Phase I/II study of MDV3100 in patients (pts) with progressive castration-resistant prostate cancer (CRPC).
Sub-category:
Prostate Cancer
Category:
Genitourinary Cancer
Meeting:
2008 ASCO Annual Meeting
Abstract No:
5006
Citation:
J Clin Oncol 26: 2008 (May 20 suppl; abstr 5006)
Author(s):
H. I. Scher, T. M. Beer, C. S. Higano, D. C. Danila, B. Montgomery, J. Shelkey, M. Hirmand, D. Hung, C. Sawyers
Abstract:
Background: CRPC is characterized by persistent, high level androgen receptor (AR) expression and remains AR-dependent in model systems. MDV3100 is a novel small molecule AR antagonist selected for its ability to overcome resistance to conventional antiandrogens in the setting of increased AR expression. Unlike bicalutamide, MDV3100 inhibits AR function by blocking nuclear translocation, DNA binding, and has no agonist activity when AR is overexpressed. A first-in-man, multi-center Phase I/II dose-escalation study was started in July 2007 to assess safety and pharmacokinetics (PK), and to evaluate antitumor effects including changes in prostate-specific antigen (PSA). Methods: MDV3100 was administered orally, once daily, to pts with CRPC. Three pts were enrolled per dose-escalation cohort starting at 30 mg. Once the safety of a dose was established, enrollment was expanded for that dose beginning at the 60 mg cohort. Results: To date, a total of 39 pts have been enrolled. Tabular summary of enrolled pts is as follows: MDV3100 has been well-tolerated to date, with no significant adverse events. PK are linear with dose with a half-life of approximately one week. In the 30 mg cohort, 3 of 3 Pts had PSA declines of 44% to 87% from baseline for 19+ weeks, and at 60 mg, 3 of 3 pts declines of 74% to 96% for 14+ weeks. None of the 6 showed evidence of clinical or radiographic progression. Overall 13 of 14 Pts followed for 4+ weeks have had PSA declines. Conclusions: MDV3100, a rationally designed AR antagonist with a novel mechanism of action, has resulted in PSA reductions in a high proportion of evaluable pts. The drug has been well-tolerated to date and appears to be a promising candidate for the treatment of progressive CRPC. Pt accrual is ongoing.
Cohort Number
Chemotherapy-
Naive Number
Post-
Chemotherapy Follow-up
(Weeks) Status
Dose Escalation
30 mg 3 0 19+ All on therapy
60 mg 3 0 14+ All on therapy
150 mg 2 1 8+ 2 of 3 on therapy
240 mg 3 0 2+ All on therapy
Dose Expansion
60 mg 11 7 3+-6+ All on therapy
150 mg 3 6 2+-3+ All on therapy |
