WO2016014390A1 - Compositions et méthodes pour polythérapie à base d'inhibiteurs de mek dans le traitement du cancer - Google Patents

Compositions et méthodes pour polythérapie à base d'inhibiteurs de mek dans le traitement du cancer Download PDF

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WO2016014390A1
WO2016014390A1 PCT/US2015/041100 US2015041100W WO2016014390A1 WO 2016014390 A1 WO2016014390 A1 WO 2016014390A1 US 2015041100 W US2015041100 W US 2015041100W WO 2016014390 A1 WO2016014390 A1 WO 2016014390A1
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pimasertib
combination
hypoxia
kinase inhibitor
cancer
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PCT/US2015/041100
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Samantha A. GOODSTAL
Brian A. ELENBAAS
Jianguo Ma
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Merck Patent Gmbh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates generally to the fields of biology, chemistry, medicine, molecular biology, toxicology, and pharmacology. More particularly, it provides compositions and methods for treating cancer with a combination of a hypoxia-activated prodrug such as TH-302, and a MEK kinase inhibitor such as pimasertib [N-((S)-2,3-Dihydroxy-propyl)-3-(2-fluoro-4-iodo-phenylamino)- isonicotinamide] .
  • a hypoxia-activated prodrug such as TH-302
  • MEK kinase inhibitor such as pimasertib [N-((S)-2,3-Dihydroxy-propyl)-3-(2-fluoro-4-iodo-phenylamino)- isonicotinamide] .
  • MEK kinase is a key cellular enzyme that regulates signaling through the mitogen-activated protein kinase (MAPK) pathway.
  • MEK kinase is a cancer target and many MEK kinase inhibitors are currently in clinical development for various solid tumor indications (as reviewed in Akintunde et al., 2013). The first MEK kinase to receive regulatory approval by the U.S. Food and Drug
  • trametinib (GSK Pharmaceuticals) in BRaf V600E mutated metastatic melanoma in 2013.
  • Pimasertib (EMD Serono, Inc.) is another MEK inhibitor in clinical development in different cancer indications.
  • Tumors often consist of highly hypoxic sub-regions known to be resistant to chemotherapy and radiotherapy. Targeting hypoxic regions with hypoxia activated prodrugs is an emerging field of pharmaceutical development.
  • TH-302 also known by the chemical name (2-bromoethyl)( ⁇ [(2- bromoethyl)amino][(2-nitro-3-methylimidazol-4-yl)methoxy]phosphoryl ⁇ )amine, is a hypoxia- targeted drug being developed by Threshold Pharmaceuticals, Inc. for the treatment of cancer including, but not limited to, pancreatic cancer.
  • TH-302 After administration to a cancer patient, TH-302 is reduced at its nitroimidazole group and selectively under hypoxic conditions releases the DNA bis- alkylator bromo-isophosphoramide mustard (Br-IPM). See PCT patent publication nos.
  • This invention provides medicines and technology for treating cancer.
  • the invention provides methods and pharmaceutical formulations for treating cancer by administration of a combination of a hypoxia-activated prodrug, such as TH-302, and a MEK kinase inhibitor such as pimasertib [N-((S)-2,3-Dihydroxy-propyl)-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamide] .
  • a hypoxia-activated prodrug such as TH-302
  • MEK kinase inhibitor such as pimasertib [N-((S)-2,3-Dihydroxy-propyl)-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamide] .
  • these two drugs can be more effective than these drugs alone.
  • the drug combinations provided by this invention are effective in the treatment of cancer including, but not limited to, solid tumor cancers such as pancreatic cancer, cholangiocarcino
  • one aspect of this invention relates to methods and pharmaceutical formulations for treating cancer in which a combination of pharmaceutical agents comprising a hypoxia-activated prodrug such as TH-302 and a MEK kinase inhibitor such as pimasertib is administered to a cancer patient.
  • the drug combination may be used for simultaneous or sequential use in the treatment of cancer.
  • Another aspect of the invention is a method of treating cancer by administering an effective combination of pharmaceutical agents comprising a hypoxia-activated prodrug such as TH-302 and a MEK kinase inhibitor such as pimasertib.
  • a further aspect of the invention is the use of a hypoxia- activated prodrug such as TH-302 and a MEK kinase inhibitor such as pimasertib in the manufacture of a medicament or medicament combination for treatment of cancer.
  • Suitable hypoxia-activated prodrugs that can be used for this purpose include those that have a structure according to Formula (I) as described in more detail later in this disclosure.
  • hypoxia activated prodrugs are the hypoxia activated prodrugs TH-302.
  • Suitable MEK kinase inhibitors that can be used for this purpose include those that have a structure according to Formula (II) as described in more detail later in this disclosure.
  • Exemplary MEK kinase inhibitors include, but are not limited to, pimasertib.
  • the MEK kinase inhibitor may be a MEK kinase inhibitor and may be encapsulated, so as to reduce cytotoxicity or improve delivery or otherwise provide benefit.
  • Pimasertib is an example of a MEK kinase inhibitor.
  • the hypoxia-activated prodrug may be administered at a dose of about 250 to 1000 mg/m 2 .
  • the MEK kinase inhibitor may be administered at any FDA (or other regulatory authority) approved dose.
  • the hypoxia-activated prodrug, the MEK kinase inhibitor may be administered in a plurality of cycles. By way of illustration, each cycle may comprise consecutively administering one or more of said drugs one after another on the same day, once a week for three consecutive weeks, followed by one week in which none of said drugs is administered.
  • the MEK inhibitor in one example, pimasertib
  • the observed scheduling effect may be a critical for the effectiveness of this combination therapy.
  • combination effects were observed in two cholangiocarcinoma models (LIX021 and LIX071).
  • TH-302 showed no significant monotherapy efficacy
  • the combination treatment with the MEK inhibitor showed greater efficacy than the MEK monotherapy group alone (see, Fig. 2 and Fig. 3).
  • This combination effect is termed 'potentiation' which describes the therapeutic effect whereby the one drug's effect is enhanced by another drug that has no effect alone.
  • this potentiation effect suggests MEK kinase inhibition in cancer cells enables TH-302 to exert an anti-tumor effect in cancers otherwise be insensitive to TH-302 alone.
