Dosing schedule of a Wnt inhibitor and an anti-PD-1 antibody molecule in combination

Abstract

The present disclosure relates to the field of pharmacy, particularly to a Wnt inhibitor and a PD-1 inhibitor for use in the treatment of cancer. Specifically, the disclosure relates to a pharmaceutical combination comprising a Wnt inhibitor, or a pharmaceutically acceptable salt thereof, and a PD-1 inhibitor, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, to a method for the treatment of cancer that involves administering the combination and to the use of the combination for the manufacture of a medicament for the treatment of cancer.

1 . A pharmaceutical combination comprising (i) 2-(2′,3-dimethyl-[2,4′-bipyridin]-5-yl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide, or a pharmaceutically acceptable salt thereof, and (ii) anti-PD-1 antibody molecule or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, wherein (i) is administered daily on days 1 to 15 of each cycle for up to 4 cycles and (ii) is administered at least once per cycle. 
     
     
         2 . The pharmaceutical combination for use in the treatment of cancer according to  claim 1 , wherein (i) is administered during days 1 to 8 of each cycle for up to 4 cycles. 
     
     
         3 . The pharmaceutical combination for use in the treatment of cancer according to  claim 1  or  2 , wherein (i) is administered during the first cycle only. 
     
     
         4 . The pharmaceutical combination for use in the treatment of cancer according to  claim 1  or  2 , wherein (i) is administered during 4 cycles only. 
     
     
         5 . The pharmaceutical combination for use in the treatment of cancer according to any one of  claims 1  to  4 , wherein each cycle is 28 days. 
     
     
         6 . The pharmaceutical combination for use in the treatment of cancer according to any one of  claims 1  to  5 , wherein (i) is administered twice daily. 
     
     
         7 . The pharmaceutical combination for use in the treatment of cancer according to  claim 6 , wherein (i) is administered at 12-hour intervals. 
     
     
         8 . The pharmaceutical combination for use in the treatment of cancer according to any one of  claims 1  to  7 , wherein the daily dose of (i) is 2.5 mg/day, 5 mg/day, 7.5 mg/day, 10 mg/day, 20 mg/day, 40 mg/day, 80 mg/day, 120 mg/day, or 180 mg/day. 
     
     
         9 . The pharmaceutical combination for use in the treatment of cancer according to  claim 8 , wherein the daily dose of (i) is 2.5 mg/day, 5 mg/day, or 10 mg/day. 
     
     
         10 . The pharmaceutical combination for use in the treatment of cancer according to anyone of  claims 8  to  9 , wherein the daily dose of (i) is 10 mg/day. 
     
     
         11 . The pharmaceutical combination for use in the treatment of cancer according to any one of  claims 1  to  10 , wherein (ii) is administered every 2 weeks or every 4 weeks in a cycle. 
     
     
         12 . The pharmaceutical combination for use in the treatment of cancer according to  claim 11 , wherein (ii) is administered, every 4 weeks. 
     
     
         13 . The pharmaceutical combination for use in the treatment of cancer according to  claim 11  or  12 , wherein (ii) is selected from nivolumab, pembrolizumab, pidilizumab, PDR-001, or a pharmaceutical salt thereof. 
     
     
         14 . The pharmaceutical combination for use in the treatment of cancer according to  claim 13 , wherein (ii) is PDR-001, or a pharmaceutical salt thereof. 
     
     
         15 . The pharmaceutical combination for use in the treatment of cancer according to  claim 13 , wherein (ii) is administered intravenously in a single dose of 300 to 400 mg/day. 
     
     
         16 . The pharmaceutical combination for use in the treatment of cancer according to  claim 15 , wherein the single dose is 400 mg/day. 
     
     
         17 . The pharmaceutical combination for use in the treatment of cancer according to any one of  claims 1 ,  2 ,  5  to  9  or  11  to  16 , wherein 2.5 mg/day of (i) is administered on days 1-8 and 400 mg/day of (ii) is administered once every 4 weeks for up to 4 cycles. 
     
     
         18 . The pharmaceutical combination for use in the treatment of cancer according to any one of  claims 1 ,  5  to  9  or  11  to  16 , wherein 2.5 mg/day of (i) is administered on days 1-15 and 400 mg/day of (ii) is administered once every 4 weeks for up to 4 cycles. 
     
     
         19 . The pharmaceutical combination for use in the treatment of cancer according to any one of  claims 3  to  9  or  11  to  18 , wherein 2.5 mg/day of (i) is administered during cycle 1 only and 400 mg/day of (ii) is administered every 4 weeks. 
     
