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 proliferation disorder in a subject, comprising orally administering a composition comprising a Hedgehog pathway (HhP) inhibitor to the subject, wherein 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. 
     
     
         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 1 , wherein the HhP inhibitor comprises an itraconazole analogue in which the native sec-butyl side chain has been replaced with one or more moieties, relative to itraconazole. 
     
     
         6 . The method of  claim 5 , wherein the native sec-butyl side chain is replaced with C 1 -C 8  alkyl, C 2 -C 8  alkenyl, or C 2 -C 8  alkynyl, that are straight, branched, or cyclic, and are unsubstituted or substituted one or more times at any position with a C 1 -C 8  alkoxy, C 6 -C 10  aryl, N 3 , OH, Cl, Br, I, F, C 6 -C 10  aryl oxy, C 1 -C 8  alkyl carboxy, aryl carboxy, wherein any substituent can be further substituted with any of the foregoing. 
     
     
         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 . (canceled) 
     
     
         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 . The method of  claim 1 , wherein the proliferation disorder is cancer. 
     
     
         15 . The method of  claim 1 , wherein the proliferation disorder is prostate cancer and said method further comprises comparing the level of prostate-specific antigen (PSA) in a sample obtained from the subject following administration of the HhP inhibitor with a reference level of PSA, and wherein the level of PSA in the sample compared to the reference level of PSA is prognostic for an outcome of treatment with the HhP inhibitor. 
     
     
         16 . The method of  claim 1 , further comprising monitoring the proliferation disorder in the subject, wherein a lack of clinical response in the proliferation disorder to the treatment is indicative that the plasma trough level of the HhP inhibitor should be increased further above about 1000 ng/mL, and wherein the occurrence of a clinical response and a plasma trough level of the HhP inhibitor substantially higher than about 1000 ng/mL indicates that one or more subsequent doses of the HhP inhibitor can be reduced. 
     
     
         17 . The method of  claim 1 , further comprising monitoring the proliferation disorder in the subject, wherein a lack of clinical response in the proliferation disorder to the treatment, after about four weeks of said administering, is indicative of a need to increase the dose of the HhP inhibitor, or increase the frequency of the dose of the HhP inhibitor, or administer an additional HhP inhibitor that inhibits the HhP by a different mechanism than the previously administered HhP inhibitor, or a combination of two or more of the foregoing. 
     
     
         18 . The method of  claim 1 , wherein the proliferation disorder is prostate cancer, 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. 
     
     
         19 . The method of  claim 1 , wherein the proliferation disorder is basal cell carcinoma, 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. 
     
     
         20 . The method of  claim 1 , wherein the proliferation disorder is lung cancer, wherein the composition comprises a SUBA® formulation of itraconazole, or a pharmaceutically acceptable salt, prodrug, stereoisomer, or active metabolite thereof, wherein the SUBA® formulation is orally administered at a dose in the range of 100 mg to 600 mg per day, and wherein the method further comprises administering an antifolate and a platinum-based chemotherapeutic agent to the subject. 
     
     
         21 . A method for treating a proliferation disorder in a subject, comprising orally administering a composition comprising a Hedgehog pathway (HhP) inhibitor to the subject, wherein the HhP inhibitor comprises itraconazole, or a pharmaceutically acceptable salt, prodrug, stereoisomer, or active metabolite thereof, and wherein the composition is a SUBA® formulation and the HhP inhibitor is administered at a dose in the range of 100 mg to 600 mg per day.