  • composition and methods of the present invention may be applied to pancreatic cancer, particularly pancreatic ductal adenocarcinoma (PDAC).
  • PDAC pancreatic ductal adenocarcinoma
  • composition and methods of the present invention may be applied to cholangiocarcinoma and gallbladder cancer.
  • the present invention describes a combination of pharmaceutical agents comprising a hypoxia-activated prodrug and a MEK kinase inhibitor for simultaneous or sequential use in the treatment cancers selected from the group consisting of pancreatic cancer,
  • the present invention describes a method of treating cancers selected from the group consisting of pancreatic cancer, cholangiocarcinoma and gall bladder cancer comprising, simultaneously or sequentially administering an effective combination of pharmaceutical agents comprising a hypoxia-activated prodrug and a MEK kinase inhibitor.
  • the present invention describes the use of a hypoxia-activated prodrug and a MEK kinase inhibitor chemotherapeutic in the manufacture of a medicament or medicament combination for the treatment of cancer.
  • the present invention describes the aforementioned combinations, methods and uses wherein the hypoxia-activated prodrug has the structure according to Formula (I) as hereinbefore described and exemplified.
  • hypoxia-activated prodrug is TH-302.
  • the MEK kinase inhibitor is a substituted 3-arylamino pyridine derivatives having a chemical structure according to Formula II as hereinbefore described and exemplified.
  • the MEK kinase inhibitor is administered about two hours before the hypoxia-activated prodrug.
  • the hypoxia-activated prodrug is TH-302 and the MEK kinase inhibitor is pimasertib.
  • hypoxia- activated prodrug and the MEK kinase inhibitor are administered in a plurality of cycles.
  • Fig. 1 shows the combination efficacy of Pimasertib and TH-302 in the MIA PaCa-2 pancreatic cancer xenograft model in mice.
  • Fig. 2 shows the combination efficacy of Pimasertib and TH-302 in the LIX021
  • Fig. 3 shows the combination efficacy of Pimasertib and TH-302 in the
  • Fig. 4 shows the combination efficacy of Pimasertib and TH-302 in the GL1208 gallbladder PDX model in mice.
  • Fig. 5 shows the combination efficacy of Pimasertib and TH-302 in the BxPC-3 pancreatic cancer xenograft model in mice.
  • Fig. 6 shows the combination efficacy of Pimasertib and TH-302 in the Hs 766T
  • pancreatic cancer xenograft model in mice pancreatic cancer xenograft model in mice.
  • Fig. 7 shows the combination efficacy of Pimasertib and TH-302 in the
  • Fig. 8 shows the combination efficacy of Pimasertib and TH-302 in the
  • Fig. 9 shows the combination efficacy of Pimasertib and TH-302 in the
  • Fig. 10 shows the combination efficacy of Pimasertib and TH-302 in the
  • Fig. 11 shows the combination efficacy of Pimasertib and TH-302 in the
  • Fig. 12 shows the combination efficacy of Pimasertib and TH-302 in the
  • Fig. 13 shows the combination efficacy of Pimasertib and TH-302 in the
  • Fig. 14 shows the combination efficacy of Pimasertib and TH-302 in the
  • Fig. 15 shows the combination efficacy of Pimasertib and TH-302 in the gallbladder
  • Fig. 16 shows the combination efficacy of Pimasertib and TH-302 in the gallbladder
  • Fig. 17 shows the combination efficacy of Pimasertib and TH-302 in the gallbladder GBC-
  • Fig. 18 shows the combination efficacy of Pimasertib and TH-302 in the gallbladder
  • Fig. 19 shows the combination efficacy of Pimasertib and TH-302 in the gallbladder
  • Drug combinations or cocktails are sometimes used in treating cancer.
  • the effect of two or more drugs in combination may not be particularly better than monotherapy, i.e. , the use of one or the other drug by itself.
  • Drugs may interact in a manner that decreases efficacy, increases unwanted side effects, or is otherwise not therapeutic for the patient.
  • This invention is based on the discovery that a hypoxia-activated prodrug such as TH-302 and a MEK kinase inhibitor such as pimasertib work especially well together in treating malignant conditions such as pancreatic cancer.
  • the combinations of the present invention substantially inhibit tumor growth in animal models of cancer and are expected to have similar benefit in human therapy.
  • the benefit provided by the drug combinations of the invention is, in a number of embodiments, more than that provided by any of the drugs alone.
  • a hypoxia-activated prodrug in combination with a MEK kinase inhibitor may be sufficiently effective so that adding a nucleoside chemotherapeutic such as gemcitabine (a current standard therapeutic used in the treatment of pancreatic cancer) is unnecessary.
  • a nucleoside chemotherapeutic such as gemcitabine (a current standard therapeutic used in the treatment of pancreatic cancer) is unnecessary.
  • the two-drug combination provided by embodiments of the present invention may be better tolerated in some patients as compared to standard therapies as described in the scientific literature.
  • Suitable for use in this invention is any hypoxia-activated prodrug that is inert or has less activity than the active form but that converts to the active form in vivo at or around a tumor site that is hypoxic, relative to normal tissues with physiological oxygenation.
  • These drugs typically contain one or more bioreducible groups.
  • the preparation and use of model hypoxia-activated prodrugs is described in WO 04/087075, WO 00/064864, WO 07/002931, and WO 08/083101, and
  • This invention may be conducted with hypoxia-activated prodrugs in the same class as bromo-isophosphoramide mustard (Br-IPM), having DNA bis-alkylator activity.
  • Br-IPM bromo-isophosphoramide mustard
  • Such compounds may have the structure shown in Formula I:
  • Y2 is O, S, NR6, NCOR6, or NSO2R6 wherein R6 is C1-C6 alkyl, C1-C6 heteroalkyl, aryl, or heteroaryl;
  • R3 and R4 are independently selected from the group consisting of 2-haloalkyl, 2-alkylsulfonyloxyalkyl, 2-heteroalkylsulfonyloxyalkyl, 2-arylsulfonyloxyalkyl, and
  • Ri has the formula L-Z 3 ;
  • L is C(Zi) 2 ; each Zi independently is hydrogen, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, aryl, heteroaryl, C3-C8 cycloalkyl, heterocyclyl, C1-C6 acyl, C1-C6 heteroacyl, aroyl, or heteroaroyl; or L is:
  • Z 3 is a bioreductive group having a formula selected from the group consisting of:
  • each Xi is independently N or CRs; X2 is NR7, S, or O; each R7 is independently C1-C6 alkyl, C 1 -C6 heteroalkyl, C3-C8 cycloalkyl, heterocyclyl, aryl or heteroaryl; and Rs is independently hydrogen, halogen, cyano, CHF2, CF3, CO2H, amino, Ci-Ce alkyl, C1-C6 heteroalkyl, C1-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, Ci-Ce dialkylamino, aryl, CON(R?)2, C1-C6 acyl, C 1 -C6 heteroacyl, aroyl or heteroaroyl; or a pharmaceutically acceptable salt thereof.