     
         20 . The pharmaceutical combination for use in the treatment of cancer according to any one of  claims 1 ,  2 ,  5  to  9  or  11  to  16 , wherein 5 mg/day of (i) is administered on days 1-8 and 400 mg/day of (ii) is administered once every 4 weeks for up to 4 cycles. 
     
     
         21 . The pharmaceutical combination for use in the treatment of cancer according to any one of  claims 1 ,  5  to  9  or  11  to  16 , wherein 5 mg/day of (i) is administered on days 1-15 and 400 mg/day of (ii) is administered once every 4 weeks for up to 4 cycles. 
     
     
         22 . The pharmaceutical combination for use in the treatment of cancer according to any one of  claim 3  to  9 ,  11  to  16 ,  20  or  21 , wherein 5 mg/day of (i) is administered during cycle 1 only and 400 mg/day of (ii) is administered every 4 weeks. 
     
     
         23 . The pharmaceutical combination for use in the treatment of cancer according to any one of  claims 1 ,  2 ,  5  to  16 , wherein 10 mg/day of (i) is administered daily on days 1-8 and 400 mg/day of (ii) is administered every 4 weeks for up to 4 cycles. 
     
     
         24 . The pharmaceutical combination for use in the treatment of cancer according to any one of  claim 1  or  5  to  16 , wherein 10 mg/day of (i) is administered on days 1-15 and 400 mg/day of (ii) is administered every 4 weeks for up to 4 cycles. 
     
     
         25 . The pharmaceutical combination for use in the treatment of cancer according to any one of  claim 1 ,  3  to  16 ,  23  or  24 , wherein 10 mg/day of (i) is administered during cycle 1 only and 400 mg/day of (ii) is administered every 4 weeks. 
     
     
         26 . The pharmaceutical combination for use in the treatment of cancer according to any one of  claims 1  to  25 , wherein (ii) is administered continuously every 4 weeks. 
     
     
         27 . Use of (i) 2-(2′,3-dimethyl-[2,4′-bipyridin]-5-yl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide, or a pharmaceutically acceptable salt thereof, in combination with anti-PD-1 antibody molecule, or a pharmaceutically acceptable salt, for the manufacture of a medicament for the treatment of cancer, wherein (i) and (ii) are administered as define in any one of the  claims 1  to  26 , preferably wherein (i) is administered daily on days 1 to 16 of each cycle for up to 4 cycles and (ii) is administered at least once per cycle. 
     
     
         28 . The use of (i) 2-(2′,3-dimethyl-[2,4′-bipyridin]-5-yl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide, or a pharmaceutically acceptable salt thereof, in combination with (ii) anti-PD-1 antibody molecule, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer according to  claim 27  wherein (i) is to be administered on days 1 to 16 of each cycle, on days 1 to 8 of each cycle for up to 4 cycles or only during the first cycle. 
     
     
         29 . The use of (i) 2-(2′,3-dimethyl-[2,4′-bipyridin]-5-yl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide, or a pharmaceutically acceptable salt thereof, in combination with (ii) anti-PD-1 antibody molecule, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer according to  claim 27  or  28  wherein the daily dose of (i) is 2.5 mg/day, 5 mg/day, 7.5 mg/day, 10 mg/day, 20 mg/day, 40 mg/day, 80 mg/day, 120 mg/day, or 180 mg/day. 
     
     
         30 . The use of (i) 2-(2′,3-dimethyl-[2,4′-bipyridin]-5-yl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide, or a pharmaceutically acceptable salt thereof, in combination with (ii) anti-PD-1 antibody molecule, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer according to any one of  claims 27  to  29  wherein the daily dose of (i) is 10 mg/day. 
     
     
         31 . The use of (i) 2-(2′,3-dimethyl-[2,4′-bipyridin]-5-yl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide, or a pharmaceutically acceptable salt thereof, in combination with (ii) anti-PD-1 antibody molecule, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer according to any one of  claims 27  to  30  wherein (ii) is to be administered in a single dose of 300-400 mg/day. 
     
     
         32 . The use of (i) 2-(2′,3-dimethyl-[2,4′-bipyridin]-5-yl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide, or a pharmaceutically acceptable salt thereof, in combination with (ii) anti-PD-1 antibody molecule, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer according to any one of  claims 27  to  30  wherein (ii) is administered in a single dose of 400 mg/day. 
     
