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 Citations (Scopus)

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)1360-1367
Number of pages8
JournalCancer Biology and Therapy
Volume6
Issue number9
StatePublished - Sep 2007
Externally publishedYes

Fingerprint

Prostatic Neoplasms
Phosphotransferases
Therapeutics
Prostate
Prostatectomy
lestaurtinib
Clinical Studies
Blood Proteins
Growth
Cause of Death
Cell Death
Western Blotting
Hormones
Neoplasm Metastasis
Safety

Keywords

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

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

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

In: Cancer Biology and Therapy, Vol. 6, No. 9, 09.2007, p. 1360-1367.

Research output: Contribution to journalArticle

Collins, C, Carducci, MA, Eisenberger, MA, Isaacs, JT, Partin, AW, Pili, R, Sinibaldi, VJ, Walczak, JS & Denmeade, SR 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, vol. 6, no. 9, pp. 1360-1367.
Collins, Connie ; Carducci, Michael A. ; Eisenberger, Mario A. ; Isaacs, John T. ; Partin, Alan W. ; Pili, Roberto ; Sinibaldi, Victoria J. ; Walczak, Janet S. ; Denmeade, Samuel R. / 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. In: Cancer Biology and Therapy. 2007 ; Vol. 6, No. 9. pp. 1360-1367.
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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.",
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AU - Collins, Connie

AU - Carducci, Michael A.

AU - Eisenberger, Mario A.

AU - Isaacs, John T.

AU - Partin, Alan W.

AU - Pili, Roberto

AU - Sinibaldi, Victoria J.

AU - Walczak, Janet S.

AU - Denmeade, Samuel R.

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N2 - 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.

AB - 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.

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