Dosing regimens for use in treating myelofibrosis and mpn-related disorders with navitoclax

Abstract

The invention described herein relates to methods for treating a human subject with myelofibrosis or an MPN-related disorder, comprising administering navitoclax to the subject optionally in combination with ruxolitinib.

1 - 36 . (canceled) 
     
     
         37 . A method for treatment of myelofibrosis in a human subject in need thereof, comprising orally administering to said subject an effective amount of navitoclax in combination with an effective amount of ruxolitinib, wherein
 (i) if the human subject has a baseline platelet count of greater than or equal to 150×10 9 /L, the effective amount of navitoclax comprises 200 mg once daily, and if the human subject has a baseline platelet count of less than 150×10 9 /L, the effective amount of navitoclax comprises 100 mg once daily, escalated to 200 mg once daily after 7 days or more if the human subject has a platelet count greater than or equal to 75×10 9 /L, and   (ii) the effective amount of ruxolitinib comprises 10 mg twice daily;   
       wherein the effective amount of navitoclax is optionally increased to 300 mg once daily if the human subject fails to achieve spleen reduction volume of at least 35% (SVR 35 ) by week 24 of treatment. 
     
     
         38 . The method of  claim 37 , wherein the myelofibrosis comprises relapsed/refractory (R/R), intermediate or high-risk primary or secondary myelofibrosis, post-polycythemia vera or post-essential thrombocytopenia myelofibrosis. 
     
     
         39 . The method of  claim 37 , wherein the effective amount of navitoclax is optionally modified or interrupted due to thrombocytopenia or neutropenia. 
     
     
         40 . The method of  claim 39 , wherein
 (i) if the subject has a platelet count between 75×10 9 /L and greater than or equal to 50×10 9 /L the effective amount of navitoclax is optionally reduced;   (ii) if the subject has a platelet count less than 50×10 9 /L, the navitoclax is interrupted or discontinued until platelets levels stabilize above a level greater than or equal to 50×10 9 /L;   (iii) if the subject has an absolute neutrophil count (ANC) less than 1.0 but greater than 0.5×10 9 /L, the subject is optionally supported with G-CSF or antibiotics until ANC is greater than 1.0×10 9 /L; and   (iv) if the subject has an absolute neutrophil count (ANC) less than 0.5×10 9 /L, the subject is optionally supported with G-CSF or antibiotics until ANC is greater than 1.0×10 9 /L and navitoclax is interrupted or discontinued until ANC is greater than 1.0×10 9 /L.   
     
     
         41 . The method of  claim 37 , wherein the effective amount of ruxolitinib is modified or interrupted due to thrombocytopenia. 
     
     
         42 . A method for treatment of myelofibrosis in a human subject in need thereof, comprising
 (a) obtaining a baseline platelet count from said human subject; and   (b) orally administering to said subject an effective amount of navitoclax in combination with an effective amount of ruxolitinib, wherein   (i) if the human subject has a baseline platelet count of greater than or equal to 150×10 9 /L, the effective amount of navitoclax comprises 200 mg once daily, and if the human subject has a baseline platelet count of less than 150×10 9 /L, the effective amount of navitoclax comprises 100 mg once daily, escalated to 200 mg once daily after 7 days or more if the human subject has a platelet count greater than or equal to 75×10 9 /L, and   (ii) the effective amount of ruxolitinib comprises 10 mg twice daily;   
       wherein the effective amount of navitoclax is optionally increased to 300 mg once daily if the human subject fails to achieve spleen reduction volume of at least 35% (SVR 35 ) by week 24 of treatment. 
     
     
         43 . The method of  claim 42 , wherein the myelofibrosis comprises relapsed/refractory (R/R), intermediate or high-risk primary or secondary myelofibrosis, post-polycythemia vera or post-essential thrombocytopenia myelofibrosis. 
     
     
         44 . The method of  claim 42 , wherein the effective amount of navitoclax is optionally modified or interrupted due to thrombocytopenia or neutropenia. 
     
     
         45 . The method of  claim 44 , wherein
 (i) if the subject has a platelet count between 75×10 9 /L and greater than or equal to 50×10 9 /L the effective amount of navitoclax is optionally reduced;   (ii) if the subject has a platelet count less than 50×10 9 /L, the navitoclax is interrupted or discontinued until platelets levels stabilize above a level greater than or equal to 50×10 9 /L;   (iii) if the subject has an absolute neutrophil count (ANC) less than 1.0 but greater than 0.5×10 9 /L, the subject is optionally supported with G-CSF or antibiotics until ANC is greater than 1.0×10 9 /L; and   (iv) if the subject has an absolute neutrophil count (ANC) less than 0.5×10 9 /L, the subject is optionally supported with G-CSF or antibiotics until ANC is greater than 1.0×10 9 /L and navitoclax is interrupted or discontinued until ANC is greater than 1.0×10 9 /L.   
     
     
         46 . The method of  claim 45 , wherein the effective amount of ruxolitinib is modified or interrupted due to thrombocytopenia.