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


METHODS
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.
Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Dana
D
Rathkopf
Glenn
G
Liu
Michael A
MA
Carducci
Mario A
MA
Eisenberger
Aseem
A
Anand
Michael J
MJ
Morris
Susan F
SF
Slovin
Yasutsuna
Y
Sasaki
Shunji
S
Takahashi
Seiichiro
S
Ozono
Nga Kit Eliza
NK
Fung
Shinta
S
Cheng
Jinping
J
Gan
Marco
M
Gottardis
Mary T
MT
Obermeier
Jyotsna
J
Reddy
Steven
S
Zhang
Blisse J
BJ
Vakkalagadda
Leila
L
Alland
George
G
Wilding
Howard I
HI
Scher
D000368:Aged; D000369:Aged, 80 and over; D000726:Androgen Antagonists / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001859:Bone Neoplasms / Q000473:pathology / Q000556:secondary*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D006801:Humans; D007094:Imides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D009919:Orchiectomy; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016896:Treatment Outcome
D000726:Androgen Antagonists; C543412:BMS 641988; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007094:Imides; D017430:Prostate-Specific Antigen