A phase I-II study of docetaxel and atrasentan in men with castration-resistant metastatic prostate cancer.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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.

• Authors: Andrew J Armstrong, Patricia Creel, James Turnbull, Cassandra Moore, Tracy A Jaffe, Sherri Haley, William Petros, Sarah Yenser, Jon P Gockerman, Darryl Sleep, Herbert Hurwitz, Daniel J George
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 14 Issue 19 Pg. 6270-6 (Oct 01 2008) ISSN: 1078-0432 [Print] United States
• PMID: 18829508 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Pyrrolidines
• Taxoids
• Docetaxel
• Atrasentan

Topics

• Aged
• Aged, 80 and over
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Atrasentan
• Disease Progression
• Disease-Free Survival
• Docetaxel
• Drug Resistance, Neoplasm
• Humans
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasm Metastasis
• Prostatic Neoplasms (drug therapy, pathology)
• Pyrrolidines (administration & dosage)
• Taxoids (administration & dosage)
• Treatment Outcome