Low dose combination cda substrate drug/cedazuridine with extended administration

Abstract

This invention relates to methods and compositions for administering an effective amount of a CDA substrate drug and an effective amount of cedazuridine. In particular, the invention relates to methods for treating cancer, inhibiting degradation of a CDA substrate drug, and reducing DNA methylation in a subject in need thereof comprising administering an effective amount of a CDA substrate drug and an effective amount of cedazuridine.

1 - 7 . (canceled) 
     
     
         8 . A method of reducing DNA methylation (e.g., LINE-1 methylation) in a subject in need thereof, comprising administering to the subject:
 (i) an effective amount of a CDA substrate drug; and   (ii) an effective amount of cedazuridine,   
       thereby reducing DNA methylation in the subject. 
     
     
         9 . The method of  claim 8 , wherein the administering of (i) is concurrent with the administering of (ii) (e.g., immediately, e.g., as a single composition). 
     
     
         10 . The method of  claim 9 , wherein the administering is performed in one composition. 
     
     
         11 . The method of  claim 8 , wherein the administering of (i) is performed prior to the administering of (ii) (e.g., within 1, 2, or 3 hrs). 
     
     
         12 . The method of  claim 8 , wherein the administering of (ii) is performed prior to the administering of (i) (e.g., within 1, 2, or 3 hrs). 
     
     
         13 . The method of  claim 8 , wherein the administering steps (i) and (ii) are performed about 1 day to about 28 days per 28-day cycle (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 days per 28-day cycle). 
     
     
         14 . The method of  claim 8 , wherein the administering steps (i) and (ii) are performed on consecutive days per 28-day cycle (e.g., 3 days MTW, TWTh, WThF, etc.; 5 days MTWThF, etc.; 7 days, MTWThFSS); 14 days (e.g., two consecutive weeks); 21 days (e.g., three consecutive weeks). 
     
     
         15 . The method of  claim 8 , wherein the administering steps (i) and (ii) are performed on non-consecutive days per 28-day cycle (e.g., 3 days MWF; 10 days (5 d on, 2 d off, 5 d on); 14 days (7 d on, 7 d off, 7 d on). 
     
     
         16 - 19 . (canceled) 
     
     
         20 . The method of  claim 8 , wherein the CDA substrate drug is decitabine. 
     
     
         21 . The method of  claim 8 , wherein the CDA substrate drug is 5-azacytidine. 
     
     
         22 . The method of  claim 20 , wherein the effective amount of decitabine is from about 5 mg per dose to about 35 mg per dose (e.g., about 5, 10, 15, 20, 25, 30, or 35 mg or any value or range therein). 
     
     
         23 . The method of  claim 20 , wherein the effective amount of decitabine is from about 15 mg to about 150 mg cumulative per 28-day cycle of treatment (e.g., about 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 70, 80, 90, 100, 110, 120, 130, 140, or 150 mg or any value or range therein). 
     
     
         24 . The method of  claim 21 , wherein the effective amount of 5-azacytidine is from about 10 mg per dose to about 450 mg per dose (e.g., about 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 430, 435, 440, 445, or 450 mg or any value or range therein). 
     
     
         25 . The method of  claim 21 , wherein the effective amount of 5-azacytidine is from about 10 mg to about 3500 mg cumulative per 28-day cycle of treatment (e.g., about 10, 20, 30, 40, 50, 75, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1250, 1500, 2000, 2250, 2500, 2750, 3000, 3250, or 3500 mg or any value or range therein). 
     
     
         26 . The method of  claim 8 , wherein the effective amount of cedazuridine is from about 40 mg per dose to about 1000 mg per dose. 
     
     
         27 . The method of  claim 26 , wherein the effective amount of cedazuridine is about 100 mg per dose. 
     
     
         28 . The method of  claim 8 , wherein the effective amount of cedazuridine is from about 100 mg to about 7000 mg cumulative per 28-day cycle of treatment (e.g., about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 6925, 6950, 6975, or 7000 mg or any value or range therein). 
     
     
         29 - 30 . (canceled) 
     
     
         31 . The method of  claim 8 , wherein the administering reduces DNA methylation (e.g., LINE-1 methylation) in the subject by at least 5% (e.g., at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15% or more) as compared to DNA methylation in the subject prior to the administering (e.g., subject baseline DNA methylation, e.g., subject baseline LINE-1 methylation). 
     
     
         32 . The method of  claim 8 , wherein the CDA substrate drug and cedazuridine are administered intravenously, orally, or subcutaneously. 
     
     
         33 . The method of  claim 8 , wherein the subject is a mammal. 
     
     
         34 . The method of  claim 33 , wherein the subject is a human.