A phase I-II study of docetaxel and atrasentan in men with castration-resistant metastatic prostate cancer.
OBJECTIVE
The primary aims of this phase I-II study were to determine the maximum tolerated dose, dose-limiting toxicity, pharmacokinetics, and preliminary efficacy of the combination of docetaxel and the endothelin A receptor antagonist atrasentan as first-line treatment for men with metastatic castration-resistant prostate cancer.


METHODS
Patients were treated with docetaxel at doses ranging from 60 to 75 mg/m(2) every 21 days, with daily oral atrasentan 10 mg starting on day 3. Patients were treated until evidence of disease progression or unacceptable toxicity.


RESULTS
Thirty-one patients were enrolled over three docetaxel dose levels (8 at 60 mg/m(2), 19 at 70 mg/m(2), and 4 at 75 mg/m(2)) including dose expansion at 70 mg/m(2). The maximum tolerated dose of docetaxel was 70 to 75 mg/m(2). Drug-related grade 3-4 toxicities included neutropenia (50-63%) and febrile neutropenia (16-25%); other grade 1-2 toxicities included fatigue, peripheral edema, diarrhea, headache, rhinitis, anorexia, and nausea. Confirmed prostate-specific antigen (PSA) responses were observed in 23% [95% confidence interval (95% CI), 10-41%]; the rate of >30% declines in PSA was 35% (95% CI, 19-55%). Median overall survival was 17.6 months (95% CI, 13.0-23.2) and median progression-free survival was 4.2 months (95% CI, 2.3-5.8). Significant declines in bone alkaline phosphatase and serum N-telopeptides were observed with therapy.


CONCLUSIONS
The maximum tolerated dose of every-3-week docetaxel with 10 mg atrasentan is 70 to 75 mg/m(2). Overall survival and progression-free survival are comparable to that seen with docetaxel and prednisone, whereas the rates of PSA decline are slightly lower than expected. A phase III study of this combination with prednisone has been initiated and is ongoing.
Armstrong
Andrew J
AJ
Duke Prostate Center, 2424 Erwin Road, Durham, NC 27705, USA. andrew.armstrong@duke.edu
Creel
Patricia
P
Turnbull
James
J
Moore
Cassandra
C
Jaffe
Tracy A
TA
Haley
Sherri
S
Petros
William
W
Yenser
Sarah
S
Gockerman
Jon P
JP
Sleep
Darryl
D
Hurwitz
Herbert
H
George
Daniel J
DJ
D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000077868:Atrasentan; D018450:Disease Progression; D018572:Disease-Free Survival; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D011759:Pyrrolidines / Q000008:administration & dosage*; D043823:Taxoids / Q000008:administration & dosage*; D016896:Treatment Outcome
D011759:Pyrrolidines; D043823:Taxoids; D000077143:Docetaxel; D000077868:Atrasentan