Androgen receptor modulator and uses thereof

Abstract

Described herein is the androgen receptor modulator of formula (I) in the treatment of prostate cancer in combination with other therapeutic options and in the treatment of diseases or conditions that are amenable to treatment with the androgen receptor modulator, as well as pharmaceutical compositions and medicaments that include such compound.

What is claimed is: 
     
         1 . A method of treating metastatic castration-resistant prostate cancer, non-metastatic castration-resistant prostate cancer, metastatic castration-sensitive prostate cancer, non-metastatic castration-sensitive prostate cancer or high-risk localized prostate cancer in a male human patient comprising orally administering the compound of Formula (I), or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
       
       to a human male patient in need of such treatment at a dose of about 30 mg per day to about 480 mg per day, in combination with:
 (a) abiraterone acetate (Zytiga); 
 (b) Ipilimumab; 
 (c) everolimus; 
 (d) leuprolide or leuprolide acetate (Lupron or Eligard); or 
 (e) goserelin acetate (Zoladex). 
 
     
     
         2 . The method of  claim 1 , wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
       
       is administered in combination with abiraterone acetate (Zytiga) at a dose in a range of from about 500 mg per day to about 1000 mg per day together with prednisone at a dose of about 5 mg twice per day. 
     
     
         3 . The method of  claim 1 , wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
       
       is administered in combination Ipilimumab, administered by intravenous infusion at a dose of about 1.5 mg/Kg to about 3.0 mg/kg IV every 3 weeks for a total of 4 doses. 
     
     
         4 . The method of  claim 1 , wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
       
       is administered in combination with everolimus, administered at a dose of about 5 mg per day to about 20 mg per day. 
     
     
         5 . The method of  claim 1 , wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
       
       is administered in combination with leuprolide or leuprolide acetate (Lupron or Eligard), administered as a depot injection at a dose of about 7.5 mg every 4 weeks, or 22.5 mg every 3 months, or about 30 mg every 4 months, or about 45 mg every 6 months. 
     
     
         6 . The method of  claim 1 , wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
       
       is administered in combination with goserelin acetate (Zoladex), administered as a subcutaneous implant at a dose of about 3.6 mg every 4 weeks or about 10.8 mg every 12 weeks. 
     
     
         7 . A method of treating metastatic castration-resistant prostate cancer, or high-risk localized prostate cancer in a male human patient comprising orally administering the compound of Formula (I), or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
       
       to a human male patient in need of such treatment at a dose of about 30 mg per day to about 480 mg per day, in combination with a taxane or tubulin inhibitor, comprising Docetaxel or Cabazitaxel. 
     
     
         8 . The method of  claim 7 , wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
       
       is administered in combination with Docetaxel, administered by intravenous infusion at a dose of about 35 mg/m 2  to about 75 mg/m 2  every 3 weeks 
     
     
         9 . The method of  claim 7 , wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
       
       is administered in combination with Cabazitaxel administered by intravenous infusion at a dose of about 13 mg/m 2  to about 25 mg/m 2  every 3 weeks 
     
     
         10 . A method of treating metastatic castration-resistant prostate cancer, non-metastatic castration-resistant prostate cancer, metastatic castration-sensitive prostate cancer, non-metastatic castration-sensitive prostate cancer or high-risk localized prostate cancer in a male human patient comprising orally administering the compound of Formula (I), or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
       
       to a human male patient in need of such treatment at a dose of about 30 mg per day to about 480 mg per day, in combination with:
 (a) a CYP17 inhibitor, wherein the CYP17 inhibitor is:
 (i) abiraterone acetate (Zytiga) administered at a dose in a range of from about 500 mg per day to about 1000 mg per day together with prednisone at a dose of about 5 mg twice per day; or 
 (ii) TAK-700 (orteronel) administered at a dose in a range of from about 300 mg twice per day to about 600 mg twice per day together with prednisone at about 5 mg twice per day; or 
 (iii) TOK-001 (galeterone); or 
 (iv) VT-464; or 
 
