Preclinical and clinical studies with the multi-kinase inhibitor CEP-701 as treatment for prostate cancer demonstrate the inadequacy of PSA response as a primary endpoint

Connie Collins, Michael A. Carducci, Mario A. Eisenberger, John T. Isaacs, Alan W. Partin, Roberto Pili, Victoria J. Sinibaldi, Janet S. Walczak, Samuel R. Denmeade

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

Purpose: CEP-701 is a potent inhibitor of trk receptors that causes cell death in prostate cancer (PC) models. CEP-701 binds to serum proteins and a preprostatectomy study was performed to assess prostate tissue penetration and clinical response to CEP-701. Methods: Growth assays and Western blot analyses were performed to evaluate CEP-701 kinase inhibition. In a preprostatectomy study, patients received CEP-701 for five days prior to prostatectomy and prostate tissue analyzed for CEP-701 levels. A phase II dose escalation study was performed in patients with hormone refractory PC with rising PSA and no metastases. Endpoints included PSA response and safety. Results: CEP-701 binds to serum proteins limiting tissue penetration. An oral dose of 40 mg bid of CEP-701 for five days produced levels of 219 ± 38 nM in prostate at time of prostatectomy. No patients in the Phase II study met the primary response criteria of >50% PSA decline. Seven/9 patients had increase in PSA slope on CEP-701 compared to PSA slope prestudy. Five/9 patients had a decrease in PSA levels after stopping CEP-701. Laboratory studies showed increased PSA production by CEP-701 growth arrested human PC cells in vitro and in vivo. Conclusions: Evaluation of PSA response is an inadequate indicator of response in CEP-701 treated PC patients. Therefore, the effectiveness of CEP-701 as treatment for prostate cancer has not been adequately tested. Based on a strong preclinical rationale, further clinical studies with CEP-701 using alternative endpoints are indicated.

Original languageEnglish (US)
Pages (from-to)1356-1363
Number of pages8
JournalCancer Biology and Therapy
Volume6
Issue number9
StatePublished - Sep 2007

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Keywords

  • CEP-701
  • Kinase
  • PSA
  • Peceptor
  • Prostate cancer

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

Cite this

Collins, C., Carducci, M. A., Eisenberger, M. A., Isaacs, J. T., Partin, A. W., Pili, R., Sinibaldi, V. J., Walczak, J. S., & Denmeade, S. R. (2007). Preclinical and clinical studies with the multi-kinase inhibitor CEP-701 as treatment for prostate cancer demonstrate the inadequacy of PSA response as a primary endpoint. Cancer Biology and Therapy, 6(9), 1356-1363.