TY - JOUR
T1 - Phase I dose-escalation study of the novel antiandrogen BMS-641988 in patients with castration-resistant prostate cancer
AU - Rathkopf, Dana
AU - Liu, Glenn
AU - Carducci, Michael A.
AU - Eisenberger, Mario A.
AU - Anand, Aseem
AU - Morris, Michael J.
AU - Slovin, Susan F.
AU - Sasaki, Yasutsuna
AU - Takahashi, Shunji
AU - Ozono, Seiichiro
AU - Fung, Nga Kit Eliza
AU - Cheng, Shinta
AU - Gan, Jinping
AU - Gottardis, Marco
AU - Obermeier, Mary T.
AU - Reddy, Jyotsna
AU - Zhang, Steven
AU - Vakkalagadda, Blisse J.
AU - Alland, Leila
AU - Wilding, George
AU - Scher, Howard I.
PY - 2011/2/15
Y1 - 2011/2/15
N2 - 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.
AB - 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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U2 - 10.1158/1078-0432.CCR-10-2955
DO - 10.1158/1078-0432.CCR-10-2955
M3 - Article
C2 - 21131556
AN - SCOPUS:79951840577
SN - 1078-0432
VL - 17
SP - 880
EP - 887
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 4
ER -