Formulations of histone deacetylase inhibitor and uses therof

Abstract

Dosing regimens, methods of treatment, controlled release formulations, and combination therapies that include an HDAC inhibitor, or a pharmaceutically acceptable salt thereof, are described.

What is claimed is: 
     
         1 . A method of treating cancer in an individual in need thereof comprising orally administering a first dose of an HDAC inhibitor at a first time and orally administering a second dose of the HDAC inhibitor at a second time, wherein an effective plasma concentration of the HDAC inhibitor is maintained for at least 6 consecutive hours. 
     
     
         2 . The method of  claim 1 , wherein the second time is 4 to 6 hours after the first time. 
     
     
         3 . The method of  claim 1 , wherein the effective plasma concentration of the HDAC inhibitor is maintained for at least 8 consecutive hours. 
     
     
         4 . The method of  claim 1 , wherein the HDAC inhibitor is administered for 5 to 9 consecutive days followed by 2 to 7 consecutive days with no administration of the HDAC inhibitor. 
     
     
         5 . The method of  claim 1 , wherein the HDAC inhibitor has the structure of Formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 X is —O—, —NR 2 —, or —S(O) n  where n is 0, 1, or 2 and R 2  is hydrogen, —CH 3 , —CH 2 CH 3 ;
 Y is ethylene, propylene, 1-methylpropylene, 2-methylpropylene, —CH(C 2 H 5 )CH 2 —, —CH(CH(CH 3 ) 2 )CH 2 —, and —CH(CH 3 )CH 2 —; 
 R 3  is hydrogen, —CH 3 , or —CH 2 CH 3 ; 
 Ar is phenyl, naphthyl, quinolinyl, benzofuranyl, benzothienyl, trans phenylCH═CH— or trans (benzofuran-2-yl)CH═CH—, wherein Ar is optionally substituted with one or two substituents independently selected from chloro, fluoro, trifluoromethyl, methyl, ethyl, methoxy, ethoxy, methylenedioxy, —OH, 1-cyclopropylpiperidin-4-yloxy, 1-(2,2,2-trifluoroethyl)piperidin-4-yloxy, N,N-dimethylaminomethyl, N,N-diethylaminomethyl, 2-methoxyethoxymethyl, phenoxymethyl, 2-methoxyethoxy, 2-morpholin-4-ylethoxy, pyridin-3-ylmethoxy, 2-hydroxyethoxy, 2-N,N-dimethylaminoethoxy, methoxymethyl, 3-i-propoxymethyl, morpholin-4-ylmethyl, 3-hydroxypropyloxymethyl, 2-fluorophenoxymethyl, 3-fluorophenoxymethyl, 4-fluorophenoxy-methyl, 3-methoxypropyloxymethyl, pyridin-4-yloxymethyl, 2,4,6-trifluorophenoxymethyl, 2-oxopyridin-1-ylmethyl, 2,2,2-trifluoroethoxymethyl, 4-imidazol-1-ylphenoxymethyl, 4-[1.2.4-triazin-1-yl-phenoxymethyl, 2-phenylethyl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, 4-trifluoromethylpiperidin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 3,3,3-trifluoropropyloxymethyl, 4-fluorophenylthiomethyl, 4-fluorophenylsulfinylmethyl, 4-fluorophenylsulfonylmethyl, pyridin-3-ylmethyloxymethyl, tetrahydropyran-4-yloxy, 2,2,2-trifluoroethyloxy, 2-pyrrolidin-1-ylethyloxy, piperidin-4-yloxy, N-methyl-N-benzylaminomethyl, N-methyl-N-2-phenylethylaminomethyl, 3-hydroxypropylthiomethyl, 3-hydroxypropylsulfinylmethyl, 3-hydroxypropylsulfonyl-methyl, N-methyl-N-2-indol-3-ylethylaminomethyl, 2-(4-trifluoromethylphenyl)ethyl, 2-(3-trifluoromethoxyphenyl)ethyl, N-hydroxyaminocarbonyl-methylaminomethyl, or 3-(2-carboxyethylamino-methyl); or 
 a pharmaceutically acceptable salt thereof. 
 
