WO2018144791A1 - Combinaison d'inhibiteurs de vps34 et d'inhibiteurs de mtor - Google Patents

Combinaison d'inhibiteurs de vps34 et d'inhibiteurs de mtor Download PDF

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WO2018144791A1
WO2018144791A1 PCT/US2018/016552 US2018016552W WO2018144791A1 WO 2018144791 A1 WO2018144791 A1 WO 2018144791A1 US 2018016552 W US2018016552 W US 2018016552W WO 2018144791 A1 WO2018144791 A1 WO 2018144791A1
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cancer
administered
pharmaceutically acceptable
mtor inhibitor
acceptable salt
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PCT/US2018/016552
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English (en)
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Jouhara CHOUITAR
Natalie Roy D'AMORE
Janice Lee
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Millennium Pharmaceuticals, Inc.
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Publication of WO2018144791A1 publication Critical patent/WO2018144791A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • This present disclosure relates to oncology and to methods for the treatment of cancer.
  • the present disclosure provides methods for treatment of various cancers by administering a VPS34 inhibitor in combination with an mTOR inhibitor .
  • kinases signaling pathways play a central role in numerous biological processes. Defects in various components of signal transduction pathways have been found to account for a vast number of diseases, including numerous forms of cancer, inflammatory disorders, metabolic disorders, vascular and neuronal diseases (Gaestel et al. Current Medicinal Chemistry (2007) 14:2214-2234). In recent years, kinases that are associated with oncogenic signaling pathways have emerged as important drug targets in cancers.
  • Phosphatidylinositol 3-kinase is a family of lipid kinases that phosphorylate phosphatidylinositol at the 3' position of the inositol ring.
  • PI3K is comprised of several classes of genes, including Class IA, IB, II and III and some of these classes contain several isoforms (reviewed in Engelman et al, Nature Review Genetics 7:606-619 (2006)).
  • Vacuolar Protein Sorting 34 (VPS34) is the sole Class III PI3K family member.
  • VPS34 functions in the formation and trafficking of multiple intracellular vesicles, including vacuoles, endosomes, multivessicular bodies, lysosomes and autophagosomes (reviewed in Backer, Biochem. J. (2008) 410: 1-17; Yan and Backer, Biochem. Soc. Trans. (2007) 35:239-241).
  • VPS34 carries out these activities by phosphorylating Ptdlns forming PtdIns3P, resulting in the recruitment and localization of a variety of FYVE and PX domain containing effector proteins that facilitate vesicular formation, elongation and movement.
  • inhibition of VPS34 results in defects in protein sorting, phagocytosis and autophagy.
  • autophagy is a regulated process whereby cells catabolize subcellular components targeted for degradation by enclosing them in double-membrane vesicles which then fuse with lysosomes.
  • Autophagy has been best characterized as occurring during times of nutrient deprivation, but also plays a role in normal cellular and tissue homeostasis and functions, including the development of multiple tissue types, the immune response, clearance of neuronal aggregates and tumor suppression.
  • VPS34 may also participate in several signal transduction pathways (reviewed in Backer, Biochem. J. (2008) 410: 1-17).
  • VPS34 plays an important role in many critical cellular processes including autophagy
  • inhibitors of VPS34 may have therapeutic application in a number of diseases, including but not limited to cancer, muscular disorders, neurodegeneration, inflammatory disease, infectious disease and other age related illnesses (reviewed in Shintani and Klionsky, Science (2004) 306:990-995; Kondo et al, Nat. Rev. Cancer (2005) 5:726-734; Delgato et al, Immunol. Rev. (2009) 227: 189-202).
  • mTOR mammalian / mechanistic target of rapamycin
  • mTOR is a serine/threonine protein kinase that regulates cell growth, translational control, angiogenesis and/or cell survival.
  • mTOR is encoded by the FK506 binding protein 12-rapamycin associated protein 1 (FRAPl) gene and is the catalytic subunit of two distinct protein complexes, mTOR complex 1 (mTORCl) and mTOR complex 2 (mTORC2).
  • mTORCl function is involved in many growth -related processes such as protein translation, ribosome biogenesis, transcription, autophagy and hypoxic adaptation.
  • mTORCl is best known as a key regulator of protein translation via its ability to phosphorylate the eukaryotic translation initiation factor 4EBP1, and S6 kinase (Hidalgo, M. J Clin One (2012) Vol 30, 1).
  • mTORC2 has best been described to regulate two major cell functions, including regulation of Akt and cell cycle-dependent organization of the actin cytoskeleton.
  • mTORC2 phosphorylates Akt on serine 473 (Ser473) in its C-terminal hydrophobic motif, which, in conjunction with PDKl-mediated phosphorylation of threonine 308 (Thr308), confers full activation of Akt (Sarbassov D.D., et al. Science (2005) 307: 1098-1101).
  • mTORC2 regulates the actin cytoskeleton through an unclear mechanism which is rapamycin insensitive (Jacinto E., et al. Nat Cell Biol. (2004) 6: 1122-1128).
  • mTORC2 phosphorylates PKC and SGK1 (serum -and glucocorticoid-induced protein kinase 1), and has also been implicated in controlling cell size (Ikenoue T., et al. EMBO J. (2008) 27: 1919-193; Rosner M, et al. Hum Mol Genet., (2009) 18: 3298-3310).
  • the mTORCl and mTORC2 complexes are often distinguished by their ability to differentially bind and be inhibited by rapamycin and its analogs (rapalogs), which is in contrast to catalytic inhibitors of mTOR that may equally inhibit mTORCl and mTORC2.
  • Rapamycin inhibits mTOR by associating with its intracellular receptor FKBP12.
  • FKBP12-rapamycin complex then binds directly to the FKBP12- Rapamycin Binding (FRB) domain of mTOR enzyme (Jacinto E., et al. Cell (2006) 127: 125-137).
  • rapamycin and rapalogs may be considered as allosteric inhibitors regulating the activity of mTORCl only. Furthermore this regulation may be considered incomplete as the ability of these inhibitors to suppress 4EBP1 phosphorylation (an important downstream effect of mTORCl inhibition) is considered to be only partial (Hidalgo, M. J Clin One (2012) Vol 30, 1).
  • FIG. 1 shows the anti-tumor activity of Compound 1-299 and TAK-228 in the ACHN xenograft model Study 1.
  • FIG. 2 shows the anti-tumor activity of Compound 1-299 and everolimus in the ACHN xenograft model Study 1.
  • FIG. 3 shows the anti-tumor activity of Compound 1-299 and TAK-228 in the A498 xenograft model study 1.
  • FIG. 4 shows the anti-tumor activity of Compound 1-299 and everolimus in the A498 xenograft model study 1.
  • FIG. 5 shows the anti-tumor activity of Compound 1-299 and AZD2014 in the A498 xenograft model study 2.
  • this disclosure relates to a method of treating cancer, comprising administering to a patient a combination of N- ⁇ 6-chloro-4-methyl-2'-[(2-methylpyrimidin-4-yl)amino]- 3,4'-bipyridin-5-yl ⁇ -2,4-difluorobenzenesulfonamide or a pharmaceutically acceptable salt thereof, and an mTOR inhibitor.
