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Clinical Trial
. 2011 Feb 15;17(4):880-7.
doi: 10.1158/1078-0432.CCR-10-2955. Epub 2010 Dec 3.

Phase I dose-escalation study of the novel antiandrogen BMS-641988 in patients with castration-resistant prostate cancer

Dana Rathkopf  1 , Glenn Liu, Michael A Carducci, Mario A Eisenberger, Aseem Anand, Michael J Morris, Susan F Slovin, Yasutsuna Sasaki, Shunji Takahashi, Seiichiro Ozono, Nga Kit Eliza Fung, Shinta Cheng, Jinping Gan, Marco Gottardis, Mary T Obermeier, Jyotsna Reddy, Steven Zhang, Blisse J Vakkalagadda, Leila Alland, George Wilding, Howard I Scher; Prostate Cancer Clinical Trials Consortium
Affiliations
Clinical Trial

Phase I dose-escalation study of the novel antiandrogen BMS-641988 in patients with castration-resistant prostate cancer

Dana Rathkopf et al. Clin Cancer Res. .

Abstract

Purpose: BMS-641988 is an androgen receptor antagonist with increased potency relative to bicalutamide in both in vitro and in vivo prostate cancer models. A first-in-man phase I study was conducted to define the safety and tolerability of oral BMS-641988 in patients with castration-resistant prostate cancer (CRPC).

Experimental design: Doses were escalated from 5 to 150 mg based on discrete pharmacokinetic parameters in cohorts of three to six subjects. After establishing safety with 20 mg of BMS-641988 in the United States, a companion study was opened in Japan to assess differences in drug metabolism between populations.

Results: Sixty-one men with CRPC were treated with daily BMS-641988. The pharmacokinetics (PK) of BMS-641988 and its active metabolites were proportional to dose. One patient experienced an epileptic seizure at a dose of 60 mg administered twice. Despite achieving target drug exposures, antitumor activity was limited to one partial response. Seventeen of 23 evaluable patients (74%) exhibited stable disease on imaging (median 15 weeks; range 8-32), and 10 of 61 patients (16%) achieved a ≥ 30% decline in levels of prostate-specific antigen (PSA). Partial agonism was seen within the context of this study upon removal of the drug as evidenced by a decrease in PSA.

Conclusions: Although the clinical outcomes of predominantly stable disease and partial agonism were similar to what was observed in the preclinical evaluation of the compound, the limited antitumor activity of BMS-641988 at therapeutic dose levels coupled with an episode of seizure activity led to study closure.

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Figures

Figure 1
Figure 1
Dependency of the mean AUCTAU values (Cycle 2, Day 8) of BMS-641988, BMS-570511, and BMS-501949 on the doses of BMS-641988 in CA185002. Data points are observed data and the solid lines are the results of regression analysis. NOAEL, No Observable Adverse Effect Level.
Figure 2
Figure 2
Maximal percentage of prostate-specific antigen (PSA) decline from baseline, stratified by dose.
See this image and copyright information in PMC

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