  • TH-302 and TH-281 which respectively have the following structures:
  • TH-302 and TH-281 convert to a cytotoxic agent selectively under hypoxic conditions in vivo at or around hypoxic tumor sites.
  • TH-302 and TH-281 are for illustrative purposes for the general class of compounds having the structure shown in Formula I. Unless expressly limited to a particular compound, the various aspects of the invention discussed in reference to TH-302 or TH-281 may be put into practice using TH-302 or TH-281 interchangeably, or using other hypoxia-activated prodrugs having the structure of Formula I, at the user's discretion.
  • hypoxia-activated prodrug is TH-302, which is administered in a daily dose of about 240 mg/m 2 to about 670 mg/m 2 .
  • Suitable administration schedules for doses of TH-302 in this range include, but are not limited to, the following:
  • Each of the above schedules can be considered a "cycle" of therapy. Patients will generally receive more than one cycle of therapy, although there may breaks of at least a day, and more generally a week or longer, between each cycle of therapy.
  • Other compounds of Formula I are generally dosed in accordance with the above schedules and amounts, with the amount adjusted to reflect how active the compound is relative to TH-302.
  • the MEK kinase inhibitors described by certain embodiments of the present invention are substituted 3-arylamino pyridine derivatives and pharmaceutically acceptable salts, solvates or prodrugs thereof. While it is not intended the claimed embodiments of the present invention be limited to any specific mechanism of action, constitutive activation of MEK1 results in cellular transformation. It therefore represents a relevant target for pharmacological intervention in proliferative and inflammatory diseases (Lee et al., Nature 1994, 372, 739-746; Dudley et al., Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 7686-7689).
  • Inhibitors of MEK have been developed that show potential therapeutic benefit in several studies. For example, small molecule MEK inhibitors have been shown to inhibit human tumour growth in nude mouse xenografts (Yeh, T. et al, Proceedings of the American Association of Cancer Research 2004, 45, Abs 3889 and Lee, P. et al., Proceedings of the American Association of Cancer Research 2004, 45, Abs 3890). MEK inhibitors also entered clinical trials, i.e.
  • ARRY142886 Wang, E. et al, Proceedings of the American Association of Cancer Research 2004, 45, Abs 3891
  • PD-0325901 Silicon C, Johnston S IDDB MEETING REPORT 2003, February 13-1
  • PD-184352 Waterhouse et al., Proceedings of the American Society for Clinical Oncology 2003, 22, Abs 816.
  • MEK kinase inhibitors that can be used in this invention include compounds conforming to the chemical structure acco
  • Pvi, P2, P9, Rio, Rn Ri2, Ri3 and Ri 4 are independently selected from hydrogen, halogen, cyano, nitro, azido, -OR 3 , -C(0)R 3 ,-C(0)OR 3 , -NR 4 C(0)OR 6 , -OC(0)R 3 , -NR 4 S(0) j R 6 , - S(0)jNR 3 R 4 , -S(0) j NR 4 C(0)R 3 , -C(0)NR 4 S(0) j R 6 , S(0) j R 6 ,-NR 4 C(0)R 3 , -C(0)NR 3 R 4 ,- NR 5 C(0)NR 3 R 4 , -NR 5 C(NCN)NR 3 R 4 ,-NR 3 R 4 and G-Cio alkyl, C2-G0 alkenyl, C2-G0 alkynyl, C3-G0 cycloalkyl, C3-C10 cycloalkylalkyl, -S(0)j(Ci
  • R 3 is selected from hydrogen, trifluoromethyl, C1-C10 alkyl, C2-10 alkenyl, C2-C10 alkynyl, C 3 -Cio cycloalkyl, C 3 -Cio cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is substituted or unsubstituted;
  • R4 is selected from hydrogen or Ci-C 6 alkyl whereby alkyl may be substituted or unsubstituted; or R3 and R4 can be taken together with the atom to which they are attached to form a 4 to 10
  • R5 is selected from hydrogen or Ci-C 6 alkyl whereby alkyl may be substituted or unsubstituted; or R4 and R5 can be taken together with the atom to which they are attached to form a 4 to 10
  • R 6 is selected from trifluoromethyl; and C1-C10 alkyl, C3-C10 cycloalkyl, aryl, arylalkyl,
  • heteroaryl heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, where each alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl substituted or unsubstituted;
  • W is selected from heteroaryl containing 1-4 heteroatoms or heterocyclyl containing 1-4
  • W is -C(0)ORi5, -C(0)NR4Ri5, -C(0)NR40Ri 5 , -C(0)(C 3 -Cio cycloalkyl), -C(0)(C 2 -Cio alkyl), -C(0)(aryl), -C(0)(heteroaryl), -C(0)(heterocyclyl), S(0)jNR4Ri 5 , S(0)jNR40Ri 5 , - S(0)jNR4C(0)Ri5, -C(0)NR4S(0)jR 6 , -C(0)NR4NR4Ri 5 , -C(0)C(0)Ri 5 , - C(0)CRR"C(0)Ri5, -NR'R", -NR'C(0)R, -NR' S(0)jR, -NRC(0)NR'R", NR' S(0)jNR'R", or -C(0)NR4NR4
  • Z is a bond, NR1 ⁇ 2, O, NRi 6 S0 2 or S.
