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

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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“…While the Trk blocker, CEP-701, has been investigated in clinical trials for the treatment of prostate and pancreatic cancer, the results have yet to show promise. An obstacle for the use of CEP-701 is its ability to bind to serum proteins, thereby limiting the amount of free drug for tumor penetration, as well as the limited ability of the drug to penetrate a tumor [31]. Therefore, new Trk blockers are needed as alternatives.…”

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“…Agus et al [32] demonstrated that pertuzumab alone may have clinical utility in castration-resistant PCa after progression from taxane-based therapy has been performed. In addition Collins et al [40] started a clinical study to evaluate the effects of CEP-701 in PCa patients with hormone refractory disease. The authors concluded that the evaluation of PSA response was an inadequate indicator of response in CEP-701 treated PC patients.…”

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“…The fact that lestaurtinib can suppress androgen-inducible gene expression is another supporting evidence that lestaurtinib can potentially be used in androgen-sensitive prostate cancer. Although previously lestaurtinib failed in a clinical study of androgen-refractory prostate cancer [17], the reason for the failure could be due to selection of a wrong population of prostate cancer. Figure 2 showed the resistance of PC3 and DU145 cells, two androgen-independent prostate cancer cell lines, and supported this possibility.…”