGFR or ErbB-2 genes or have overexpression of EGFR or ErbB2 protein are identified by known methods.
For example, wild type or mutant Ras/Raf, PIK3CA/PTEN, AKT EGFR or ErbB-2 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 or in-situ hybridization. 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 immunocytochemistry.
This invention provides a combination comprising 5-[[4-[(2,3- dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2- methylbenzenesulfonamide, or a pharmaceutically acceptable salt, suitably the monohydrochloride salt, thereof, and /\/-{(1 S)-2-amino-1 -[(3- fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1 -methyl-1 H-pyrazol-5-yl)-2- thiophenecarboxamide, or a pharmaceutically acceptable salt, suitably the hydrochloride salt, thereof.
This invention also provides for a combination comprising 5-[[4-[(2,3- dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2- methylbenzenesulfonamide, or a pharmaceutically acceptable salt, suitably the monohydrochloride salt, thereof, and /\/-{(1 S)-2-amino-1 -[(3- fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1 -methyl-1 H-pyrazol-5-yl)-2- thiophenecarboxamide, or a pharmaceutically acceptable salt, suitably the hydrochloride salt, thereof.
This invention also provides for a combination comprising 5-[[4-[(2,3- dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2- methylbenzenesulfonamide, or a pharmaceutically acceptable salt, suitably the monohydrochloride salt, thereof, and /\/-{(1 S)-2-amino-1 -[(3- fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1 -methyl-1 H-pyrazol-5-yl)-2- thiophenecarboxamide, or a pharmaceutically acceptable salt, suitably the hydrochloride salt, thereof, for use in treating cancer. This invention also provides a pharmaceutical composition comprising a combination of 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2- pyrimidinyl]amino]-2-methylbenzenesulfonamide, or a pharmaceutically acceptable salt, suitably the monohydrochloride salt, thereof, and /\/-{(1 S)-2-amino-1 -[(3- fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1 -methyl-1 H-pyrazol-5-yl)-2- thiophenecarboxamide, or a pharmaceutically acceptable salt, suitably the hydrochloride salt, thereof.
This invention also provides a combination kit comprising 5-[[4-[(2,3- dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2- methylbenzenesulfonamide, or a pharmaceutically acceptable salt, suitably the monohydrochloride salt, thereof, and /\/-{(1 S)-2-amino-1 -[(3- fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1 -methyl-1 H-pyrazol-5-yl)-2- thiophenecarboxamide, or a pharmaceutically acceptable salt, suitably the hydrochloride salt, thereof. This invention also provides for the use of a combination comprising 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2- methylbenzenesulfonamide, or a pharmaceutically acceptable salt, suitably the monohydrochloride salt, thereof, and /\/-{(1 S)-2-amino-1 -[(3- fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1 -methyl-1 H-pyrazol-5-yl)-2- thiophenecarboxamide, or a pharmaceutically acceptable salt, suitably the hydrochloride salt, thereof, in the manufacture of a medicament.
This invention also provides for the use of a combination comprising 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2- methylbenzenesulfonamide, or a pharmaceutically acceptable salt, suitably the monohydrochloride salt, thereof, and /\/-{(1 S)-2-amino-1 -[(3- fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1 -methyl-1 H-pyrazol-5-yl)-2- thiophenecarboxamide, or a pharmaceutically acceptable salt, suitably the hydrochloride salt, thereof, in the manufacture of a medicament to treat cancer.
This invention also provides a method of treating cancer which comprises administering a combination of 5-[[4-[(2,3-dimethyl-2H-indazol-6- yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulforiamide, or a pharmaceutically acceptable salt, suitably the monohydrochloride salt, thereof, and Λ/-{(1 S)-2-amino-1 -[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1 -methyl-1 H- pyrazol-5-yl)-2-thiophenecarboxamide, or a pharmaceutically acceptable salt, suitably the hydrochloride salt, thereof, to a subject in need thereof. The following examples are intended for illustration only and are not intended to limit the scope of the invention in any way.