  • the mTOR inhibitor is an mTORCl/2 inhibitor. [019] In some embodiments, the mTORCl/2 inhibitor is administered orally.
  • the mTORCl/2 inhibitor is 3-(2-amino-l,3-benzoxazol-5-yl)-l-(propan-2- yl)- lH-pyrazolo [3, 4-d] pyrimidin-4-amine, or a pharmaceutically acceptable salt thereof.
  • the mTORCl/2 inhibitor is AZD2014, or a pharmaceutically acceptable salt thereof.
  • the mTOR inhibitor is an allosteric mTOR inhibitor.
  • the allosteric mTOR inhibitor is administered orally, or intravenously.
  • the allosteric mTOR inhibitor is administered orally.
  • the allosteric mTOR inhibitor is administered intravenously.
  • the allosteric mTOR inhibitor is everolimus, or a pharmaceutically acceptable salt thereof.
  • the allosteric mTOR inhibitor is temsirolimus, or a pharmaceutically acceptable salt thereof.
  • the cancer is solid tumor.
  • the cancer is breast cancer, lung cancer, pancreatic cancer, or renal cancer.
  • the cancer is breast cancer. [031] In some embodiments, the cancer is renal cancer. [032] In some embodiments, the cancer is hematological DESCRIPTION
  • mTOR refers to the catalytic subunit of two complexes, mTORC 1 and/or mTORC2.
  • mTOR inhibitor or "inhibitor of mTOR” is used to signify a compound which is capable of interacting with mTOR and inhibiting its enzymatic activity. Inhibiting mTOR enzymatic activity means reducing the ability of mTOR to phosphorylate a substrate peptide or protein. In various embodiments, such reduction of mTOR activity is at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99%. In various embodiments, the concentration of mTOR inhibitor required to reduce mTOR enzymatic activity is less than about 1 ⁇ , less than about 500 nM, less than about 100 nM, less than about 50 nM, or less than about 10 nM.
  • such inhibition is selective, i.e., the mTOR inhibitor reduces the ability of mTOR to phosphorylate a substrate peptide or protein at a concentration that is lower than the concentration of the inhibitor that is required to produce another, unrelated or undesired biological effect, e.g. , reduction of the enzymatic activity of a different kinase.
  • the mTOR inhibitor also reduces the enzymatic activity of another kinase, preferably one that is implicated in cancer.
  • the mTOR inhibitor selectively inhibits both mTORCl and mTORC2 activity relative to one or more type I phosphatidylinositol 3 -kinases (PI3 -kinase) as ascertained by a cell- based assay or an in vitro kinase assay.
  • PI3 -kinase type I phosphatidylinositol 3 -kinases
  • an mTORCl/2 inhibitor when used herein refers to a catalytic mTOR inhibitor that interacts with and reduces the kinase activity of both mTORCl and mTORC2 complexes.
  • the mTOR inhibitor binds to and directly inhibits both mTORCl and mTORC2.
  • the mTOR inhibitor inhibits both mTORCl and mTORC2 with an IC50 value of about 500 nM or less, 400 nM or less, 300 nM or less, 200 nM or less, 100 nM or less, 50 nM or less, 10 nM or less, or InM or less, as ascertained in an in vitro kinase assay.
  • the mTOR inhibitor inhibits both mTORCl and mTORC2 with an IC50 value of about 10 nM or less as ascertained in an in vitro kinase assay, and the mTOR inhibitor is substantially inactive against one or more types I PI3-kinases selected from the group consisting of PI3-kinase a, PI3-kinase ⁇ , PI3-kinase ⁇ , and PI3- kinase ⁇ .
  • the mTOR inhibitor inhibits both mTORCl and mTORC2 with an IC50 value of about 100 nM or less as ascertained in an in vitro kinase assay, and the IC50 value is at least 2, 5 or 10 times less than its IC50 value against all other type I PI3 -kinases selected from the group consisting of PI3- kinase ⁇ , PI3 -kinase ⁇ , PI3 -kinase ⁇ , and PI3 -kinase ⁇ .
  • an allosteric mTOR inhibitor when used herein refers to an mTOR inhibitor that regulates the activity of mTORCl only.
  • the derivatives of rapamycin, called rapalogs, are allosteric inhibitors that target only the TORC 1 complex.
  • cancer refers to a cellular disorder characterized by uncontrolled or dysregulated cell proliferation, decreased cellular differentiation, inappropriate ability to invade surrounding tissue, and/or ability to establish new growth at ectopic sites.
  • cancer includes solid tumors and hematological tumors.
  • cancer encompasses diseases of skin, tissues, organs, bone, cartilage, blood, and vessels.
  • cancer further encompasses primary and metastatic cancers.
  • the term "effective amount” or “therapeutically effective amount” refers to an amount of a compound, or combination of one or more compounds that, when administered (either sequentially or simultaneously) elicits the desired biological or medicinal response, e.g., either destroys the target cancer cells or slows or arrests the progression of the cancer in a patient.
  • the therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the patient and disease condition being treated, e.g., the weight and age of the patient, the severity of the disease condition, the manner of administration and the like, which may readily be determined by one skilled in the art.
  • the term also applies to a dose that will induce a particular response in target cells, e.g., reduction of platelet adhesion and/or cell migration.
  • the "therapeutically effective amount” as used herein refers to the amount of a VPS34 inhibitor and the amount of an mTOR inhibitor that, when administered in combination, have a beneficial effect.
  • the combined effect is additive.
  • the combined effect is synergistic.
  • the amount of the VPS34 inhibitors and/or the amount of the mTOR inhibitor may be used in a "sub-therapeutic amount", i.e., less than the therapeutically effective amount of the VPS34 or mTOR inhibitor alone.
  • the administered dose(s) or the therapeutically effective (total) amount may be expressed as amount(s) of therapeutic substance(s) per patient as either based on (i) BSA, e.g., as mg/m 2 , or (ii) amount e.g. as mg.
  • patient means a human being diagnosed with, exhibiting symptoms of or otherwise believed to be afflicted with a disease, disorder or condition.
  • body surface area is calculated using a standard nomogram, e.g., Ht (cm) x Wt (kg) Ht (in) x Wt (l b)
  • Combination administration refers to administering of more than one pharmaceutically active ingredients (including, but not limited to, a VPS34 inhibitor and an mTOR inhibitor as disclosed herein) to a patient.
  • Combination administration may refer to simultaneous administration or may refer to sequential administration of the VPS34 inhibitor and the mTOR inhibitor as disclosed herein.
  • the terms “simultaneous” and “simultaneously” refer to the administration of the VPS34 inhibitor and the mTOR inhibitor as disclosed herein, to a patient at the same time, or at two different time points that are separated by no more than 2 hours.
  • the simultaneous administration of the VPS34 inhibitor and the mTOR inhibitor may be in a single dosage form or in separate dosage forms.