  • Ri5 is independently selected from hydrogen, trifluoromethyl, C1-C10 alkyl, C 2 -Cio alkenyl, C 2 - C10 alkynyl, C3-C10 cycloalkyl, C3-C10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is substituted or unsubstituted;
  • R16 is selected from hydrogen or C1-C10 alkyl, or R15 and R1 ⁇ 2 form together a 4 to 10 membered cyclic ring with 1 or 2 N atoms and optionally an O atom, said ring being substituted or unsubstituted;
  • X is N or N ⁇ 0;
  • n 0, 1, 2, 3, 4 or 5;
  • j 1 or 2.
  • Ri, R 2 , R9, Rio, R11 R12, Ri3 and R14 are independently selected from hydrogen, halogen, cyano, nitro, azido, -OR3, -NR4C(0)OR 6 , -OC(0)R 3 , -NR4S(0)jR 6 , -S(0)jNR 3 R4, - S(0)jNR4C(0)R 3 , -C(0)NR4S(0)jR 6 , S(0)jR6,-NR4C(0)R 3 , -C(0)NR3R4,-NR5C(0)NR 3 R4, -NR5C(NCN)NR3R4,-NR 3 R4 and C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C3-C10 cycloalkylalkyl, -S(0)j(Ci-C 6 alkyl), -S(0)j(CR4R 5 )m-aryl, aryl, aryl
  • R3 is selected from hydrogen, trifluoromethyl, C1-C10 alkyl, C2-10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C3-C10 cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl and heterocyclyl is substituted or unsubstituted; or aryl which is unsubstituted or substituted with 1 to 5 groups independently selected from oxo, halogen, nitro, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F, azido, NR'S0 2 R"", SO2NR", C(0)R', C(0)OR', OC(0)R', NR'C(0)OR”", NR'C(0)R", C(0)NR'R",
  • R4 is selected from hydrogen or Ci-C 6 alkyl whereby alkyl may be substituted or unsubstituted; or R3 and R4 can be taken together with the atom to which they are attached to form a 4 to 10
  • R5 is selected from hydrogen or Ci-C 6 alkyl whereby alkyl may be substituted or unsubstituted; or R4 and R5 can be taken together with the atom to which they are attached to form a 4 to 10
  • R 6 is selected from trifluoromethyl; and Ci-Cio alkyl, C3-C10 cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, where each alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl substituted or unsubstituted;
  • R' , R" and R" ' are independently selected from hydrogen, C1-C4 alkyl, C2-C4 alkenyl, aryl and arylalkyl;
  • R" is selected from C1-C4 alkyl, C1-C4 alkenyl, aryl and arylalkyl;
  • W is selected from heteroaryl containing 1-4 heteroatoms or heterocyclyl containing 1-4
  • W is -C(0)ORi5, -C(0)NR4Ri5, -C(0)NR40Ri 5 , -C(0)(C 3 -Cio cycloalkyl), - C(0)(heterocyclyl), S(0)jNR4Ri 5 , S(0)jNR40Ri 5 , -S(0)jNR4C(0)Ri 5 , -C(0)NR4S(0)jR 6 , - C(0)NR4NR4Ri5, -C(0)C(0)Ri5, -C(0)CRR"C(0)Ri 5 , -NR'R", -NR'C(0)R, -NR'S(0)jR, -NRC(0)NR'R", NR'S(0)jNR'R", or -C(0)NR4NR4C(0)Ri 5 ;
  • Ri, R 2 , R12, R13 and R14 are independently selected from hydrogen, halogen, cyano, nitro, azido, -NR4C(0)OR6, -OC(0)R3, -S-C1-C2 alkyl substituted with 1 to 5 F, -NR4S(0)jR 6 , -S(0)jNR 3 R4, -S(0)jNR4C(0)R 3 , -C(0)NR4S(0)jR 6 , S(0)jR 6 ,- NR4C(0)R 3 , -NR 5 C(0)NR 3 R4, -NR 5 C(NCN)NR 3 R4 and C1-C10 alkyl, C2-G0 alkenyl, C 2 - C10 alkynyl, C3-C10 cycloalkyl, C3-C10 cycloalkylalkyl, -S(0)j(G-C6 alkyl), - S(0) j (CR4R5)m-aryl, aryl
  • heterocyclylalkyl -OCCRtRsV-aryl, -NRtCCRtRsV-aryl, -0(CR4R5) m -heteroaryl, - NR4(CR4R5)m, heteroaryl, -OCCRtRsV-heterocyclyl and -NR4(CR4R5) m -heterocyclyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are substituted or unsubstituted; -NR33R44, C(0)NR3Ri4, or OR33, whereby R33 is selected from hydrogen, CF3, CHF2, CH2F, C2-C10 alkyl, C2-10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C3-C10 cycloalkylalkyl, arylalkyl, heteroaryl, heteroaryl
  • heterocyclylalkyl where each alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl and heterocyclyl is substituted or unsubstituted, and R44 is selected from hydrogen, CF3, CHF2, CH2F and C 2 -C 6 alkyl;
  • Z is a bond, NR1 ⁇ 2, O, NRi 6 S0 2 or S.
  • Ri5 is independently selected from hydrogen, trifluoromethyl, C1-C10 alkyl, C2-C10 alkenyl, C2- C10 alkynyl, C3-C10 cycloalkyl, C3-C10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is substituted or unsubstituted;
  • R16 is selected from hydrogen or C1-C10 alkyl, or R15 and R1 ⁇ 2 form together a 4 to 10 membered cyclic ring with 1 or 2 N atoms and optionally an O atom, said ring being substituted or unsubstituted;
  • X is N or N ⁇ 0;
  • n 0, 1, 2, 3, 4 or 5;
  • j 1 or 2.
  • Exemplary MEK kinase inhibitors include pimasertib, which has the following structure conforming to Formula II:
  • pimasertib is for illustrative purposes for the general class of compounds having the structure shown in Formula II. Unless expressly limited to a particular compound, the various aspects of the invention discussed in reference to pimasertib may be put into practice using drugs having the structure of Formula II at the user's discretion. As detailed in the EXAMPLES section of the instant application, in the MEK kinase inhibitor pimasertib was administered orally to mice at a dose of 30mg/kg.
  • This invention encompasses the use of a hypoxia-activated prodrug, exemplified by compounds of Formula I, such as TH-302 and a MEK kinase inhibitor as exemplified by compounds of Formula II such as the MEK kinase pimasertib in the manufacture of a single medicament used for therapy as described below.