Experimental Details Example 1 - Capsule Composition
An oral dosage form for administering a combination of the present invention is produced by filing a standard two piece hard gelatin capsule with the ingredients in the proportions shown in Table I, below.
Table I INGREDIENTS
5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2- pyrimidinyl]amino]-2-methylbenzenesulfonamide
hydrochloride (the monohydrochloride salt of Compound A)
Λ/-{(1 S)-2-amino-1 -[(3-fluorophenyl)methyl]ethyl}-5-chloro- 4-(4-chloro-1 -methyl-1 H-pyrazol-5-yl)-2- thiophenecarboxamide hydrochloride (the hydrochloride
salt of Compound B)
Mannitol
Talc
Magnesium Stearate
Example 2 - Capsule Composition
An oral dosage form for administering one of the compounds of the present invention is produced by filing a standard two piece hard gelatin capsule with the ingredients in the proportions shown in Table II, below.
Table II
INGREDIENTS AMOUNTS
5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2- 200mg
pyrimidinyl]amino]-2-methylbenzenesulfonamide
hydrochloride (the monohydrochloride salt of Compound A)
Mannitol 150mg
Talc 16mg
Magnesium Stearate 4mg
Example 3 - Capsule Composition
An oral dosage form for administering one of the compounds of the present invention is produced by filing a standard two piece hard gelatin capsule with the ingredients in the proportions shown in Table III, below. Table III
INGREDIENTS
Λ/-{(1 S)-2-amino-1 -[(3-fluorophenyl)methyl]ethyl}-5-chloro-
Figure imgf000041_0001
Magnesium Stearate
Example 4 - Tablet Composition
The sucrose, microcrystalline cellulose and the compounds of the invented combination, as shown in Table IV below, are mixed and granulated in the proportions shown with a 10% gelatin solution. The wet granules are screened, dried, mixed with the starch, talc and stearic acid, then screened and compressed into a tablet.
Table IV
INGREDIENTS AMOUNTS
5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2- 200mg
pyrimidinyl]amino]-2-methylbenzenesulfonamide
hydrochloride (the monohydrochloride salt of Compound
A)
Λ/-{(1 S)-2-amino-1 -[(3-fluorophenyl)methyl]ethyl}-5-chloro- 75mg
4-(4-chloro-1 -methyl-1 H-pyrazol-5-yl)-2- thiophenecarboxamide hydrochloride (the hydrochloride
salt of Compound B)
Microcrystalline cellulose 300mg
sucrose 10mg
starch 40mg
talc 20mg
stearic acid 5mg
Example 5 - Tablet Composition The sucrose, microcrystalline cellulose and one of the compounds of the invented combination, as shown in Table V below, are mixed and granulated in the proportions shown with a 10% gelatin solution. The wet granules are screened, dried, mixed with the starch, talc and stearic acid, then screened and compressed into a tablet.
Table V
INGREDIENTS AMOUNTS
5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2- 200mg
pyrimidinyl]amino]-2-methylbenzenesulfonamide
hydrochloride (the monohydrochloride salt of Compound
A)
Microcrystalline cellulose 200mg
sucrose 4mg
starch 2mg
talc 1 mg
stearic acid 0.5mg
Example 6 - Tablet Composition
The sucrose, microcrystalline cellulose and one of the compounds of the invented combination, as shown in Table VI below, are mixed and granulated in the proportions shown with a 10% gelatin solution. The wet granules are screened, dried, mixed with the starch, talc and stearic acid, then screened and compressed into a tablet.
Table VI
INGREDIENTS AMOUNTS
Λ/-{(1 S)-2-amino-1 -[(3-fluorophenyl)methyl]ethyl}-5-chloro- 75mg
4-(4-chloro-1 -methyl-1 H-pyrazol-5-yl)-2- thiophenecarboxamide hydrochloride (the hydrochloride
salt of Compound B)
Microcrystalline cellulose 300mg
sucrose 40mg
starch 20mg
talc 10mg
stearic acid 5mg
While the preferred embodiments of the invention are illustrated by the above, it is to be understood that the invention is not limited to the precise instructions herein disclosed and that the right to all modifications coming within the scope of the following claims is reserved.

