Abstract | PURPOSE: 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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Authors | Dana 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 |
Journal | Clinical 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 |
PMID | 21131556
(Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, N.I.H., Extramural)
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Copyright | ©2010 AACR. |
Chemical References |
- Androgen Antagonists
- BMS 641988
- Bridged Bicyclo Compounds, Heterocyclic
- Imides
- Prostate-Specific Antigen
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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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