Dosage regimen for an alpha-isoform selective phosphatidylinositol 3-kinase inhibitor

Abstract

The present invention relates to methods of treating or preventing a proliferative disease in a patient in need thereof by orally administering a therapeutically effective amount of an alpha-isoform selective phosphatidylinositol 3-kinase inhibitor compound of formula (I) or a pharmaceutically acceptable salt thereof for at least two five-consecutive day cycle, wherein said compound is not administered to the patient for a period of about two days to about three days between said five-consecutive day cycles; the use of said compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing a proliferative disease administered in accordance with said dosage regimen; therapeutic regimen comprising administration of said compound of formula (I) or a pharmaceutically acceptable salt thereof in accordance with said dosage regimen; and related pharmaceutical compositions and packages thereof.

1 . A method of treating or preventing a proliferative disease in a patient in need thereof, comprising orally administering a therapeutically effective amount of the compound of formula (I) 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof to the patient in a daily dose of about 100 mg to about 450 mg for at least two five-consecutive day cycles, wherein said compound or a pharmaceutically acceptable salt thereof is not administered to the patient for a period of about 2 days to about 3 days between one five-consecutive day cycle and its subsequent five-consecutive day cycle. 
     
     
         2 . A method of treating or preventing a proliferative disease comprising first administering to a patient in need thereof a compound of formula (I) according to  claim 1  or a pharmaceutically acceptable salt thereof in amount of about 100 mg to about 450 mg daily on a continuous daily schedule via oral administration, second determining said patient has a side effect selected from neutropenia, elevated bilirubin, cardiac toxicity, unstable angina, myocardial infarction, persistent hypertension, peripheral sensory or motor neuropathy/pain, hepatic dysfunction, reduced red and/or white blood cell count, hyperglycemia, nausea, decreased appetite, diarrhea, rash and hypersensitivity, photosensitivity, asthenia/fatigue, vomiting, stomatitis, oral mucositis, pancreatitis, dysgeusia, and dyspepsia after administration of said compound of formula (I) or a pharmaceutically acceptable salt thereof to said patient, and third reducing the administration of said compound of formula (I) or a pharmaceutically acceptable salt thereof to a daily dose of about 100 mg to about 450 mg via oral administration for at least two five-consecutive day cycles via oral administration, wherein said compound or a pharmaceutically acceptable salt thereof is not administered to the patient for a period of about 2 days to about 3 days between one five-consecutive day cycle and its subsequent five-consecutive day cycle. 
     
     
         3 . (canceled) 
     
     
         4 . A method according to  claim 1 , wherein the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is about 200 mg to about 400 mg. 
     
     
         5 . A method according to  claim 1 , wherein the compound of formula (I) or a pharmaceutically acceptable salt is orally administered once per day (q.d.) in a daily dose of about 100 mg to about 450 mg for at least two five-consecutive day cycles. 
     
     
         6 . A method according to  claim 1 , wherein the compound of formula (I) or a pharmaceutically acceptable salt is orally administered twice per day (b.i.d) in a daily dose of about 100 mg to about 450 mg for at least two five-consecutive day cycles. 
     
     
         7 . A method according to any one of  claims 1  to  6 , wherein said compound or a pharmaceutically acceptable salt thereof is not administered to the patient for a period of about 2 days between one five-consecutive day cycle and its subsequent five-consecutive day cycle. 
     
     
         8 . A method according to  claim 5 , wherein said compound or a pharmaceutically acceptable salt thereof is not administered to the patient for a period of about 3 days between the last administration of said compound or a pharmaceutically acceptable salt thereof in one five-consecutive day cycle and the first administration of said compound or a pharmaceutically acceptable salt thereof in its subsequent five-consecutive day cycle. 
     
     
         9 . A method according to  claim 6 , wherein said compound or a pharmaceutically acceptable salt thereof is not administered to the patient for a period of about 2.5 days between the last administration of said compound or a pharmaceutically acceptable salt thereof in one five-consecutive day cycle and the first administration of said compound or a pharmaceutically acceptable salt thereof in its subsequent five-consecutive day cycle. 
     
     
         10 . A method according to  claim 1 , wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in two or more of said five-consecutive day cycles until the relief, reduction, or alleviation of the severity, occurrence rate, or frequency of at least one side effect in said patient. 
     
     
         11 . A method according to  claim 10 , wherein the side effect is a condition selected from neutropenia, elevated bilirubin, cardiac toxicity, unstable angina, myocardial infarction, persistent hypertension, peripheral sensory or motor neuropathy/pain, hepatic dysfunction, reduced red and/or white blood cell count, hyperglycemia, nausea, decreased appetite, diarrhea, rash (e.g, maculopapular, acneiform, etc.) and hypersensitivity (e.g., increased sensitivity to bruise), photosensitivity, asthenia/fatigue, vomiting, stomatitis, oral mucositis, pancreatitis, dysgeusia, and dyspepsia. 
     
     
         12 . A method according to  claim 1 , wherein the proliferative disease is a cancer. 
     
     
         13 . A method according to  claim 1 , wherein the proliferative disease is a cancer selected from a cancer of the lung, bronchus, prostate, breast (including sporadic breast cancers and sufferers of Cowden disease), colon, rectum, colon carcinoma, colorectal adenoma, pancreas, gastrointestine, hepatocellular, stomach, gastric, ovary, squamous cell carcinoma, and head and neck. 
     
     
         14 . A method according to  claim 1 , wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with at least one additional therapeutic agent. 
     
     
         15 . (canceled) 
     
     
         16 . A package comprising a pharmaceutical composition comprising a compound of formula (I) according to  claim 1  or a pharmaceutically acceptable salt thereof in a daily dose of about 100 mg to about 450 mg together with one or more pharmaceutically acceptable excipients in combination with instructions to orally administer said pharmaceutical composition for at least two five-consecutive day cycles and to not administered said composition for a period of about 2 days to about 3 days between one five-consecutive day cycle and its subsequent five-consecutive day cycle.