Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
  • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• compositions comprising a therapeutically effective amount of an ACK inhibitor compound, a therapeutically effective amount of an HDAC inhibitor compound, and a pharmaceutically acceptable excipient.
• the ACK inhibitor compound is a BTK inhibitor.
• the BTK inhibitor is an irreversible BTK inhibitor.
• the ACK inhibitor is a compound of Formula (A):
• A is independently selected from N or CR 5 ;
• R 2 and R3 are independently selected from H, lower alkyl and substituted lower alkyl
• R 4 is L 3 -X-L4-G, wherein,
• L 3 is optional, and when present is a bond, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted alkynyl;
• R 6 , R 7 and Rg are independently selected from among H, lower alkyl or substituted lower alkyl, lower heteroalkyl or substituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, and substituted or unsubstituted lower heterocycloalkyl;
• each R is independently selected from among H, substituted or unsubstituted lower alkyl, and substituted or unsubstituted lower cycloalkyl;
• each Rio is independently H, substituted or unsubstituted lower alkyl, or substituted or unsubstituted lower cycloalkyl; or
• two Rio groups can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring;
• R 9 and Rio can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring
• the ACK inhibitor is (R)-l-(3-(4-amino-3-(4-phenoxyphenyl)-lH- pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one (i.e. PCI-32765/ibrutinib).
• the ACK inhibitor is AVL-263 (Avila Therapeutics/Celgene Corporation), AVL-292 (Avila Therapeutics/Celgene Corporation), AVL-291 (Avila
• the HDAC inhibitor is a compound of Formula (B):
• Pv 1 is hydrogen or alkyl
• X is -0-, -NR -, or -S(0) n where n is 0-2 and R is hydrogen or alkyl;
• Y is alkylene optionally substituted with cycloalkyl, optionally substituted phenyl, alkylthio, alkylsulfmyl, alkysulfonyl, optionally substituted phenylalkylthio, optionally substituted phenylalkylsulfonyl, hydroxy, or optionally substituted phenoxy;
• Ar 1 is phenylene or heteroarylene wherein said Ar 1 is optionally substituted with one or two groups independently selected from alkyl, halo, hydroxy, alkoxy, haloalkoxy, or haloalkyl; R is hydrogen, alkyl, hydroxyalkyl, or optionally substituted phenyl; and
• Ar is aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl.
• the HDAC inhibitor is 3-[(dimethylamino)methyl]-N- ⁇ 2-[4-(hydroxycarbamoyl)phenoxy]ethyl ⁇ -l- benzofuran-2- carboxamide (i.e. PCI-24781/abexinostat)
• the HDAC inhibitor is 3-[(dimethylamino)methyl]-N- ⁇ 2-[4- (hydroxycarbamoyl)phenoxy] ethyl ⁇ -l-benzofuran-2- carboxamide (i.e. PCI-24781/abexinostat)
• the ACK inhibitor is (R)-l-(3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l- yl)piperidin-l-yl)prop-2-en-l-one -32765/ibrutinib)
• the composition is in the form of a solid dosage form. In some embodiments, the composition is in the form of a capsule. In some embodiments, the
• composition is in the form of a solution. In some embodiments, the composition is in the form of a solution for intravenous administration. In some embodiments, the compositions comprise 140 mg of ibrutinib. In some embodiments, the composition is for use in treatment of a solid tumor. In some embodiments, the composition is for use in treatment of a sarcoma or carcinoma. In some embodiments, the composition is for use in treatment of a sarcoma. In some embodiments, the composition is for use in treatment of a carcinoma. In some embodiments, the sarcoma is selected from alveolar rhabdomyosarcoma; alveolar soft part sarcoma; ameloblastoma;
• angiosarcoma chondrosarcoma; chordoma; clear cell sarcoma of soft tissue; dedifferentiated liposarcoma; desmoid; desmoplastic small round cell tumor; embryonal rhabdomyosarcoma; epithelioid fibrosarcoma; epithelioid hemangioendothelioma; epithelioid sarcoma;
• esthesioneuroblastoma Ewing sarcoma; extrarenal rhabdoid tumor; extraskeletal myxoid chondrosarcoma; extrasketetal osteosarcoma; fibrosarcoma; giant cell tumor;
• hemangiopericytoma infantile fibrosarcoma; inflammatory myofibroblastic tumor; Kaposi sarcoma; leiomyosarcoma of bone; liposarcoma; liposarcoma of bone; malignant fibrous histiocytoma (MFH); malignant fibrous histiocytoma (MFH) of bone; malignant
• mesenchymoma malignant peripheral nerve sheath tumor; mesenchymal chondrosarcoma; myxofibrosarcoma; myxoid liposarcoma; myxoinflammatory fibroblastic sarcoma; neoplasms with perivascular epitheioid cell differentiation; osteosarcoma; parosteal osteosarcoma;
• neoplasm with perivascular epitheioid cell differentiation periosteal osteosarcoma; pleomorphic liposarcoma; pleomorphic rhabdomyosarcoma; PNET/extraskeletal Ewing tumor;
• the carcinoma is selected from an adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, or small cell carcinoma.
• the carcinoma is selected from anal cancer; appendix cancer; bile duct cancer (i.e., cholangiocarcinoma);
• the carcinoma is breast cancer.
• the breast cancer is invasive ductal carcinoma, ductal carcinoma in situ, invasive lobular carcinoma, or lobular carcinoma in situ.
• the carcinoma is pancreatic cancer. In some embodiments, the pancreatic cancer is adenocarcinoma, or islet cell carcinoma. In some embodiments, the carcinoma is colorectal cancer. In some embodiments, the colorectal cancer is adenocarcinoma. In some embodiments, the solid tumor is a colon polyp. In some embodiments, the colon polyp is associated with familial adenomatous polyposis. In some embodiments, the carcinoma is bladder cancer. In some embodiments, the bladder cancer is transitional cell bladder cancer, squamous cell bladder cancer, or adenocarcinoma. In some embodiments, the carcinoma is lung cancer. In some embodiments, the lung cancer is a non- small cell lung cancer.
• the non-small cell lung cancer is adenocarcinoma, squamous-cell lung carcinoma, or large-cell lung carcinoma. In some embodiments, the non- small cell lung cancer is large eel lung cancer. In some embodiments, the lung cancer is a small cell lung cancer. In some embodiments, the carcinoma is prostate cancer. In some embodiments, the prostate cancer is adenocarcinoma or small cell carcinoma. In some embodiments, the carcinoma is ovarian cancer. In some embodiments, the ovarian cancer is epithelial ovarian cancer. In some embodiments, the carcinoma is bile duct cancer. In some embodiments, the bile duct cancer is proximal bile duct carcinoma or distal bile duct carcinoma.
• the combination of ibrutinib and abexinostat is 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% or 60% more efficacious than administration of abexinostat alone. In some embodiments, the combination of the ibrutinib and abexinostat is 50% more efficacious than administration of abexinostat alone. In some embodiments, the combination of ibrutinib and abexinostat is 5%, 10%>, 15%, 20%>, 25%, 30%>, or 35% more efficacious than administration of ibrutinib alone. In some embodiments, the combination of ibrutinib and abexinostat is 25% more efficacious than administration of ibrutinib alone.
• the ACK inhibitor compound is a BTK inhibitor.
• the BTK inhibitor is an irreversible BTK inhibitor.
• the ACK inhibitor is a compound of Formula (A):
• A is independently selected from N or CR 5 ;
• R 2 and R 3 are independently selected from H, lower alkyl and substituted lower alkyl
• R 4 is L 3 -X-L 4 -G, wherein, L 3 is optional, and when present is a bond, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted alkynyl;
• L 4 is optional, and when present is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle;
• R 6 , R 7 and Rg are independently selected from among H, lower alkyl or substituted lower alkyl, lower heteroalkyl or substituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, and substituted or unsubstituted lower heterocycloalkyl;
• each R 9 is independently selected from among H, substituted or unsubstituted lower alkyl, and substituted or unsubstituted lower cycloalkyl;
• each Rio is independently H, substituted or unsubstituted lower alkyl, or substituted or unsubstituted lower cycloalkyl; or
• two Rio groups can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring;
• R 9 and Rio can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring
• the ACK inhibitor is (R)-l-(3-(4-amino-3-(4-phenoxyphenyl)-lH- pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one (i.e. PCI-32765/ibrutinib).
• the ACK inhibitor is AVL-263 (Avila Therapeutics/Celgene Corporation), AVL-292 (Avila Therapeutics/Celgene Corporation), AVL-291 (Avila
• the HDAC inhibitor is a compound of Formula (B):
• Pv 1 is hydrogen or alkyl
• X is -0-, -NR -, or -S(0) n where n is 0-2 and R is hydrogen or alkyl;
• Y is alkylene optionally substituted with cycloalkyl, optionally substituted phenyl, alkylthio, alkylsulfmyl, alkysulfonyl, optionally substituted phenylalkylthio, optionally substituted phenylalkylsulfonyl, hydroxy, or optionally substituted phenoxy;
• Ar 1 is phenylene or heteroarylene wherein said Ar 1 is optionally substituted with one or two groups independently selected from alkyl, halo, hydroxy, alkoxy, haloalkoxy, or haloalkyl; R is hydrogen, alkyl, hydroxyalkyl, or optionally substituted phenyl; and 2
• Ar is aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl.
• the HDAC inhibitor is 3 - [(dimethylamino)methyl] -N- ⁇ 2-[4-(hydroxycarbamoyl)phenoxy] ethyl ⁇ - 1 - benzofuran-2- carboxamide (i.e. PCI-24781/abexinostat)
• the HDAC inhibitor is 3-[(dimethylamino)methyl]-N- ⁇ 2-[4- (hydroxycarbamoyl)phenoxy] ethyl ⁇ -l-benzofuran-2- carboxamide (i.e. PCI-24781/abexinostat)
• the ACK inhibitor is (R)-l-(3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l- yl)piperidin-l-yl)prop-2-en-l-one (i.e. PCI-32765/ibrutinib)
• the combination is administered in a solid dosage form. In some embodiments the combination is administered in a capsule. In some embodiments the combination is administered in a solution. In some embodiments the combination is
• the combination comprises 140 mg of ibrutinib.
• the combination is for use in treatment of a solid tumor.
• the combination is for use in treatment of a sarcoma or carcinoma.
• the combination is for use in treatment of a sarcoma.
• the combination is for use in treatment of a carcinoma.
• the sarcoma is selected from alveolar rhabdomyosarcoma; alveolar soft part sarcoma; ameloblastoma; angiosarcoma; chondrosarcoma; chordoma; clear cell sarcoma of soft tissue; dedifferentiated liposarcoma; desmoid; desmoplastic small round cell tumor; embryonal rhabdomyosarcoma; epithelioid fibrosarcoma; epithelioid hemangioendothelioma; epithelioid sarcoma; esthesioneuroblastoma; Ewing sarcoma; extrarenal rhabdoid tumor; extraskeletal myxoid chondrosarcoma; extrasketetal osteosarcoma; fibrosarcoma; giant cell tumor;
• hemangiopericytoma infantile fibrosarcoma; inflammatory myofibroblastic tumor; Kaposi sarcoma; leiomyosarcoma of bone; liposarcoma; liposarcoma of bone; malignant fibrous histiocytoma (MFH); malignant fibrous histiocytoma (MFH) of bone; malignant
• mesenchymoma malignant peripheral nerve sheath tumor; mesenchymal chondrosarcoma; myxofibrosarcoma; myxoid liposarcoma; myxoinflammatory fibroblastic sarcoma; neoplasms with perivascular epitheioid cell differentiation; osteosarcoma; parosteal osteosarcoma;
• neoplasm with perivascular epitheioid cell differentiation periosteal osteosarcoma; pleomorphic liposarcoma; pleomorphic rhabdomyosarcoma; PNET/extraskeletal Ewing tumor;
• the carcinoma is selected from an adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, or small cell carcinoma.
• the carcinoma is selected from anal cancer; appendix cancer; bile duct cancer (i.e., cholangiocarcinoma);
• the carcinoma is breast cancer.
• the breast cancer is invasive ductal carcinoma, ductal carcinoma in situ, invasive lobular carcinoma, or lobular carcinoma in situ.
• the carcinoma is pancreatic cancer. In some embodiments, the pancreatic cancer is adenocarcinoma, or islet cell carcinoma. In some embodiments, the carcinoma is colorectal cancer. In some embodiments, the colorectal cancer is adenocarcinoma. In some embodiments, the solid tumor is a colon polyp. In some embodiments, the colon polyp is associated with familial adenomatous polyposis. In some embodiments, the carcinoma is bladder cancer. In some embodiments, the bladder cancer is transitional cell bladder cancer, squamous cell bladder cancer, or adenocarcinoma. In some embodiments, the carcinoma is lung cancer. In some embodiments, the lung cancer is a non- small cell lung cancer.
• the non-small cell lung cancer is adenocarcinoma, squamous-cell lung carcinoma, or large-cell lung carcinoma. In some embodiments, the non- small cell lung cancer is large eel lung cancer. In some embodiments, the lung cancer is a small cell lung cancer. In some embodiments, the carcinoma is prostate cancer. In some embodiments, the prostate cancer is adenocarcinoma or small cell carcinoma. In some embodiments, the carcinoma is ovarian cancer. In some embodiments, the ovarian cancer is epithelial ovarian cancer. In some embodiments, the carcinoma is bile duct cancer. In some embodiments, the bile duct cancer is proximal bile duct carcinoma or distal bile duct carcinoma.