     
         33 . The use of (i) 2-(2′,3-dimethyl-[2,4′-bipyridin]-5-yl)-N-(5-(pyrazin-2-yl)pyridin yl)acetamide, or a pharmaceutically acceptable salt thereof, in combination with (ii) anti-PD-1 antibody molecule, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer according to  claim 27  wherein (i) and (ii) are administered as defined in any one of  claims 17  to  25 . 
     
     
         34 . A method for the treatment of cancer, said method comprising administering an effective amount of (i) and (ii) to a patient in need thereof, wherein (i) is administered daily during days 1 to 15 of each cycle for up to 4 cycles and (ii) is administered at least once per cycle. 
     
     
         35 . The method for the treatment of cancer according to  claim 34 , said method comprising administering an effective amount of (i) and (ii) as defined in any one of  claims 1  to  26 . 
     
     
         36 . The pharmaceutical combination for use in the treatment of cancer according to  claims 1  to  26 , the use of (i) 2-(2′,3-dimethyl-[2,4′-bipyridin]-5-yl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide, or a pharmaceutically acceptable salt thereof, in combination with (ii) anti-PD-1 antibody molecule, or a pharmaceutically acceptable salt thereof, according to  claims 27  to  33 , or the method for the treatment of cancer according to  claims 34  to  36  wherein the cancer is triple-negative breast cancer (TNBC), head and neck squamous cell carcinoma, pancreatic cancer, gastrointestinal cancer, colorectal cancer, squamous cell cancer of the lung, squamous cell cancer of the esophagus, squamous cell cancer of the cervix or melanoma. 
     
     
         37 . The pharmaceutical combination for use in the treatment of cancer according to  claim 1  to  26  or  36 , the use of 2-(2′,3-dimethyl-[2,4′-bipyridin]-5-yl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide, or a pharmaceutically acceptable salt thereof, in combination with an anti-PD-1 antibody molecule, or a pharmaceutical salt thereof according to  claim 27  to  33  or  36 , or the method for the treatment of cancer according to  claims 34  to  36 , wherein the cancer is triple-negative breast cancer (TNBC), pancreatic cancer or melanoma. 
     
     
         38 . The pharmaceutical combination for use in the treatment of cancer according to  claim 1  to  26 ,  36  or  37 , the use of (i) 2-(2′,3-dimethyl-[2,4′-bipyridin]-5-yl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide, or a pharmaceutically acceptable salt thereof, in combination with (ii) anti-PD-1 antibody molecule, or a pharmaceutically acceptable salt thereof, according to  claim 27  to  33 ,  36  or  37 , or the method for the treatment of cancer according to  claims 34  to  37 , wherein (i) and (ii) are synergistically active at reducing bone resorption. 
     
     
         39 . The pharmaceutical combination for use in the treatment of cancer according to  claims 1  to  26 , or  36  to  38 , the use of (i) 2-(2′,3-dimethyl-[2,4′-bipyridin]-5-yl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide, or a pharmaceutically acceptable salt thereof, in combination with an anti-PD-1 antibody molecule, or a pharmaceutical salt thereof, according to  claims 27  to  33 , or  36  to  38 , or the method for the treatment of cancer according to  claims 34  to  38 , wherein (i) 2-(2′,3-dimethyl-[2,4′-bipyridin]-5-yl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide, or a pharmaceutically acceptable salt thereof, is administered orally or intravenously, most preferably orally. 
     
     
         40 . The pharmaceutical combination for use in the treatment of cancer according to  claims 1  to  26  or  36  to  39 , the use of (i) 2-(2′,3-dimethyl-[2,4′-bipyridin]-5-yl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide, or a pharmaceutically acceptable salt thereof, in combination with an anti-PD-1 antibody molecule according to  claims 27  to  33  or  36  to  39 , or the method for the treatment of cancer according to  claims 34  to  39 , wherein the anti-PD-1 antibody molecule (ii) is selected from nivolumab, pembrolizumab, pidilizumab, PDR-001, or a pharmaceutical salt thereof. 
     
     
         41 . The pharmaceutical combination for use in the treatment of cancer according to  claims 1  to  26  or  36  to  40 , the use of (i) 2-(2′,3-dimethyl-[2,4′-bipyridin]-5-yl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide, or a pharmaceutically acceptable salt thereof in combination with an anti-PD-1 antibody molecule according to  claims 27  to  33  or  36  to  40 , or a method for the treatment of cancer according to  claims 34  to  40 , wherein the anti-PD-1 antibody molecule (ii) is PDR-001, or a pharmaceutical salt thereof.