 
     
     
         6 . The method of  claim 1 , wherein the HDAC inhibitor has the structure of Formula (II): 
       
         
           
           
               
               
           
         
       
       wherein:
 X is —O—, —NR 2 —, or —S(O) n  where n is 0, 1, or 2 and R 2  is hydrogen, —CH 3 , —CH 2 CH 3 ;
 Y is ethylene, propylene, 1-methylpropylene, 2-methylpropylene, —CH(C 2 H 5 )CH 2 —, —CH(CH(CH 3 ) 2 )CH 2 —, and —CH(CH 3 )CH 2 —; 
 
 R 3  is hydrogen, —CH 3 , or —CH 2 CH 3 ;
 Ar is phenyl, naphthyl, quinolinyl, benzofuranyl, or benzothienyl, wherein Ar is optionally substituted with one or two substituents independently selected from chloro, fluoro, trifluoromethyl, methyl, ethyl, methoxy, ethoxy, methylenedioxy, —OH; 
 R 5  is trifluoromethyl, methyl, ethyl, N,N-dimethylaminomethyl, N,N-diethylaminomethyl, 2-methoxyethoxymethyl, phenoxymethyl, methoxymethyl, 3-i-propoxymethyl, morpholin-4-ylmethyl, 3-hydroxypropyloxymethyl, 2-fluorophenoxymethyl, 3-fluorophenoxymethyl, 4-fluorophenoxy-methyl, 3-methoxypropyloxymethyl, pyridin-4-yloxymethyl, 2,4,6-trifluorophenoxymethyl, 2-oxopyridin-1-ylmethyl, 2,2,2-trifluoroethoxymethyl, 4-imidazol-1-ylphenoxymethyl, 2-phenylethyl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, 4-trifluoromethylpiperidin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 3,3,3-trifluoropropyloxymethyl, 4-fluorophenylthiomethyl, 4-fluorophenylsulfinylmethyl, 4-fluorophenylsulfonylmethyl, pyridin-3-ylmethyloxymethyl, N-methyl-N-benzylaminomethyl, N-methyl-N-2-phenylethylaminomethyl, 3-hydroxypropylthiomethyl, 3-hydroxypropylsulfinylmethyl, 3-hydroxypropylsulfonyl-methyl, N-methyl-N-2-indol-3-ylethylaminomethyl, 2-(4-trifluoromethylphenyl)ethyl, 2-(3-trifluoromethoxyphenyl)ethyl, N-hydroxyaminocarbonyl-methylaminomethyl, or 3-(2-carboxyethylamino-methyl); or 
 a pharmaceutically acceptable salt thereof. 
 
 
     
     
         7 . The method of  claim 1 , wherein the HDAC inhibitor is 3-((dimethylamino)methyl)-N-(2-(4-(hydroxycarbamoyl)phenoxy)ethyl)benzofuran-2-carboxamide. 
     
     
         8 . The method of  claim 1 , wherein the cancer is a hematological cancer, solid tumor or a sarcoma. 
     
     
         9 . The method of  claim 1 , wherein the cancer is selected from: breast cancer, colon cancer, colorectal carcinomas, non-small cell lung cancer, small-cell lung cancer, liver cancer, ovarian cancer, prostate cancer, uterine cervix cancer, urinary bladder cancer, gall bladder carcinoma, gastric carcinoma, esophageal cancer, gastrointestinal stromal tumor, pancreatic cancer, germ cell tumors, mast cell tumors, neuroblastoma, retinoblastoma, mesothelioma, mastocytosis, testicular cancers, glioblastomas, astrocytomas, sarcoma, osteosarcoma, B cell lymphoma, T cell lymphoma, NK cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, melanoma, basal cell carcinoma, skin cancer, myeloma, leukemia, acute myelocytic leukemia (AML), acute lymphocytic leukemia (ALL), myelodysplastic syndrome, chronic lymphocytic leukemia (CLL) and chronic myelogenous leukemia (CML). 
     
     
         10 . The method of  claim 1 , wherein the cancer is selected from: breast cancer, colon cancer, colorectal carcinomas, non-small cell lung cancer, liver cancer, ovarian cancer, uterine cervix cancer, gastric carcinoma, pancreatic cancer, glioblastomas, B cell lymphoma, T cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, myeloma, myelodysplastic syndrome (MDS). 
     