• the combination of ibrutinib and abexinostat is 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% or 60% more efficacious than administration of abexinostat alone. In some embodiments, the combination of the ibrutinib and abexinostat is 50% more efficacious than administration of abexinostat alone. In some embodiments, the combination of ibrutinib and abexinostat is 5%, 10%>, 15%, 20%>, 25%, 30%>, or 35% more efficacious than administration of ibrutinib alone.
• the combination of ibrutinib and abexinostat is 25% more efficacious than administration of ibrutinib alone.
• the combination is administered in a unified dosage form or separate dosage forms. In some embodiments the combination is administered simultaneously or sequentially.
• the ACK inhibitor is (R)-l-(3-(4-amino- 3-(4-phenoxyphenyl)- 1 H-pyrazolo[3 ,4-d]pyrimidin- 1 -yl)piperidin- 1 -yl)prop-2-en- 1 -one (i.e. PCI-32765/ibrutinib)
• the HDAC inhibitor is 3-[(dimethylamino)methyl]-N- ⁇ 2-[4- (hydroxycarbamoyl)phenoxy] ethyl ⁇ -l-benzofuran-2- carboxamide (i.e. PCI-24781/abexinostat)
• the solid tumor is a carcinoma.
• the carcinoma is breast cancer.
• the carcinoma is pancreatic cancer.
• the carcinoma is colorectal cancer.
• the carcinoma is bladder cancer.
• the carcinoma is lung cancer.
• the lung cancer is a non-small cell lung cancer.
• the lung cancer is a large cell lung cancer.
• the carcinoma is prostate cancer.
• the carcinoma is ovarian cancer.
• the carcinoma is bile duct cancer.
• co -administration of the ACK inhibitor and the HDAC inhibitor is 50% more efficacious than administration of the HDAC inhibitor alone.
• coadministration of the ACK inhibitor and the HDAC inhibitor is 25% more efficacious than administration of the ACK inhibitor alone.
• the ACK inhibitor and the HDAC inhibitor are administered in a unified dosage form or separate dosage forms.
• the ACK inhibitor and the HDAC inhibitor are administered simultaneously or sequentially.
• ACK inhibitor compound is a BTK inhibitor.
• BTK inhibitor is an irreversible BTK inhibitor.
• the ACK inhibitor is a compound of Formula (A):
• A is independently selected from N or CR 5 ;
• R2 and R3 are independently selected from H, lower alkyl and substituted lower alkyl
• R 4 is L3-X-L4-G, wherein,
• L 3 is optional, and when present is a bond, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted alkynyl;
• L 4 is optional, and when present is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle;
• R 6 , R 7 and Rg are independently selected from among H, lower alkyl or substituted lower alkyl, lower heteroalkyl or substituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, and substituted or unsubstituted lower heterocycloalkyl;
• each R9 is independently selected from among H, substituted or unsubstituted lower alkyl, and substituted or unsubstituted lower cycloalkyl;
• each Rio is independently H, substituted or unsubstituted lower alkyl, or substituted or unsubstituted lower cycloalkyl; or
• two Rio groups can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring;
• R 9 and Rio can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring
• the ACK inhibitor is (R)-l-(3-(4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one (i.e. PCI-32765/ibrutinib).
• the ACK inhibitor is AVL-263 (Avila Therapeutics/Celgene Corporation), AVL-292 (Avila Therapeutics/Celgene Corporation), AVL-291 (Avila
• the HDAC inhibitor is a compound of Formula (B):
• Pv 1 is hydrogen or alkyl
• X is -0-, -NR -, or -S(0) n where n is 0-2 and R is hydrogen or alkyl;
• Y is alkylene optionally substituted with cycloalkyl, optionally substituted phenyl, alkylthio, alkylsulfmyl, alkysulfonyl, optionally substituted phenylalkylthio, optionally substituted phenylalkylsulfonyl, hydroxy, or optionally substituted phenoxy;
• Ar 1 is phenylene or heteroarylene wherein said Ar 1 is optionally substituted with one or two groups independently selected from alkyl, halo, hydroxy, alkoxy, haloalkoxy, or haloalkyl; R is hydrogen, alkyl, hydroxyalkyl, or optionally substituted phenyl; and 2
• Ar is aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, cycloalkyl,
• the HDAC inhibitor is 3 - [(dimethylamino)methyl] -N- ⁇ 2-[4-(hydroxycarbamoyl)phenoxy] ethyl ⁇ - 1 - benzofuran-2- carboxamide (i.e. PCI-24781/abexinostat)
• the solid tumor is a sarcoma or carcinoma. In some embodiments, the solid tumor is a sarcoma. In some embodiments, the solid tumor is a carcinoma. In some embodiments, the sarcoma is selected from alveolar rhabdomyosarcoma; alveolar soft part sarcoma; ameloblastoma; angiosarcoma; chondrosarcoma; chordoma; clear cell sarcoma of soft tissue; dedifferentiated liposarcoma; desmoid; desmoplastic small round cell tumor; embryonal rhabdomyosarcoma; epithelioid fibrosarcoma; epithelioid hemangioendothelioma; epithelioid sarcoma; esthesioneuroblastoma; Ewing sarcoma; extrarenal rhabdoid tumor; extraskeletal myxoid chondrosarcoma
• hemangiopericytoma infantile fibrosarcoma; inflammatory myofibroblastic tumor; Kaposi sarcoma; leiomyosarcoma of bone; liposarcoma; liposarcoma of bone; malignant fibrous histiocytoma (MFH); malignant fibrous histiocytoma (MFH) of bone; malignant
• mesenchymoma malignant peripheral nerve sheath tumor; mesenchymal chondrosarcoma; myxofibrosarcoma; myxoid liposarcoma; myxoinflammatory fibroblastic sarcoma; neoplasms with perivascular epitheioid cell differentiation; osteosarcoma; parosteal osteosarcoma;
• neoplasm with perivascular epitheioid cell differentiation periosteal osteosarcoma; pleomorphic liposarcoma; pleomorphic rhabdomyosarcoma; PNET/extraskeletal Ewing tumor;
• the carcinoma is selected from an adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, or small cell carcinoma.
• the carcinoma is selected from anal cancer; appendix cancer; bile duct cancer (i.e., cholangiocarcinoma);
• the carcinoma is breast cancer.
• the breast cancer is invasive ductal carcinoma, ductal carcinoma in situ, invasive lobular carcinoma, or lobular carcinoma in situ.
• the carcinoma is pancreatic cancer. In some embodiments, the pancreatic cancer is adenocarcinoma, or islet cell carcinoma. In some embodiments, the carcinoma is colorectal cancer. In some embodiments, the colorectal cancer is adenocarcinoma. In some embodiments, the solid tumor is a colon polyp. In some embodiments, the colon polyp is associated with familial adenomatous polyposis. In some embodiments, the carcinoma is bladder cancer. In some embodiments, the bladder cancer is transitional cell bladder cancer, squamous cell bladder cancer, or adenocarcinoma. In some embodiments, the carcinoma is lung cancer. In some embodiments, the lung cancer is a non- small cell lung cancer.
• the non-small cell lung cancer is adenocarcinoma, squamous-cell lung carcinoma, or large-cell lung carcinoma.
• the lung cancer is a small cell lung cancer.
• the carcinoma is prostate cancer.
• the prostate cancer is adenocarcinoma or small cell carcinoma.
• the carcinoma is ovarian cance.
• the ovarian cancer is epithelial ovarian cancer.
• the carcinoma is bile duct cancer.
• the bile duct cancer is proximal bile duct carcinoma or distal bile duct carcinoma.
• co-administration of the ACK inhibitor and the HDAC inhibitor is 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% or 60% more efficacious than administration of the HDAC inhibitor alone. In some embodiments, co-administration of the ACK inhibitor and the HDAC inhibitor is 50% more efficacious than administration of the HDAC inhibitor alone. In some embodiments, co-administration of the ACK inhibitor and the HDAC inhibitor is 5%, 10%, 15%, 20%, 25%, 30%, or 35% more efficacious than
• the ACK inhibitor alone is administered in a unified dosage form or separate dosage forms. In some embodiments, the ACK inhibitor and the HDAC inhibitor are administered simultaneously or sequentially.
• a solid tumor comprising co -administering to an individual in need thereof an HDAC inhibitor compound and (R)- 1 -(3 -(4-amino-3 -(4-phenoxyphenyl)- 1 H-pyrazolo [3 ,4-d]pyrimidin- 1 -yl)piperidin- 1 -yl)prop- -en-l-one (i.e. PCI-32765/ibrutinib).
• R 1 is hydrogen or alkyl
• X is -0-, -NR -, or -S(0) n where n is 0-2 and R is hydrogen or alkyl;
• Y is alkylene optionally substituted with cycloalkyl, optionally substituted phenyl, alkylthio, alkylsulfmyl, alkysulfonyl, optionally substituted phenylalkylthio, optionally substituted phenylalkylsulfonyl, hydroxy, or optionally substituted phenoxy;
• Ar 1 is phenylene or heteroarylene wherein said Ar 1 is optionally substituted with one or two groups independently selected from alkyl, halo, hydroxy, alkoxy, haloalkoxy, or haloalkyl; R is hydrogen, alkyl, hydroxyalkyl, or optionally substituted phenyl; and
• Ar is aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, cycloalkyl,
• cycloalkylalkyl cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl.
• the HDAC inhibitor is 3-[(dimethylamino)methyl]-N- ⁇ 2-[4- (hydroxycarbamoyl)phenoxy] ethyl ⁇ -l-benzofuran-2- carboxamide (i.e. PCI-24781/abexinostat)
• the solid tumor is a sarcoma or carcinoma. In some embodiments, the solid tumor is a sarcoma. In some embodiments, the solid tumor is a carcinoma. In some embodiments, the sarcoma is selected from alveolar rhabdomyosarcoma; alveolar soft part sarcoma; ameloblastoma; angiosarcoma; chondrosarcoma; chordoma; clear cell sarcoma of soft tissue; dedifferentiated liposarcoma; desmoid; desmoplastic small round cell tumor; embryonal rhabdomyosarcoma; epithelioid fibrosarcoma; epithelioid hemangioendothelioma; epithelioid sarcoma; esthesioneuroblastoma; Ewing sarcoma; extrarenal rhabdoid tumor; extraskeletal myxoid chondrosarcoma
• hemangiopericytoma infantile fibrosarcoma; inflammatory myofibroblastic tumor; Kaposi sarcoma; leiomyosarcoma of bone; liposarcoma; liposarcoma of bone; malignant fibrous histiocytoma (MFH); malignant fibrous histiocytoma (MFH) of bone; malignant
• mesenchymoma malignant peripheral nerve sheath tumor; mesenchymal chondrosarcoma; myxofibrosarcoma; myxoid liposarcoma; myxoinflammatory fibroblastic sarcoma; neoplasms with perivascular epitheioid cell differentiation; osteosarcoma; parosteal osteosarcoma;
• neoplasm with perivascular epitheioid cell differentiation periosteal osteosarcoma; pleomorphic liposarcoma; pleomorphic rhabdomyosarcoma; PNET/extraskeletal Ewing tumor;
• the carcinoma is selected from an adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, or small cell carcinoma.
• the carcinoma is selected from anal cancer; appendix cancer; bile duct cancer (i.e., cholangiocarcinoma);
• the carcinoma is breast cancer.
• the breast cancer is invasive ductal carcinoma, ductal carcinoma in situ, invasive lobular carcinoma, or lobular carcinoma in situ.
• the carcinoma is pancreatic cancer. In some embodiments, the pancreatic cancer is adenocarcinoma, or islet cell carcinoma. In some embodiments, the carcinoma is colorectal cancer. In some embodiments, the colorectal cancer is adenocarcinoma. In some embodiments, the solid tumor is a colon polyp. In some embodiments, the colon polyp is associated with familial adenomatous polyposis. In some embodiments, the carcinoma is bladder cancer. In some embodiments, the bladder cancer is transitional cell bladder cancer, squamous cell bladder cancer, or adenocarcinoma. In some embodiments, the carcinoma is lung cancer. In some embodiments, the lung cancer is a non- small cell lung cancer.
• the non-small cell lung cancer is adenocarcinoma, squamous-cell lung carcinoma, or large-cell lung carcinoma.
• the lung cancer is a small cell lung cancer.
• the carcinoma is prostate cancer.
• the prostate cancer is adenocarcinoma or small cell carcinoma.
• the carcinoma is ovarian cancer.
• the ovarian cancer is epithelial ovarian cancer.
• the carcinoma is bile duct cancer.
• the bile duct cancer is proximal bile duct carcinoma or distal bile duct carcinoma.
• co-administration of ibrutinib and the HDAC inhibitor is 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% or 60% more efficacious than administration of the HDAC inhibitor alone. In some embodiments, co-administration of ibrutinib and the HDAC inhibitor is 50% more efficacious than administration of the HDAC inhibitor alone. In some embodiments, co -administration of ibrutinib and the HDAC inhibitor is 5%, 10%, 15%, 20%, 25%, 30%, or 35% more efficacious than administration of ibrutinib alone. In some
• co -administration of ibrutinib and the HDAC inhibitor is 25% more efficacious than administration of ibrutinib alone.
• ibrutinib and the HDAC inhibitor are administered in a unified dosage form or separate dosage forms.
• ibrutinib and the HDAC inhibitor are administered simultaneously or sequentially.
• the ACK inhibitor compound is a BTK inhibitor.
• the BTK inhibitor is an irreversible BTK inhibitor.