  • a “medicament combination”, as used herein, refers to two or more medications that are used in combination and may be co-formulated (admixed together) or separately formulated (not admixed or otherwise combined together in a single unit dose form).
  • Formulations of TH-302 or TH-281 suitable for parenteral or intravenous injection and methods for administering them in the treatment of cancer that are suitable for use in practice of the present invention are described in WO 07/002931, WO 08/083101, WO 10/048330, WO 12/142520, and WO 13/126539.
  • a hypoxia-activated prodrug and a MEK kinase inhibitor may be distributed and administered separately in a treatment of a particular disease or condition.
  • Alternatives are as follows: a hypoxia-activated prodrug may be combined with a MEK kinase inhibitor for administration together and administered with a hypoxia-activated prodrug in a separate formulation and administered with a MEK kinase inhibitor in a separate formulation; or a hypoxia-activated prodrug and a MEK kinase inhibitor may be combined in a single formulation; or the drugs may be separately formulated and administered.
  • the invention also encompasses various combinations of agents for marketing or distribution together. Such combinations are optionally marketed and distributed in kit form.
  • the combinations or kits may comprise separate packs of an effective amount of a hypoxia-activated prodrug, exemplified by Formula I, such as TH-302 and a MEK kinase inhibitor as exemplified in Formula II, such as pimasertib.
  • the combination or kit will be suitably packaged and may also contain or be marketed in combination with written instructions that direct the clinician on the use of the combination or elements of the kit for chemotherapy in accordance with the invention.
  • This invention encompasses the commercial and clinical use of a hypoxia-activated prodrug, exemplified by Formula I, such as TH-302 and a MEK kinase inhibitor as exemplified in Formula II, such as pimasertib.
  • a hypoxia-activated prodrug exemplified by Formula I, such as TH-302
  • a MEK kinase inhibitor as exemplified in Formula II, such as pimasertib.
  • Such combinations are used in the prophylactic or therapeutic treatment of a condition or disease, such as cancer, that is caused, mediated, or propagated by undesired cell growth, hyperproliferation, malignancy, or tumor formation.
  • the drug combinations of this invention can be used therapeutically in cancers of various types, especially solid tumors comprising or expected to develop hypoxic regions.
  • cancers of various types especially solid tumors comprising or expected to develop hypoxic regions.
  • examples include but are not limited to cancer of the adrenal gland, bone, brain, breast, bronchi, colon and/or rectum, gallbladder, bile duct, head and neck, kidneys, larynx, liver, lung, neural tissue, pancreas, prostate, parathyroid, skin, stomach, and thyroid.
  • ⁇ and chronic lymphocytic and granulocytic tumors include acute and chronic lymphocytic and granulocytic tumors, adenocarcinoma, adenoma, basal cell carcinoma, cervical dysplasia and in situ carcinoma, Ewing's sarcoma, epidermoid carcinomas, giant cell tumor, glioblastoma multiforma, hairy-cell tumor, intestinal ganglioneuroma, hyperplastic corneal nerve tumor, islet cell carcinoma, Kaposi's sarcoma, leiomyoma, malignant carcinoid, malignant melanomas, malignant hypercalcemia, marfanoid habitus tumor, medullary carcinoma, metastatic skin carcinoma, mucosal neuroma, myeloma, mycosis fungoides, neuroblastoma, osteosarcoma, osteogenic and other sarcoma, ovarian tumor, pheochromocytoma, polycythermia vera, gli
  • hypoxia-activated prodrug and the MEK kinase inhibitor may be administered simultaneously or sequentially in any effective combination at the election of the managing clinician, upon consideration of previous experience, and the condition and history of the patient.
  • the MEK kinase inhibitor is administered first followed by an interval of about two hours prior to the administration of the hypoxia activated prodrug.
  • the treatment methods of the invention may result in side effects, which may be treated in accordance with other treatments of the invention.
  • Intertriginous rash may be prevented or treated by application of PREPARATION H to the perineal area, around the anus, under the arms, and other areas where there are skin folds.
  • Prophylactic treatment may begin prior to TH-302 administration (15 minutes prior to infusion).
  • a cool pack may be applied to the inguinal region during TH-302 infusion.
  • desitin cream maximal strength
  • SILVADENE 1% cream and triamcinclone 0.1% cream can be applied to affected areas. In severe cases, discontinue treatment until the rash clears.
  • Anal mucositis can be prevented or treated with the same treatments; however, cryotherapy during infusion and pain control (NSAIDS, CGRP inhibitors, or narcotics) may also be required for anal mucositis.
  • Hand-foot skin reaction can be prevented with ammonium lactate 12% cream (AMLACTIN) or heavy moisturizer (VASELINE) twice daily or with cryotherapy.
  • Hand-foot skin reaction can be treated with ammonium lactate 12% cream twice daily and clobetasol 0.05% cream once daily. Pain control may also be required and obtained using NSAIDS, CGRP inhibitors, or narcotics.
  • Oral mucositis can be prevented or treated with oral cryotherapy during infusion.
  • Treatment can be achieved with elixir (nydrocortisone 200 mg, Nystatin 2 million units, tetracycline 1500 mg, BENADRYL equal to 250 cc) by swish and swallow 1 tsp tid and pain control (as above).
  • Injection site reaction can be treated with extremity elevation and daily warm compresses. Severe cases may require treatment as with a wound, plastic surgery, and oral antibiotics. Hyperpigmentation can be prevented with sunscreen (SPF 30) to all exposed skin.
  • Treatment can be achieved with ammonium lactate 12% cream (and continued use of sunscreen) or, for more severe cases, hydroquinone 4% cream. [0056] VII. Definitions
  • Reference to any drug or active agent in this disclosure includes any and all isomers, stereoisomers, pharmaceutically compatible salts, solvates, and pharmaceutical compositions thereof that retain at least some of the physiological or chemotherapeutic effects of the drug itself, unless such isomers, salts, solvates, and/or compositions are explicitly excluded. Any such compound may be used as an alternative to the drug itself to improve efficacy, tolerability, delivery, or pharmacokinetics, or simply by choice within the good judgment of the manufacturer, distributor, pharmacist, clinician, or end user.
  • the therapeutic agents referred to as “TH-302" and “TH-281” are exemplary hypoxia- activated prodrugs, which are described in more detail above.