Claims

We claim:
A combination comprising compound of Structure (I):
Figure imgf000044_0001
or a pharmaceutically acceptable salt thereof; and
(ii) a compound of Structure (II):
Figure imgf000044_0002
or a pharmaceutically acceptable salt thereof.
2. A combination according to claim 1 where the compounds of Structure (I) and Structure (II) are in the form of a monohydrochloride salt.
3. A combination kit comprising a combination according to claim 1 or claim 2 together with a pharmaceutically acceptable carrier or carriers.
4. A combination according to any one of claims 1 to 3 where the amount of the compound of Structure (I) is an amount selected from 50mg to 1 ,200mg, and that amount is administered once per day in one or more tablets, and the amount of the compound of Structure (II) is an amount selected from 5mg to 500mg, and that amount is administered once per day.
5. Use of a combination according to any of claims 1 to 4 in the manufacture of a medicament or medicaments for the treatment of cancer.
6. A method of treating cancer in a human in need thereof which comprises the in vivo administration of a therapeutically effective amount of a combination of 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2- pyrimidinyl]amino]-2-methylbenzenesulfonamide, or a pharmaceutically acceptable salt thereof, and /\/-{(1 S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4- chloro-1-methyl-1 H-pyrazol-5-yl)-2-thiophenecarboxamide, or a pharmaceutically acceptable salt thereof, to such human,
wherein the combination is administered within a specified period, and wherein the combination is administered for a duration of time.
7. A method according to claim 6 wherein the amount of 5-[[4-[(2,3- dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2- methylbenzenesulfonamide, or a pharmaceutically acceptable salt thereof, is selected from about 100mg to about 1 ,000mg, and that amount is administered once per day in one or more tablets, and the amount of /\/-{(1 S)-2-amino-1 -[(3- fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1 -methyl-1 H-pyrazol-5-yl)-2- thiophenecarboxamide, or a pharmaceutically acceptable salt thereof, is selected from about 50mg to about 300mg, and that amount is administered once per day.
8. A method according to claim 7 wherein the amount of 5-[[4-[(2,3- dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2- methylbenzenesulfonamide, or a pharmaceutically acceptable salt thereof, is selected from about 100mg to about 800mg, and that amount is administered once per day in one or more tablets, and the amount of /\/-{(1 S)-2-amino-1 -[(3- fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1 -methyl-1 H-pyrazol-5-yl)-2- thiophenecarboxamide, or a pharmaceutically acceptable salt thereof, is selected from about 60mg to about 300mg, and that amount is administered once per day.
9. A method according to claim 8 wherein 5-[[4-[(2,3-dimethyl-2H- indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide monohydrochloride and /\/-{(1 S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4- (4-chloro-1-methyl-1 H-pyrazol-5-yl)-2-thiophenecarboxamide hydrochloride are administered within 12 hours of each other for from 1 to 3 consecutive days followed by administration of 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2- pyrimidinyl]amino]-2-methylbenzenesulfonamide monohydrochloride for from 3 to 7 consecutive days, optionally followed by one or more cycles of repeat dosing.
10. A method treating a cancer selected from: brain (gliomas), glioblastomas, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast, inflammatory breast cancer, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, prostate, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid,
Lymphoblastic T cell leukemia, Chronic myelogenous leukemia, Chronic lymphocytic leukemia, Hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, Chronic neutrophilic leukemia, Acute lymphoblastic T cell leukemia, Plasmacytoma, Immunoblastic large cell leukemia, Mantle cell leukemia, Multiple myeloma Megakaryoblastic leukemia, multiple myeloma, acute megakaryocyte 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, lung cancer, vulval cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor) and testicular cancer; in a human in need thereof which comprises the in vivo administration of a therapeutically effective amount of a combination of 5-[[4-[(2,3-dimethyl-2H-indazol- 6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulforiamide, or a pharmaceutically acceptable salt thereof, and /\/-{(1 S)-2-amino-1 -[(3- fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1 -methyl-1 H-pyrazol-5-yl)-2- thiophenecarboxamide or a pharmaceutically acceptable salt thereof, to such human, wherein the combination is administered within a specified period, and wherein the combination is administered for a duration of time.