     
         11 . The method of  claim 1 , further comprising administering to the individual at least one additional therapy selected from anti-cancer agents, anti-emetic agents, radiation therapy, or combinations thereof. 
     
     
         12 . The method of  claim 1 , further comprising administering to the individual at least one additional therapeutic agent selected from: DNA-damaging agents; topoisomerase I or II inhibitors; alkylating agents; PARP inhibitors; proteasome inhibitors; RNA/DNA antimetabolites; antimitotics; immunomodulatory agents; antiangiogenics; aromatase inhibitors; hormone-modulating agents; apoptosis inducing agents; kinase inhibitors; monoclonal antibodies; or combinations thereof. 
     
     
         13 . The method of  claim 1 , further comprising administering to the individual at least one additional therapeutic agent selected from: abarelix; ABT-888; aldesleukin; aldesleukin; alemtuzumab; alitretinoin; allopurinol; altretamine; amifostine anastrozole; arsenic trioxide; asparaginase; azacitidine; AZD-2281; arsenic trioxide; bendamustine; bevacizumab; bexarotene; bleomycin; bortezomib; BSI-201; busulfan; busulfan; calusterone; capecitabine; carboplatin; carfilzomib; carmustine; carmustine; celecoxib; cetuximab; chlorambucil; cisplatin; cladribine; clofarabine; cyclophosphamide; cytarabine; cytarabine liposomal; dacarbazine; dactinomycin; darbepoetin alfa; dasatinib; daunorubicin liposomal; daunorubicin; decitabine; denileukin; dexrazoxane; docetaxel; doxorubicin; doxorubicin liposomal; dromostanolone propionate; epirubicin; epoetin alfa; erlotinib; estramustine; etoposide phosphate; etoposide; exemestane; filgrastim; floxuridine; fludarabine; fluorouracil; fulvestrant; gefitinib; gemcitabine; gemtuzumab ozogamicin; goserelin acetate; histrelin acetate; hydroxyurea; Ibritumomab tiuxetan; idarubicin; ifosfamide; imatinib mesylate; interferon alfa 2a; Interferon alfa-2b; irinotecan; lenalidomide; letrozole; leucovorin; leuprolide Acetate; levamisole; lomustine; meclorethamine; megestrol acetate; melphalan; mercaptopurine; methotrexate; methoxsalen; mitomycin C; mitomycin C; mitotane; mitoxantrone; nandrolone phenpropionate; nelarabine; NPI-0052; nofetumomab; oprelvekin; oxaliplatin; paclitaxel; paclitaxel protein-bound particles; palifermin; pamidronate; panitumumab; pegademase; pegaspargase; pegfilgrastim; pemetrexed disodium; pentostatin; pipobroman; plicamycin, mithramycin; porfimer sodium; procarbazine; quinacrine; RAD001; rasburicase; rituximab; sargramostim; Sargramostim; sorafenib; streptozocin; sunitinib malate; tamoxifen; temozolomide; teniposide; testolactone; thalidomide; thioguanine; thiotepa; topotecan; toremifene; tositumomab; tositumomab/I-131 tositumomab; trastuzumab; tretinoin; uracil Mustard; valrubicin; vinblastine; vincristine; vinorelbine; vorinostat; zoledronate; zoledronic acid; vandetanib; lapatinib; nilotinib; axitinib; or combinations thereof. 
     
     
         14 . The method of  claim 1 , further comprising administering to the individual at least one additional therapeutic agent selected from: azacitidine; bendamustine; bevacizumab; bleomycin; bortezomib; carboplatin; chlorambucil; cisplatin; cyclophosphamide; cytarabine; dacarbazine; darbepoetin alfa; daunorubicin liposomal; daunorubicin; decitabine; docetaxel; doxorubicin; doxorubicin liposomal; epirubicin; epoetin alfa; erlotinib; etoposide; fludarabine; fluorouracil; gemcitabine; Ibritumomab tiuxetan; irinotecan; lenalidomide; leucovorin; melphalan; methotrexate; oxaliplatin; paclitaxel; paclitaxel protein-bound particles; pemetrexed disodium; pentostatin; RAD001; rituximab; sorafenib; sunitinib malate; tamoxifen; temozolomide; topotecan; tositumomab; tositumomab/I-131 tositumomab; trastuzumab; vincristine; vinorelbine; or combinations thereof. 
     