  • the terms “sequential” and “sequentially” refer to the administration of the VPS34 inhibitor and the mTOR inhibitor as disclosed herein, to a patient at two different time points that are separated by more than 2 hours, e.g., about 3 hours, 4 hours, 5 hours, abot 8 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days or even longer.
  • the term "intermission” refers to a period that is that subsequent to the administration of one or more particular pharmaceutically active ingredients to a patient in an intermittent regimen. Intermission refers to a rest period wherein a particular pharmaceutically active ingredient is not administered for at least one day.
  • the term "synergistic effect” refers to a situation where the combination of two or more agents produces a greater effect than the sum of the effects of each of the individual agents.
  • the term encompasses not only a reduction in symptoms of the disorder to be treated, but also an improved side effect profile, improved tolerability, improved patient compliance, improved efficacy, or any other improved clinical outcome.
  • structures depicted herein are meant to include chemical entities which differ only in the presence of one or more isotopically enriched atoms.
  • chemical entities having the present structure except for the replacement of a hydrogen atom by a deuterium or tritium, or the replacement of a carbon atom by a 13 C- or 14 C -enriched carbon are within the scope of the invention.
  • stereochemical configuration Unless stereochemical configuration is denoted, structures depicted herein are meant to include all stereochemical forms of the structure, i.e., the R and S configurations for each asymmetric center. Therefore, unless otherwise indicated, single stereochemical isomers as well as enantiomeric, racemic and diastereomeric mixtures of the present chemical entities are within the scope of the invention.
  • the diastereoisomeric or enantiomeric excess of the compound is at least 99.0%, 99.5%, 99.6%, 99.7%, 99.8% or 99.9%.
  • the present disclosure relates to a method of treating cancer by administering to a patient a combination of a VPS34 inhibitor and an mTOR inhibitor.
  • the present disclosure relates to the use of a VPS34 inhibitor in combination with an mTOR inhibitor for the treatment of cancer in a patient.
  • the present disclosure relates to a kit comprising a medicament for use in treating cancer in a patient in need of such treatment.
  • the kit comprises a medicament comprising a VPS34 inhibitor, and instructions for administering the VPS34 inhibitor and an mTOR inhibitor; or the kit comprises a medicament comprising an mTOR inhibitor, and instructions for administering the mTOR inhibitor and a VPS34 inhibitor.
  • the kit may contain a medicament comprising a VPS34 inhibitor and an mTOR inhibitor, and instructions for administering the VPS34 inhibitor and the mTOR inhibitor, wherein the medicament is in single dosage form or in separate dosage forms.
  • the present disclosure relates to a medicament for use in treating cancer in a patient in need of such treatment.
  • the medicament comprises a VPS34 inhibitor and an mTOR inhibitor, and is in single dosage form or in separate dosage forms.
  • the present disclosure relates to the use of a VPS34 inhibitor in the manufacture of a medicament for treating cancer, wherein the VPS34 inhibitor is administered with an mTOR inhibitor, and wherein the medicament is in single dosage form or in separate dosage forms.
  • the present disclosure relates to the use of a VPS34 inhibitor for the manufacture of a medicament in treating cancer in a patient, wherein the patient is also treated with an mTOR inhibitor.
  • the VPS34 inhibitor may be administered simultaneously or sequentially with the mTOR inhibitor.
  • the present disclosure relates to the use of a VPS34 inhibitor for the manufacture of a medicament in treating cancer in a patient, wherein the VPS34 inhibitor is in combination with an mTOR inhibitor.
  • the VPS34 inhibitor is in the same composition as the mTOR inhibitor.
  • the VPS34 inhibitor is in a separate composition as the mTOR inhibitor.
  • the present disclosure relates to a composition comprising a VPS34 inhibitor for use in treating cancer in a patient, wherein the patient is also treated with an mTOR inhibitor.
  • the disclosure relates to a composition comprising VPS34 inhibitor for use in treating cancer in a patient, wherein the VPS34 inhibitor is in combination with the mTOR inhibitor.
  • the VPS34 inhibitor can be administered simultaneously or sequentially with the mTOR inhibitor.
  • the present disclosure relates to methods of treating cancer comprising administering to a patient in need of such treatment, a therapeutically effective amount of a combination of a VPS34 inhibitor and an mTOR inhibitor.
  • the VPS34 inhibitor is N- ⁇ 6-chloro-4-methyl-2'-[(2-methylpyrimidin- 4-yl)amino] -3 ,4'-bipyridin-5 -yl ⁇ -2,4-difluorobenzenesulfonamide :
  • N- ⁇ 6-chloro-4-methyl-2'-[(2-methylpyrimidin-4-yl)amino]- 3, 4'-bipyridin-5-yl ⁇ -2,4-difluorobenzenesulfonamide is also referred to herein as Compound 1-299.
  • the VPS34 inhibitor is N- ⁇ 6-chloro-4-methyl-2'-[(2-methylpyrimidin- 4-yl)amino] -3, 4'-bipyridin-5-yl ⁇ -2,4-difluorobenzenesulfonamide, or a pharmaceutically acceptable salt thereof.
  • the VPS34 inhibitor is N- ⁇ 6-chloro-4-methyl-2'-[(2-methylpyrimidin- 4-yl)amino]-3,4'-bipyridin-5-yl ⁇ -2,4-difluorobenzenesulfonamide, or Compound 1-299.
  • VPS34 inhibitors as disclosed herein are described, for example, in WO 2015/108861. They may be prepared by methods known to one skilled in the art and/or according to the methods described in WO 2015/108861, which is hereby incorporated by reference in this entirety.
  • the mTOR inhibitor is a small molecular weight compound. In some embodiments, the mTOR inhibitor is a catalytic mTOR inhibitor, or an mTORCl/2 inhibitor.
  • the mTOR inhibitor is 3-(2-amino-l,3-benzoxazol-5-yl)-l-(propan-2-yl)- lH-pyrazolo [3, 4-d] pyrimidin-4-amine:
  • the mTOR inhibitor is 3-(2-amino- l,3-benzoxazol-5-yl)-l-(propan-2-yl)-lH-pyrazolo [3, 4-d] pyrimidin-4-amine, or a pharmaceutically acceptable salt thereof.
  • TAK-228 is described in WO 2010/051043, which is hereby incorporated by reference in its entirety. TAK-228 may be prepared by methods known to one skilled in the art, or by the method described in WO 2010/051043.
  • the mTOR inhibitor is CC223 (Celgene), OSI027 (OSI Pharmaceuticals), DS3078 (Daiichi), AZD8055 (Astra Zeneca), or AZD2014 (Astra Zeneca).
  • the mTOR inhibitor is 3-[2,4-bis[(3S)-3-methylmo ⁇ holin-4-yl]pyrido[2,3-d]pyrimidin-7-yl]-N- methylbenzamide (AZD2014), or a pharmaceutically acceptable salt thereof.
  • the mTOR inhibitors described herein may be prepared by methods known to one skilled in the art.
  • the mTOR inhibitor is an allosteric mTOR inhibitor.
  • the mTOR inhibitor is everolimus, temsirolimus, sirolimus, or deforolimus.