  • the therapeutic agent referred to as pimasertib EMD Serono, Inc. is currently in clinical development for various cancer indications.
  • an "active agent” or “pharmaceutical” is a compound with a desired pharmacological effect. It includes all pharmaceutically acceptable forms of the active agent described. Unless explicitly stated otherwise, all embodiments of the invention may be practiced with any one or more different isomers, stereoisomers, and pharmaceutical salts of each of the active ingredients that has the desired effect.
  • a "chemotherapeutic agent” is a pharmaceutical compound that is given to a cancer patient primarily to eradicate, diminish, stabilize, or decrease the growth rate or metabolism of one or more malignant tumors in the patient. Included are nucleoside analogs such as gemcitabine. The more general term “therapeutic agent” includes chemotherapeutics and radiation therapy.
  • a “prodrug” is a compound that, after administration, is metabolized or otherwise converted to a biologically active or more active agent with respect to at least one beneficial property or effect.
  • a "hypoxia-activated prodrug” is a prodrug that is less active or inactive, relative to the active form of the drug, to which it is activated in vivo. It contains one or more bioreducible groups.
  • the term includes prodrugs that are activated by reducing agents and enzymes, including single electron transferring enzymes (such as NADPH cytochrome P450 reductases) and two electron transferring (or hydride transferring) enzymes. Exemplary are 2-nitroimidazole triggered hypoxia-activated prodrugs.
  • patient and “subject” are used in this disclosure to refer to a mammal being treated or in need of treatment for a condition such as cancer.
  • the terms include human patients and volunteers, non-human mammals such as a non-human primates, large animal models and rodents.
  • administering or "administration of a drug to a patient refers to direct administration, which may be administration to a patient by a medical professional or may be self-administration, and/or indirect administration, which may be the act of prescribing a drug.
  • direct administration which may be administration to a patient by a medical professional or may be self-administration
  • indirect administration which may be the act of prescribing a drug.
  • a physician or clinic that instructs a patient to self-administer a drug or provides a patient with a prescription for a drug is administering the drug to the patient.
  • dose refers to a specific amount of active or therapeutic agent(s) for administration at one time.
  • a “dosage form” is a physically discrete unit that has been packaged or provided as unitary dosages for subjects being treated. It contains a predetermined quantity of active agent calculated to produce the desired onset, tolerability, and therapeutic effect.
  • a "therapeutically effective amount" of a drug refers to an amount of a drug that, when administered to a patient to treat a condition such as cancer, will have a beneficial effect, such as alleviation, amelioration, palliation or elimination of one or more symptoms, signs, or laboratory markers associated with the active or pathological form of the condition. Desirable effects for cancer patients may include reducing the rate of tumor growth, causing tumors to shrink, causing circulating markers of the cancer to decrease, and improving progression-free or overall survival.
  • TH-302 as a representative species of hypoxia-activated drugs
  • pimasertib as a representative species of MEK kinase inhibitors.
  • the combination of TH-302 and pimasertib was tested in 4 tumor xenograft models (1 pancreatic, 2 cholangiocarcinoma, and 1 gall bladder model). Combination activity was observed in all 4 models.
  • the scheduling effect of the 2 drugs was tested in the MIA PaCa-2 pancreatic cancer model. The best efficacy of the combination was observed when pimasertib was administered first, two hour prior to TH-302 (see, Fig. 1). A combination effect was observed in the 2
  • cholangiocarcinoma models (LIX021 and LIX071).
  • TH-302 showed no significant monotherapy efficacy
  • the combination treatment with the MEK inhibitor clearly showed greater efficacy than the MEK monotherapy group alone (see, Fig. 2 and Fig. 3).
  • This combination effect is also referred to as 'potentiation' which describes the phenomenon whereby the one drug's effect is enhanced by another drug that has no effect alone.
  • This potentiation effect suggests that MEK kinase inhibition in cancer cells enables the TH-302 drug to exert its anti-tumor effect in cancers that would otherwise be insensitive to the drug.
  • MIA PaCa-2 cells [lOxlO 6 in a 200 ⁇ 1 PBS:Matrigel (1 : 1) suspension] or Hs 766T cells [5xl0 6 in a 200 ⁇ 1 PBS:Matrigel (1:1) suspension] were subcutaneously injected into the right shoulder area of female nude (Cr ⁇ :NU-Foxnl nu ) mice (6-8 weeks old, Charles River Laboratories, Wilmington, MA). Mice were housed and maintained in individually- ventilated cages under specific pathogen-free conditions and received a standard diet with free access to water. All mice were acclimated for at least 48 hours prior to study initiation and were used according to the guidelines approved by the EMD Serono Institutional Care and Animal Use Committee (IACUC).
  • IACUC Institutional Care and Animal Use Committee
  • mice were treated with a combination of Pimasertib at 30 mg/kg and TH- 302 at 75 mg/kg in different sequences.
  • Pimasertib and TH-302 were given simultaneously (TH-302+Pimasertib).
  • Pimasertib and TH-302 were given sequentially with 2 hours in between administration: Pimasertib followed by TH-302 in group 5 (TH-302->Pimasertib) and the reverse for group 6 (Pimasertib->TH-302).
  • the treatments began on the eighth and nine days following implantation of the MIA-PaCa-2 cells and Hs 766T respectively and twenty seven days in BxPC-3 that were designated as Day 0 for data evaluation purposes. Animals were treated for a period as indicated in the legend in Figs. 1, 5 and 6. Body weights and tumor volumes were assessed twice per week post treatment initiation. After treatments stopped, animals were kept to observe for tumor re-growth and received no further treatments, tumor volume and body weight measurements continued once per week. On Day 30, animals from the vehicle and single agent groups were euthanized via progressive hypoxia with CO 2 . The survival endpoint was established as a tumor volume of 1500mm 3 , when an animal's tumor volume reached this limit it was euthanized.
  • mice All human PDX tumor xenograft efficacy models in mice were performed at Chempartner or Crown Biosciences. Briefly, tumor fragments for PDX models were implanted subcutaneously in athymic nu/nu mice and grown to a size of approximately 200 mm 3 . Mice were randomized into groups of 6-10 mice each and dosed with either vehicle or TH-302 at 60mg/kg i.p. twice per week (BIW) or Pimasertib at 30mg/kg p.o. QD (or 5D+/2D- as indicated due to the tolerability) for approximately 3-5 weeks based on the tumor grow and response. Dosing periods are described in the legends of Figs. 7 - 20. Tumor measurements were done with digital calipers twice per week.
