US2016287569A1PendingUtilityA1

Combination therapy including an mdm2 inhibitor and one or more additional pharmaceutically active agents for the treatment of cancers

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Assignee: AMGEN INCPriority: Nov 11, 2013Filed: Nov 11, 2014Published: Oct 6, 2016
Est. expiryNov 11, 2033(~7.3 yrs left)· nominal 20-yr term from priority
Inventors:Sean CaenepeelJude Robert CanonPaul HughesJonathan Daniel OlinerAnne Y. SaikiRichard J. Rickles
A61P 35/02A61K 31/704A61K 31/4045A61K 31/506A61K 31/7048A61K 31/519A61K 31/5025A61K 31/635A61K 31/451A61K 31/706A61K 31/4439A61K 45/00A61K 31/496A61K 31/365A61K 31/7068A61K 31/437A61K 31/166A61K 31/44A61K 31/45A61K 9/0019A61K 9/0053A61P 1/00A61P 35/00A61P 1/16A61K 2300/00A61P 17/00A61P 43/00A61P 13/12A61P 13/10A61P 11/00A61K 45/06
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Claims

Abstract

The present invention provides combination therapy that includes an MDM2 inhibitor and one or more additional pharmaceutically active agents, particularly for the treatment of cancers. The invention also relates to pharmaceutical compositions that contain an MDM2 inhibitor and one or more additional pharmaceutically active agents for the treatment of cancers.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A method of treating melanoma, the method comprising administering to a patient in need thereof a therapeutically effective amount of an MDM2 inhibitor and a BRAF inhibitor. 
     
     
         2 . A method of treating colon cancer, the method comprising administering to a patient in need thereof a therapeutically effective amount of an MDM2 inhibitor and a BRAF inhibitor. 
     
     
         3 . The method of  claim 2  wherein the colon cancer has a BRAF V600E or V600K mutation. 
     
     
         4 . A method of treating liver cancer, the method comprising administering to a patient in need thereof a therapeutically effective amount of an MDM2 inhibitor and a BRAF inhibitor. 
     
     
         5 . A method of treating melanoma, the method comprising administering to a patient in need thereof a therapeutically effective amount of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid, dabrafenib and trametinib. 
     
     
         6 . A method of treating melanoma, the method comprising administering to a patient in need thereof a therapeutically effective amount of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid, and dabrafenib. 
     
     
         7 . The method of any one of  claims 1 ,  5  to  6  wherein the melanoma has a BRAF V600E or V600K mutation. 
     
     
         8 . The method of any one of  claims 1 - 4  and  7 , wherein the BRAF inhibitor is dabrafenib. 
     
     
         9 . The method of any one of  claim 1 - 4  or  7 , wherein the BRAF inhibitor is AMG 2112819 or vemurafenib. 
     
     
         10 . A method of treating melanoma, the method comprising administering to a patient in need thereof a therapeutically effective amount of an MDM2 inhibitor and a MEK inhibitor. 
     
     
         11 . A method of treating colon cancer, the method comprising administering to a patient in need thereof a therapeutically effective amount of an MDM2 inhibitor and a MEK inhibitor. 
     
     
         12 . A method of treating liver cancer, the method comprising administering to a patient in need thereof a therapeutically effective amount of an MDM2 inhibitor and a MEK inhibitor. 
     
     
         13 . The method of  claim 12  wherein the liver cancer has a BRAF V600E or V600K mutation. 
     
     
         14 . A method of treating bladder cancer, the method comprising administering to a patient in need thereof a therapeutically effective amount of an MDM2 inhibitor and a MEK inhibitor. 
     
     
         15 . A method of treating AML, the method comprising administering to a patient in need thereof a therapeutically effective amount of an MDM2 inhibitor and a MEK inhibitor. 
     
     
         16 . The method of  claim 15  wherein the AML has a FLT3-ITD mutation. 
     
     
         17 . A method of treating NSCLC, the method comprising administering to a patient in need thereof a therapeutically effective amount of an MDM2 inhibitor and a MEK inhibitor. 
     
     
         18 . The method of  claim 17  wherein the NSCLC had a KRAS mutation. 
     
     
         19 . A method of treating kidney cancer, the method comprising administering to a patient in need thereof a therapeutically effective amount of an MDM2 inhibitor and a MEK inhibitor. 
     
     
         20 . A method of treating stomach cancer, the method comprising administering to a patient in need thereof a therapeutically effective amount of an MDM2 inhibitor and a MEK inhibitor. 
     
     
         21 . The method of any one of  claims 10  to  20  wherein the MEK inhibitor is trametinib. 
     
     
         22 . The method of any one of  claims 10  to  20  wherein the MEK inhibitor is pimasertib, PD0325901, MEK162, TAK-733, GDC-0973 or AZD8330. 
     