• the ACK inhibitor is a compound of Formula
• A is independently selected from N or CR 5 ;
• R 2 and R3 are independently selected from H, lower alkyl and substituted lower alkyl
• R 4 is L3-X-L4-G, wherein,
• L 3 is optional, and when present is a bond, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted alkynyl;
• L 4 is optional, and when present is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle;
• R 6 , R 7 and Rg are independently selected from among H, lower alkyl or substituted lower alkyl, lower heteroalkyl or substituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, and substituted or unsubstituted lower heterocycloalkyl;
• each R is independently selected from among H, substituted or unsubstituted lower alkyl, and substituted or unsubstituted lower cycloalkyl;
• each Rio is independently H, substituted or unsubstituted lower alkyl, or substituted or unsubstituted lower cycloalkyl; or
• two Rio groups can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring;
• R and Rio can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring
• the ACK inhibitor is (R)-l-(3-(4-amino-3-(4- phenoxyphenyl)- 1 H-pyrazolo[3 ,4-d]pyrimidin- 1 -yl)piperidin- 1 -yl)prop-2-en- 1 -one (i.e. PCI-
• the ACK inhibitor is AVL-263 (Avila Therapeutics/Celgene Corporation), AVL-292 (Avila Therapeutics/Celgene Corporation), AVL-291 (Avila
• the solid tumor is a sarcoma or carcinoma. In some embodiments, the solid tumor is a sarcoma. In some embodiments, the solid tumor is a carcinoma. In some embodiments, the sarcoma is selected from alveolar rhabdomyosarcoma; alveolar soft part sarcoma; ameloblastoma;
• angiosarcoma chondrosarcoma; chordoma; clear cell sarcoma of soft tissue; dedifferentiated liposarcoma; desmoid; desmoplastic small round cell tumor; embryonal rhabdomyosarcoma; epithelioid fibrosarcoma; epithelioid hemangioendothelioma; epithelioid sarcoma;
• esthesioneuroblastoma Ewing sarcoma; extrarenal rhabdoid tumor; extraskeletal myxoid chondrosarcoma; extrasketetal osteosarcoma; fibrosarcoma; giant cell tumor;
• hemangiopericytoma infantile fibrosarcoma; inflammatory myofibroblastic tumor; Kaposi sarcoma; leiomyosarcoma of bone; liposarcoma; liposarcoma of bone; malignant fibrous histiocytoma (MFH); malignant fibrous histiocytoma (MFH) of bone; malignant
• mesenchymoma malignant peripheral nerve sheath tumor; mesenchymal chondrosarcoma; myxofibrosarcoma; myxoid liposarcoma; myxoinflammatory fibroblastic sarcoma; neoplasms with perivascular epitheioid cell differentiation; osteosarcoma; parosteal osteosarcoma;
• the carcinoma is selected from an adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, or small cell carcinoma.
• the carcinoma is selected from anal cancer; appendix cancer; bile duct cancer (i.e., cholangiocarcinoma);
• the carcinoma is breast cancer.
• the breast cancer is invasive ductal carcinoma, ductal carcinoma in situ, invasive lobular carcinoma, or lobular carcinoma in situ.
• the carcinoma is pancreatic cancer. In some embodiments, the pancreatic cancer is adenocarcinoma, or islet cell carcinoma. In some embodiments, the carcinoma is colorectal cancer. In some embodiments, the colorectal cancer is adenocarcinoma. In some embodiments, the solid tumor is a colon polyp. In some embodiments, the colon polyp is associated with familial adenomatous polyposis. In some embodiments, the carcinoma is bladder cancer. In some embodiments, the bladder cancer is transitional cell bladder cancer, squamous cell bladder cancer, or adenocarcinoma. In some embodiments, the carcinoma is lung cancer. In some embodiments, the lung cancer is a non- small cell lung cancer.
• the non-small cell lung cancer is adenocarcinoma, squamous-cell lung carcinoma, or large-cell lung carcinoma.
• the lung cancer is a small cell lung cancer.
• the carcinoma is prostate cancer.
• the prostate cancer is adenocarcinoma or small cell carcinoma.
• the carcinoma is ovarian cancer.
• the ovarian cancer is epithelial ovarian cancer.
• the carcinoma is bile duct cancer.
• the bile duct cancer is proximal bile duct carcinoma or distal bile duct carcinoma.
• co-administration of the abexinostat and the ACK inhibitor is 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% or 60% more efficacious than administration of abexinostat alone. In some embodiments, co -administration of the abexinostat and the ACK inhibitor is 50% more efficacious than administration of abexinostat alone. In some
• co -administration of the abexinostat and the ACK inhibitor is 5%, 10%, 15%, 20%, 25%, 30%, or 35% more efficacious than administration of the ACK inhibitor alone. In some embodiments, co -administration of the abexinostat and the ACK inhibitor is 25% more efficacious than administration of the ACK inhibitor alone. In some embodiments, the ACK inhibitor and abexinostat are administered in a unified dosage form or separate dosage forms. In some embodiments, the ACK inhibitor and abexinostat are administered simultaneously or sequentially.
• a solid tumor comprising administering to an individual in need thereof a combination of (R)-l-(3-(4-amino-3- (4-phenoxyphenyl)- 1 H-pyrazolo[3 ,4-d]pyrimidin- 1 -yl)piperidin- 1 -yl)prop-2-en- 1 -one (i.e. PCI- 32765/ibrutinib)
• the solid tumor is a sarcoma or carcinoma. In some embodiments, the solid tumor is a sarcoma. In some embodiments, the solid tumor is a carcinoma. In some embodiments, the sarcoma is selected from alveolar rhabdomyosarcoma; alveolar soft part sarcoma; ameloblastoma; angiosarcoma; chondrosarcoma; chordoma; clear cell sarcoma of soft tissue; dedifferentiated liposarcoma; desmoid; desmoplastic small round cell tumor; embryonal rhabdomyosarcoma; epithelioid fibrosarcoma; epithelioid hemangioendothelioma; epithelioid sarcoma; esthesioneuroblastoma; Ewing sarcoma; extrarenal rhabdoid tumor; extraskeletal myxoid chondrosarcoma
• hemangiopericytoma infantile fibrosarcoma; inflammatory myofibroblastic tumor; Kaposi sarcoma; leiomyosarcoma of bone; liposarcoma; liposarcoma of bone; malignant fibrous histiocytoma (MFH); malignant fibrous histiocytoma (MFH) of bone; malignant
• mesenchymoma malignant peripheral nerve sheath tumor; mesenchymal chondrosarcoma; myxofibrosarcoma; myxoid liposarcoma; myxoinflammatory fibroblastic sarcoma; neoplasms with perivascular epitheioid cell differentiation; osteosarcoma; parosteal osteosarcoma;
• neoplasm with perivascular epitheioid cell differentiation periosteal osteosarcoma; pleomorphic liposarcoma; pleomorphic rhabdomyosarcoma; PNET/extraskeletal Ewing tumor;
• the carcinoma is selected from an adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, or small cell carcinoma.
• the carcinoma is selected from anal cancer; appendix cancer; bile duct cancer (i.e., cholangiocarcinoma);
• the carcinoma is breast cancer.
• the breast cancer is invasive ductal carcinoma, ductal carcinoma in situ, invasive lobular carcinoma, or lobular carcinoma in situ.
• the carcinoma is pancreatic cancer. In some embodiments, the pancreatic cancer is adenocarcinoma, or islet cell carcinoma. In some embodiments, the carcinoma is colorectal cancer. In some embodiments, the colorectal cancer is adenocarcinoma. In some embodiments, the solid tumor is a colon polyp. In some embodiments, the colon polyp is associated with familial adenomatous polyposis. In some embodiments, the carcinoma is bladder cancer. In some embodiments, the bladder cancer is transitional cell bladder cancer, squamous cell bladder cancer, or adenocarcinoma. In some embodiments, the carcinoma is lung cancer. In some embodiments, the lung cancer is a non- small cell lung cancer.
• the non-small cell lung cancer is adenocarcinoma, squamous-cell lung carcinoma, or large-cell lung carcinoma.
• the lung cancer is a small cell lung cancer.
• the carcinoma is prostate cancer.
• the prostate cancer is adenocarcinoma or small cell carcinoma.
• the carcinoma is ovarian cancer.
• the ovarian cancer is epithelial ovarian cancer.
• the carcinoma is bile duct cancer.
• the bile duct cancer is proximal bile duct carcinoma or distal bile duct carcinoma.
• co-administration of ibrutinib and abexinostat is 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% or 60% more efficacious than administration of abexinostat alone. In some embodiments, co-administration of the ibrutinib and abexinostat is 50% more efficacious than administration of abexinostat alone. In some embodiments, coadministration of ibrutinib and abexinostat is 5%, 10%>, 15%, 20%>, 25%, 30%, or 35% more efficacious than administration of ibrutinib alone.
• co-administration of ibrutinib and abexinostat is 25% more efficacious than administration of ibrutinib alone.
• abexinostat and ibrutinib are administered in a unified dosage form or separate dosage forms. In some embodiments, abexinostat and ibrutinib are administered simultaneously or sequentially.
• compositions comprising a therapeutically effective amount of an ACK inhibitor compound, a therapeutically effective amount of an HDAC inhibitor compound, and a pharmaceutically acceptable excipient.
• the ACK inhibitor compound is a BTK inhibitor.
• the BTK inhibitor is an irreversible BTK inhibitor.
• the ACK inhibitor is a compound of Formula
• A is independently selected from N or CR 5 ;
• R 2 and R3 are independently selected from H, lower alkyl and substituted lower alkyl
• R 4 is L3-X-L4-G, wherein,
• L 3 is optional, and when present is a bond, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted alkynyl;
• L 4 is optional, and when present is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle;
• R 6 , R 7 and Rg are independently selected from among H, lower alkyl or substituted lower alkyl, lower heteroalkyl or substituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, and substituted or unsubstituted lower heterocycloalkyl;
• each R 9 is independently selected from among H, substituted or unsubstituted lower alkyl, and substituted or unsubstituted lower cycloalkyl;
• each Rio is independently H, substituted or unsubstituted lower alkyl, or substituted or unsubstituted lower cycloalkyl; or
• two Rio groups can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring;
• the ACK inhibitor is (R)-l-(3-(4-amino-3-(4- phenoxyphenyl)- 1 H-pyrazolo[3 ,4-d]pyrimidin- 1 -yl)piperidin- 1 -yl)prop-2-en- 1 -one (i.e. PCI- 32765/ibrutinib)
• the ACK inhibitor is AVL-263 (Avila Therapeutics/Celgene Corporation), AVL-292 (Avila Therapeutics/Celgene Corporation), AVL-291 (Avila
• the HDAC inhibitor is a compound of Formula (B):
• R is hydrogen or alkyl
• X is -0-, -NR -, or -S(0) n where n is 0-2 and R is hydrogen or alkyl;
• Y is alkylene optionally substituted with cycloalkyl, optionally substituted phenyl, alkylthio, alkylsulfinyl, alkysulfonyl, optionally substituted phenylalkylthio, optionally substituted phenylalkylsulfonyl, hydroxy, or optionally substituted phenoxy;
• Ar 1 is phenylene or heteroarylene wherein said Ar 1 is optionally substituted with one or two groups independently selected from alkyl, halo, hydroxy, alkoxy, haloalkoxy, or haloalkyl; R is hydrogen, alkyl, hydroxyalkyl, or optionally substituted phenyl; and
• Ar is aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl.
• the HDAC inhibitor is 3 - [(dimethylamino)methyl] -N- ⁇ 2-[4-(hydroxycarbamoyl)phenoxy] ethyl ⁇ - 1 - benzofuran-2- carboxamide (i.e. PCI-24781/abexinostat)
• the HDAC inhibitor is 3-[(dimethylamino)methyl]-N- ⁇ 2-[4- (hydroxycarbamoyl)phenoxy] ethyl ⁇ -! -benzofuran-2- carboxamide (i.e. PCI-24781/abexinostat)
• the ACK inhibitor is (R)-l-(3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4- d]pyrimidin- 1 -yl)piperidin- 1 -yl)prop-2-en- 1 -one (i.e. PCI-32765/ibrutinib)
• the composition is in the form of a solid dosage form. In some embodiments, the composition is in the form of a capsule. In some embodiments, the
• composition is in the form of a solution. In some embodiments, the composition is in the form of a solution for intravenous administration. In some embodiments, the composition comprises 140 mg of ibrutinib.
• Figure 1 Is an illustrative example of the average number of tumors on the lung surface for control and drug-treated (abexinostat, ibrutinib, or abexinostat + ibrutinib) Grgl transgenic mice.
• the bars at the left show mice treated for 4 weeks beginning at 2 months (3 month samples) and the bars in the middle show mice treated for 4 weeks beginning at 5 months (6 month samples).
• the average number of tumors over 1 mm for 6 month samples is also shown.
• Figure 2 Is an illustrative example of the number of surface tumors per Grgl transgenic mice at 3 months after 4 weeks of treatment with abexinostat, ibrutinib, or the combination of abexinostat and ibrutinib.
• FIG. 3 Is an illustrative example of tumor sections from Grgl transgenic mice at 3 months.
• Tumor sections from control mice A, B
• Abexinostat-treated mice C, D
• Ibrutinib-treated mice E, F
• Original magnification of images in the left column was 5 OX and in the right column was 400X.
• Figure 4 Is an illustrative example of the number of surface tumors per Grgl transgenic mice at 6 months after 4 weeks of treatment with abexinostat, ibrutinib, or the combination of abexinostat and ibrutinib.
• Figure 5 Is an illustrative example of tumor diameter in tissue sections at 6 months for Grgl transgenic mice after 4 weeks of treatment with abexinostat, ibrutinib, or the combination of abexinostat and ibrutinib.
• Each column represents one mouse sample, and the size of each tumor present in the sectioned slides for that mouse sample is given in the column.
• Each bar in the graph represents the diameter of one tumor and each group of bars represents one mouse.
• Four mice were analyzed from the control group, and two mice were analyzed for each of the drug-treated groups.