1 1 . A method according to claim 10 wherein the amount of 5-[[4-[(2,3- dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2- methylbenzenesulfonamide, or a pharmaceutically acceptable salt thereof, is selected from about 100mg to about 1 , OOOmg, and that amount is administered once per day in one or more tablets, and the amount of /\/-{(1 S)-2-amino-1 -[(3- fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1 -methyl-1 H-pyrazol-5-yl)-2- thiophenecarboxamide, or a pharmaceutically acceptable salt thereof, is selected from about 50mg to about 300mg, and that amount is administered once per day.
12. A method according to claim 1 1 wherein the amount of 5-[[4-[(2,3- dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2- methylbenzenesulfonamide, or a pharmaceutically acceptable salt thereof, is selected from about 100mg to about 800mg, and that amount is administered once per day in one or more tablets, and the amount of /\/-{(1 S)-2-amino-1 -[(3- fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1 -methyl-1 H-pyrazol-5-yl)-2- thiophenecarboxamide or a pharmaceutically acceptable salt thereof, is selected from about 60mg to about 300mg, and that amount is administered once per day.
13. A method according to claim 12 wherein 5-[[4-[(2,3-dimethyl-2H- indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide monohydrochloride and Λ/-{(1 S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4- (4-chloro-1 -methyl-1 H-pyrazol-5-yl)-2 -thiophenecarboxamide hydrochloride are administered within 12 hours of each other for from 1 to 3 consecutive days followed by administration of 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2- pyrimidinyl]amino]-2-methylbenzenesulfonamide monohydrochloride for from 3 to 7 consecutive days, optionally followed by one or more cycles of repeat dosing.
14. A method according to claim 10 wherein the cancer selected from ovarian, breast, pancreatic and prostate.
15. A method according to claim 1 1 wherein the cancer selected from ovarian, breast, pancreatic and prostate.
16. A method according to claim 12 wherein the cancer selected from ovarian, breast, pancreatic and prostate.
17. A method according to claim 13 wherein the cancer selected from ovarian, breast, pancreatic and prostate.
18. A method of treating a cancer that is either wild type or mutant for Ras/Raf, PIK3CA/PTEN, AKT, EGFR or ErbB-2 or have amplification of PIK3CA, AKT, EGFR or ErbB-2 genes or have overexpression of EGFR or ErbB2 protein, in a human in need thereof which comprises the in vivo administration of a therapeutically effective amount of a combination of 5-[[4-[(2,3-dimethyl-2H-indazol-6- yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulforiamide, or a pharmaceutically acceptable salt thereof, and /\/-{(1 S)-2-amino-1 -[(3- fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1 -methyl-1 H-pyrazol-5-yl)-2- thiophenecarboxamide, or a pharmaceutically acceptable salt thereof, to such human,
wherein the combination is administered within a specified period, and wherein the combination is administered for a duration of time.
19. A method according to claim 18 wherein the amount of 5-[[4-[(2,3- dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2- methylbenzenesulfonamide, or a pharmaceutically acceptable salt thereof, is selected from about 100mg to about 1 , OOOmg, and that amount is administered once per day in one or more tablets, and the amount of /\/-{(1 S)-2-amino-1 -[(3- fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1 -methyl-1 H-pyrazol-5-yl)-2- thiophenecarboxamide, or a pharmaceutically acceptable salt thereof, is selected from about 50mg to about 300mg, and that amount is administered once per day.
20. A method according to claim 19 wherein the amount of 5-[[4-[(2,3- dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2- methylbenzenesulfonamide, or a pharmaceutically acceptable salt thereof, is selected from about 100mg to about 800mg, and that amount is administered once per day in one or more tablets, and the amount of /\/-{(1 S)-2-amino-1 -[(3- fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1 -methyl-1 H-pyrazol-5-yl)-2- thiophenecarboxamide, or a pharmaceutically acceptable salt thereof, is selected from about 60mg to about 300mg, and that amount is administered once per day.