  • the mTOR inhibitor is everolimus, or a pharmaceutically acceptable salt thereof.
  • the mTOR inhibitor is temsirolimus, or a pharmaceutically acceptable salt thereof.
  • the mTOR inhibitors described herein may be prepared by methods known to one skilled in the art.
  • the present disclosure relates to a method of treating cancer by administering to a patient a combination of Compound 1-299, or pharmaceutically acceptable salt thereof, and an mTOR inhibitor.
  • the present disclosure relates to the use of Compound 1-299, or a pharmaceutically acceptable salt thereof, in combination with an mTOR inhibitor for the treatment of cancer.
  • the present disclosure relates to the use of Compound 1-299, or a pharmaceutically acceptable salt thereof in combination with an mTOR inhibitor in the manufacture of a medicament for use in treating cancer.
  • the present disclosure relates to the use of Compound 1-299, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer, wherein Compound 1-299 or a pharmaceutically acceptable salt thereof is administered with an mTOR inhibitor.
  • the present disclosure relates to a kit for treating cancer comprising at least one medicament comprising at least one dose of Compound 1-299 or a pharmaceutically acceptable salt thereof, and at least one medicament comprising at least one dose of an mTOR inhibitor, said kit for treating cancer further comprising dosing instructions for administering the medicaments for treatment of the patient in recognized need thereof.
  • Compound 1-299 or a pharmaceutically acceptable salt thereof may be administered in combination with the mTOR inhibitor in a single dosage form or as a separate dosage forms.
  • the mTOR inhibitor when administered as a separate dosage form, may be administered prior to, at the same time as, or following administration of 1-299 or a pharmaceutically acceptable salt thereof.
  • one or more doses of 1-299 or a pharmaceutically acceptable salt thereof when administered as a separate dosage form, may be administered prior to the the mTOR inhibitor.
  • the mTOR inhibitor is administered prior to the administration of Compound 1-299 or a pharmaceutically acceptable salt thereof.
  • the administration in "combination" of Compound 1-299 or a pharmaceutically acceptable salt thereof and an mTOR inhibitor refers not only to simultaneous or sequential administration of the two agents, but also to the administration of both compounds during a single treatment cycle, as understood by one skilled in the art.
  • a therapeutically effective amount of the combination is administered.
  • the VPS34 inhibitor may be administered by any method known to one skilled in the art.
  • the VPS34 inhibitor may be administered in the form of a pharmaceutical composition of the VPS34 inhibitor and a pharmaceutically acceptable carrier, such as those described herein.
  • the pharmaceutical composition is suitable for oral administration.
  • the pharmaceutical composition is a tablet or a capsule that is suitable for oral administration.
  • the pharmaceutical composition is a liquid dosage form suitable for oral administration.
  • these compositions optionally further comprise one or more additional therapeutic agents.
  • the mTOR inhibitor may be administered by any method known to one skilled in the art.
  • the mTOR inhibitor is administered intravenously (IV).
  • the mTOR inhibitor is administered orally.
  • the mTOR inhibitor may be administered in the form of a second composition, in some embodiments, a pharmaceutical composition of the mTOR inhibitor and a pharmaceutically acceptable carrier, such as those described herein.
  • the pharmaceutical composition is suitable for oral administration.
  • the pharmaceutical composition is a tablet or a capsule that is suitable for oral administration.
  • the pharmaceutical composition is a liquid dosage form suitable for oral administration.
  • these compositions optionally further comprise one or more additional therapeutic agents.
  • the cancer is a solid tumor.
  • solid tumors include pancreatic cancer; bladder cancer, including invasive bladder cancer; colorectal cancer; thyroid cancer; gastric cancer; breast cancer, including metastatic breast cancer; prostate cancer, including androgen- dependent and androgen-independent prostate cancer; renal cancer, including, e.g., metastatic renal cell carcinoma; liver cancer including e.g.
  • lung and bronchus cancer including non-small cell lung cancer (NSCLC), squamous lung cancer, brochioloalveolar carcinoma (BAC), adenocarcinoma of the lung, and small cell lung cancer (SCLC); ovarian cancer including, e.g., progressive epithelial and primary peritoneal cancer; cervical cancer; uterine cancer including e.g.
  • uterine corpus and uterine cervix endometrial cancer; esophageal cancer; head and neck cancer, including, e.g., squamous cell carcinoma of the head and neck, nasopharyngeal caner, oral cavity and pharynx; melanoma; neuroendocrine cancer, including metastatic neuroendocrine tumors; brain cancer, including, e.g., glioma/glioblastoma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma; neuroendocrine cancer, including metastatic neuroendocrine tumors; bone cancer; gastro-esophageal junction cancer, and soft tissue sarcoma.
  • brain cancer including, e.g., glioma/glioblastoma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocyto
  • the cancer is breast cancer, cervical cancer, renal cancer, pancreatic cancer, colorectal cancer, ovarian cancer, lung cancer, prostate cancer, gastric cancer, or head and neck cancer.
  • the cancer is breast cancer, renal cancer, pancreatic cancer, colorectal cancer, ovarian cancer, ganstric cancer, or lung cancer.
  • the cancer is breast cancer, renal cancer, or pancreatic cancer.
  • the cancer is breast cancer, lung cancer, renal cancer, or pancreatic cancer.
  • the cancer is breast cancer, or renal cancer.
  • the cancer is lung cancer.
  • Lung cancer includes different sub-types such as small cell lung cancer (SCLC); non-small cell lung cancer (NSCLC) including squamous NSCLC; bronchioloalveolar carcinoma (BAC); and adenocarcinoma.
  • SCLC small cell lung cancer
  • NSCLC non-small cell lung cancer
  • BAC bronchioloalveolar carcinoma
  • adenocarcinoma adenocarcinoma.
  • the cancer is small cell lung cancer.
  • the cancer is non-small cell lung cancer.
  • the cancer is breast cancer.
  • Breast cancer includes different sub-types such as luminal A, luminal B, triple-negative (basal-like) and HER-2 type.
  • the cancer is triple -negative breast cancer.
  • the cancer is cervical cancer. Cervical cancer includes different sub-types such as squamous cell carcinomas, adenocarcinomas and adenosquamous carcinomas. In some embodiments, the cancer is squamous cell carcinomas.
  • the cancer is liver cancer.
  • Liver cancer includes different sub-types such as hepatocellular carcinoma and intrahepatic bile duct cancer.
  • the cancer is hepatocellular carcinoma.
  • the cancer is renal cancer.
  • Renal cancer includes different sub-types such as renal cell carcinoma, transitional cell carcinoma, wilms tumor, renal sarcoma.
  • the cancer is renal cell carcinoma.
  • the cancer is pancreatic cancer.
  • Pancreatic cancer includes different subtypes such as exocrine pancreatic cancers, which further includes pancreatic adenocarcinoma, acinar cell carcinoma, adenosquamous carcinomas, squamous cell carcinomas, signet ring cell carcinomas, undifferentiated carcinomas, and undifferentiated carcinomas with giant cells, and pancreatic neuroendocrine tumors or islet cell tumors.