 (b) an osteoprotective agent, that is:
 (i) Denosumab, administered by subcutaneous injection at a dose of about 60 mg to about 120 mg every 4 weeks to every 6 months; or 
 (ii) Zoledronic acid, it is administered by intravenous infusion at a dose of about 4 mg 5 every 4 weeks to every 12 weeks; or 
 (iii) AMG-0007, CEP-37251, ALX-0141, Alendronate sodium (Fosamax), Pamidronate disodium (Aredia), Neridronic acid (Nerixia), Minodronic acid (Recalbon) or Risedronate sodium (Actonel); or 
 
 (c) a radiation therapy that comprises:
 (i) Alpharadin, administered by intravenous infusion at a dose of about 25 to about 50 kBq/kg every 4 weeks; 
 (ii) 177 Lu-J591, administered by intravenous infusion at a dose of about 30 mCi/m 2  to about 70 mCi/m 2 ; or 
 (iii) external beam radiation therapy (including Proton beam), or brachytherapy; or 
 
 (d) Provenge administered in 3 doses at approximately 2 weeks interval; or 
 (e) Prostvac administered by subcutaneous injection Ipilimumab; or 
 (f) BMS-936558 administered by intravenous infusion at a dose of about 1.0 mg/kg to about 10 mg/kg on days 1, 15 and 29 of 6-week cycles; or 
 (g) Ipilimumab administered by intravenous infusion at a dose of about 1.5 mg/Kg to about 3.0 mg/kg IV every 3 weeks for a total of 4 doses; or 
 (h) an anti-STEAP-1 antibody drug conjugate, comprising RG7450 (DSTP3086S); or 
 (i) a HSP90 or HSP27 pathway modulator, comprising:
 (i) OGX-011 (Custirsen), administered by intravenous infusion at a dose of about 320 mg to about 640 mg every week; or 
 (ii) OGX-427, administered by intravenous infusion at a loading dose of about 300 mg to about 600 mg followed by about 500 mg to about 1000 mg every week, 
 (iii) AUY922, HSP990, PF-04928473, PF-04929113 (SNX-5422), Retaspimycin or AT13387. 
 
 
     
     
         11 . The method of  claim 10 , further comprising administering a therapeutically effective amount of a gonadotropin-releasing hormone agonist or antagonist to the male human patient. 
     
     
         12 . A method of treating post-abiraterone acetate treated metastatic castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, non-metastatic castration-resistant prostate cancer, metastatic castration-sensitive prostate cancer, non-metastatic castration-sensitive prostate cancer or high-risk localized prostate cancer in a male human patient comprising orally administering the compound of Formula (I), or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       to a human male patient in need of such treatment at a dose of about 30 mg per day to about 480 mg per day in combination with:
 (a) a phosphoinositide 3-kinase (PI3K) inhibitor, TORC inhibitor, or dual PI3K/TORC inhibitor, that comprises everolimus, BEZ-235, BKM120, BGT226, BYL-719, GDC0068, GDC-0980, GDC0941, GDC0032, MK-2206, OSI-027, CC-223, AZD8055, SAR245408, SAR245409, PF04691502, WYE125132, GSK2126458, GSK-2636771, BAY806946, PF-05212384, SF1126, PX866, AMG319, ZSTK474, Cal101, PWT33597, LY-317615 (enzastaurin hydrochloride), CU-906, or CUDC-907, and if the TORC inhibitor is everolimus, it is administered at a dose of about 5 mg per day to about 20 mg per day; or 
 (b) a kinase inhibitor, comprising:
 (i) a MET or VEGFR kinase inhibitor, comprising Cabozantinib (XL184), PF-2341066 (Crizotinib), ARQ-197 (Tivantinib), MK-2461, JNJ-38877605, MK-8033, INCB-28060, BMS-777607, AMG-208, LY-2801653, EMD-1214063, EMD-1204831, AMG-337, HMPL-504 (Volitinib), SAR-125844, LY2875358, ABR-215050 (Tasquinimod), CHIR-258 (Dovitinib), EXEL-7647, OSI-930, BIBF-1120, BAY-73-4506 (Regorafenib), BMS-582664 (Brivanib), JNJ-26483327, AZD-2171 (Cediranib), Sorafenib, Aflibercept, Enzastaurin, AG-013736 (Axitinib), OSI-632, or GSK-786034 (Pazopanib), and if Cabozantinib, it is administered orally at a dose of about 40 mg per day to about 100 mg per day; or 
 (ii) an EGFR, MEK, or SRC kinase inhibitor, comprising Erlotinib, Cetuximab, Gefitinib, Canertinib, Panitumumab, Nimotuzumab, Lapatinib, Vandetanib, Afatinib, MP-412, AEE-788, Neratinib, XL-647, AC-480, Dacomitinib, AZD-8931, CUDC-101, AP-26113, CO-1686, Trametinib, Selumetinib, MEK-162, Refametinib, TAK-733, RO-5126766, BI-847325, AZD6244, GSK1120212, PF-5208763 (Bosutinib), or AZD-0530 (Saracatinib), and if Erlotinib, it is administered orally at a dose in a range of from about 100 mg to about 150 mg; and if Gefitinib, it is administered orally at a dose of about 250 mg; and if Trametinib, it is administered orally at a dose of about 1 mg to about 2 mg; or 
 (iii) an AKT, RAF, FGFR, or CDK4/6 kinase inhibitor, comprising GDC0068, MK-2206, AT7867, GSK2110183, GSK2141795, GSK690693, Vemurafenib (PLX4032/RG7204), GSK2118436, Dabrafenib (GSK208436), LGX818, RAF265, LY2780301, Dovitinib (TKI258), BGJ398, AZD4547, PD-0332991 or LEE011. 
 