21 . A method according to claim 20 wherein 5-[[4-[(2,3-dimethyl-2H- indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide monohydrochloride and Λ/-{(1 S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4- (4-chloro-1-methyl-1 H-pyrazol-5-yl)-2 -thiophenecarboxamide hydrochloride are administered within 12 hours of each other for from 1 to 3 consecutive days followed by administration of 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2- pyrimidinyl]amino]-2-methylbenzenesulfonamide monohydrochloride for from 3 to 7 consecutive days, optionally followed by one or more cycles of repeat dosing.
22. A method according to claim 18 wherein the cancer selected from ovarian, breast, pancreatic and prostate.
23. A method according to claim 19 wherein the cancer selected from ovarian, breast, pancreatic and prostate.
24. A method according to claim 20 wherein the cancer selected from ovarian, breast, pancreatic and prostate.
25. A method according to claim 21 wherein the cancer selected from ovarian, breast, pancreatic and prostate.
26. A method treating a cancer selected from: brain (gliomas), glioblastomas, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast, inflammatory breast cancer, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, prostate, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid,
Lymphoblastic T cell leukemia, Chronic myelogenous leukemia, Chronic lymphocytic leukemia, Hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, Chronic neutrophilic leukemia, Acute lymphoblastic T cell leukemia, Plasmacytoma, Immunoblastic large cell leukemia, Mantle cell leukemia, Multiple myeloma Megakaryoblastic leukemia, multiple myeloma, acute megakaryocyte 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, lung cancer, vulval cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor) and testicular cancer;
in a human in need thereof which comprises the in vivo administration of a therapeutically effective amount of a combination of 5-[[4-[(2,3-dimethyl-2H-indazol- 6-yl)methylamino]-2-pynmidinyl]amino]-2-methylbenzenesulfonamide, or a pharmaceutically acceptable salt thereof, and /\/-{(1 S)-2-amino-1 -[(3- fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1 -methyl-1 H-pyrazol-5-yl)-2- thiophenecarboxamide, or a pharmaceutically acceptable salt thereof, to such human,
wherein the compounds of the combination are administered sequentially.
27. A method according to claim 26 wherein the amount of 5-[[4-[(2,3- dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2- methylbenzenesulfonamide, or a pharmaceutically acceptable salt thereof, is selected from about 100mg to about 1 , OOOmg, and that amount is administered once per day in one or more tablets, and the amount of /\/-{(1 S)-2-amino-1 -[(3- fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1 -methyl-1 H-pyrazol-5-yl)-2- thiophenecarboxamide, or a pharmaceutically acceptable salt thereof, is selected from about 50mg to about 300mg, and that amount is administered once per day.
28. A method according to claim 27 wherein the amount of 5-[[4-[(2,3- dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2- methylbenzenesulfonamide, or a pharmaceutically acceptable salt thereof, is selected from about 100mg to about 800mg, and that amount is administered once per day in one or more tablets, and the amount of /\/-{(1 S)-2-amino-1 -[(3- fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1 -methyl-1 H-pyrazol-5-yl)-2- thiophenecarboxamide, or a pharmaceutically acceptable salt thereof, is selected from about 60mg to about 300mg, and that amount is administered once per day.
29. A method according to claim 28 wherein 5-[[4-[(2,3-dimethyl-2H- indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide monohydrochloride is administered for from 1 to 30 consecutive days, followed by an optional drug holiday of from 1 to 14 days, followed by administration of /\/-{(1 S)-2- amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1 /-/-pyrazol-5- yl)-2-thiophenecarboxamide hydrochloride for from 1 to 30 days.
30. A method according to claim 26 wherein the cancer selected from ovarian, breast, pancreatic and prostate.
31 . A method according to claim 27 wherein the cancer selected from ovarian, breast, pancreatic and prostate.
32. A method according to claim 28 wherein the cancer selected from ovarian, breast, pancreatic and prostate.
33. A method according to claim 29 wherein the cancer selected from ovarian, breast, pancreatic and prostate.
34. A method of treating a cancer that is either wild type or mutant for Ras/Raf, PIK3CA/PTEN, AKT, EGFR or ErbB-2 or have amplification of PIK3CA, AKT, EGFR or ErbB-2 genes or have overexpression of EGFR or ErbB2 protein, in a human in need thereof which comprises the in vivo administration of a therapeutically effective amount of a combination of 5-[[4-[(2,3-dimethyl-2H-indazol-6- yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulforiamide, or a pharmaceutically acceptable salt thereof, and /\/-{(1 S)-2-amino-1 -[(3- fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1 -methyl-1 H-pyrazol-5-yl)-2- thiophenecarboxamide, or a pharmaceutically acceptable salt thereof, to such human,