• Figure 6 Is an illustrative example of the number of tumors over 1 mm in 6 month samples from Grgl transgenic mice after 4 weeks of treatment with abexinostat, ibrutinib, or the combination of abexinostat and ibrutinib.
• Each number in the table and bar in the graph represents the number of tumors >1 mm for one mouse.
• the average number of large tumors per mouse for each treatment group is shown in the bottom row of the table and the right-most bar for each group.
• Figure 7 Is an illustrative example of whole left lung lobes from 6 month Grgl transgenic mice after 4 weeks of treatment with abexinostat, ibrutinib, or the combination of abexinostat and ibrutinib. Three large tumors and one small tumor are visible in the control sample (A); medium and small tumors are visible in Abexinostat-treated (B), Ibrutinib-treated (C) and Abexinostat + Ibrutinib-treated (D) samples.
• Figure 8 Is an illustrative example of whole lung lobes from 3 month Grgl transgenic mice after 4 weeks of treatment with abexinostat, ibrutinib, or the combination of abexinostat and ibrutinib.
• Abexinostat ibrutinib
• ibrutinib the combination of abexinostat and ibrutinib.
• Figure 9 Is a table exemplifying the effects on tumor diameter in 6 month sections of the combination of abexinostat and ibrutinib.
• the first bar is the control.
• the second bar shows the results following treatment with abexinostat alone.
• the third bar shows the results following treatment with ibrutinib alone.
• the fourth bar shows the results following treatment with abexinostat and ibrutinib.
• Figure 10 Is an illustrative example of lung tissue sections from 6 month Grgl transgenic mice after 4 weeks of treatment with abexinostat, ibrutinib, or the combination of abexinostat and ibrutinib.
• tumors in control mice exhibit lymphocyte infiltration (L), necrosis (N) and a high number of apoptotic macrophages (Figure 8A and B).
• Tumors from Abexinostat-treated mice have lymphocyte infiltration, necrosis and large areas with apoptotic cells ( Figure 8C and 8D).
• Tumors from Ibrutinib -treated mice have lymphocyte infiltration but not the apoptotic macrophages seen in the control and in Abexinostat-treated mice ( Figure 8E and 8F).
• Tumors from Abexinostat+Ibrutinib-treated mice have lymphocyte infiltration and macrophage present but not a high number of apoptotic macrophage ( Figure 8G and 8H).
• FIG 11 Is a table exemplifying the effects of the combination of abexinostat and ibrutinib is MDA-MB-453 cells (breast carcinoma), DLD-1 cells (colorectal adenocarcinoma), NCI-H460 cells (large cell lung cancer), A549 cells (lung carcinoma) and LNCap cells (prostate carcinoma).
• the combination showed synergy for MDA-MB-453 cells, weak synergy for DLD- 1 cells, additivity for NCI-H460 cells, and no additional effect for A549 and LNCaP cells.
• Figure 15 Is an illustrative example of the the effects of the combination of abexinostat and ibrutinib in A549 cells (lung carcinoma). 24781 is abexinostat and 32765 is ibrutinib.
• Figure 16 Is an illustrative example of the the effects of the combination of abexinostat and ibrutinib in LNCaP cells (prostate carcinoma). 24781 is abexinostat and 32765 is ibrutinib.
• ACK inhibitor compound e.g., a BTK inhibitor, such as for example an irreversible BTK inhibitor, such as for example ibrutinib
• HDAC inhibitor compound e.g., a BTK inhibitor, such as for example an irreversible BTK inhibitor, such as for example ibrutinib
• the ACK inhibitor compound is a compound of Formula (A).
• the ACK inhibitor compound is (R)-l-(3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4- d]pyrimidin- 1 -yl)piperidin-l -yl)p 5/ibrutinib).
• the ACK inhibitor is AVL-263 (Avila Therapeutics/Celgene
• AVL-292 (Avila Therapeutics/Celgene Corporation)
• AVL-291 (Avila
• the HDAC inhibitor is a compound of Formula (B).
• the HDAC inhibitor is 3- [(dimethylamino)methyl]-N- ⁇ 2-[4-(hydroxycarbamoyl)phenoxy]ethyl ⁇ - 1 -benzofuran-2- carboxamide (i.e. PCI-24781/abexinostat).
• ACK and "Accessible Cysteine Kinase” are synonyms. They mean a kinase with an accessible cysteine residue.
• ACKs include, but are not limited to, BTK, ITK, Bmx/ETK, TEC, EFGR, HER4, HER4, LCK, BLK, C-src, FGR, Fyn, HCK, Lyn, YES, ABL, Brk, CSK, FER, JAK3, SYK.
• the ACK is HER4.
• amelioration refers to any lessening of severity, delay in onset, slowing of growth, slowing of metastasis, or shortening of duration of a solid tumor, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the compound or composition.
• Bruton's tyrosine kinase refers to Bruton's tyrosine kinase from Homo sapiens, as disclosed in, e.g., U.S. Patent No. 6,326,469 (GenBank Accession No. NP 000052).
• Bruton's tyrosine kinase homolog refers to orthologs of Bruton's tyrosine kinase, e.g., the orthologs from mouse (GenBank Accession No. AAB47246), dog (GenBank Accession No. XP 549139.), rat (GenBank Accession No. NP 001007799), chicken (GenBank Accession No. NP 989564), or zebra fish (GenBank Accession No.
• XP 698117 fusion proteins of any of the foregoing that exhibit kinase activity towards one or more substrates of Bruton's tyrosine kinase (e.g. a peptide substrate having the amino acid sequence "AVLESEEELYSSARQ").
• HER4 also known as ERBB4, also known as "V-erb-a erythroblastic leukemia viral oncogene homolog 4" means either (a) the nucleic acid sequence encoding a receptor tyrosine kinase that is a member of the epidermal growth factor receptor subfamily, or (b) the protein thereof.
• nucleic acid sequence that comprises the human HER4 gene see GenBank Accession No. NM OO 1042599.
• amino acid sequence that comprises the human HER4 protein see GenBank Accession No. NP 001036064.
• co-administration encompass administration of an ACK inhibitor compound and an HDAC inhibitor compound to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration, in the same or a different dosage form, and at the same or different time.
• cysteine 482 is the homologous cysteine of the rat ortholog of Bruton's tyrosine kinase
• cysteine 479 is the homologous cysteine of the chicken ortholog
• cysteine 481 is the homologous cysteine in the zebra fish ortholog.
• the homologous cysteine of TXK, a Tec kinase family member related to Bruton's tyrosine is Cys 350.
• irreversible Btk inhibitor refers to an inhibitor of Btk that can form a covalent bond with an amino acid residue of Btk.
• the irreversible inhibitor of Btk can form a covalent bond with a Cys residue of Btk; in particular embodiments, the irreversible inhibitor can form a covalent bond with a Cys 481 residue (or a homolog thereof) of Btk or a cysteine residue in the homologous corresponding position of another tyrosine kinase, as shown in Fig. 7.
• pERK refers to phosphorylated ERK1 and ERK2 at
• Thr202/Tyr 204 as detected by commercially available phospho-specific antibodies (e.g. Cell Signaling Technologies #4377).
• the terms "individual”, “patient” and “subject” are used interchangeable. They refer to a mammal (e.g., a human) which is the object of treatment, or observation. The term is not to be construed as requiring the supervision of a medical practitioner (e.g., a physician, physician's assistant, nurse, orderly, hospice care worker).
• a medical practitioner e.g., a physician, physician's assistant, nurse, orderly, hospice care worker.
• treat include lessening of severity of a solid tumor, delay in onset of a solid tumor, slowing the growth of a solid tumor, slowing metastasis of cells of a solid tumor, shortening of duration of a solid tumor, arresting the development of o a solid tumor, causing regression of a solid tumor, relieving a condition caused by of a solid tumor, or stopping symptoms which result from a solid tumor.
• the terms “treat,” “treating” or “treatment”, include, but are not limited to, prophylactic and/or therapeutic treatments.
• ACK inhibitor compound e.g., a BTK inhibitor, such as for example an irreversible BTK inhibitor, such as for example ibrutinib
• HDAC inhibitor compound e.g., a BTK inhibitor, such as for example an irreversible BTK inhibitor, such as for example ibrutinib
• the ACK inhibitor compound is a compound of Formula (A).
• the ACK inhibitor compound is (R)-l-(3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4- d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one (i.e. PCI-32765/ibrutinib).
• the ACK inhibitor is AVL-263 (Avila Therapeutics/Celgene Corporation), AVL- 292 (Avila Therapeutics/Celgene Corporation), AVL-291 (Avila Therapeutics/Celgene
• BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI-1746 (CGI Pharma/Gilead Sciences), CTA-056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG- F-54930), ONO-4059 (Ono Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), or HM71224 (Hanmi Pharmaceutical Company Limited).
• the HDAC inhibitor is a compound of Formula (B). In some embodiments, the HDAC inhibitor is 3 -[(dimethyl amino)methyl]-N- ⁇ 2- [4-(hydroxycarbamoyl)phenoxy]ethyl ⁇ -l-benzofuran-2- carboxamide (i.e. PCI- 24781/abexinostat).
• a "solid tumor” is an abnormal mass of tissue resulting from the abnormal growth or division of cells (i.e., neoplasia). Solid tumors are characterized by an absence of liquid areas. In some embodiments, the solid tumor is benign. In some embodiments, the solid tumor is malignant (i.e., a cancer).
• the solid tumor is a sarcoma, or carcinoma.
• the solid tumor is a sarcoma.
• Sarcomas are cancers of the bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue.
• Sarcomas include, but are not limited to, alveolar rhabdomyosarcoma; alveolar soft part sarcoma; ameloblastoma; angiosarcoma; chondrosarcoma; chordoma; clear cell sarcoma of soft tissue; dedifferentiated liposarcoma; desmoid; desmoplastic small round cell tumor; embryonal rhabdomyosarcoma; epithelioid fibrosarcoma; epithelioid hemangioendothelioma; epithelioid sarcoma;
• esthesioneuroblastoma Ewing sarcoma; extrarenal rhabdoid tumor; extraskeletal myxoid chondrosarcoma; extrasketetal osteosarcoma; fibrosarcoma; giant cell tumor;
• hemangiopericytoma infantile fibrosarcoma; inflammatory myofibroblastic tumor; Kaposi sarcoma; leiomyosarcoma of bone; liposarcoma; liposarcoma of bone; malignant fibrous histiocytoma (MFH); malignant fibrous histiocytoma (MFH) of bone; malignant
• mesenchymoma malignant peripheral nerve sheath tumor; mesenchymal chondrosarcoma; myxofibrosarcoma; myxoid liposarcoma; myxoinflammatory fibroblastic sarcoma; neoplasms with perivascular epitheioid cell differentiation; osteosarcoma; parosteal osteosarcoma;
• neoplasm with perivascular epitheioid cell differentiation periosteal osteosarcoma; pleomorphic liposarcoma; pleomorphic rhabdomyosarcoma; PNET/extraskeletal Ewing tumor;
• rhabdomyosarcoma round cell liposarcoma; small cell osteosarcoma; solitary fibrous tumor; synovial sarcoma; telangiectatic osteosarcoma.
• the solid tumor is a carcinoma.
• Carcinomas are cancers that begin in the epithelial cells. Carcinomas are classified as adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, small cell carcinoma.
• carcinomas include , anal cancer; appendix cancer; bile duct cancer (i.e., cholangiocarcinoma); bladder cancer; brain tumor; breast cancer; cervical cancer; colon cancer; cancer of Unknown Primary (CUP); esophageal cancer; eye cancer;
• fallopian tube cancer kidney cancer; liver cancer; lung cancer; medulloblastoma; melanoma; oral cancer; ovarian cancer; pancreatic cancer; parathyroid disease; penile cancer; pituitary tumor; prostate cancer; rectal cancer; skin cancer (e.g., basal cell carcinoma, squamous cell carcinoma, malignant melanoma); stomach cancer; testicular cancer; throat cancer; thyroid cancer; uterine cancer; vaginal cancer; or vulvar cancer.
• skin cancer e.g., basal cell carcinoma, squamous cell carcinoma, malignant melanoma
• stomach cancer testicular cancer
• throat cancer thyroid cancer
• vaginal cancer vaginal cancer
• vulvar cancer e.g., basal cell carcinoma, squamous cell carcinoma, malignant melanoma
• the solid tumor is breast cancer.
• the breast cancer is invasive ductal carcinoma (e.g., triple-negative breast cancer), ductal carcinoma in situ, invasive lobular carcinoma, or lobular carcinoma in situ.
• the solid tumor is pancreatic cancer. In some embodiments, the pancreatic cancer is adenocarcinoma, or islet cell carcinoma. [0066] In some embodiments, the solid tumor is colorectal cancer. In some embodiments, the colorectal cancer is adenocarcinoma. In some embodiments, the solid tumor is a colon polyp, for example associated with familial adenomatous polyposis.
• the solid tumor is bladder cancer.
• the bladder cancer is transitional cell bladder cancer, squamous cell bladder cancer, or
• the solid tumor is lung cancer.
• the lung cancer is a non-small cell lung cancer.
• the lung cancer is a small cell lung cancer.
• the non-small cell lung cancer is adenocarcinoma, squamous-cell lung carcinoma, or large-cell lung carcinoma.
• the lung cancer is large cell lung cancer.
• the solid tumor is prostate cancer.
• the prostate cancer is adenocarcinoma or small cell carcinoma.
• the solid tumor is ovarian cancer (e.g., epithelial ovarian cancer).
• the solid tumor is bile duct cancer.
• the bile duct cancer is proximal bile duct carcinoma or distal bile duct carcinoma.