  • the cancer is ovarian cancer.
  • Ovarian cancer includes different sub-types such as epithelial, germ -cell and sex-cord stromal.
  • Primary peritoneal carcinoma is a related cancer that starts in the lining of the pelvis and abdomen.
  • the cancer is epithelial ovarian cancer.
  • the cancer is prostate cancer.
  • Prostate cancer includes androgen-dependent and androgen independent prostate cancer and adenocarcinomas.
  • the cancer is gastric cancer.
  • Adenocarcinoma is the most common type of gastric cancer.
  • Other gastric cancers may include gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, and lymphomas.
  • the cancer is esophageal cancer.
  • esophageal cancer The most common types of esophageal cancer are squamous cell carcinoma and adenocarcinoma.
  • Gastro-esophageal cancer is a related cancer that develops at the point where the esophagus joins the stomach.
  • the cancer is colorectal cancer.
  • Adenocarcinoma is the most common type of colorectal cancer.
  • Other colorectal cancers may include gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, and squamous cell carcinoma.
  • the cancer is head and neck cancer.
  • Head and neck cancer are those that arise in the head and neck region and the cancer may be found in areas such as nasal cavities, sinuses, lips, mouth, salivary glands, pharynx or larynx.
  • 90% of head and neck cancers are squamous cell carcinomas (SCCHN), which originate from the mucosal lining (epithelium) of these regions.
  • SCCHN squamous cell carcinomas
  • the cancer is a hematological cancer.
  • the cancer is multiple myeloma, Hodgkin's lymphoma, or non-Hodgkin's lymphoma including Diffuse large B-cell lymphoma (DLBCL) and Waldentroms Macroglobulinemia.
  • DLBCL Diffuse large B-cell lymphoma
  • the cancer is relapsed.
  • relapsed cancer is cancer which has returned after a period of time in which no cancer could be detected.
  • the cancer is refractory. In some embodiments, refractory cancer does not respond to cancer treatment; it is also known as resistant cancer. In some embodiments, the cancer is resistant to a platin. In some embodiments, the cancer does not respond to the treatment of a platin. In some embodiments, the cancer is platin-resistant recurrent cancer. In some embodiments, the patient has become refractory to a platin-containing regimen. In some embodiments, the tumor is unresectable. In some embodiments, an unresectable tumor is unable to be removed by surgery. In some embodiments, the cancer has not been previously treated. In some embodiments, the cancer is locally advanced.
  • “locally advanced” refers to cancer that is somewhat extensive but still confined to one area. In some instances, “locally advanced” may refer to a small tumor that hasn't spread but has invaded nearby organs or tissues that make it difficult to remove with surgery alone.
  • the cancer is metastatic. In some embodiments, metastatic cancer is a cancer that has spread from the part of the body where it started (the primary site) to other parts of the body.
  • the cancer is a VPS34-mediated disorder. In some embodiments, the cancer is an mTOR-mediated disorder.
  • the amounts or suitable doses of the methods of this disclosure depends upon a number of factors, including the nature of the severity of the condition to be treated, the particular inhibitor, the route of administration and the age, weight, general health, and response of the individual patient.
  • the suitable dose level is one that achieves a therapeutic response as measured by tumor regression, or other standard measures of disease progression, progression free survival or overall survival.
  • the suitable dose level is one that achieves this therapeutic response and also minimizes any side effects associated with the administration of the therapeutic agent.
  • the suitable dose levels may be ones that prolong the therapeutic response and/or prolong life.
  • a suitable dose of the VPS34 inhibitor and the mTOR inhibitor may be taken at any time of the day or night. In some embodiments, a suitable dose of each inhibitor is taken in the morning. In some other embodiments, a suitable dose of each inhibitor is taken in the evening. In some embodiments, a suitable dose of each of the inhibitors is taken both in the morning and the evening. It will be understood that a suitable dose of each inhibitor may be taken with or without food. In some embodiments a suitable dose of an inhibitor is taken with a meal. In some embodiments a suitable dose of an inhibitor is taken while fasting.
  • Compound 1-299 or a pharmaceutically acceptable salt thereof is administered on a daily schedule. In some embodiments, Compound 1-299 or a pharmaceutically acceptable salt thereof is administered every other day. In some embodiments, Compound 1-299 or a pharmaceutically acceptable salt thereof is administered once every three days. In some embodiments, Compound 1-299 or a pharmaceutically acceptable salt thereof is administered on a twice -weekly schedule. In some embodiments, Compound 1-299 or a pharmaceutically acceptable salt thereof is administered on a weekly schedule. [0100] In some embodiments, the amount of Compound 1-299 or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 0.5 mg to about 30 mg.
  • the amount of Compound 1-299 or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 0.5 mg to about 5 mg. In some embodiments, the amount of Compound 1-299 or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 1 mg to about 3 mg. In some embodiments, the amount of Compound 1-299 or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 2 mg to about 5 mg. In some embodiments, the amount of Compound 1-299 or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 5 mg to about 10 mg.
  • the amount of Compound 1-299 or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 5 mg to about 15 mg. In some embodiments, the amount of Compound 1-299 or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 10 mg to about 20 mg. In some embodiments, the amount of Compound 1-299 or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 15 mg to about 25 mg. In some embodiments, the amount of Compound 1-299 or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is between about 20 mg to about 30 mg.
  • the amount of Compound 1-299 or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 0.5 mg. In some embodiments, the amount of Compound 1-299 or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 1 mg. In some embodiments, the amount of Compound 1-299 or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 2 mg. In some embodiments, the amount of Compound 1-299 or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 4 mg. In some embodiments, the amount of Compound 1-299 or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 6 mg.
  • the amount of Compound 1-299 or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 8 mg. In some embodiments, the amount of Compound 1-299 or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 10 mg. In some embodiments, the amount of Compound 1-299 or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 12 mg. All dosing amounts refer to the amount of Compound 1-299 administered, and do not include the weight amount of any pharmaceutically acceptable salt.
  • the mTOR inhibitor is administered daily. In some embodiments, the mTOR inhibitor is administered twice a day. In some embodiments, the mTOR inhibitor is administered weekly. In some embodiments, the mTOR inhibitor is administered at least 3 times on alternate days within a 7-day cycle. In some embodiments, the mTOR inhibitor is administered on day 1 and day 4 of a 7-day cycle.
  • the mTOR inhibitor is administered on consecutive days in a 7-day cycle followed by an intermission. In some embodiments, the mTOR inhibitor is administered for 3 consecutive days followed by an intermission of 4 consecutive days for at least one 7-day cycle. In some embodiments, the mTOR inhibitor is administered for 3 consecutive days followed by an intermission of 4 consecutive days per 7-day cycle. In some embodiments, the mTOR inhibitor is administered for 4 consecutive days followed by an intermission of 3 consecutive days for at least one 7-day cycle. In some embodiments, the mTOR inhibitor is administered for 5 consecutive days followed by an intermission of 2 consecutive days for at least one 7-day cycle. In some embodiments, the mTOR inhibitor is administered for 2 consecutive days followed by an intermission of 5 consecutive days for at least one 7-day cycle.