wherein the compounds of the combination are administered sequentially.
35. A method according to claim 34 wherein the amount of 5-[[4-[(2,3- dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2- methylbenzenesulfonamide, or a pharmaceutically acceptable salt thereof, is selected from about 100mg to about 1 ,000mg, and that amount is administered once per day in one or more tablets, and the amount of /\/-{(1 S)-2-amino-1 -[(3- fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1 -methyl-1 H-pyrazol-5-yl)-2- thiophenecarboxamide, or a pharmaceutically acceptable salt thereof, is selected from about 50mg to about 300mg, and that amount is administered once per day.
36. A method according to claim 35 wherein the amount of 5-[[4-[(2,3- dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2- methylbenzenesulfonamide, or a pharmaceutically acceptable salt thereof, is selected from about 100mg to about 800mg, and that amount is administered once per day in one or more tablets, and the amount of /\/-{(1 S)-2-amino-1 -[(3- fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1 -methyl-1 H-pyrazol-5-yl)-2- thiophenecarboxamide, or a pharmaceutically acceptable salt thereof, is selected from about 60mg to about 300mg, and that amount is administered once per day.
37. A method according to claim 36 wherein 5-[[4-[(2,3-dimethyl-2H- indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide monohydrochloride is administered for from 1 to 30 consecutive days, followed by a drug holiday of from 1 to 14 days, followed by administration of /\/-{(1 S)-2-amino-1 - [(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1 -methyl-1 H-pyrazol-5-yl)-2- thiophenecarboxamide hydrochloride for from 1 to 30 days.
38. A method according to claim 34 wherein the cancer selected from ovarian, breast, pancreatic and prostate.
39. A method according to claim 35 wherein the cancer selected from ovarian, breast, pancreatic and prostate.
40. A method according to claim 36 wherein the cancer selected from ovarian, breast, pancreatic and prostate.
41 . A method according to claim 37 wherein the cancer selected from ovarian, breast, pancreatic and prostate.
42. A method according to claim 36 wherein 5-[[4-[(2,3-dimethyl-2H- indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide monohydrochloride and /\/-{(1 S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4- (4-chloro-1-methyl-1 H-pyrazol-5-yl)-2-thiophenecarboxamide hydrochloride are administered within 12 hours of each other for from 1 to 3 consecutive days followed by administration of 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2- pyrimidinyl]amino]-2-methylbenzenesulfonamide monohydrochloride for from 3 to 7 consecutive days, optionally followed by one or more cycles of repeat dosing.
43. A method according to claim 42 wherein the cancer selected from ovarian, breast, pancreatic and prostate.
44. A method according to claim 29 wherein 5-[[4-[(2,3-dimethyl-2H- indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide monohydrochloride is administered for from 1 to 21 consecutive days, followed by a drug holiday of from 3 to 10 days, followed by administration of /\/-{(1 S)-2-amino-1 - [(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1 -methyl-1 H-pyrazol-5-yl)-2- thiophenecarboxamide hydrochloride for from 1 to 21 days.
45. A method according to claim 44 wherein the cancer selected from ovarian, breast, pancreatic and prostate.
46. A method according to claim 9 wherein 5-[[4-[(2,3-dimethyl-2H- indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide monohydrochloride and Λ/-{(1 S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4- (4-chloro-1-methyl-1 H-pyrazol-5-yl)-2-thiophenecarboxamide hydrochloride are administered within 12 hours of each other for 2 consecutive days followed by administration of 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2- pyrimidinyl]amino]-2-methylbenzenesulfonamide monohydrochloride for from 4 to 6 consecutive days, optionally followed by one or more cycles of repeat dosing.
47. A method according to claim 8 wherein 5-[[4-[(2,3-dimethyl-2H- indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide monohydrochloride and Λ/-{(1 S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4- (4-chloro-1-methyl-1 H-pyrazol-5-yl)-2-thiophenecarboxamide hydrochloride are administered within 12 hours of each other for 2 days over a 7 day period, and during the other days of the 7 day period 5-[[4-[(2,3-dimethyl-2H-indazol-6- yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulforiamide
monohydrochloride is administered alone, optionally followed by one or more cycles of repeat dosing.
48. A method according to claim 13 wherein 5-[[4-[(2,3-dimethyl-2H- indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide monohydrochloride and Λ/-{(1 S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4- (4-chloro-1-methyl-1 H-pyrazol-5-yl)-2-thiophenecarboxamide hydrochloride are administered within 12 hours of each other for 2 consecutive days followed by administration of 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2- pyrimidinyl]amino]-2-methylbenzenesulfonamide monohydrochloride for from 4 to 6 consecutive days, optionally followed by one or more cycles of repeat dosing.
49. A method according to claim 12 wherein 5-[[4-[(2,3-dimethyl-2H- indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide monohydrochloride and Λ/-{(1 S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4- (4-chloro-1-methyl-1 H-pyrazol-5-yl)-2-thiophenecarboxamide hydrochloride are administered within 12 hours of each other for 2 days over a 7 day period, and during the other days of the 7 day period 5-[[4-[(2,3-dimethyl-2H-indazol-6- yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulforiamide
monohydrochloride is administered alone, optionally followed by one or more cycles of repeat dosing.
50. A method according to claim 21 wherein 5-[[4-[(2,3-dimethyl-2H- indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide monohydrochloride and Λ/-{(1 S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4- (4-chloro-1-methyl-1 H-pyrazol-5-yl)-2-thiophenecarboxamide hydrochloride are administered within 12 hours of each other for 2 consecutive days followed by administration of 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2- pyrimidinyl]amino]-2-methylbenzenesulfonamide monohydrochloride for from 4 to 6 consecutive days, optionally followed by one or more cycles of repeat dosing.
51 . A method according to claim 20 wherein 5-[[4-[(2,3-dimethyl-2H- indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide monohydrochloride and Λ/-{(1 S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4- (4-chloro-1-methyl-1 H-pyrazol-5-yl)-2-thiophenecarboxamide hydrochloride are administered within 12 hours of each other for 2 days over a 7 day period, and during the other days of the 7 day period 5-[[4-[(2,3-dimethyl-2H-indazol-6- yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulforiamide
monohydrochloride is administered alone, optionally followed by one or more cycles of repeat dosing.
52. A method according to claim 8 wherein 5-[[4-[(2,3-dimethyl-2H- indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide monohydrochloride and /\/-{(1 S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4- (4-chloro-1-methyl-1 H-pyrazol-5-yl)-2-thiophenecarboxamide hydrochloride are administered within 12 hours of each other for 5 consecutive days followed by administration of 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2- pyrimidinyl]amino]-2-methylbenzenesulfonamide monohydrochloride for 2 consecutive days, optionally followed by one or more cycles of repeat dosing.
53. A method according to claim 12 wherein 5-[[4-[(2,3-dimethyl-2H- indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide monohydrochloride and /\/-{(1 S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4- (4-chloro-1-methyl-1 H-pyrazol-5-yl)-2-thiophenecarboxamide hydrochloride are administered within 12 hours of each other for 5 consecutive days followed by administration of 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2- pyrimidinyl]amino]-2-methylbenzenesulfonamide monohydrochloride for 2 consecutive days, optionally followed by one or more cycles of repeat dosing.
54. A method according to claim 20 wherein 5-[[4-[(2,3-dimethyl-2H- indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide monohydrochloride and /\/-{(1 S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4- (4-chloro-1-methyl-1 H-pyrazol-5-yl)-2-thiophenecarboxamide hydrochloride are administered within 12 hours of each other for 5 consecutive days followed by administration of 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2- pyrimidinyl]amino]-2-methylbenzenesulfonamide monohydrochloride for 2 consecutive days, optionally followed by one or more cycles of repeat dosing.
PCT/US2011/037881 2010-05-26 2011-05-25 Combination WO2011150044A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP11787314.1A EP2575460A4 (en) 2010-05-26 2011-05-25 Combination
JP2013512197A JP2013526613A (en) 2010-05-26 2011-05-25 combination
US13/699,103 US20130237554A1 (en) 2010-05-26 2011-05-25 Combination
US14/565,691 US20150094283A1 (en) 2010-05-26 2014-12-10 Combination