• ACK inhibitor compound e.g., a BTK inhibitor, such as for example an irreversible BTK inhibitor, such as for example ibrutinib
• HDAC inhibitor compound e.g., a BTK inhibitor, such as for example an irreversible BTK inhibitor, such as for example ibrutinib
• the ACK inhibitor compound is a compound of Formula (A).
• the ACK inhibitor compound is (R)-l-(3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4- d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one (i.e. PCI-32765/ibrutinib).
• the ACK inhibitor is AVL-263 (Avila Therapeutics/Celgene Corporation), AVL- 292 (Avila Therapeutics/Celgene Corporation), AVL-291 (Avila Therapeutics/Celgene
• BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI-1746 (CGI Pharma/Gilead Sciences), CTA-056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG- F-54930), ONO-4059 (Ono Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), or HM71224 (Hanmi Pharmaceutical Company Limited).
• the HDAC inhibitor is a compound of Formula (B). In some embodiments, the HDAC inhibitor is 3 - [(dimethyl amino)methyl]-N- ⁇ 2- [4-(hydroxycarbamoyl)phenoxy]ethyl ⁇ -l-benzofuran-2- carboxamide (i.e. PCI- 24781/abexinostat).
• the co-administration of and ACK inhibitor (e.g., ibrutinib) and an HDAC inhibitor (e.g., abexinostat) results in a synergistic effect for the treatment of a solid tumor (e.g., reduction in the number of tumors, growth/size of tumors, metastasis of tumors)
• co-administration of an ACK inhibitor (e.g., ibrutinib) and an HDAC inhibitor (e.g., abexinostat) is 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% or 60% more efficacious than administration of an HDAC inhibitor (e.g., abexinostat) alone.
• co-administration of an ACK inhibitor (e.g., ibrutinib) and an HDAC inhibitor (e.g., abexinostat) is 50% more efficacious than administration of an HDAC inhibitor (e.g., abexinostat) alone.
• co -administration of an ACK inhibitor (e.g., ibrutinib) and an HDAC inhibitor (e.g., abexinostat) is l . lx, 1.2x, 1.3x, 1.4x, 1.5x, or 1.6x more efficacious than administration of an HDAC inhibitor (e.g., abexinostat) alone.
• co -administration of an ACK inhibitor (e.g., ibrutinib) and an HDAC inhibitor (e.g., abexinostat) is 1.5x more efficacious than administration of an HDAC inhibitor (e.g., abexinostat) alone.
• co-administration of an ACK inhibitor (e.g., ibrutinib) and an HDAC inhibitor (e.g., abexinostat) is 5%, 10%, 15%, 20%, 25%, 30%, or 35% more efficacious than administration of an ACK inhibitor (e.g., ibrutinib) alone.
• coadministration of an ACK inhibitor (e.g., ibrutinib) and an HDAC inhibitor (e.g., abexinostat) is 25% more efficacious than administration of an ACK inhibitor (e.g., ibrutinib) alone.
• co -administration of an ACK inhibitor (e.g., ibrutinib) and an HDAC inhibitor (e.g., abexinostat) is l . lx, 1.15x, 1.2x, 1.25x, or 1.3x more efficacious than administration of an ACK inhibitor (e.g., ibrutinib) alone.
• co-administration of an ACK inhibitor (e.g., ibrutinib) and an HDAC inhibitor (e.g., abexinostat) is 1.25x more efficacious than administration of an ACK inhibitor (e.g., ibrutinib) alone.
• co-administration of ibrutinib and abexinostat is 5%>, 10%>, 15%>, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% or 60% more efficacious than administration of abexinostat alone. In some embodiments, co-administration of ibrutinib and abexinostat is 50% more efficacious than administration of abexinostat alone. In some embodiments, coadministration of ibrutinib and abexinostat is l .lx, 1.2x, 1.3x, 1.4x, 1.5x, or 1.6x more efficacious than administration of abexinostat alone.
• co-administration of ibrutinib and abexinostat is 1.5x more efficacious than administration of abexinostat alone.
• co-administration of ibrutinib and abexinostat is 5%, 10%, 15%, 20%, 25%, 30%, or 35% more efficacious than administration of ibrutinib alone.
• co -administration of ibrutinib and abexinostat is 25% more efficacious than administration of ibrutinib alone.
• co-administration of ibrutinib and abexinostat is l .
• co-administration of ibrutinib and abexinostat is 1.25x more efficacious than administration of ibrutinib alone.
• ACK inhibitor compound e.g., a BTK inhibitor, such as for example an irreversible BTK inhibitor, such as for example ibrutinib
• HDAC inhibitor compound e.g., a BTK inhibitor, such as for example an irreversible BTK inhibitor, such as for example ibrutinib
• the ACK inhibitor compound is a compound of Formula (A).
• the ACK inhibitor compound is (R)-l-(3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4- d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one (i.e. PCI-32765/ibrutinib).
• the ACK inhibitor is AVL-263 (Avila Therapeutics/Celgene Corporation), AVL- 292 (Avila Therapeutics/Celgene Corporation), AVL-291 (Avila Therapeutics/Celgene
• BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI-1746 (CGI Pharma/Gilead Sciences), CTA-056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG- F-54930), ONO-4059 (Ono Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), or HM71224 (Hanmi Pharmaceutical Company Limited).
• the HDAC inhibitor is a compound of Formula (B). In some embodiments, the HDAC inhibitor is 3 -[(dimethyl amino)methyl]-N- ⁇ 2- [4-(hydroxycarbamoyl)phenoxy]ethyl ⁇ -l-benzofuran-2- carboxamide (i.e. PCI- 24781/abexinostat).
• the ACK inhibitor compound (e.g., a BTK inhibitor, such as for example, an irreversible BTK inhibitor, such as for example, ibrutinib) and the HDAC inhibitor are administered in the same composition.
• the ACK inhibitor compound (e.g., a BTK inhibitor, such as for example an irreversible BTK inhibitor, such as for example ibrutinib) and the HDAC inhibitor are not administered in the same composition.
• the ACK inhibitor compound (e.g., a BTK inhibitor, such as for example an irreversible BTK inhibitor, such as for example ibrutinib) and the HDAC inhibitor are administered by different routes.
• the ACK inhibitor compound (e.g., a BTK inhibitor, such as for example an irreversible BTK inhibitor, such as for example ibrutinib) and the HDAC inhibitor are administered simultaneously or sequentially.
• the multiple therapeutic agents are optionally provided in a single, unified form, or in multiple forms (by way of example only, either as a single pill or as two separate pills).
• one of the therapeutic agents is given in multiple doses, or both are given as multiple doses. If not simultaneous, the timing between the multiple doses is from about more than zero weeks to less than about four weeks.
• the ACK inhibitor compound e.g., a BTK inhibitor, such as for example an irreversible BTK inhibitor, such as for example ibrutinib
• the HDAC inhibitor are administered in a combined dosage form, or in separate dosage forms intended for substantially simultaneous administration.
• the ACK inhibitor compound e.g., a BTK inhibitor, such as for example an irreversible BTK inhibitor, such as for example ibrutinib
• the HDAC inhibitor are administered sequentially, with either therapeutic compound being administered by a regimen calling for two-step administration.
• the two-step administration regimen calls for sequential administration of the active agents or spaced-apart administration of the separate active agents.
• the time period between the multiple administration steps ranges from a few minutes to several hours, depending upon the properties of each pharmaceutical agent, such as potency, solubility, bioavailability, plasma half-life and kinetic profile of the pharmaceutical agent.
• circadian variation of the target molecule concentration determines the optimal dose interval.
• the ACK inhibitor compound e.g., a BTK inhibitor, such as for example an
• the irreversible BTK inhibitor such as for example ibrutinib
• the HDAC inhibitor compounds described herein are administered before, during or after the development of a solid tumor.
• the ACK inhibitor compound e.g., a BTK inhibitor, such as for example an irreversible BTK inhibitor, such as for example ibrutinib
• the HDAC inhibitor compounds are used as a prophylactic and are administered continuously to subjects with a propensity to develop a solid tumor.
• the ACK inhibitor compound e.g., a BTK inhibitor, such as for example an irreversible BTK inhibitor, such as for example ibrutinib
• the HDAC inhibitor compounds are administered to an individual during or as soon as possible after the development of a solid tumor.
• the administration of the ACK inhibitor compound (e.g., a BTK inhibitor, such as for example an irreversible BTK inhibitor, such as for example ibrutinib) and the HDAC inhibitor compounds is initiated within the first 48 hours of the onset of the symptoms, within the first 6 hours of the onset of the symptoms, or within 3 hours of the onset of the symptoms.
• the initial administration of the ACK inhibitor compound e.g., a BTK inhibitor, such as for example an irreversible BTK inhibitor, such as for example ibrutinib
• the HDAC inhibitor compounds is via any route practical, such as, for example, an intravenous injection, a bolus injection, infusion over 5 minutes to about 5 hours, a pill, a capsule, transdermal patch, buccal delivery, and the like, or combination thereof.
• the ACK inhibitor compound e.g., a BTK inhibitor, such as for example an irreversible BTK inhibitor, such as for example ibrutinib
• the HDAC inhibitor compounds should be administered as soon as is practicable after the onset of a disorder is detected or suspected, and for a length of time necessary for the treatment of the disease, such as, for example, from about 1 month to about 3 months.
• the length of treatment can vary for each subject, and the length can be determined using the known criteria.
• the ACK inhibitor compound e.g., a BTK inhibitor, such as for example an irreversible BTK inhibitor, such as for example ibrutinib
• the HDAC inhibitor compounds are administered for at least 2 weeks, between about 1 month to about 5 years, or from about 1 month to about 3 years.
• Therapeutically effective amounts will depend on the severity and course of the disorder, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician. Prophalactically effective amounts depend on the patient's state of health, weight, the severity and course of the disease, previous therapy, response to the drugs, and the judgment of the treating physician.
• the ACK inhibitor compound e.g., a BTK inhibitor, such as for example an irreversible BTK inhibitor, such as for example ibrutinib
• HDAC inhibitor compounds are administered to the patient on a regular basis, e.g., three times a day, two times a day, once a day, every other day or every 3 days.
• the ACK inhibitor compound e.g., a BTK inhibitor, such as for example an irreversible BTK inhibitor, such as for example ibrutinib
• ACK inhibitor compound e.g., a BTK inhibitor, such as for example an irreversible BTK inhibitor, such as for example ibrutinib
• HDAC inhibitor compounds are administered to the patient on an intermittent basis, e.g., twice a day followed by once a day followed by three times a day; or the first two days of every week; or the first, second and third day of a week.
• intermittent dosing is as effective as regular dosing.
• the ACK inhibitor compound e.g., a BTK inhibitor, such as for example an irreversible BTK inhibitor, such as for example ibrutinib
• HDAC inhibitor compounds are administered only when the patient exhibits a particular symptom, e.g., the onset of pain, or the onset of a fever, or the onset of an inflammation, or the onset of a skin disorder. Dosing schedules of each compound may depend on the other or may be independent of the other.
• the administration of the compounds may be administered chronically, that is, for an extended period of time, including throughout the duration of the patient's life in order to ameliorate or otherwise control or limit the symptoms of the patient's disorder.
• the administration of the compounds may be given continuously; alternatively, the dose of drug being administered may be temporarily reduced or temporarily suspended for a certain length of time (i.e., a "drug holiday").
• the length of the drug holiday can vary between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days.
• the dose reduction during a drug holiday may be from 10%- 100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.
• a maintenance regimen is administered if necessary.
• the dosage or the frequency of administration, or both, of one or both of the ACK inhibitor compound e.g., a BTK inhibitor, such as for example an irreversible BTK inhibitor, such as for example ibrutinib
• HDAC inhibitor compounds can be reduced, as a function of the symptoms, to a level at which the individual's improved condition is retained.
• Individuals can, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.
• the amount of the ACK inhibitor compound e.g., a BTK inhibitor, such as for example an irreversible BTK inhibitor, such as for example ibrutinib
• HDAC inhibitor compounds will vary depending upon factors such as the particular compound, disorder and its severity, the identity (e.g., weight) of the subject or host in need of treatment, and is determined according to the particular circumstances surrounding the case, including, e.g., the specific agents being administered, the routes of administration, the solid tumor being treated, and the subject or host being treated. In general, however, doses employed for adult human treatment will typically be in the range of 0.02-5000 mg per day, or from about 1-1500 mg per day of each compound.
• the desired dose of each compound may be presented in a single dose or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub-doses per day.
• the amount of the ACK inhibitor e.g., a BTK inhibitor, such as for example an irreversible BTK inhibitor, such as for example ibrutinib
• the amount of the irreversible Btk inhibitor is from 420 mg/day up to, and including, 840 mg/day.
• the amount of the irreversible Btk inhibitor is about 420 mg/day, about 560 mg/day, or about 840 mg/day.
• the amount of the irreversible Btk inhibitor is about 420 mg/day.
• the HDAC inhibitor e.g., abexinostat
• the HDAC inhibitor is administerd for 4 consecutive days, followed by three consecutive days without administration of the HDAC inhibitor (e.g., abexinostat).
• the ACK inhibitor compound e.g., a BTK inhibitor, such as for example an
• irreversible BTK inhibitor such as for example ibrutinib
• HDAC inhibitor compounds described herein may be individually or combined into unit dosage forms suitable for single administration of precise dosages.
• the formulation is divided into unit doses containing appropriate quantities of one or both compounds.
• the unit dosage may be in the form of a package containing discrete quantities of the formulation. Non-limiting examples are packaged tablets or capsules, and powders in vials or ampoules.
• compositions can be packaged in single-dose non-reclosable containers.
• multiple- dose reclosable containers can be used, in which case it is typical to include a preservative in the composition.
• formulations for parenteral injection may be presented in unit dosage form, which include, but are not limited to ampoules, or in multi-dose containers, with an added preservative.
