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Phase 1b trial of docetaxel, prednisone, and pazopanib in men with metastatic castration-resistant prostate cancer.

Publication ,  Journal Article
George, DJ; Halabi, S; Healy, P; Barak, I; Winters, C; Anand, M; Wilder, R; Klein, M; Martinez, E; Nixon, AB; Harrison, MR; Szmulewitz, R ...
Published in: Prostate
November 2019

BACKGROUND: Docetaxel prednisone is a standard of care for men with metastatic castration-resistant prostate cancer (mCRPC), and plasma vascular endothelial growth factor (VEGF) levels are a poor prognostic factor in this population; therefore, we evaluated the combination of docetaxel prednisone with pazopanib, an oral VEGF receptor inhibitor, for safety and preliminary efficacy. METHODS: This is a two-site phase 1b Department of Defense Prostate Cancer Clinical Trials Consortium trial of docetaxel, prednisone, and pazopanib once daily and ongoing androgen deprivation therapy and prophylactic pegfilgrastim in men with mCRPC. The primary endpoint was safety and the determination of a maximum tolerated dose (MTD) through a dose-escalation and expansion design; secondary endpoints included progression-free and overall survival (OS), prostate specific antigen (PSA) declines, radiographic responses, and pharmacokinetic and plasma angiokine biomarker analyses. RESULTS: Twenty-five men were treated over six dose levels. Pegfilgrastim was added to the regimen after myelosuppression limited dose escalation. With pegfilgrastim, our target MTD of docetaxel 75 mg/m2 q3 weeks; prednisone 10 mg daily; and pazopanib 800 mg daily was reached. Eleven additional patients were accrued at this dose level for a total of 36 patients. Dose-limiting toxicities included neutropenia, syncope, and hypertension. Three deaths attributed to study treatment occurred. The objective response rate was 31%; median PFS was 14.1 months (95% confidence interval [CI]: 7.1 and 22.2); and OS was 18.6 months (95% CI: 11.8 and 22.2). CONCLUSIONS: The combination of docetaxel, prednisone, and pazopanib (with pegfilgrastim) was tolerable at full doses and demonstrated promising efficacy in a relatively poor risk patients with mCRPC. Further development of predictive biomarkers may enrich for patients who receive clinical benefit from this regimen.

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Published In

Prostate

DOI

EISSN

1097-0045

Publication Date

November 2019

Volume

79

Issue

15

Start / End Page

1752 / 1761

Location

United States

Related Subject Headings

  • Treatment Outcome
  • Survival Rate
  • Sulfonamides
  • Pyrimidines
  • Prostatic Neoplasms, Castration-Resistant
  • Progression-Free Survival
  • Prednisone
  • Oncology & Carcinogenesis
  • Middle Aged
  • Maximum Tolerated Dose
 

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George, D. J., Halabi, S., Healy, P., Barak, I., Winters, C., Anand, M., … Armstrong, A. J. (2019). Phase 1b trial of docetaxel, prednisone, and pazopanib in men with metastatic castration-resistant prostate cancer. Prostate, 79(15), 1752–1761. https://doi.org/10.1002/pros.23899
George, Daniel J., Susan Halabi, Patrick Healy, Ian Barak, Carolyn Winters, Monika Anand, Rhonda Wilder, et al. “Phase 1b trial of docetaxel, prednisone, and pazopanib in men with metastatic castration-resistant prostate cancer.Prostate 79, no. 15 (November 2019): 1752–61. https://doi.org/10.1002/pros.23899.
George DJ, Halabi S, Healy P, Barak I, Winters C, Anand M, et al. Phase 1b trial of docetaxel, prednisone, and pazopanib in men with metastatic castration-resistant prostate cancer. Prostate. 2019 Nov;79(15):1752–61.
George, Daniel J., et al. “Phase 1b trial of docetaxel, prednisone, and pazopanib in men with metastatic castration-resistant prostate cancer.Prostate, vol. 79, no. 15, Nov. 2019, pp. 1752–61. Pubmed, doi:10.1002/pros.23899.
George DJ, Halabi S, Healy P, Barak I, Winters C, Anand M, Wilder R, Klein M, Martinez E, Nixon AB, Harrison MR, Szmulewitz R, Armstrong AJ. Phase 1b trial of docetaxel, prednisone, and pazopanib in men with metastatic castration-resistant prostate cancer. Prostate. 2019 Nov;79(15):1752–1761.
Journal cover image

Published In

Prostate

DOI

EISSN

1097-0045

Publication Date

November 2019

Volume

79

Issue

15

Start / End Page

1752 / 1761

Location

United States

Related Subject Headings

  • Treatment Outcome
  • Survival Rate
  • Sulfonamides
  • Pyrimidines
  • Prostatic Neoplasms, Castration-Resistant
  • Progression-Free Survival
  • Prednisone
  • Oncology & Carcinogenesis
  • Middle Aged
  • Maximum Tolerated Dose