     
         23 . The method of  claim 20  wherein the stomach cancer has a KRAS mutation. 
     
     
         24 . A method of treating AML, the method comprising administering to a patient in need thereof a therapeutically effective amount of an MDM2 inhibitor and ponatinib. 
     
     
         25 . The method of  claim 24  wherein the AML has a FLT3 ITD mutation. 
     
     
         26 . A method of treating AML, the method comprising administering to a patient in need thereof a therapeutically effective amount of an MDM2 inhibitor and bosutinib. 
     
     
         27 . The method of  claim 26  wherein the AML has a FLT3 ITD mutation 
     
     
         28 . A pharmaceutical composition comprising: 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid, or a pharmaceutically acceptable salt thereof; dabrafenib; and a pharmaceutically acceptable excipient. 
     
     
         29 . A pharmaceutical composition comprising: 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid, or a pharmaceutically acceptable salt thereof; trametinib; and a pharmaceutically acceptable excipient. 
     
     
         30 . A pharmaceutical composition comprising: 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid, or a pharmaceutically acceptable salt thereof; nilotinib; and a pharmaceutically acceptable excipient. 
     
     
         31 . A pharmaceutical composition comprising: 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid, or a pharmaceutically acceptable salt thereof; pimasertinib; and a pharmaceutically acceptable excipient. 
     
     
         32 . A pharmaceutical composition comprising: 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid, or a pharmaceutically acceptable salt thereof; PD0325901; and a pharmaceutically acceptable excipient. 
     
     
         33 . A pharmaceutical composition comprising: 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid, or a pharmaceutically acceptable salt thereof; vemurafenib; and a pharmaceutically acceptable excipient. 
     
     
         34 . A pharmaceutical composition comprising: 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid, or a pharmaceutically acceptable salt thereof; navitoclax; and a pharmaceutically acceptable excipient. 
     
     
         35 . A pharmaceutical composition comprising: 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid, or a pharmaceutically acceptable salt thereof; dasatinib; and a pharmaceutically acceptable excipient. 
     
     
         36 . A pharmaceutical composition comprising: 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid, or a pharmaceutically acceptable salt thereof; panobinostat; and a pharmaceutically acceptable excipient. 
     
     
         37 . A pharmaceutical composition comprising: 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid, or a pharmaceutically acceptable salt thereof; decitabine; and a pharmaceutically acceptable excipient. 
     
     
         38 . A pharmaceutical composition comprising: 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid, or a pharmaceutically acceptable salt thereof; cytarabine; and a pharmaceutically acceptable excipient. 
     
     
         39 . A pharmaceutical composition comprising: 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid, or a pharmaceutically acceptable salt thereof; doxorubicin; and a pharmaceutically acceptable excipient. 
     
     
         40 . A pharmaceutical composition comprising: 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid, or a pharmaceutically acceptable salt thereof; etoposide; and a pharmaceutically acceptable excipient. 
     
     
         41 . A pharmaceutical composition comprising: 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid, or a pharmaceutically acceptable salt thereof; imatinib; and a pharmaceutically acceptable excipient. 
     
     
         42 . A pharmaceutical composition comprising: 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid, or a pharmaceutically acceptable salt thereof; ponatinib; and a pharmaceutically acceptable excipient. 
     
     
         43 . A pharmaceutical composition comprising: 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid, or a pharmaceutically acceptable salt thereof; bosutinib; and a pharmaceutically acceptable excipient. 
     
     
         44 . A pharmaceutical composition comprising: 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid, or a pharmaceutically acceptable salt thereof; dabrafenib; trametinib; and a pharmaceutically acceptable excipient. 
     
     
         45 . The method of any one of  claim 1 - 4 , or  7 - 29  wherein the MDM2 inhibitor is 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid, or a pharmaceutically acceptable salt thereof. 
     
     
         46 . A combination of an MDM2 inhibitor medicament and a MEK inhibitor medicament for treating a solid tumor. 
     
     
         47 . A combination of an MDM2 inhibitor medicament and a MEK inhibitor medicament for treating AML. 
     
     
         48 . A combination of an MDM2 inhibitor medicament and a BRAF inhibitor medicament for treating a solid tumor. 
     
     
         49 . A combination of an MDM2 inhibitor medicament and a BRAF inhibitor medicament for treating AML. 
     
     
         50 . Use of an MDM2 inhibitor in combination with a BRAF inhibitor for manufacture of a medicament for the management or treatment of melanoma, liver cancer, AML or colon cancer in a subject. 
     
     
         51 . Use of an MDM2 inhibitor in combination with a MEK inhibitor for manufacture of a medicament for the management or treatment of melanoma, liver cancer, AML or colon cancer in a subject.

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