• ACK inhibitor compound e.g., a BTK inhibitor, such as for example an irreversible BTK inhibitor, such as for example ibrutinib
• HDAC inhibitor compound an ACK inhibitor compound
• a BTK inhibitor such as for example an irreversible BTK inhibitor, such as for example ibrutinib
• HDAC inhibitor compound an HDAC inhibitor compound
• Standard techniques are optionally used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients. Standard techniques are optionally used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection). Reactions and purification techniques are performed using documented
• the terms used for complex moieties are to be read equivalently either from left to right or right to left.
• group alkylenecycloalkylene refers both to an alkylene group followed by a cycloalkylene group or as a cycloalkylene group followed by an alkylene group.
• a methylene is a diradical of a methyl group, that is, it is a -CH 2 - group; and an ethylene is a diradical of an ethyl group, i.e.,-CH 2 CH 2 -.
• alkyl refers to an aliphatic hydrocarbon group.
• the alkyl moiety includes a "saturated alkyl” group, which means that it does not contain any alkene or alkyne moieties.
• the alkyl moiety also includes an "unsaturated alkyl” moiety, which means that it contains at least one alkene or alkyne moiety.
• An “alkene” moiety refers to a group that has at least one carbon- carbon double bond
• an “alkyne” moiety refers to a group that has at least one carbon- carbon triple bond.
• the alkyl moiety, whether saturated or unsaturated includes branched, straight chain, or cyclic moieties.
• an alkyl group includes a monoradical or a diradical (i.e., an alkylene group), and if a "lower alkyl” having 1 to 6 carbon atoms.
• Ci-C x includes Ci-C 2 , C 1 -C3 . . . Ci-C x .
• the "alkyl” moiety optionally has 1 to 10 carbon atoms (whenever it appears herein, a numerical range such as “1 to 10" refers to each integer in the given range; e.g., "1 to 10 carbon atoms” means that the alkyl group is selected from a moiety having 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term "alkyl” where no numerical range is designated).
• the alkyl group of the compounds described herein may be designated as "Ci-C 4 alkyl" or similar designations.
• C 1 -C 4 alkyl indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, iso- butyl, sec-butyl, and t-butyl.
• C1-C4 alkyl includes C1-C2 alkyl and C1-C3 alkyl.
• Alkyl groups are optionally substituted or unsubstituted.
• Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
• the alkenyl moiety is optionally branched, straight chain, or cyclic (in which case, it is also known as a "cyclo alkenyl” group).
• an alkenyl group includes a monoradical or a diradical (i.e., an alkenylene group).
• Alkenyl groups are optionally substituted.
• Alkenyl groups optionally have 2 to 10 carbons, and if a "lower alkenyl" having 2 to 6 carbon atoms.
• alkynyl refers to a type of alkyl group in which the first two atoms of the alkyl group form a triple bond. That is, an alkynyl group begins with the atoms -C ⁇ C-R, wherein R refers to the remaining portions of the alkynyl group, which is either the same or different.
• R refers to the remaining portions of the alkynyl group, which is either the same or different.
• the "R" portion of the alkynyl moiety may be branched, straight chain, or cyclic.
• an alkynyl group includes a monoradical or a diradical (i.e., an alkynylene group). Alkynyl groups are optionally substituted.
• Non-limiting examples of an alkynyl group include, but are not limited to, -C ⁇ CH, -C ⁇ CCH 3 , -C ⁇ CCH 2 CH 3 , -C ⁇ C-, and - C ⁇ CCH 2 -.
• Alkynyl groups optionally have 2 to 10 carbons, and if a "lower alkynyl" having 2 to 6 carbon atoms.
• alkoxy refers to a (alkyl)O- group, where alkyl is as defined herein.
• Hydroxyalkyl refers to an alkyl radical, as defined herein, substituted with at least one hydroxy group.
• Non-limiting examples of a hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1 -(hydroxymethyl)- 2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1- (hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and
• Alkoxyalkyl refers to an alkyl radical, as defined herein, substituted with an alkoxy group, as defined herein.
• Alkylaminoalkyl refers to an alkyl radical, as defined herein, substituted with an alkylamine, as defined herein.
• Hydroxyalkylaminoalkyl refers to an alkyl radical, as defined herein, substituted with an alkylamine, and alkylhydroxy, as defined herein.
• Alkoxyalkylaminoalkyl refers to an alkyl radical, as defined herein, substituted with an alkylamine and substituted with an alkylalkoxy, as defined herein.
• an "amide” is a chemical moiety with the formula -C(0)NHR or -NHC(0)R, where R is selected from among alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon).
• R is selected from among alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon).
• an amide moiety forms a linkage between an amino acid or a peptide molecule and a compound described herein, thereby forming a prodrug. Any amine, or carboxyl side chain on the compounds described herein can be amidified.
• esters refers to a chemical moiety with formula -COOR, where R is selected from among alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and
• Rings refers to any covalently closed structure. Rings include, for example, carbocycles (e.g., aryls and cycloalkyls), heterocycles (e.g., heteroaryls and non- aromatic heterocycles), aromatics (e.g. aryls and heteroaryls), and non-aromatics (e.g., cycloalkyls and non-aromatic heterocycles). Rings can be optionally substituted. Rings can be monocyclic or polycyclic.
• ring system refers to one, or more than one ring.
• membered ring can embrace any cyclic structure.
• membered is meant to denote the number of skeletal atoms that constitute the ring.
• cyclohexyl, pyridine, pyran and thiopyran are 6-membered rings and cyclopentyl, pyrrole, furan, and thiophene are 5 -membered rings.
• fused refers to structures in which two or more rings share one or more bonds.
• Carbocyclic or “carbocycle” refers to a ring wherein each of the atoms forming the ring is a carbon atom.
• Carbocycle includes aryl and cycloalkyl. The term thus distinguishes carbocycle from heterocycle ("heterocyclic") in which the ring backbone contains at least one atom which is different from carbon (i.e. a heteroatom).
• Heterocycle includes heteroaryl and heterocycloalkyl. Carbocycles and heterocycles can be optionally substituted.
• aromatic refers to a planar ring having a delocalized ⁇ -electron system containing 4n+2 ⁇ electrons, where n is an integer. Aromatic rings can be formed from five, six, seven, eight, nine, or more than nine atoms. Aromatics can be optionally substituted.
• aromatic includes both carbocyclic aryl (e.g., phenyl) and heterocyclic aryl (or “heteroaryl” or “heteroaromatic”) groups (e.g., pyridine).
• the term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups.
• aryl refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom.
• Aryl rings can be formed by five, six, seven, eight, nine, or more than nine carbon atoms.
• Aryl groups can be optionally substituted. Examples of aryl groups include, but are not limited to phenyl, naphthalenyl, phenanthrenyl, anthracenyl, fluorenyl, and indenyl.
• an aryl group can be a monoradical or a diradical (i.e., an arylene group).
• aryloxy refers to an (aryl)O- group, where aryl is as defined herein.
• carbonyl refers to a group containing a moiety selected from the group consisting of -C(O)-, -S(O)-, -S(0)2-, and -C(S)-, including, but not limited to, groups containing a least one ketone group, and/or at least one aldehyde group, and/or at least one ester group, and/or at least one carboxylic acid group, and/or at least one thioester group.
• Such carbonyl groups include ketones, aldehydes, carboxylic acids, esters, and thioesters. In some embodiments, such groups are a part of linear, branched, or cyclic molecules.
• cycloalkyl refers to a monocyclic or polycyclic radical that contains only carbon and hydrogen, and is optionally saturated, partially unsaturated, or fully unsaturated.
• Cycloalkyl groups include groups having from 3 to 10 ring atoms.
• Illustrative examples of cycloalkyl groups include the following moieties:
• a cycloalkyl group is either a monoradical or a diradical (e.g., an cycloalkylene group), and if a "lower cycloalkyl" having 3 to 8 carbon atoms.
• Cycloalkylalkyl means an alkyl radical, as defined herein, substituted with a cycloalkyl group.
• Non- limiting cycloalkylalkyl groups include cyclopropylmethyl,
• heterocycle refers to heteroaromatic and heteroalicyclic groups containing one to four heteroatoms each selected from O, S and N, wherein each heterocyclic group has from 4 to 10 atoms in its ring system, and with the proviso that the ring of said group does not contain two adjacent O or S atoms.
• a heterocycle e.g., Ci-C 6 heterocycle
• the heteroatom must be present in the ring.
• Designations such as "Ci-C 6 heterocycle” refer only to the number of carbon atoms in the ring and do not refer to the total number of atoms in the ring.
• heterocylic ring can have additional heteroatoms in the ring.
• Designations such as "4-6 membered heterocycle” refer to the total number of atoms that are contained in the ring (i.e., a four, five, or six membered ring, in which at least one atom is a carbon atom, at least one atom is a heteroatom and the remaining two to four atoms are either carbon atoms or heteroatoms).
• 4-6 membered heterocycle refer to the total number of atoms that are contained in the ring (i.e., a four, five, or six membered ring, in which at least one atom is a carbon atom, at least one atom is a heteroatom and the remaining two to four atoms are either carbon atoms or heteroatoms).
• heterocycles that have two or more heteroatoms those two or more
• heteroatoms can be the same or different from one another.
• Heterocycles can be optionally substituted. Binding to a heterocycle can be at a heteroatom or via a carbon atom.
• Non-aromatic heterocyclic groups include groups having only 4 atoms in their ring system, but aromatic heterocyclic groups must have at least 5 atoms in their ring system.
• the heterocyclic groups include benzo-fused ring systems.
• An example of a 4-membered heterocyclic group is azetidinyl (derived from azetidine).
• An example of a 5-membered heterocyclic group is thiazolyl.
• An example of a 6-membered heterocyclic group is pyridyl, and an example of a 10-membered heterocyclic group is quinolinyl.
• Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1 ,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, in
• aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinox
• a group derived from pyrrole includes pyrrol- 1-yl (TV- attached) or pyrrol-3-yl (C- attached).
• a group derived from imidazole includes imidazol-l-yl or imidazol-3-yl (both TV-attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-attached).
• a heterocycle group can be a monoradical or a diradical (i.e., a heterocyclene group).
• heteroaryl or, alternatively, “heteroaromatic” refers to an aromatic group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur.
• An TV- containing “heteroaromatic” or “heteroaryl” moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom.
• heteroaryl groups include the following moieties:
• a heteroaryl group can be a monoradical or a diradical (i.e., a heteroarylene group).
• a heteroarylene group i.e., a monoradical or a diradical (i.e., a heteroarylene group).
• non-aromatic heterocycle refers to a non-aromatic ring wherein one or more atoms forming the ring is a heteroatom.
• a “non-aromatic heterocycle” or “heterocycloalkyl” group refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen and sulfur. In some embodiments, the radicals are fused with an aryl or heteroaryl.
• Heterocycloalkyl rings can be formed by three, four, five, six, seven, eight, nine, or more than nine atoms. Heterocycloalkyl rings can be optionally substituted.
• non-aromatic heterocycles contain one or more carbonyl or thiocarbonyl groups such as, for example, oxo- and thio-containing groups.
• heterocycloalkyls include, but are not limited to, lactams, lactones, cyclic imides, cyclic thioimides, cyclic carbamates, tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxathiane, 1,4- oxathiin, 1 ,4-oxathiane, tetrahydro-l,4-thiazine, 2H-l,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-l,3,5-triazine, tetrahydrothio
• heterocycloalkyl groups also referred to as non-aromatic heterocycles, include:
• heteroalicyclic also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides.
• a heterocycloalkyl group can be a monoradical or a diradical (i.e., a
• halo or, alternatively, "halogen” or “halide” means fluoro, chloro, bromo and iodo.
• haloalkyl refers to alkyl structures in which at least one hydrogen is replaced with a halogen atom. In certain embodiments in which two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms are all the same as one another. In other embodiments in which two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms are not all the same as one another.
• fluoroalkyl refers to alkyl group in which at least one hydrogen is replaced with a fluorine atom.
• fluoroalkyl groups include, but are not limited to, -CF 3 , -CH 2 CF 3 , -CF 2 CF 3 , -CH 2 CH 2 CF 3 and the like.
• heteroalkyl refers to optionally substituted alkyl radicals in which one or more skeletal chain atoms is a heteroatom, e.g., oxygen, nitrogen, sulfur, silicon, phosphorus or combinations thereof.
• the heteroatom(s) are placed at any interior position of the heteroalkyl group or at the position at which the heteroalkyl group is attached to the remainder of the molecule.
• up to two heteroatoms are consecutive, such as, by way of example, -CH 2
• heteroatom refers to an atom other than carbon or hydrogen. Heteroatoms are typically independently selected from among oxygen, sulfur, nitrogen, silicon and phosphorus, but are not limited to these atoms. In embodiments in which two or more heteroatoms are present, the two or more heteroatoms can all be the same as one another, or some or all of the two or more heteroatoms can each be different from the others.
• bond refers to a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure.
• moiety refers to a specific segment or functional group of a molecule.
• Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.
• a "thioalkoxy" or “alkylthio” group refers to a -S-alkyl group.
• a "SH” group is also referred to either as a thiol group or a sulfhydryl group.
• the term "optionally substituted” or “substituted” means that the referenced group may be substituted with one or more additional group(s) individually and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, cyano, halo, acyl, nitro, haloalkyl, fluoroalkyl, amino, including mono- and di-substituted amino groups, and the protected derivatives thereof.
• the protecting groups that form the protective derivatives of the above substituents include
• ACK inhibitor compound e.g., a BTK inhibitor, such as for example an irreversible BTK inhibitor, such as for example ibrutinib
• HDAC inhibitor compound e.g., a BTK inhibitor, such as for example an irreversible BTK inhibitor, such as for example ibrutinib
• the HDAC inhibitor is a compound of Formula (B).
