An open-label, multicenter, phase I/II study of single-agent AT-101 in men with castrate-resistant prostate cancer.
OBJECTIVE
AT-101 binds and inhibits the antiapoptotic function of Bcl-2, Bcl-xL, Mcl-1, and Bcl-w and is a potent stimulator of proapoptotic proteins. In this multi-institution phase I/II trial, we evaluated the safety and efficacy of single-agent AT-101, in men with chemotherapy naïve, castrate-resistant prostate cancer (CRPC).


METHODS
Patients with progressive CRPC were to be treated with escalating doses of AT-101 on a continuous daily basis until the maximally tolerated dose was achieved. At the recommended phase 2 dose, an additional 21 patients were planned to assess for preliminary evidence of efficacy.


RESULTS
Twenty-three patients were enrolled. The phase I starting dose was 30 mg/day on a continuous basis; however, ongoing trials with AT-101 showed increased gastrointestinal toxicity with this daily schedule when given for repetitive cycles. As a result, the phase II starting dose was chosen to be 30 mg/day for 21 of 28 days. The most frequent observed adverse events (any grade) were diarrhea (43.5%), fatigue (34.8%), nausea (21.7%), anorexia (21.7%), and small intestinal obstruction (21.7%). Due to the high incidence of grade 3 small intestinal obstruction (n = 5; 21.7%), a reduction in dose to 20 mg/day for 21 of 28 days was mandated for all patients. Two patients had a confirmed > or =50% posttherapy prostate-specific antigen decline. No objective responses (Response Evaluation Criteria in Solid Tumors) were observed.


CONCLUSIONS
AT-101 administered at 20 mg/day for 21 of 28 days was well-tolerated. Evidence of single-agent clinical activity was observed with prostate-specific antigen declines in some patients. Further investigation of AT-101 in prostate cancer is warranted and trials combining AT-101 with androgen deprivation, as well as with docetaxel chemotherapy are ongoing.
University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, Madison, Wisconsin, USA. gxl@medicine.wisc.edu
Glenn
G
Liu
W Kevin
WK
Kelly
George
G
Wilding
Lance
L
Leopold
Kimberli
K
Brill
Bradley
B
Somer
D000230:Adenocarcinoma / Q000097:blood / Q000188:drug therapy* / Q000556:secondary; D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D015331:Cohort Studies; D004334:Drug Administration Schedule; D006072:Gossypol / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D009376:Neoplasms, Hormone-Dependent / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D009919:Orchiectomy; D011379:Prognosis; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D016896:Treatment Outcome
D000972:Antineoplastic Agents, Phytogenic; D017430:Prostate-Specific Antigen; D006072:Gossypol; C028178:gossypol acetic acid