  • Example 1 Combination efficacy of Pimasertib and TH-302 in the MIA PaCa-2 pancreatic cancer xenograft model in mice
  • Pimasertib were tested in the MIA PaCa-2 xenograft model at three combination sequences;
  • TH-302 was administered at 75 mg/kg i.p. once every three days (Q3D) and Pimasertib was administered at 30 mg/kg p.o., once per day.
  • the three scheduling sequences refer to days in which both drugs were administered. Animals were treated for 29 days (10 administrations for TH-302 total) (see, panel A of Fig. 1).
  • Example 2 Combination efficacy of Pimasertib and TH-302 in the LIX021
  • TH-302 was administered at 60mg/kg i.p. twice per week (2QW), Pimasertib at 30mg/kg, p.o. once per day, and combination of TH-302 and Pimasertib with the Pimasertib->TH-302 dosing schedule (Pimasertib 2 hours prior to dosing of TH-302). Tumor volumes were measured twice per week and plotted. See, Fig. 2.
  • Example 3 Combination efficacy of Pimasertib and TH-302 in the
  • TH-302 was administered at 60mg/kg i.p. twice per week (2QW), Pimasertib 30mg/kg, p.o. once per day, and combination of TH-302 and Pimasertib with the Pimasertib->TH-302 dosing schedule (Pimasertib 2 hours prior to dosing of TH-302). Tumor volumes were measured twice per week and plotted. See, Fig. 3.
  • Example 4 Combination efficacy of Pimasertib and TH-302 in the GL1208 gallbladder PDX model in mice
  • TH-302 was administered at 60mg/kg i.p. twice per week (2QW), Pimasertib 30mg/kg, p.o. 5 days on and 2 days off (5D+/2D-) schedule, and combination of TH-302 and Pimasertib with the Pimasertib->TH-302 dosing schedule (Pimasertib 2 hours prior to dosing of TH-302). Tumor volumes were measured twice per week and plotted. See, Fig. 4. [0092] Example 5: Combination efficacy of Pimasertib and TH-302 in the BxPC-3 pancreatic cancer xenograft model in mice
  • Pimasertib were tested in the BxPC-3 pancreatic cancer xenograft model at three combination sequences; simultaneously, (Pimasertib+TH-302); TH-302 first and followed by Pimasertib 2 hours later, (TH-302->Pimasertib); and Pimasertib first followed by TH-302 2 hours
  • TH-302 was administered at 75 mg/kg i.p. once every three days (Q3D) and Pimasertib was administered at 30 mg/kg p.o., once per day.
  • the three scheduling sequences refer to days in which both drugs were administered. Animals were treated for 28 days (see, Fig. 5). After treatments stopped, animals were kept to observe for tumor re-growth and received no further treatments for additional 22 days and tumor volume and body weight measurements were continued once per week.
  • Example 6 Combination efficacy of Pimasertib and TH-302 in the Hs 766T pancreatic cancer xenograft model in mice
  • Pimasertib were tested in the Hs 766T pancreatic cancer xenograft model at three combination sequences; simultaneously, (Pimasertib+TH-302); TH-302 first and followed by Pimasertib 2 hours later, (TH-302->Pimasertib); and Pimasertib first followed by TH-302 2 hours
  • TH-302 was administered at 75 mg/kg i.p. once every three days (Q3D) and Pimasertib was administered at 30 mg/kg p.o., once per day.
  • the three scheduling sequences refer to days in which both drugs were administered. Animals were treated for 21 days (see, Fig. 6). After treatments stopped, animals were kept to observe for tumor re-growth and received no further treatments for additional 115 days and tumor volume and body weight measurements were continued once per week.
  • Example 7 Combination efficacy of Pimasertib and TH-302 in the cholangiocarcinoma LIX028 PDX model in mice
  • TH-302 The antitumor activities of Pimasertib, TH-302, and combination of TH302 with Pimasertib in the LIX028 PDX cholangiocarcinoma mouse model is shown in Fig. 7.
  • TH-302 was administered at 60mg/kg i.p. twice per week (BrW), Pimasertib at 30mg/kg, p.o. once per day and combination of TH302 and Pimasertib at Pimasertib->TH302 dosing schedule (2 hours apart).
  • Treatment time for this study is indicated by the arrow running parallel to the x-axis in Fig. 7. Tumor volumes were measured twice per week and plotted.
  • Example 8 Combination efficacy of Pimasertib and TH-302 in the cholangiocarcinoma
  • Treatment time for this study is indicated by the arrow running parallel to the x-axis in Fig. 8. Tumor volumes were measured twice per week and plotted.
  • Example 9 Combination efficacy of Pimasertib and TH-302 in the cholangiocarcinoma LIX127 PDX model in mice
  • TH-302 The antitumor activities of Pimasertib, TH-302, and combination of TH302 with Pimasertib in the LIX127 PDX cholangiocarcinoma mouse model is shown in Fig. 9.
  • TH-302 was administered at 60mg/kg i.p. twice per week (BIW), Pimasertib at 30mg/kg, p.o. once per day and combination of TH302 and Pimasertib at Pimasertib->TH302 dosing schedule (2 hours apart).
  • Treatment time for this study is indicated by the arrow running parallel to the x-axis in Fig. 9. Tumor volumes were measured twice per week and plotted.
  • Example 10 Combination efficacy of Pimasertib and TH-302 in the cholangiocarcinoma LD 152 PDX model in mice
  • TH-302 The antitumor activities of Pimasertib, TH-302, and combination of TH302 with Pimasertib in the LIX152 PDX cholangiocarcinoma mouse model is shown in Fig. 10.
  • TH-302 was administered at 60mg/kg i.p. twice per week (BIW), Pimasertib at 30mg/kg, p.o. once per day and combination of TH302 and Pimasertib at Pimasertib->TH302 dosing schedule (2 hours apart).
  • Treatment time for this study is indicated by the arrow running parallel to the x-axis in Fig. 10.
  • Tumor volumes were measured twice per week and plotted.