• the HDAC inhibitor is 3- [(dimethylamino)methyl]-N- ⁇ 2-[4-(hydroxycarbamoyl)phenoxy]ethyl ⁇ - 1 -benzofuran-2- carboxamide (i.e. PCI-24781/abexinostat).
• the ACK inhibitor compounds described herein are selective for kinases having an accessible cysteine that is able to form a covalent bond with a Michael acceptor moiety on the inhibitor compound.
• the cysteine residue is accessible or becomes accessible when the binding site moiety of the irreversible inhibitor binds to the kinase.
• the binding site moiety of the irreversible inhibitor binds to an active site of the ACK and the Michael acceptor moiety of irreversible inhibitor gains access (in one embodiment the step of binding leads to a conformational change in the ACK, thus exposing the cysteine) or is otherwise exposed to the cysteine residue of the ACK; as a result a covalent bond is formed between the "S" of the cysteine residue and the Michael acceptor of the irreversible inhibitor. Consequently, the binding site moiety of the irreversible inhibitor remains bound or otherwise blocks the active site of the ACK.
• the ACK is Btk, a homolog of Btk or a tyrosine kinase having a cysteine residue in an amino acid sequence position that is homologous to the amino acid sequence position of cysteine 481 in Btk.
• the ACK is HER4.
• Inhibitor compounds described herein include a Michael acceptor moiety, a binding site moiety and a linker that links the binding site moiety and the Michael acceptor moiety (and in some embodiments, the structure of the linker provides a conformation, or otherwise directs the Michael acceptor moiety, so as to improve the selectivity of the irreversible inhibitor for a particular ACK).
• the ACK inhibitor is a compound of Formula (A):
• A is independently selected from N or CR 5 ;
• R 2 and R 3 are independently selected from H, lower alkyl and substituted lower alkyl
• R 4 is L 3 -X-L 4 -G, wherein,
• L 3 is optional, and when present is a bond, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted alkynyl;
• R 6 , R7 and R 8 are independently selected from among H, lower alkyl or substituted lower alkyl, lower heteroalkyl or substituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, and substituted or unsubstituted lower heterocycloalkyl;
• R 5 is H, halogen, ⁇ -(substituted or unsubstituted C 1 -C3 alkyl), ⁇ -(substituted or
• each R is independently selected from among H, substituted or unsubstituted lower alkyl, and substituted or unsubstituted lower cycloalkyl;
• each Rio is independently H, substituted or unsubstituted lower alkyl, or substituted or
• two Rio groups can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring;
• R and Rio can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring
• the ACK inhibitor is R)-l-(3-(4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one (i.e. PCI-32765/ibrutinib) . .
• the ACK inhibitor is AVL-263 (Avila Therapeutics/Celgene Corporation), AVL-292 (Avila Therapeutics/Celgene Corporation), AVL-291 (Avila
• the ACK inhibitor is 4-(tert-butyl)-N-(2-methyl-3-(4-methyl-6- ((4-(morpholine-4-carbonyl)phenyl)amino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)benzamide (CGI-1746); 7-benzyl-l-(3-(piperidin-l-yl)propyl)-2-(4-(pyridin-4-yl)phenyl)-lH-imidazo[4,5- g]quinoxalin-6(5H)-one (CTA-056); (R)-N-(3-(6-(4-(l ,4-dimethyl-3-oxopiperazin-2- yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7- tetrahydrobenzo[b
• the ACK inhibitor is:
• ACK inhibitor compound e.g., a BTK inhibitor, such as for example an irreversible BTK inhibitor, such as for example ibrutinib
• HDAC inhibitor compound e.g., a BTK inhibitor, such as for example an irreversible BTK inhibitor, such as for example ibrutinib
• the ACK inhibitor compound is a compound of Formula (A).
• the ACK inhibitor compound is (R)-l-(3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4- d]pyrimidin- 1 -yl)piperidin-l -yl)p 5/ibrutinib).
• the ACK inhibitor is AVL-263 (Avila Therapeutics/Celgene
• AVL-292 (Avila Therapeutics/Celgene Corporation), AVL-291 (Avila Therapeutics/Celgene Corporation), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CTA-056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono Pharmaceutical Co., Ltd.), ONO- WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), or HM71224 (Hanmi Pharmaceutical Company Limited).
• the HDAC inhibitor has the structure of Formula (B):
• Pv 1 is hydrogen or alkyl
• X is -0-, -NR -, or -S(0) n where n is 0-2 and R is hydrogen or alkyl;
• Y is alkylene optionally substituted with cycloalkyl, optionally substituted phenyl, alkylthio, alkylsulfmyl, alkysulfonyl, optionally substituted phenylalkylthio, optionally substituted phenylalkylsulfonyl, hydroxy, or optionally substituted phenoxy;
• Ar 1 is phenylene or heteroarylene wherein said Ar 1 is optionally substituted with one or two groups independently selected from alkyl, halo, hydroxy, alkoxy, haloalkoxy, or haloalkyl; R is hydrogen, alkyl, hydroxyalkyl, or optionally substituted phenyl; and
• Ar is aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl;
• the histone deacetylase inhibitor is 3-((dimethylamino)methyl)- N-(2-(4-(hydroxycarbamoyl)phenoxy)ethyl)benzofuran-2-carboxamide (i.e. PCI- 24781/abexinostat).
• compositions comprising a
• compositions comprising a therapeutically effective amount of an ACK inhibitor compound, a therapeutically effective amount of an HDAC inhibitor compound, and a pharmaceutically acceptable excipient.
• the ACK inhibitor compound e.g., a BTK inhibitor, such as for example an irreversible BTK inhibitor, such as for example ibrutinib
• the ACK inhibitor compound is a compound of Formula (A).
• the ACK inhibitor compound is (R)-l-(3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4- d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one (i.e. PCI-32765/ibrutinib).
• the ACK inhibitor is AVL-263 (Avila Therapeutics/Celgene Corporation), AVL- 292 (Avila Therapeutics/Celgene Corporation), AVL-291 (Avila Therapeutics/Celgene
• BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI-1746 (CGI Pharma/Gilead Sciences), CTA-056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG- F-54930), ONO-4059 (Ono Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), or HM71224 (Hanmi Pharmaceutical Company Limited).
• the HDAC inhibitor is a compound of Formula (B). In some embodiments, the HDAC inhibitor is 3 -[(dimethyl amino)methyl]-N- ⁇ 2- [4-(hydroxycarbamoyl)phenoxy]ethyl ⁇ -l-benzofuran-2- carboxamide (i.e. PCI- 24781/abexinostat).
• compositions of ACK inhibitor compound e.g., a BTK inhibitor, such as for example an irreversible BTK inhibitor, such as for example ibrutinib
• HDAC inhibitor compound e.g., a BTK inhibitor, such as for example an irreversible BTK inhibitor, such as for example ibrutinib
• ACK inhibitor compound e.g., a BTK inhibitor, such as for example an irreversible BTK inhibitor, such as for example ibrutinib
• HDAC inhibitor compound e.g., a BTK inhibitor, such as for example an irreversible BTK inhibitor, such as for example ibrutinib
• HDAC inhibitor compound e.g., a BTK inhibitor, such as for example an irreversible BTK inhibitor, such as for example ibrutinib
• HDAC inhibitor compound e.g., a BTK inhibitor, such as for example an irreversible BTK inhibitor, such as for example ibrutinib
• HDAC inhibitor compound
• a pharmaceutical composition refers to a mixture of an ACK inhibitor compound (e.g., a BTK inhibitor, such as for example an irreversible BTK inhibitor, such as for example ibrutinib) and/or HDAC inhibitor compound with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
• a BTK inhibitor such as for example an irreversible BTK inhibitor, such as for example ibrutinib
• HDAC inhibitor compound e.g., HDAC inhibitor compound with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
• compositions are optionally manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.
• compositions described herein are administered by any suitable administration route, including but not limited to, oral, parenteral (e.g., intravenous,
• compositions described herein are formulated into any suitable dosage form, including but not limited to, aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries, suspensions and the like, for oral ingestion by an individual to be treated, solid oral dosage forms, aerosols, controlled release formulations, fast melt formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate release and controlled release formulations.
• the compositions are formulated into capsules.
• the compositions are formulated into solutions (for example, for IV administration).
• the pharmaceutical solid dosage forms described herein optionally include a compound described herein and one or more pharmaceutically acceptable additives such as a compatible carrier, binder, filling agent, suspending agent, flavoring agent, sweetening agent, disintegrating agent, dispersing agent, surfactant, lubricant, colorant, diluent, solubilizer, moistening agent, plasticizer, stabilizer, penetration enhancer, wetting agent, anti-foaming agent, antioxidant, preservative, or one or more combination thereof.
• a compatible carrier such as a compatible carrier, binder, filling agent, suspending agent, flavoring agent, sweetening agent, disintegrating agent, dispersing agent, surfactant, lubricant, colorant, diluent, solubilizer, moistening agent, plasticizer, stabilizer, penetration enhancer, wetting agent, anti-foaming agent, antioxidant, preservative, or one or more combination thereof.
• compositions are formulated into particles (for example for administration by capsule) and some or all of the particles are coated.
• the compositions are formulated into particles (for example for administration by capsule) and some or all of the particles are microencapsulated.
• the compositions are formulated into particles (for example for administration by capsule) and some or all of the particles are not microencapsulated and are uncoated.
• the pharmaceutical compositions are formulated such that the amount of the ACK inhibitor (e.g., a BTK inhibitor, such as for example an irreversible BTK inhibitor, such as for example ibrutinib) in each unit dosage form is about 140 mg per.
• a BTK inhibitor such as for example an irreversible BTK inhibitor, such as for example ibrutinib
• ACK inhibitor compound e.g., a BTK inhibitor, such as for example an irreversible BTK inhibitor, such as for example ibrutinib
• HDAC inhibitor compound e.g., a BTK inhibitor, such as for example an irreversible BTK inhibitor, such as for example ibrutinib
• the ACK inhibitor compound is a compound of Formula (A).
• the ACK inhibitor compound is (R)-l-(3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4- d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one (i.e. PCI-32765/ibrutinib).
• the ACK inhibitor is AVL-263 (Avila Therapeutics/Celgene Corporation), AVL- 292 (Avila Therapeutics/Celgene Corporation), AVL-291 (Avila Therapeutics/Celgene
• BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI-1746 (CGI Pharma/Gilead Sciences), CTA-056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG- F-54930), ONO-4059 (Ono Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), or HM71224 (Hanmi Pharmaceutical Company Limited).
• the HDAC inhibitor is a compound of Formula (B).
• the HDAC inhibitor is 3 -[(dimethyl amino)methyl]-N- ⁇ 2- [4-(hydroxycarbamoyl)phenoxy]ethyl ⁇ -l-benzofuran-2- carboxamide (i.e. PCI- 24781/abexinostat).
• kits and articles of manufacture are also described herein.
• such kits include a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) including one of the separate elements to be used in a method described herein.
• Suitable containers include, for example, bottles, vials, syringes, and test tubes.
• the containers can be formed from a variety of materials such as glass or plastic.
• the articles of manufacture provided herein contain packaging materials.
• packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment.
• a wide array of formulations of the compounds and compositions provided herein are contemplated as are a variety of treatments for any disorder that benefit by inhibition of Btk, or in which Btk is a mediator or contributor to the symptoms or cause.
• a container may include one or both of the irreversible BTK inhibitor and HDAC inhibitor compounds.
• the container(s) optionally have a sterile access port (for example the container is an intravenous solution bag or a vial having a stopper pierceable by a
• kits optionally comprising a compound with an identifying description or label or instructions relating to its use in the methods described herein.
• a kit will typically include one or more additional containers, each with one or more of various materials (such as reagents, optionally in concentrated form, and/or devices) desirable from a commercial and user standpoint for use of a compound described herein.
• materials include, but not limited to, buffers, diluents, filters, needles, syringes; carrier, package, container, vial and/or tube labels listing contents and/or instructions for use, and package inserts with instructions for use.
• a set of instructions will also typically be included.
• a label is on or associated with the container.
• a label can be on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself; a label can be associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert.
• a label can be used to indicate that the contents are to be used for a specific therapeutic application. The label can also indicate directions for use of the contents, such as in the methods described herein.
• a pharmaceutical composition comprising one or both the ACK inhibitor compound (e.g., a BTK inhibitor, such as for example an irreversible BTK inhibitor, such as for example ibrutinib) and the HDAC inhibitor compounds is presented in a pack or dispenser device which can contain one or more unit dosage forms.
• the pack can for example contain metal or plastic foil, such as a blister pack.
• the pack or dispenser device can be accompanied by instructions for administration.
• the pack or dispenser can also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration.
• compositions containing a compound provided herein formulated in a compatible pharmaceutical carrier can also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
• the aim of the experiment is to evaluate the effect of two drugs on tumor development in a mouse model of non-small cell lung cancer.
• Grgl transgenic mice were used to evaluate the drugs.
• mice overexpress the Groucho -related gene 1 (Grgl).
• the mice develop lung tumors that resemble human non-small cell lung cancer. Tumors initiate at 1 month of age and progress to invasive adenocarcinoma by 8 months of age.
• the drugs were administered to 2 month-old mice or to 5 month-old mice, and mice were treated for 4 weeks.
• the former group is referred to as the 3 month samples and the latter as the 6 month samples.
