title: 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: OBJECTIVE
  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. 7/9 patients had increase in PSA slope on CEP-701 compared to PSA slope prestudy. 5/9 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.
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Connie
authors.initials: C
authors.lastname: Collins
authors.forename: Michael A
authors.initials: MA
authors.lastname: Carducci
authors.forename: Mario A
authors.initials: MA
authors.lastname: Eisenberger
authors.forename: John T
authors.initials: JT
authors.lastname: Isaacs
authors.forename: Alan W
authors.initials: AW
authors.lastname: Partin
authors.forename: Roberto
authors.initials: R
authors.lastname: Pili
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: Sinibaldi
authors.forename: Janet S
authors.initials: JS
authors.lastname: Walczak
authors.forename: Samuel R
authors.initials: SR
authors.lastname: Denmeade
mesh_terms: D016475:3T3 Cells; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002227:Carbazoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005663:Furans; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D017430:Prostate-Specific Antigen / Q000096:biosynthesis* / Q000737:chemistry*; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology