Use of tivozanib to treat subjects with refractory cancer

Abstract

Disclosed is a method of treating cancer, e.g., refractory cancer, with tivozanib. The methods disclosed include, for example, administering tivozanib as a second or third-line therapy to subjects suffering from refractory advanced renal cell carcinoma where traditional therapies as well as more recent targeted and immune-oncology therapies have not adequately treated the subject.

We claim: 
     
         1 . A method of treating a subject suffering from refractory cancer wherein the subject has previously been treated with at least one anti-cancer therapy, the method comprising administering to the subject an effective amount of tivozanib. 
     
     
         2 . A method of treating a subject suffering from refractory renal cell carcinoma wherein the subject has previously been treated with at least one anti-cancer therapy, the method comprising administering to the subject an effective amount of tivozanib. 
     
     
         3 . The method of  claim 1  or  2 , wherein the method comprises administering to the subject a pharmaceutical composition comprising 1.5 mg tivozanib for 21 days followed by 7 days without administration of tivozanib, wherein administering the tivozanib for 21 days followed by 7 days without administration constitutes a treatment cycle. 
     
     
         4 . A method of treating a subject suffering from refractory cancer wherein the subject has previously been treated with at least one anti-cancer therapy, comprising administering to the subject a pharmaceutical composition comprising 1.5 mg tivozanib for 21 days followed by 7 days without administration of tivozanib, wherein administering the tivozanib for 21 days followed by 7 days without administration constitutes a treatment cycle. 
     
     
         5 . A method of treating a subject suffering from refractory renal cell carcinoma wherein the subject has previously been treated with at least one anti-cancer therapy comprising administering to the subject a pharmaceutical composition comprising 1.5 mg tivozanib for 21 days followed by 7 days without administration of tivozanib, wherein administering the tivozanib for 21 days followed by 7 days without administration constitutes a treatment cycle. 
     
     
         6 . The method of any one of  claims 1 - 5 , wherein:
 (a) the subject has previously been treated with at least one checkpoint inhibitor;   (b) the subject has previously been treated with at least one vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR TKI);   (c) the subject has previously been treated with a vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR TKI) and a checkpoint inhibitor; or   (d) the subject has previously been treated with two vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKI).   
     
     
         7 . The method of any one of  claims 1 - 6 , wherein the subject was previously treated with at least a first line anti-cancer therapy and a second line anti-cancer therapy. 
     
     
         8 . The method of  claim 7 , wherein the first line and second line anti-cancer therapies were both vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR TKI) therapies. 
     
     
         9 . The method of  claim 7 , wherein the first line and second line anti-cancer therapies were selected from a VEGFR TKI and a checkpoint inhibitor. 
     
     
         10 . The method of  claim 7 , wherein the first line and second line anti-cancer therapies were selected from a VEGFR TKI and a systemic anti-cancer agent. 
     
     
         11 . The method of  claim 7 , wherein the first line and second line anti-cancer therapies were selected from a checkpoint inhibitor and a systemic anti-cancer agent. 
     
     
         12 . A method of treating a subject suffering from refractory renal cell carcinoma comprising administering to the subject an effective amount of tivozanib in combination with a checkpoint inhibitor. 
     
     
         13 . The method of  claim 12 , wherein tivozanib is administered concurrent with the checkpoint inhibitor. 
     
     
         14 . The method of  claim 12 , wherein tivozanib is administered subsequent to the checkpoint inhibitor. 
     
     
         15 . The method of any one of  claims 1 - 14 , wherein the subject is identified as having an International Metastatic-RCC Database Consortium (IMDC) risk score of favorable or intermediate prior to treating the subject. 
     
     
         16 . The method of  claim 15 , wherein the IMDC risk category is favorable. 
     
     
         17 . The method of  claim 15 , wherein the IMDC risk category is intermediate. 
     
     
         18 . The method of any one of  claim 1 ,  3 ,  4 , or  6 - 17 , wherein the refractory cancer is refractory renal cell carcinoma (RCC). 
     
     
         19 . The method of any one of  claims 1 - 18 , wherein the tivozanib is tivozanib hydrochloride monohydrate. 
     
     
         20 . The method of any one of  claims 1 - 19 , wherein the subject undergoes one or more treatment cycles with tivozanib. 
     
     
         21 . The method of any one of  claim 6  or  8 - 10 , wherein the VEGFR TKI is sunitinib, sorafenib, pazopanib, crizotinib, vandetinib, axitinib, cabozantinib, regorafenib, axinitib, or nintedanib. 
     
     
         22 . The method of any one of  claim 6 ,  9 , or  11 - 14 , wherein the checkpoint inhibitor is an anti-PDL1 or anti-PD1 inhibitor. 
     
     
         23 . The method of  claim 22 , wherein the checkpoint inhibitor is nivolumab, pembrolizumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, prolgolimab cetrelimab, pidilizumab, BMS-936559, MDX-1105, atezolizumab, durvalumab, or avelumab. 
     
     
         24 . The method of  claim 10  or  11 , wherein the systemic anti-cancer-agent is everolimus or temsirolimus. 
     
     
         25 . The method of any one of  claims 1 - 24 , wherein the subject exhibits a complete or partial response to tivozanib after one treatment cycle, after two treatment cycles, after three treatment cycles, after four treatment cycles or after five treatment cycles. 
     
     
         26 . The method of any one of  claims 1 - 25 , wherein the subject undergoes one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, or more than twelve treatment cycles. 
     
     
         27 . The method of any one of  claims 1 - 26 , wherein the dose of tivozanib is reduced when a subject experiences a ≥Grade 3 drug-related adverse event. 
     
     
         28 . The method of any one of  claims 1 - 26 , wherein the dose of tivozanib is reduced for a subject experiencing moderate hepatic impairment (Child-Pugh class B). 
     
     
         29 . The method of any one of  claims 1 - 26 , wherein the dose of tivozanib is reduced for a subject experiencing severe hepatic impairment (Child-Pugh class C). 
     
     
         30 . The method of any one of  claim 27 - 29 , wherein the dose is reduced to 1.0 mg daily. 
     
     
         31 . The method of any one of  claims 27 - 29 , wherein the dose is reduced to 1.5 mg every other day. 
     
     
         32 . The method of any one of  claims 27 - 29 , wherein the dose is reduced to 1.0 mg every other day. 
     
     
         33 . A pharmaceutical composition comprising tivozanib for use in treating a subject suffering from refractory cancer, wherein the subject has previously been treated with at least one anti-cancer therapy. 
     
     
         34 . A pharmaceutical composition comprising tivozanib for use in treating a subject suffering from refractory renal cell carcinoma, wherein the subject has previously been treated with at least one anti-cancer therapy. 
     
     
         35 . The pharmaceutical composition for use according to  claim 33  or  34 , wherein the composition comprises 1.5 mg tivozanib and is to be administered to the subject for 21 days followed by 7 days without administration, wherein administration of the pharmaceutical composition for 21 days followed by 7 days without administration constitutes a treatment cycle. 
     
     
         36 . A pharmaceutical composition comprising tivozanib for use in treating a subject suffering from refractory cancer, wherein the subject has previously been treated with at least one anti-cancer therapy, the composition comprises 1.5 mg tivozanib and is to be administered to the subject for 21 days followed by 7 days without administration, and administration of the pharmaceutical composition for 21 days followed by 7 days without administration constitutes a treatment cycle. 
     
     
         37 . A pharmaceutical composition comprising tivozanib for use in treating a subject suffering from refractory renal cell carcinoma, wherein the subject has previously been treated with at least one anti-cancer therapy, the composition comprises 1.5 mg tivozanib and is to be administered to the subject for 21 days followed by 7 days without administration, and administration of the pharmaceutical composition for 21 days followed by 7 days without administration constitutes a treatment cycle. 
     
     
         38 . The pharmaceutical composition for use according to any one of  claims 33 - 37 , wherein:
 (a) the subject has previously been treated with at least one checkpoint inhibitor;   (b) the subject has previously been treated with at least one vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR TKI);   (c) the subject has previously been treated with a vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR TKI) and a checkpoint inhibitor; or   (d) the subject has previously been treated with two vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKI).   
     
     
         39 . The pharmaceutical composition for use according to any one of  claims 33 - 38 , wherein the subject is identified as having an International Metastatic-RCC Database Consortium (IMDC) risk score of favorable or intermediate prior to treating the subject. 
     