  • the amount of the mTOR inhibitor that is administered on each day of dosing is about 0.1 mg to about 60 mg. In some embodiments, the amount of the mTOR inhibitor that is administered on each day of dosing is about 0.1 mg to about 0.5 mg. In some embodiments, the amount of the mTOR inhibitor that is administered on each day of dosing is about 0.2 mg to about 1.0 mg. In some embodiments, the amount of the mTOR inhibitor that is administered on each day of dosing is about 0.5 mg to about 5 mg. In some embodiments, the amount of the mTOR inhibitor that is administered on each day of dosing is about 1 mg to about 3 mg.
  • the amount of the mTOR inhibitor that is administered on each day of dosing is about 2 mg to about 5 mg. In some embodiments, the amount of the mTOR inhibitor that is administered on each day of dosing is about 4 mg to about 10 mg. In some embodiments, the amount of the mTOR inhibitor that is administered on each day of dosing is about 5 mg to about 15 mg. In some embodiments, the amount of the mTOR inhibitor that is administered on each day of dosing is about 10 mg to about 20 mg. In some embodiments, the amount of the mTOR inhibitor that is administered on each day of dosing is about 15 mg to about 25 mg.
  • the amount of the mTOR inhibitor that is administered on each day of dosing is between about 20 mg to about 30 mg. In some embodiments, the amount of the mTOR inhibitor that is administered on each day of dosing is between about 25 mg to about 35 mg. In some embodiments, the amount of the mTOR inhibitor that is administered on each day of dosing is between about 30 mg to about 40 mg. In some embodiments, the amount of the mTOR inhibitor that is administered on each day of dosing is between about 35 mg to about 45 mg. In some embodiments, the amount of the mTOR inhibitor that is administered on each day of dosing is between about 40 mg to about 50 mg.
  • the amount of the mTOR inhibitor that is administered on each day of dosing is between about 45 mg to about 55 mg. In some embodiments, the amount of the mTOR inhibitor that is administered on each day of dosing is between about 50 mg to about 60 mg. All dosing amounts refer to the amount of the mTOR inhibitor administered, and do not include the weight amount of any pharmaceutically acceptable salt.
  • the amount of the mTOR inhibitor that is administered on each day of dosing is about 50 mg to about 300 mg. In some embodiments, the amount of the mTOR inhibitor that is administered on each day of dosing is about 50 mg to about 100 mg. In some embodiments, the amount of the mTOR inhibitor that is administered on each day of dosing is about 70 mg to about 120 mg. In some embodiments, the amount of the mTOR inhibitor that is administered on each day of dosing is about 100 mg to about 150 mg. In some embodiments, the amount of the mTOR inhibitor that is administered on each day of dosing is about 120 mg to about 170 mg.
  • the amount of the mTOR inhibitor that is administered on each day of dosing is about 150 mg to about 200 mg. In some embodiments, the amount of the mTOR inhibitor that is administered on each day of dosing is about 220 mg to about 270 mg. In some embodiments, the amount of the mTOR inhibitor that is administered on each day of dosing is about 250 mg to about 300 mg. All dosing amounts refer to the amount of the mTOR inhibitor administered, and do not include the weight amount of any pharmaceutically acceptable salt.
  • the mTOR inhibitor is TAK-228, or a pharmaceutically acceptable salt thereof.
  • the amount of TAK-228 or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 0.5 mg to about 60 mg. In some embodiments, the amount of TAK-228 or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 0.5 mg to about 5 mg. In some embodiments, the amount of TAK-228 or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 1 mg to about 3 mg. In some embodiments, the amount of TAK-228 or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 2 mg to about 5 mg.
  • the amount of TAK-228 or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 4 mg to about 10 mg. In some embodiments, the amount of TAK-228 or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 5 mg to about 15 mg. In some embodiments, the amount of TAK-228 or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 10 mg to about 20 mg. In some embodiments, the amount of TAK-228 or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 15 mg to about 25 mg .
  • the amount of TAK-228 or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is between about 20 mg to about 30 mg. In some embodiments, the amount of TAK-228 or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is between about 25 mg to about 35 mg. In some embodiments, the amount of TAK-228 or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is between about 30 mg to about 40 mg. In some embodiments, the amount of TAK-228 or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is between about 35 mg to about 45 mg.
  • the amount of TAK- 228 or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is between about 40 mg to about 50 mg. In some embodiments, the amount of TAK-228 or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is between about 45 mg to about 55 mg. In some embodiments, the amount of TAK-228 or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is between about 50 mg to about 60 mg. All dosing amounts refer to the amount of TAK-228 or a pharmaceutically acceptable salt thereof administered, and do not include the weight amount of any pharmaceutically acceptable salt.
  • the mTOR inhibitor is AZD2014, or a pharmaceutically acceptable salt thereof.
  • the amount of AZD2014 or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 10 mg to about 300 mg.
  • the amount of AZD2014 or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 25 mg.
  • the amount of AZD2014 or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 50 mg.
  • the amount of AZD2014 or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 75 mg.
  • the amount of AZD2014 or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 100 mg. In some embodiments, the amount of AZD2014 or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 125 mg. In some embodiments, the amount of AZD2014 or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 150 mg. In some embodiments, the amount of AZD2014 or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 175 mg. In some embodiments, the amount of AZD2014 or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 200 mg.
  • the amount of AZD2014 or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 225 mg. All dosing amounts refer to the amount of AZD2014 or a pharmaceutically acceptable salt thereof administered, and do not include the weight amount of any pharmaceutically acceptable salt.
  • the mTOR inhibitor is everolimus, or a pharmaceutically acceptable salt thereof.
  • the amount of everolimus or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 0.5 mg to about 20 mg.
  • the amount of everolimus or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 0.5 mg to about 5 mg.
  • the amount of everolimus or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 1 mg to about 3 mg.
  • the amount of everolimus or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 2 mg to about 5 mg.
  • the amount of everolimus or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 4 mg to about 10 mg. In some embodiments, the amount of everolimus or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 5 mg to about 15 mg. In some embodiments, the amount of everolimus or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 10 mg to about 20 mg. In some embodiments, the amount of everolimus or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 0.25 mg. In some embodiments, the amount of everolimus or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 0.5 mg.
  • the amount of everolimus or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 0.75 mg. In some embodiments, the amount of everolimus or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 2 mg. In some embodiments, the amount of everolimus or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 2.5 mg. In some embodiments, the amount of everolimus or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 3 mg. In some embodiments, the amount of everolimus or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 5 mg.
  • the amount of everolimus or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 7.5 mg. In some embodiments, the amount of everolimus or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 10 mg. All dosing amounts refer to the amount of everolimus administered, and do not include the weight amount of any pharmaceutically acceptable salt.
  • the mTOR inhibitor is temsirolimus, or a pharmaceutically acceptable salt thereof.
  • the amount of temsirolimus or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 15 mg.
  • the amount of temsirolimus or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 20 mg.