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US34838510P 2010-05-26 2010-05-26
US61/348,385 2010-05-26

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US13/699,103 A-371-Of-International US20130237554A1 (en) 2010-05-26 2011-05-25 Combination
US14/565,691 Continuation US20150094283A1 (en) 2010-05-26 2014-12-10 Combination

Publications (1)

Publication Number Publication Date
WO2011150044A1 true WO2011150044A1 (en) 2011-12-01

Family

ID=45004353

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2011/037881 WO2011150044A1 (en) 2010-05-26 2011-05-25 Combination

Country Status (4)

Country Link
US (2) US20130237554A1 (en)
EP (1) EP2575460A4 (en)
JP (2) JP2013526613A (en)
WO (1) WO2011150044A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2908816A4 (en) * 2012-10-22 2016-06-15 Novartis Ag Combination

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010045309A1 (en) * 2008-10-16 2010-04-22 Glaxosmithkline Llc Inhibitors of akt activity

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NZ526542A (en) * 2000-12-21 2005-01-28 Glaxo Group Ltd Pyrimidineamines as angiogenesis modulators
UY30892A1 (en) * 2007-02-07 2008-09-02 Smithkline Beckman Corp AKT ACTIVITY INHIBITORS
PE20120003A1 (en) * 2009-01-30 2012-02-12 Glaxosmithkline Llc N - {(1S) -2-AMINO-1 - [(3-FLUOROPHENYL) METHYL) ETHYL HYDROCHLORIDE} -5-CHLORO-4- (4-CHLORO-1-METHYL-1H-PIRAZOL-5-IL) - CRYSTALLINE 2-THIOPHENOCARBOXAMIDE

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010045309A1 (en) * 2008-10-16 2010-04-22 Glaxosmithkline Llc Inhibitors of akt activity

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HARRIS ET AL.: "Discovery of 5-[4-[(2,3-Dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]- 2-methylbenzenesulfonamide (Pazopanib), a Novel and Potent Vascular Endothelial Growth Factor Receptor Inhibitor.", JOURNAL OF MEDICINAL CHEMISTRY, vol. 51, 2008, pages 4632 - 4640, XP055054577 *
See also references of EP2575460A4 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2908816A4 (en) * 2012-10-22 2016-06-15 Novartis Ag Combination

Also Published As

Publication number Publication date
US20130237554A1 (en) 2013-09-12
JP2016193903A (en) 2016-11-17
EP2575460A4 (en) 2013-10-16
EP2575460A1 (en) 2013-04-10
US20150094283A1 (en) 2015-04-02
JP2013526613A (en) 2013-06-24

Similar Documents

Publication Publication Date Title
AU2012205601B2 (en) Combination
US20160213672A1 (en) Combination
US9402846B2 (en) Combination of inhibitor of B-Raf and inhibitor of AKT in the treatment of cancer
EP2485594B1 (en) Combination
US20150094283A1 (en) Combination
US20150272950A1 (en) Combination
US20150272952A1 (en) Combination

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11787314

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 13699103

Country of ref document: US

ENP Entry into the national phase

Ref document number: 2013512197

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

REEP Request for entry into the european phase

Ref document number: 2011787314

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2011787314

Country of ref document: EP