     
         40 . The pharmaceutical composition for use according to  claim 39 , wherein the IMDC risk category is favorable. 
     
     
         41 . The pharmaceutical composition for use according to  claim 39 , wherein the IMDC risk category is intermediate. 
     
     
         42 . The pharmaceutical composition for use according to any one of  claim 33 ,  35 ,  36 , or  38 - 41 , wherein the refractory cancer is refractory renal cell carcinoma (RCC). 
     
     
         43 . The pharmaceutical composition for use according to any one of  claims 33 - 42 , wherein the tivozanib is tivozanib hydrochloride monohydrate. 
     
     
         44 . The pharmaceutical composition for use according to any one of  claims 33 - 43 , wherein the subject undergoes one or more treatment cycles with tivozanib. 
     
     
         45 . The pharmaceutical composition for use according to any one of  claims 33 - 44 , wherein the subject was previously treated with at least a first line anti-cancer therapy and a second line anti-cancer therapy. 
     
     
         46 . The pharmaceutical composition for use according to  claim 45 , wherein the first line and second line anti-cancer therapies were both vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR TKI) therapies. 
     
     
         47 . The pharmaceutical composition for use according to  claim 45 , wherein the first line and second line anti-cancer therapies were selected from a VEGFR TKI and a checkpoint inhibitor. 
     
     
         48 . The pharmaceutical composition for use according to  claim 45 , wherein the first line and second line anti-cancer therapies were selected from a VEGFR TKI and a systemic anti-cancer agent. 
     
     
         49 . The pharmaceutical composition for use according to  claim 45 , wherein the first line and second line anti-cancer therapies were selected from a checkpoint inhibitor and a systemic anti-cancer agent. 
     
     
         50 . The pharmaceutical composition for use according to any one of  claim 38  or  46 - 49 , wherein the VEGFR TKI is sunitinib, sorafenib, pazopanib, crizotinib, vandetinib, axitinib, cabozantinib, regorafenib, axinitib, or nintedanib. 
     
     
         51 . The pharmaceutical composition for use according to any one of  claim 38 ,  47 , or  49 , wherein the checkpoint inhibitor is an anti-PDL1 or anti-PD1 inhibitor. 
     
     
         52 . The pharmaceutical composition for use according to  claim 51 , wherein the checkpoint inhibitor is nivolumab, pembrolizumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, prolgolimab cetrelimab, pidilizumab, BMS-936559, MDX-1105, atezolizumab, durvalumab, or avelumab. 
     
     
         53 . The pharmaceutical composition for use according to  claim 48  or  49 , wherein the systemic anti-cancer-agent is everolimus or temsirolimus. 
     
     
         54 . The pharmaceutical composition for use according to any one of  claims 33 - 53 , wherein the subject exhibits a complete or partial response to tivozanib after one treatment cycle, after two treatment cycles, after three treatment cycles, after four treatment cycles or after five treatment cycles. 
     
     
         55 . The pharmaceutical composition for use according to any one of  claims 33 - 54 , wherein the subject undergoes one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, or more than twelve treatment cycles. 
     
     
         56 . The pharmaceutical composition for use according to any one of  claims 33 - 55 , wherein the dose of tivozanib is reduced when a subject experiences a ≥Grade 3 drug-related adverse event. 
     
     
         57 . The pharmaceutical composition for use of any one of  claims 33 - 55 , wherein the dose of tivozanib is reduced for a subject experiencing moderate hepatic impairment (Child-Pugh class B). 
     
     
         58 . The pharmaceutical composition for use according to any one of  claims 33 - 55 , wherein the dose of tivozanib is reduced for a subject experiencing severe hepatic impairment (Child-Pugh class C). 
     
     
         59 . The pharmaceutical composition for use according to any one of  claim 56 - 58 , wherein the dose is reduced to 1.0 mg daily. 
     
     
         60 . The pharmaceutical composition for use according to any one of  claims 56 - 58 , wherein the dose is reduced to 1.5 mg every other day. 
     
     
         61 . The pharmaceutical composition for use according to any one of  claims 56 - 58 , wherein the dose is reduced to 1.0 mg every other day.