 
     
     
         13 . The method of  claim 12 , further comprising administering a therapeutically effective amount of a gonadotropin-releasing hormone agonist or antagonist to the male human. 
     
     
         14 . A method of treating metastatic castration-resistant prostate cancer, non-metastatic castration-resistant prostate cancer, metastatic castration-sensitive prostate cancer, non-metastatic castration-sensitive prostate cancer or high-risk localized prostate cancer in a male human patient comprising orally administering the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a human male patient in need of such treatment at a dose of about 30 mg per day to about 480 mg per day, 
       
         
           
           
               
               
           
         
       
       in combination with a gonadotropin-releasing hormone agonist or antagonist, comprising Lupron, Zoladex (Goserelin), Degarelix, Ozarelix, ABT-620 (Elagolix), TAK-385 (Relugolix), EP-100 or KLH-2109, and if Lupron, it is administered as a depot injection at a dose of about 7.5 mg every 4 weeks, or 22.5 mg every 3 months, or about 30 mg every 4 months, or about 45 mg every 6 months, and if Zoladex (Goserelin), it is administered as a subcutaneous implant at a dose of about 3.6 mg every 4 weeks or about 10.8 mg every 12 weeks, and if Degarelix, it is administered as a subcutaneous injection at a dose of about 240 mg followed by about 80 mg administered every 4 weeks. 
     
     
         15 . A method of treating breast cancer, androgen dependent hirsutism, androgenic alopecia, uterine fibroids, leiomyoma, endometrial carcinoma or endometriosis in a human patient, said method comprising orally administering the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a human patient in need of such treatment at a dose in a range of from about 30 mg per day to about 480 mg per day on a continuous daily dosing schedule 
       
         
           
           
               
               
           
         
       
     
     
         16 . The method of  claim 15 , further comprising administering a therapeutically effective amount of a gonadotropin-releasing hormone agonist or antagonist to the male human patient. 
     
     
         17 . A method of treating a male human patient having advanced castration-sensitive prostate cancer, castration-resistant prostate cancer, or high-risk localized prostate cancer comprising administering the compound of Formula (I), 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, at a dose in a range of from about 30 mg per day to about 480 mg per day to a male human patient in need of such treatment. 
     
     
         18 . The method of  claim 17 , wherein the treating results in a decrease in the patient's prostate-specific antigen levels of at least 50% from baseline after 3 months of the compound of Formula (I), 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, on a continuous daily dosing schedule.