• mice were housed and treated following the applicable Standard Operating Procedures and according to the Canadian Animal Care Committee standards. [00171] Mice were bred to generate double transgenic (Grgl/Cre recombinase) mice on a CD1 background. Four groups of female double transgenic mice were established:
• Group 1 - Control no treatment, injection of PBS, or water with carrier and no drug
• mice in each group were treated at 2 months old and 8 mice in each group were treated at 5 months old. Treatments lasted 4 weeks, and mice were sacrificed at 3 months and 6 months. Therefore samples are referred to as 3 month samples or 6 month samples.
• Abexinostat was administered by intraperitoneal (i.p.) injection, twice per day for five days each week. Mice were weighed and injected with 6 ⁇ per gram body weight of a 1 mg/ml solution. The dosage was 12 mg/kg BID.
• Ibrutinib was administered by supplying it in the drinking water, for a dosage of ⁇ 22 mg/kg/day.
• mice were treated for 4 weeks. After treatment, mice were euthanized and lung tissue was examined.
• Formulation Add DMSO to powder stock in vial to make a 200mg/ml solution. Aliquot out into 100 ⁇ . Every two weeks, as required, thaw a 100 ⁇ aliquot and add 900 ⁇ sterile water. Aliquot into 20 ⁇ aliquots of 20 mg/ml. Store this stock at 4 C.
• Formulation 100 ml of the lOx concentrate of Ibrutinib. Dilute 1 part of concentrate with 9 parts water. Both the lOx and lx dilutions can be stored at room temperature. PCI-32765 is >99% stable in this formulation after 6 weeks at room temperature (22°C).
• the total visible tumors on the lung surface were counted using a dissecting microscope.
• the left lung lobe was fixed in 4% PFA, paraffin- embedded and 5 ⁇ sections were taken for 100 ⁇ at two levels. The first level began 30 ⁇ below the lung surface and the second level began 130 ⁇ below the lung surface. Alternate slides were H&E stained, and tumors were detected and counted using a dissecting microscope. Tumor diameter was measured using an inverted microscope and reticule.
• the right lung lobes were snap-frozen and stored for DNA or protein analysis.
• PBMC peripheral blood mononuclear cells
• Tumors in the 3 month samples were further analyzed for four mice in each treatment group by sectioning the left lung lobe, and H&E staining alternate slides.
• the tumor histology is presented in Figure 3 and all images are available on disk.
• the tumors are carcinoma that are less than 400 ⁇ .
• the tumor histology appears similar in treated and control mice.
• the tumors were further analyzed for two to four mice in each group by sectioning the left lung lobe, and H&E staining alternate slides. To measure and compare the tumor load in the mice in the 6 month samples, the tumor diameter in the tissue sections was measured. The number of tumors in the sections and the size of each tumor is recorded in the table and corresponding bar graph in Figure 5. Each column in the table and group of bars in the graph shows the tumor sizes for one mouse.
• mice had fewer large tumors than the control mice.
• the number of tumors over 1 mm in diameter for each mouse is shown in Figure 6.
• Control mice had an average of 1.5 large tumors per mouse
• Abexinostat- and Ibrutinib-treated mice had an average of 0.5 large tumors per mouse
• Abexinostat+Ibrutinib-treated mice had 0 large tumors per mouse.
• the tumor number is variable, but in treated mice the number of large tumors (over 1 mm) is much lower.
• the drugs also appear to act synergistically at this stage to reduce the number of large tumors.
• the tumors for control and treated mice have lymphocyte infiltration.
• tumors in mice receiving Abexinostat have a high number of apoptotic cells.
• Tumors in mice receiving Ibrutinib lack the high number of apoptotic macrophages seen in the control and Abexinostat-treated mice, and have less tumor necrosis than the control samples.
• Intervention Model Single Group Assignment
• Patients will be treated three times daily ibrutinib (140 mg/dose) and once daily with abexinostat for 4 consecutive days, followed by 3 days off of abexinostat (a cycle is 7 days). At day 1 of each cycle a physical exam and blood work will be performed. Reassessment of tumor size will be conducted at 6 weeks, 12 weeks and then every 9 weeks thereafter. Patients will remain on treatment until one of the following occur: disease progression, illness that prevents further treatment or unacceptable adverse events.
• Clinically significant cardiac disease e.g. congestive heart failure, symptomatic coronary artery disease and cardiac arrhythmias not well controlled with medication or heart attack within the last 12 months).
• Patients will be treated three times daily ibrutinib (140 mg/dose) and once daily with abexinostat for 4 consecutive days, followed by 3 days off of abexinostat (a cycle is 7 days). At day 1 of each cycle a physical exam and blood work will be performed. Reassessment of tumor size will be conducted at 6 weeks, 12 weeks and then every 9 weeks thereafter. Patients will remain on treatment until one of the following occur: disease progression, illness that prevents further treatment or unacceptable adverse events.
• Randomization must occur during the three-week interval beginning on postoperative day 29 and ending on postoperative day 50
• Patients must have histologically confirmed adenocarcinoma of the colon that meets one of the following criteria: Stage II carcinoma (T3,4 NO M0); the tumor invades through the muscularis intestinal into the subserosa or into non-peritonealized consic or perirectal tissues (T3); or directly invades other organs or structures, and/or perforates visceral peritoneum (T4); Stage III carcinoma (any T Nl,2 MO); the tumor has invaded to any depth, with involvement of regional lymph nodes
• T4 tumors that have involved an adjacent structure (e.g., bladder, small intestine, ovary, etc.) by direct extension from the primary tumor are eligible if all of the following conditions are met: All or a portion of the adjacent structure was removed en bloc with the primary tumor; In the opinion of the surgeon, all grossly visible tumor was completely resected ("curative resection"); Histologic evaluation by the pathologist confirms the margins of the resected specimen are not involved by malignant cells; and Local radiation therapy will not be utilized
• Alkaline phosphatase must be ⁇ 2.5 x ULN for the lab
• AST must be ⁇ 1.5 x ULN for the lab. If AST is > ULN, serologic testing for hepatitis B and C must be performed and results must be negative
• Serum creatinine ⁇ 1.5 x ULN for the lab
• Urine protein/creatinine (UPC) ratio of ⁇ 1.0; patients with a UPC ratio > 1.0 must undergo a 24-hour urine collection, which must be an adequate collection and must demonstrate
• Rectal tumors i.e. a tumor located ⁇ 12 cm from the anal verge on endoscopy, or by surgical exam if the patient is not a candidate for endoscopy
• Invasive procedures defined as follows: Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to randomization; Anticipation of need for major surgical procedures during the course of the study; Core biopsy or other minor procedure, excluding placement of a vascular access device, within 7 days prior to randomization
• Uncontrolled blood pressure defined as > 150/90 mmHg
• Non-malignant systemic disease (cardiovascular, renal, hepatic, etc.) that would preclude any of the study therapy drugs; specifically excluded are the following cardiac conditions: New York Heart Association Class III or IV cardiac disease; History of myocardial infarction within 12 months before study entry; Unstable angina within 12 months before study entry; and Symptomatic arrhythmia
• Intervention Model Single Group Assignment
• Patients will be treated three times daily ibrutinib (140 mg/dose) and once daily with abexinostat for 4 consecutive days, followed by 3 days off of abexinostat (a cycle is 7 days). At day 1 of each cycle a physical exam and blood work will be performed. Reassessment of tumor size will be conducted at 6 weeks, 12 weeks and then every 9 weeks thereafter. Patients will remain on treatment until one of the following occur: disease progression, illness that prevents further treatment or unacceptable adverse events.
• Patients must have breast and/or epithelial ovarian cancer, primary peritoneal cancer, and/or fallopian tube cancer histologically or cytologically confirmed at the NCI that is metastatic or unresectable and for which standard curative measures do not exist or are no longer effective.
• Patients must have normal organ and marrow function defined as follows: hemoglobin greater than or equal to lOg/dL; leukocytesgreater than or equal to 3,000/mcL; absolute neutrophil count greater than or equal to 1,500/mcL; platelets greater than or equal to
• Group B For patients enrolling in the sporadic serous epithelial ovarian cancer group, Group B, a negative family history (BRCAPRO score less than or equal to 20% or negative BRCA 1/2 mutation test).
• Group B For patients enrolling in the triple negative breast cancer (ER-/PR- /Her2-) group, Group B, a negative family history and /or BRCAPRO score less than or equal to 10% or negative BRCA 1/2 mutation test).
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD2281.
• these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy such as carboplatin.
• TCC No prior upper tract TCC
• TCC No history of grade 3 TCC, carcinoma in situ including severe dysplasia, non-TCC histology, or TCC greater than or equal to T2
• irPFS is defined as the time between the randomization date and date of immune -related Progressive Disease (irPD) (at least 25% increase percentage change in total tumor burden, including new lesions) or death, whichever occurs first.
• irPFS is censored at randomization. Participant who die without reported irPD are considered to have progressed on the date of death. For those who remain alive and have no irPD, irPFS is censored on the date of last evaluable tumor assessment.
• Patients will be treated three times daily ibrutinib (140 mg/dose) and once daily with abexinostat for 4 consecutive days, followed by 3 days off of abexinostat (a cycle is 7 days). At day 1 of each cycle a physical exam and blood work will be performed. Reassessment of tumor size will be conducted at 6 weeks, 12 weeks and then every 9 weeks thereafter. Patients will remain on treatment until one of the following occur: disease progression, illness that prevents further treatment or unacceptable adverse events.
• Measurable tumor lesion (as long as it is not located in a previously irradiated area) as defined by modified World Health Organization criteria
• Inadequate hematologic function defined by an absolute neutrophil count ⁇ l,500/mm A 3, a platelet count ⁇ 100,000/mm A 3, or hemoglobin level ⁇ 9 g/dL.
• Inadequate hepatic function defined by a total bilirubin level >2.0 times the upper limit of normal (ULN), or >2.5 times the ULN if liver metastases are present, aspartate
• aminotransferase and alanine aminotransferase levels >2.5 times the ULN or >5 times the ULN if liver metastases are present.
• Intervention Model Single Group Assignment
• Patients will be treated three times daily ibrutinib (140 mg/dose) and once daily with abexinostat for 4 consecutive days, followed by 3 days off of abexinostat (a cycle is 7 days). At day 1 of each cycle a physical exam and blood work will be performed. Reassessment of tumor size will be conducted at 6 weeks, 12 weeks and then every 9 weeks thereafter. Patients will remain on treatment until one of the following occur: disease progression, illness that prevents further treatment or unacceptable adverse events.
• PSA-only progression despite androgen deprivation therapy PSA progression is defined as 3 rising levels, with a minimum interval of 2 weeks between each determination. The last determination must have a minimum value of lng/ml and be determined within two weeks prior to registration. If the second or third confirmatory value is less than the previous value, the patient will still be eligible if a repeat value (No. 4) is found to be greater than all the prior values.
• PSA progression after withdrawal period 28 days for flutamide and 42 days for bicalutamide or nilutamide is required.
• Inadequately controlled hypertension (defined as systolic blood pressure >150 and/or diastolic blood pressure > 100 mmHg on antihypertensive medications).
• vascular disease e.g., aortic aneurysm, aortic dissection.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Patients will be treated three times daily ibrutinib (140 mg/dose) and once daily with abexinostat for 4 consecutive days, followed by 3 days off of abexinostat (a cycle is 7 days). At day 1 of each cycle a physical exam and blood work will be performed. Reassessment of tumor size will be conducted at 6 weeks, 12 weeks and then every 9 weeks thereafter. Patients will remain on treatment until one of the following occur: disease progression, illness that prevents further treatment or unacceptable adverse events.
• cholangiocarcinoma Histologically and cytologically proven cholangiocarcinoma of any type (including intrahepatic cholangiocarcinoma, extrahepatic primary cholangiocarcinoma, hilar
• cholangiocarcinomas cholangiocarcinomas located in the gall bladder or hepatic capsule effraction, and carcinoma of the Ampulla of Vater, etc.
• chemotherapies such as gemcitabine with or without platinum
• WBC White blood cell
• Bilirubin ⁇ 1.5 x UNL
• Serum creatinine ⁇ 2.0 mg/dL or 177 ⁇ /L
• Active heart disease including but not limited to symptomatic congestive heart failure, symptomatic coronary artery disease, symptomatic angina pectoris, symptomatic myocardial infarction, arrhythmias requiring medication, or symptomatic congestive heart failure; also patients with a history of myocardial infarction that is ⁇ 1 year prior to registration, or patients with previous congestive heart failure ( ⁇ 1 year prior to registration) requiring pharmacologic support or with left ventricular ejection fraction ⁇ 50%)
• QTc QT/corrected QT
• a history of additional risk factors for torsade de pointes e.g., heart failure, hypokalemia, family history of long QT syndrome
• Intervention Model Single Group Assignment
• Patients will be treated three times daily ibrutinib (140 mg/dose) and once daily with abexinostat for 4 consecutive days, followed by 3 days off of abexinostat (a cycle is 7 days). At day 1 of each cycle a physical exam and blood work will be performed. Reassessment of tumor size will be conducted at 6 weeks, 12 weeks and then every 9 weeks thereafter. Patients will remain on treatment until one of the following occur: disease progression, illness that prevents further treatment or unacceptable adverse events. Eligibility

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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

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• 2014
  • 2014-08-01 EP EP14831872.8A patent/EP3027192A4/en not_active Withdrawn
  • 2014-08-01 US US14/450,068 patent/US9421208B2/en active Active
  • 2014-08-01 CA CA2919996A patent/CA2919996A1/en not_active Abandoned
  • 2014-08-01 AR ARP140102910A patent/AR097204A1/es unknown
  • 2014-08-01 JP JP2016531935A patent/JP6800750B2/ja not_active Expired - Fee Related
  • 2014-08-01 TW TW103126513A patent/TWI649081B/zh not_active IP Right Cessation
  • 2014-08-01 WO PCT/US2014/049459 patent/WO2015017812A1/en not_active Ceased

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