     
         15 . A method of treating cancer in an individual in need thereof comprising orally administering a first dose of an HDAC inhibitor, and orally administering a second dose of an HDAC inhibitor about 4 to about 6 hours after the first dose. 
     
     
         16 . The method of  claim 15 , wherein the administration of the HDAC inhibitor maintains an effective plasma concentration of the HDAC inhibitor for at least 6 consecutive hours. 
     
     
         17 . The method of  claim 15 , wherein the administration of the HDAC inhibitor maintains an effective plasma concentration of the HDAC inhibitor for at least 8 consecutive hours. 
     
     
         18 . The method of  claim 15 , wherein the HDAC inhibitor is administered for 5 to 9 consecutive days followed by 2 to 7 consecutive days with no administration of the HDAC inhibitor. 
     
     
         19 . The method of  claim 15 , wherein the HDAC inhibitor has the structure of Formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 X is —O—, —NR 2 —, or —S(O) n  where n is 0, 1, or 2 and R 2  is hydrogen, —CH 3 , —CH 2 CH 3 ;
 Y is ethylene, propylene, 1-methylpropylene, 2-methylpropylene, —CH(C 2 H 5 )CH 2 —, —CH(CH(CH 3 ) 2 )CH 2 —, and —CH(CH 3 )CH 2 —; 
 R 3  is hydrogen, —CH 3 , or —CH 2 CH 3 ; 
 Ar is phenyl, naphthyl, quinolinyl, benzofuranyl, benzothienyl, trans phenylCH═CH— or trans (benzofuran-2-yl)CH═CH—, wherein Ar is optionally substituted with one or two substituents independently selected from chloro, fluoro, trifluoromethyl, methyl, ethyl, methoxy, ethoxy, methylenedioxy, —OH, 1-cyclopropylpiperidin-4-yloxy, 1-(2,2,2-trifluoroethyl)piperidin-4-yloxy, N,N-dimethylaminomethyl, N,N-diethylaminomethyl, 2-methoxyethoxymethyl, phenoxymethyl, 2-methoxyethoxy, 2-morpholin-4-ylethoxy, pyridin-3-ylmethoxy, 2-hydroxyethoxy, 2-N,N-dimethylaminoethoxy, methoxymethyl, 3-i-propoxymethyl, morpholin-4-ylmethyl, 3-hydroxypropyloxymethyl, 2-fluorophenoxymethyl, 3-fluorophenoxymethyl, 4-fluorophenoxy-methyl, 3-methoxypropyloxymethyl, pyridin-4-yloxymethyl, 2,4,6-trifluorophenoxymethyl, 2-oxopyridin-1-ylmethyl, 2,2,2-trifluoroethoxymethyl, 4-imidazol-1-ylphenoxymethyl, 4-[1.2.4-triazin-1-yl-phenoxymethyl, 2-phenylethyl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, 4-trifluoromethylpiperidin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 3,3,3-trifluoropropyloxymethyl, 4-fluorophenylthiomethyl, 4-fluorophenylsulfinylmethyl, 4-fluorophenylsulfonylmethyl, pyridin-3-ylmethyloxymethyl, tetrahydropyran-4-yloxy, 2,2,2-trifluoroethyloxy, 2-pyrrolidin-1-ylethyloxy, piperidin-4-yloxy, N-methyl-N-benzylaminomethyl, N-methyl-N-2-phenylethylaminomethyl, 3-hydroxypropylthiomethyl, 3-hydroxypropylsulfinylmethyl, 3-hydroxypropylsulfonyl-methyl, N-methyl-N-2-indol-3-ylethylaminomethyl, 2-(4-trifluoromethylphenyl)ethyl, 2-(3-trifluoromethoxyphenyl)ethyl, N-hydroxyaminocarbonyl-methylaminomethyl, or 3-(2-carboxyethylamino-methyl); or 
 a pharmaceutically acceptable salt thereof. 
 
 
     
     
         20 . The method of  claim 15 , wherein the HDAC inhibitor has the structure of Formula (II): 
       
         
           
           
               
               
           
         
       
       wherein:
 X is —O—, —NR 2 —, or —S(O) n  where n is 0, 1, or 2 and R 2  is hydrogen, —CH 3 , —CH 2 CH 3 ;
 Y is ethylene, propylene, 1-methylpropylene, 2-methylpropylene, —CH(C 2 H 5 )CH 2 —, —CH(CH(CH 3 ) 2 )CH 2 —, and —CH(CH 3 )CH 2 —; 
 
 R 3  is hydrogen, —CH 3 , or —CH 2 CH 3 ;
 Ar is phenyl, naphthyl, quinolinyl, benzofuranyl, or benzothienyl, wherein Ar is optionally substituted with one or two substituents independently selected from chloro, fluoro, trifluoromethyl, methyl, ethyl, methoxy, ethoxy, methylenedioxy, —OH; 
 R 5  is trifluoromethyl, methyl, ethyl, N,N-dimethylaminomethyl, N,N-diethylaminomethyl, 2-methoxyethoxymethyl, phenoxymethyl, methoxymethyl, 3-i-propoxymethyl, morpholin-4-ylmethyl, 3-hydroxypropyloxymethyl, 2-fluorophenoxymethyl, 3-fluorophenoxymethyl, 4-fluorophenoxy-methyl, 3-methoxypropyloxymethyl, pyridin-4-yloxymethyl, 2,4,6-trifluorophenoxymethyl, 2-oxopyridin-1-ylmethyl, 2,2,2-trifluoroethoxymethyl, 4-imidazol-1-ylphenoxymethyl, 2-phenylethyl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, 4-trifluoromethylpiperidin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 3,3,3-trifluoropropyloxymethyl, 4-fluorophenylthiomethyl, 4-fluorophenylsulfinylmethyl, 4-fluorophenylsulfonylmethyl, pyridin-3-ylmethyloxymethyl, N-methyl-N-benzylaminomethyl, N-methyl-N-2-phenylethylaminomethyl, 3-hydroxypropylthiomethyl, 3-hydroxypropylsulfinylmethyl, 3-hydroxypropylsulfonyl-methyl, N-methyl-N-2-indol-3-ylethylaminomethyl, 2-(4-trifluoromethylphenyl)ethyl, 2-(3-trifluoromethoxyphenyl)ethyl, N-hydroxyaminocarbonyl-methylaminomethyl, or 3-(2-carboxyethylamino-methyl); or 
 a pharmaceutically acceptable salt thereof. 
 
 
     
     
         21 . The method of  claim 15 , wherein the HDAC inhibitor is 3-((dimethylamino)methyl)-N-(2-(4-(hydroxycarbamoyl)phenoxy)ethyl)benzofuran-2-carboxamide. 
     
     
         22 . The method of  claim 15 , wherein the cancer is a hematological cancer, solid tumor or a sarcoma. 
     
     
         23 . The method of  claim 15 , wherein the cancer is selected from: breast cancer, colon cancer, colorectal carcinomas, non-small cell lung cancer, small-cell lung cancer, liver cancer, ovarian cancer, prostate cancer, uterine cervix cancer, urinary bladder cancer, gall bladder carcinoma, gastric carcinoma, esophageal cancer, gastrointestinal stromal tumor, pancreatic cancer, germ cell tumors, mast cell tumors, neuroblastoma, retinoblastoma, mesothelioma, mastocytosis, testicular cancers, glioblastomas, astrocytomas, sarcoma, osteosarcoma, B cell lymphoma, T cell lymphoma, NK cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, melanoma, basal cell carcinoma, skin cancer, myeloma, leukemia, acute myelocytic leukemia (AML), acute lymphocytic leukemia (ALL), myelodysplastic syndrome, chronic lymphocytic leukemia (CLL) and chronic myelogenous leukemia (CML). 
     
     
         24 . The method of  claim 15 , wherein the cancer is selected from: breast cancer, colon cancer, colorectal carcinomas, non-small cell lung cancer, liver cancer, ovarian cancer, uterine cervix cancer, gastric carcinoma, pancreatic cancer, glioblastomas, B cell lymphoma, T cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, myeloma, myelodysplastic syndrome (MDS). 
     
     
         25 . The method of  claim 15 , further comprising administering to the individual at least one additional therapy selected from anti-cancer agents, anti-emetic agents, radiation therapy, or combinations thereof. 
     