  • the amount of temsirolimus or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 25 mg. All dosing amounts refer to the amount of temsirolimus administered, and do not include the weight amount of any pharmaceutically acceptable salt.
  • any of therapeutic agents described herein may be in the form of a pharmaceutically acceptable salt.
  • such salts are derived from inorganic or organic acids or bases.
  • suitable salts see, e.g. , Berge et al, J. Pharm. Sci., 1977, 66, 1-19 and Remington: The Science and Practice of Pharmacy, 20th Ed., A. Gennaro (ed.), Lippincott Williams & Wilkins (2000).
  • Suitable acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzene sulfonate, bisulfate, butyrate, citrate, camphorate, camphor sulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, lucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3 -phenyl -propionate, picrate, pivalate, propionate, succinate, tart
  • suitable base addition salts include ammonium salts; alkali metal salts, such as sodium and potassium salts; alkaline earth metal salts, such as calcium and magnesium salts; salts with organic bases, such as dicyclohexylamine salts, N-methyl-D-glucamine; and salts with amino acids such as arginine, lysine, and the like.
  • pharmaceutically acceptable carrier refers to a material that is compatible with a recipient subject (a human) and is suitable for delivering an active agent to the target site without terminating the activity of the agent.
  • the toxicity or adverse effects, if any, associated with the carrier preferably are commensurate with a reasonable risk/benefit ratio for the intended use of the active agent.
  • compositions for use in the methods of the present disclosure may be manufactured by methods well known in the art such as conventional granulating, mixing, dissolving, encapsulating, lyophilizing, or emulsifying processes, among others.
  • Compositions may be produced in various forms, including granules, precipitates, or particulates, powders, including freeze dried, rotary dried or spray dried powders, amorphous powders, tablets, capsules, syrup, suppositories, injections, emulsions, elixirs, suspensions or solutions.
  • Formulations may contain stabilizers, pH modifiers, surfactants, solubilizing agents, bioavailability modifiers and combinations of these.
  • compositions include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates or carbonates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, poly aery late s, waxes, polyethylene -poly oxypropylene -block polymers, polyethylene glycol and wool fat.
  • ion exchangers alumina, aluminum stearate, lecithin
  • serum proteins such as human serum albumin
  • buffer substances such as phosphates or carbonates
  • compositions are formulated for pharmaceutical administration to a human being.
  • Such compositions may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intravenous, intraperitoneal, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the compositions are administered orally, intravenously or subcutaneously.
  • the compositions are administered orally.
  • the compositions are administered intravenously.
  • These formulations may be designed to be short-acting, fast-releasing, or long -acting.
  • the compositions may be administered in a local rather than systemic means, such as administration (e.g. , by injection) at a tumor site.
  • compositions may be prepared as liquid suspensions or solutions using a liquid, such as an oil, water, an alcohol, and combinations of these. Solubilizing agents such as cyclodextrins may be included. Pharmaceutically suitable surfactants, suspending agents, or emulsifying agents, may be added for oral or parenteral administration. Suspensions may include oils, such as peanut oil, sesame oil, cottonseed oil, corn oil and olive oil. Suspension preparations may also contain esters of fatty acids such as ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides.
  • Suspension formulations may include alcohols, such as ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol and propylene glycol; ethers, such as poly (ethylenegly col); petroleum hydrocarbons such as mineral oil and petrolatum; and water.
  • alcohols such as ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol and propylene glycol
  • ethers such as poly (ethylenegly col)
  • petroleum hydrocarbons such as mineral oil and petrolatum
  • Sterile injectable forms of these pharmaceutical compositions may be aqueous or oleaginous suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides.
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • oils such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • compositions may be formulated for parenteral administration by injection such as by bolus injection or continuous infusion.
  • a unit dosage form for injection may be in ampoules or in multi-dose containers.
  • compositions may be orally administered in any orally acceptable dosage form including capsules, tablets, aqueous suspensions or solutions.
  • aqueous suspensions When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
  • useful diluents include lactose and dried cornstarch.
  • carriers that are commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • Coatings may be used for a variety of purposes, e.g., to mask taste, to affect the site of dissolution or absorption, or to prolong drug action. Coatings may be applied to a tablet or to granulated particles for use in a capsule.
  • these pharmaceutical compositions may be administered in the form of suppositories for rectal administration.
  • suppositories may be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, beeswax and polyethylene glycols.
  • compositions may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
  • Topical application for the lower intestinal tract may be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically -transdermal patches may also be used.
  • the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of the compounds of the present disclosure include mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • the pharmaceutical compositions may be formulated in a suitable lotion or cream containing the active component(s) suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with our without a preservative such as benzylalkonium chloride.
  • the pharmaceutical compositions may be formulated in an ointment such as petrolatum.
  • compositions may also be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • kits are any article of manufacture (e.g., a package or container) comprising at least one reagent or chemotherapeutic agent.
  • a kit for use in the methods herein may comprise a VPS34 inhibitor, such as a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the kit may further include an mTOR inhibitor.
  • the kit may include a compound of formula (I) or a pharmaceutically acceptable salt thereof and an mTOR inhibitor.
  • the kit may include a compound of formula (I) or a pharmaceutically acceptable salt thereof and a compound of formula (II) or a pharmaceutically acceptable salt thereof.
  • a kit comprising a VPS34 inhibitor and an mTOR inhibitor may further include another component or reagent.
  • a reagent in the kit may be a diluent for preparing the VPS34 inhibitor for administration.
  • a reagent in the kit may be a diluent for preparing the mTOR inhibitor for administration.
  • a component in the kit may be a vessel for mixing the combination of the VPS34 inhibitor and the mTOR inhibitor.
  • Example 1 In vivo tumor efficacy models
  • A498 Study 2 A498 is a renal cell carcinoma cell-line derived xenograft.
  • a 0.66 mg/mL (ACHN Study 1), 0.72 mg/mL (A498 Study 1), or 0.75 mg/mL (A498 Study 2) stock solution of Compound 1-299 was formulated weekly by adding 10% HPbCD + 3.5% NaHCC .
  • Compound 1-299 was administered orally on the basis of exact animal body weight on each day of treatment, using a dosing volume of 0.05 mL/10 g body weight.
  • a 0.13 mg/mL, 0.07 mg/ml (ACHN Study 1), or 0.15 mg/ml (A498 Study 1) stock solution of TAK-228 was formulated by adding 0.5% CMC + 0.05% Tween 80.
  • TAK-228 was administered orally on the basis of exact animal body weight on each day of treatment, using a dosing volume of 0.05 mL/10 g body weight.
  • Everolimus was administered orally on the basis of exact animal body weight on each day of treatment, using a dosing volume of 0.05 mL/10 g body weight.
  • a 2.40 mg/mL stock solution of AZD2014 (Selleckchem, Wanchai, Hong Kong) was formulated by adding 30% HPbCD.
  • AZD2014 was administered orally on the basis of exact animal body weight on each day of treatment, using a dosing volume of 0.05 mL/10 g body weight.
