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

AbstractPURPOSE:
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.
AuthorsDana Rathkopf, 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
JournalClinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 17 Issue 4 Pg. 880-7 (Feb 15 2011) ISSN: 1557-3265 [Electronic] United States
PMID21131556 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, N.I.H., Extramural)
Copyright©2010 AACR.
Chemical References
  • Androgen Antagonists
  • BMS 641988
  • Bridged Bicyclo Compounds, Heterocyclic
  • Imides
  • Prostate-Specific Antigen
Topics
  • Aged
  • Aged, 80 and over
  • Androgen Antagonists (administration & dosage, adverse effects, pharmacokinetics)
  • Bone Neoplasms (pathology, secondary)
  • Bridged Bicyclo Compounds, Heterocyclic (administration & dosage, adverse effects, pharmacokinetics)
  • Humans
  • Imides (administration & dosage, adverse effects, pharmacokinetics)
  • Male
  • Middle Aged
  • Orchiectomy
  • Prostate-Specific Antigen (metabolism)
  • Prostatic Neoplasms (drug therapy, pathology)
  • Treatment Outcome

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