Phase II study of first-line sagopilone plus prednisone in patients with castration-resistant prostate cancer: a phase II study of the Department of Defense Prostate Cancer Clinical Trials Consortium

Abstract

Background:Preclinical studies in prostate cancer (PC) models demonstrated the anti-tumour activity of the first fully synthetic epothilone, sagopilone. This is the first study to investigate the activity and safety of sagopilone in patients with metastatic castration-resistant PC (CRPC).Methods:Chemotherapy-naïve patients with metastatic CRPC received sagopilone (one cycle: 16 mg m−2 intravenously over 3 h q3w) plus prednisone (5 mg twice daily). The primary efficacy evaluation was prostate-specific antigen (PSA) response rate (⩾50% PSA reduction confirmed ⩾28 days apart). According to the Simon two-stage design, ⩾3 PSA responders were necessary within the first 13 evaluable patients for recruitment to continue until 46 evaluable patients were available.Results:In all, 53 patients received ⩾2 study medication cycles, with high compliance. Mean individual dose was 15.1±1.4 mg m−2 during initial six cycles, mean dose intensity 94±9%. The confirmed PSA response rate was 37%. Median overall progression-free survival was 6.4 months. The most commonly reported adverse events (>10% of patients) were peripheral neuropathy (94.3%), fatigue (54.7%) and pain in the extremities (47.2%). Sagopilone was associated with very little haematological toxicity.Conclusion:This study shows that first-line sagopilone has noteworthy anti-tumour activity and a clinically significant level of neuropathy for patients with metastatic chemotherapy-naïve CRPC.

Perspectives on Treatment of Metastatic Castration-Resistant Prostate Cancer

“…In contrast to Europe, abiraterone acetate plus prednisone may now be given earlier in the disease and enzalutamide is also available for patients after docetaxel as an alternative to cabazitaxel in the U.S. Many more drugs are currently being investigated in phase I/II studies of CRPC including tyrosine kinase inhibitors (sunitinib [96], sorafinib [97]), estrogens [98,99], antisense molecules (OGX-011 [99]), immunotherapies (Biosante Pharmaceuticals, USA [101], Bavarian Nordic, Denmark [102]), a selective inhibitor of CYP17 (orteronel [103]), novel antiandrogens (ARN-509 [104], ODM-201 [105]), antiangiogenesis agents (lenalidomide [106 -108]), and epothilones [109]. In addition, Src kinase inhibitors are being investigated for mCRPC; however, when dasatanib was The negative result from the READY study adds to the growing list of drugs that have failed to report an OS benefit.…”

Epothilones

“…78 A PSA (prostate-specific antigen) response of 37% was observed in the prostate trial, but in the presence of significant neuropathy; the study would have been considered positive for a PSA response of 43%. 79 Phase II studies were also conducted in patients with non-small cell lung cancer (NSCLC) 80 or melanoma. 81 In contrast to other epothilones, sagopilone (3) was found to be active against melanoma even in pretreated patients with an objective response rate of 11.4% (one confirmed complete response, two confirmed partial responses, and one unconfirmed partial response).…”

“…[74][75][76] In 2008 sagopilone (3) entered Phase II clinical trials for the treatment of different cancers, such as platinum-resistant 77 and recurrent platinum sensitive ovarian cancer (in combination with carboplatin) 78 or androgen-independent prostate cancer (in combination with prednisone). 79 In the ovarian trial the primary efficacy end point was met (29 responders out of a total of 45 patients), while toxicities where manageable. 78 A PSA (prostate-specific antigen) response of 37% was observed in the prostate trial, but in the presence of significant neuropathy; the study would have been considered positive for a PSA response of 43%.…”

Rational Categorization of the Pipeline of New Treatments for Advanced Cancer – Prostate Cancer as an Example

“…Clinical development of several members of this family in prostate cancer continues. Patupilone or naturally occurring Epothilone B and sagopilone (a fully synthetic compound) have also shown activity in post docetaxel and chemo naïve CRPC patients respectively [12,13].…”