  • mice are euthanized when the average tumor volume of a treatment or control group reached approximately 1000 mm 3 .
  • Tumor volumes on study Days 22 or 29 from the day of treatment initiation are shown in Tables la, 2a, 3a, 4a and 5a. Average tumor volume is reported as a function of time for selected arms of selected studies in Figures 1, 2, 3, 4 and 5.
  • GRI Growth Rate Inhibition
  • the tumor growth rates were analyzed over specified time intervals. This analysis was performed in the same way as the pairwise comparisons, except that the data used to estimate the growth rates was taken only from specified time intervals.
  • mice were inoculated, randomized on Day 0 (24 days post inoculation), and treatments began on day 1 for all groups.
  • Compound 1-299 was tested at 3mg/kg administered PO on a QWx4 (once weekly for 4 weeks) schedule.
  • TAK-228 was tested at doses of 0.6 and 0.3 mg/kg administered PO on a QDx28 (once daily for 28 consecutive days) schedule.
  • Compound 1-299 was administered first, followed immediately by the administration of TAK-228.
  • One group served as a vehicle-treated control group (Group 1) receiving PO treatment with the vehicles used for administration of both agents on their respective schedule.
  • Table lb Classification for in vivo combination of Compound 1-299 and TAK-228 in the ACHN xenograft model
  • mice were inoculated, randomized on Day 0 (24 days post inoculation), and treatments began on day 1 for all groups.
  • Compound 1-299 was tested at 3mg/kg administered PO on a QWx4 (once weekly for 4 weeks) schedule.
  • Everolimus was tested at 3mg/kg administered PO on a QDx28 (once daily for 28 consecutive days) schedule.
  • Compound 1-299 was administered first, followed immediately by the administration of everolimus.
  • One group served as a vehicle-treated control group (Group 1).
  • Table 2a Combination of Compound 1-299 and Everolimus in the ACHN xenograft model
  • Table 2b Classification for in vivo combination of Compound 1-299 and Everolimus in the ACHN xenograft model
  • mice were inoculated, randomized on Day 0 (26 days post inoculation), and treatments began on day 1 for all groups.
  • Compound 1-299 was tested at 3mg/kg administered PO on a QWx3 (once weekly for 3 weeks) schedule.
  • TAK-228 was tested at 0.6mg/kg administered PO on a QDx21 (once daily for 21 consecutive days) schedule.
  • Compound 1-299 was administered first, followed immediately by the administration of TAK-228.
  • One group served as a vehicle-treated control group (Group 1) receiving PO treatment with the vehicles used for administration of both agents on their respective schedule.
  • Table 3b Classification for in vivo combination of Compound 1-299 and TAK-228 in the A498 xenograft model
  • mice were inoculated, randomized on Day 0 (26 days post inoculation), and treatments began on day 1 for all groups.
  • Compound 1-299 was tested at 3mg/kg administered PO on a QWx3 (once weekly for 3 weeks) schedule.
  • Everolimus was tested at 3mg/kg administered PO on a QDx21 (once daily for 21 consecutive days) schedule.
  • In the combination treatment group Compound 1-299 was administered first, followed immediately by the administration of everolimus.
  • One group served as a vehicle-treated control group (Group 1).
  • the combination arm of Compound 1-299 with everolimus yielded additive anti-tumor effects.
  • the treatment groups from the study are shown in Table 4a.
  • the combination benefit for this combination is shown in Table 4b.
  • Tumor growth curves are shown during the treatment period ( Figure 4). Error bars shown in Figure 4 indicate the standard error of the mean (SEM).
  • Table 4a Combination of Compound 1-299 and Everolimus in the A498 xenograft model
  • Table 4b Classification for in vivo combination of Compound 1-299 and Everolimus in the A498 xenograft model
  • mice were inoculated, randomized on Day 0 (19 days post inoculation), and treatments began on day 1 for all groups.
  • Compound 1-299 was tested at 3mg/kg administered PO on a QWx3 (once weekly for 3 weeks) schedule.
  • AZD2014 was tested at lOmg/kg administered PO on a QDx21 (once daily for 21 consecutive days) schedule.
  • Compound 1-299 was administered first, followed immediately by the administration of AZD2014.
  • One group served as a vehicle-treated control group (Group 1) receiving PO treatment with the vehicles used for administration of both agents on their respective schedule
  • Table 5b Classification for in vivo combination of Compound 1-299 and AZD2014 in the A498 xenograft model

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Abstract

La présente invention concerne des méthodes pour le traitement du cancer chez des patients en attente d'un tel traitement. Les méthodes comprennent l'administration à un tel patient d'un inhibiteur de VPS34 tel que le N-{6-chloro-4-méthyl-2'-[(2-méthylpyrimidin-4-yl)amino]-3,4'-bipyridin-5-yl} -2,4-difluorobenzènesulfonamide ou un sel pharmaceutiquement acceptable en combinaison avec un inhibiteur de mTOR. L'invention concerne également des médicaments destinés à être utilisés dans le traitement du cancer.
PCT/US2018/016552 2017-02-03 2018-02-02 Combinaison d'inhibiteurs de vps34 et d'inhibiteurs de mtor WO2018144791A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060094674A1 (en) * 2002-07-05 2006-05-04 Neel Benjamin G Combination of mtor inhibitor and a tyrosine kinase inhibitor for the treatment of neoplasms
US20080194546A1 (en) * 2005-11-22 2008-08-14 Kudos Pharmaceuticals Limited Pyrido-, Pyrazo- and Pyrimido-Pyrimidine Derivatives as mTOR Inhibitors
US20100184760A1 (en) * 2008-11-03 2010-07-22 Pingda Ren Benzoxazole kinase inhibitors and methods of use
US20130225518A1 (en) * 2012-02-24 2013-08-29 Signal Pharmaceuticals, Llc Methods for treating cancer using tor kinase inhibitor combination therapy
US20150225422A1 (en) * 2014-01-14 2015-08-13 Millennium Pharmaceuticals, Inc. Heteroaryls and uses thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060094674A1 (en) * 2002-07-05 2006-05-04 Neel Benjamin G Combination of mtor inhibitor and a tyrosine kinase inhibitor for the treatment of neoplasms
US20080194546A1 (en) * 2005-11-22 2008-08-14 Kudos Pharmaceuticals Limited Pyrido-, Pyrazo- and Pyrimido-Pyrimidine Derivatives as mTOR Inhibitors
US20100184760A1 (en) * 2008-11-03 2010-07-22 Pingda Ren Benzoxazole kinase inhibitors and methods of use
US20130225518A1 (en) * 2012-02-24 2013-08-29 Signal Pharmaceuticals, Llc Methods for treating cancer using tor kinase inhibitor combination therapy
US20150225422A1 (en) * 2014-01-14 2015-08-13 Millennium Pharmaceuticals, Inc. Heteroaryls and uses thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE PubChem [O] 18 May 2009 (2009-05-18), XP055533940, Database accession no. 25262792 *
DATABASE PUBCHEM [O] 18 May 2009 (2009-05-18), XP055533946, Database accession no. AZD2014 *

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