  • Example 11 Combination efficacy of Pimasertib and TH-302 in the cholangiocarcinoma LIX298 PDX model in mice
  • TH-302 The antitumor activities of Pimasertib, TH-302, and combination of TH302 with Pimasertib in the LIX298 PDX cholangiocarcinoma mouse model is shown in Fig. 11.
  • TH-302 was administered at 60mg/kg i.p. twice per week (BIW), Pimasertib at 30mg/kg, p.o. once per day and combination of TH302 and Pimasertib at Pimasertib->TH302 dosing schedule (2 hours apart).
  • Treatment time for this study is indicated by the arrow running parallel to the x-axis in Fig. 11. Tumor volumes were measured twice per week and plotted.
  • Example 12 Combination efficacy of Pimasertib and TH-302 in the cholangiocarcinoma LIX278 PDX model in mice
  • the antitumor activities of Pimasertib, TH-302, and combination of TH302 with Pimasertib in the LIX278 PDX cholangiocarcinoma mouse model is shown in Fig. 12.
  • TH-302 was administered at 60mg/kg i.p. twice per week (BIW), Pimasertib at 30mg/kg, p.o. once per day and combination of TH302 and Pimasertib at Pimasertib->TH302 dosing schedule (2 hours apart).
  • Treatment time for this study is indicated by the arrow running parallel to the x-axis in Fig. 12.
  • Tumor volumes were measured twice per week and plotted.
  • Example 13 Combination efficacy of Pimasertib and TH-302 in the cholangiocarcinoma LI1470 PDX model in mice
  • TH-302 was administered at 60mg/kg i.p. twice per week (BIW), Pimasertib at 30mg/kg, p.o. 5 days on 2 days off (5D+/2D-) and combination of TH302 and Pimasertib at Pimasertib->TH302 dosing schedule (2 hours apart).
  • Treatment time for this study is indicated by the arrow running parallel to the x-axis in Fig. 13. Tumor volumes were measured twice per week and plotted.
  • Example 14 Combination efficacy of Pimasertib and TH-302 in the cholangiocarcinoma LIX0449 PDX model in mice
  • TH-302 was administered at 60mg/kg i.p. twice per week (BIW), Pimasertib at 30mg/kg, p.o. 5 days on 2 days off (5D+/2D-) and combination of TH302 and Pimasertib at Pimasertib->TH302 dosing schedule (2 hours apart).
  • Treatment time for this study is indicated by the arrow running parallel to the x-axis in Fig. 16. Tumor volumes were measured twice per week and plotted.
  • Example 15 Combination efficacy of Pimasertib and TH-302 in the gallbladder GL0608 PDX model in mice
  • TH-302 The antitumor activities of Pimasertib, TH-302, and combination of TH302 with Pimasertib in the GL0608 PDX gallbladder mouse model is shown in Fig. 15.
  • TH-302 was administered at 60mg/kg i.p. twice per week (BIW), Pimasertib at 30mg/kg, p.o. once per day and combination of TH302 and Pimasertib at Pimasertib->TH302 dosing schedule (2 hours apart).
  • Treatment time for this study is indicated by the arrow running parallel to the x-axis in Fig. 15.
  • Tumor volumes were measured twice per week and plotted.
  • Example 16 Combination efficacy of Pimasertib and TH-302 in the gallbladder GBCQAJ
  • PDX model in mice [0115] The antitumor activities of Pimasertib, TH-302, and combination of TH302 with Pimasertib in the GBCQAJ PDX gallbladder mouse model is shown in Fig. 16.
  • TH-302 was administered at 60mg/kg i.p. twice per week (BrW), Pimasertib at 30mg/kg, p.o. once per day and combination of TH302 and Pimasertib at Pimasertib->TH302 dosing schedule (2 hours apart).
  • Treatment time for this study is indicated by the arrow running parallel to the x-axis in Fig. 16. Tumor volumes were measured twice per week and plotted.
  • Example 17 Combination efficacy of Pimasertib and TH-302 in the gallbladder GBC-WP PDX model in mice
  • TH-302 was administered at 60mg/kg i.p. twice per week (BIW), Pimasertib at 30mg/kg, p.o. once per day and combination of TH302 and Pimasertib at Pimasertib->TH302 dosing schedule (2 hours apart).
  • Treatment time for this study is indicated by the arrow running parallel to the x-axis in Fig. 17. Tumor volumes were measured twice per week and plotted.
  • Example 18 Combination efficacy of Pimasertib and TH-302 in the gallbladder BCGALOOl PDX model in mice
  • TH-302 was administered at 60mg/kg i.p. twice per week (BIW), Pimasertib at 30mg/kg, p.o. once per day and combination of TH302 and Pimasertib at Pimasertib->TH302 dosing schedule (2 hours apart).
  • Treatment time for this study is indicated by the arrow running parallel to the x-axis in Fig. 18. Tumor volumes were measured twice per week and plotted.
  • Example 19 Combination efficacy of Pimasertib and TH-302 in the gallbladder GL440 PDX model in mice
  • TH-302 was administered at 60mg/kg i.p. twice per week (BIW), Pimasertib at 30mg/kg, p.o. 5 days on 2 days off (5D+/2D-) and combination of TH302 and Pimasertib at Pimasertib->TH302 dosing schedule (2 hours apart).
  • Treatment time for this study is indicated by the arrow running parallel to the x-axis in Fig. 19. Tumor volumes were measured twice per week and plotted.

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Abstract

L'invention concerne l'administration combinée d'un promédicament activé par l'hypoxie, tel que TH 302, et un inhibiteur de kinase MEK tel que le pimasertib, qui sont efficaces pour traiter le cancer, en particulier le cancer du pancréas.
PCT/US2015/041100 2014-07-25 2015-07-20 Compositions et méthodes pour polythérapie à base d'inhibiteurs de mek dans le traitement du cancer WO2016014390A1 (fr)

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WO2023025312A1 (fr) 2021-08-27 2023-03-02 深圳艾欣达伟医药科技有限公司 Patient résistant aux inhibiteurs de parp traités avec th-302
WO2023025291A1 (fr) 2021-08-27 2023-03-02 深圳艾欣达伟医药科技有限公司 Solution de formulation lyophilisée, formulation lyophilisée, procédé et utilisation associés

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