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

Authors: Rathkopf, D.; Liu, G.; Carducci, M. A.; Eisenberger, M. A.; Anand, A.; Morris, M. J.; Slovin, S. F.; Sasaki, Y.; Takahashi, S.; Ozono, S.; Fung, N. K. E.; Cheng, S.; Gan, J.; Gottardis, M.; Obermeier, M. T.; Reddy, J.; Zhang, S.; Vakkalagadda, B. J.; Alland, L.; Wilding, G.; Scher, H. I.
Article Title: Phase I dose-escalation study of the novel antiandrogen BMS-641988 in patients with castration-resistant prostate cancer
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. ©2010 AACR.
Keywords: adult; treatment response; aged; unclassified drug; major clinical study; constipation; drug tolerability; fatigue; area under the curve; diarrhea; drug safety; hypertension; side effect; united states; outcome assessment; antineoplastic agent; anorexia; prostate specific antigen; edema; infection; neutrophil count; pain; sensory neuropathy; gastrointestinal symptom; mucosa inflammation; nausea; randomized controlled trial; thrombocytopenia; vomiting; myalgia; qt prolongation; antineoplastic activity; docetaxel; arthralgia; dizziness; drug dose escalation; prostate cancer; rash; drug response; xerostomia; pleura effusion; seizure; hot flush; drug metabolism; phase 1 clinical trial; antiandrogen; drug metabolite; epilepsy; double blind procedure; dyspepsia; flatulence; japanese; japan; drug exposure; blurred vision; bms 641988; hyperhidrosis; castration resistant prostate cancer; weight; decreased appetite; eructation; bms 501949; bms 570511; consciousness disorder; dry throat; hypersalivation; musculoskeletal stiffness; partial agonism
Journal Title: Clinical Cancer Research
Volume: 17
Issue: 4
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2011-02-15
Start Page: 880
End Page: 887
Language: English
DOI: 10.1158/1078-0432.ccr-10-2955
PROVIDER: scopus
PMCID: PMC3070382
PUBMED: 21131556
Notes: --- - "Export Date: 23 June 2011" - "CODEN: CCREF" - "Source: Scopus"
Altmetric Score
MSK Authors
  1. Susan Slovin
    184 Slovin
  2. Michael Morris
    274 Morris
  3. Dana Elizabeth Rathkopf
    142 Rathkopf
  4. Howard Scher
    816 Scher
  5. Aseem Anand
    45 Anand