Treatment and prognostic monitoring of proliferation disorders using hedgehog pathway inhibitors

Abstract

The present invention concerns methods for treating a proliferation disorder, such as prostate cancer, basal cell carcinoma, lung cancer, and other cancers, using an inhibitor of the Hedgehog pathway (HhP); and methods for monitoring subjects undergoing such treatments based on biomarkers and other criteria predictive of efficacy.

1 . A method for treating a non-cancerous proliferation disorder in a subject, comprising orally administering a composition comprising a Hedgehog pathway (HhP) inhibitor to the subject, wherein: (a) the composition is orally administered in an effective amount to achieve a plasma trough level of at least about 1,000 ng/mL of the HhP inhibitor; or (b) the composition is orally administered at a dose in the range of 100 mg to 600 mg HhP inhibitor per day. 
     
     
         2 . The method of  claim 1 , wherein the HhP inhibitor comprises itraconazole, or a pharmaceutically acceptable salt, prodrug, stereoisomer, or active metabolite thereof. 
     
     
         3 . The method of  claim 2 , wherein the composition comprises a SUBA® formulation of itraconazole, or a pharmaceutically acceptable salt, prodrug, stereoisomer, or active metabolite thereof; and wherein the SUBA® formulation is orally administered at a dose in the range of 100 mg to 600 mg per day. 
     
     
         4 . The method of  claim 2 , wherein the HhP inhibitor therapy comprises administration of a capsule or powder of 50 mg of the itraconazole, or a pharmaceutically acceptable salt, prodrug, stereoisomer, or active metabolite thereof, twice per day. 
     
     
         5 . The method of  claim 3 , wherein the SUBA® formulation is a Suba-CAP formulation. 
     
     
         6 . The method of  claim 1 , wherein the composition is administered in an effective amount to achieve a plasma trough level of at least 1,000 ng/mL of the HhP inhibitor. 
     
     
         7 . The method of  claim 1 , wherein the composition is administered in an effective amount to achieve a plasma trough level of at least about 1,000 ng/mL of the HhP inhibitor after about 4 weeks of initiation of treatment with the HhP inhibitor. 
     
     
         8 . The method of  claim 1 , wherein the composition is administered in an effective amount to achieve a plasma trough level of at least about 1,000 ng/mL of the HhP inhibitor within about 2 weeks after initiation of treatment, and to maintain the plasma trough level of at least about 1,000 ng/mL of the HhP inhibitor for the duration of the treatment. 
     
     
         9 . The method of  claim 1 , further comprising measuring the plasma level of the HhP inhibitor, or a metabolite thereof, in the subject one or more times. 
     
     
         10 . The method of  claim 9 , wherein said measuring is carried out one or more times about 4 weeks after initiation of treatment with the HhP inhibitor. 
     
     
         11 . The method of  claim 1 , further comprising measuring the plasma level of the HhP inhibitor, or a metabolite thereof, one or more times in a period of time from about 4 weeks to about 12 weeks. 
     
     
         12 . The method of  claim 11 , further comprising increasing a subsequent dose of the HhP inhibitor if the plasma trough level of at least about 1,000 ng/mL of the HhP inhibitor is not maintained. 
     
     
         13 . The method of  claim 11 , further comprising reducing a subsequent dose of an HhP inhibitor if the plasma trough level at about 4 weeks is at least 1000 ng/mL and the patient is experiencing one or more side effects. 
     
     
         14 - 20 . (canceled) 
     
     
         21 . The method of  claim 1 , wherein the orally administered composition is in the form of a capsule comprising a solid dispersion of an HhP inhibitor and at least one polymer having one or more acidic functional groups. 
     
     
         22 . The method of  claim 21 , wherein the polymer is a polycarboxylic acid polymer. 
     
     
         23 . The method of  claim 22 , wherein the polycarboxylic acid polymer is hypromellose phthalate (hydroxypropyl methylcellulose phthalate). 
     
     
         24 . The method of  claim 1 , wherein the non-cancerous proliferation disorder is smooth muscle cell proliferation, systemic sclerosis, cirrhosis of the liver, adult respiratory distress syndrome, idiopathic cardiomyopathy, lupus erythematosus, retinopathy, cardiac hyperplasia, benign prostatic hyperplasia, ovarian cyst, pulmonary fibrosis, endometriosis, fibromatosis, hamartomas, lymphangiomatosis, sarcoidosis, or desmoid tumors. 
     
     
         25 . The method of  claim 1 , wherein the non-cancerous proliferation disorder is a hyperproliferation of cells in the skin, Reiter's syndrome, pityriasis rubra pilaris, scleroderma, seborrheic keratoses, intraepidermal nevi, common wart, or benign epithelial tumor. 
     
     
         26 . The method of  claim 1 , wherein the non-cancerous proliferation disorder is a hyper-proliferative variant of a disorder of keratinization.