     
         26 . The method of  claim 15 , further comprising administering to the individual at least one additional therapeutic agent selected from: DNA-damaging agents; topoisomerase I or II inhibitors; alkylating agents; PARP inhibitors; proteasome inhibitors; RNA/DNA antimetabolites; antimitotics; immunomodulatory agents; antiangiogenics; aromatase inhibitors;
 hormone-modulating agents; apoptosis inducing agents; kinase inhibitors; monoclonal antibodies; or combinations thereof.   
     
     
         27 . The method of  claim 15 , further comprising administering to the individual at least one additional therapeutic agent selected from: abarelix; ABT-888; aldesleukin; aldesleukin; alemtuzumab; alitretinoin; allopurinol; altretamine; amifostine anastrozole; arsenic trioxide; asparaginase; azacitidine; AZD-2281; arsenic trioxide; bendamustine; bevacizumab; bexarotene; bleomycin; bortezomib; BSI-201; busulfan; busulfan; calusterone; capecitabine; carboplatin; carfilzomib; carmustine; carmustine; celecoxib; cetuximab; chlorambucil; cisplatin; cladribine; clofarabine; cyclophosphamide; cytarabine; cytarabine liposomal; dacarbazine; dactinomycin; darbepoetin alfa; dasatinib; daunorubicin liposomal; daunorubicin; decitabine; denileukin; dexrazoxane; docetaxel; doxorubicin; doxorubicin liposomal; dromostanolone propionate; epirubicin; epoetin alfa; erlotinib; estramustine; etoposide phosphate; etoposide; exemestane; filgrastim; floxuridine; fludarabine; fluorouracil; fulvestrant; gefitinib; gemcitabine; gemtuzumab ozogamicin; goserelin acetate; histrelin acetate; hydroxyurea; Ibritumomab tiuxetan; idarubicin; ifosfamide; imatinib mesylate; interferon alfa 2a; Interferon alfa-2b; irinotecan; lenalidomide; letrozole; leucovorin; leuprolide Acetate; levamisole; lomustine; meclorethamine; megestrol acetate; melphalan; mercaptopurine; methotrexate; methoxsalen; mitomycin C; mitomycin C; mitotane; mitoxantrone; nandrolone phenpropionate; nelarabine; NPI-0052; nofetumomab; oprelvekin; oxaliplatin; paclitaxel; paclitaxel protein-bound particles; palifermin; pamidronate; panitumumab; pegademase; pegaspargase; pegfilgrastim; pemetrexed disodium; pentostatin; pipobroman; plicamycin, mithramycin; porfimer sodium; procarbazine; quinacrine; RAD001; rasburicase; rituximab; sargramostim; Sargramostim; sorafenib; streptozocin; sunitinib malate; tamoxifen; temozolomide; teniposide; testolactone; thalidomide; thioguanine; thiotepa; topotecan; toremifene; tositumomab; tositumomab/I-131 tositumomab; trastuzumab; tretinoin; uracil Mustard; valrubicin; vinblastine; vincristine; vinorelbine; vorinostat; zoledronate; zoledronic acid; vandetanib; lapatinib; nilotinib; axitinib; or combinations thereof. 
     
     
         28 . The method of  claim 15 , further comprising administering to the individual at least one additional therapeutic agent selected from: azacitidine; bendamustine; bevacizumab; bleomycin; bortezomib; carboplatin; chlorambucil; cisplatin; cyclophosphamide; cytarabine; dacarbazine; darbepoetin alfa; daunorubicin liposomal; daunorubicin; decitabine; docetaxel; doxorubicin; doxorubicin liposomal; epirubicin; epoetin alfa; erlotinib; etoposide; fludarabine; fluorouracil; gemcitabine; Ibritumomab tiuxetan; irinotecan; lenalidomide; leucovorin; melphalan; methotrexate; oxaliplatin; paclitaxel; paclitaxel protein-bound particles; pemetrexed disodium; pentostatin; RAD001; rituximab; sorafenib; sunitinib malate; tamoxifen; temozolomide; topotecan; tositumomab; tositumomab/I-131 tositumomab; trastuzumab; vincristine; vinorelbine; or combinations thereof.