Phase I clinical trial of CEP-2563 dihydrochloride, a receptor tyrosine kinase inhibitor, in patients with refractory solid tumors

Samir D. Undevia, Nicholas J. Vogelzang, Ann M. Mauer, Linda Janisch, Sridhar Mani, Mark J. Ratain

Research output: Contribution to journalArticlepeer-review

39 Scopus citations


CEP-2563 dihydrochloride (CEP-2563) is a soluble lysinyl-β-alanyl ester of CEP-751, a potent inhibitor of the trk family of receptor tyrosine kinases and the platelet-derived growth factor (PDGF) receptor tyrosine kinase. CEP-2563 was developed because of the limited aqueous solubility of CEP-751. Preclinical models have demonstrated that both CEP-751 and CEP-2563 have antitumor activity in a variety of tumors. A Phase I clinical trial involving 18 patients was conducted to determine the toxicity profile, maximum tolerated dose (MTD), toxicity profile, and pharmacokinetics of CEP-2563 in patients with advanced solid tumors refractory to standard therapy. CEP-2563 was administered over 1 hour via a central venous catheter once daily for five consecutive days every three weeks. A rapid dose titration strategy with initial single patient cohorts and 100% dose escalations was used. With the appearance of drug-related toxicity, escalations were decreased to 50% or 25% and cohorts were expanded to 3 or 6 patients until establishment of the MTD. Dose escalation rapidly proceeded to 320 mg/m 2/d. The dose limiting toxicities (DLTs) observed were grade 3 hypotension and grade 2 allergic reaction. Other toxicities included anemia, thrombocytopenia, anorexia, asthenia, diarrhea, fatigue, headache, nausea, vomiting, and rash. Pharmacokinetic analysis showed that CEP-2563 is reliably converted to CEP-751. This study demonstrated that single agent CEP-2563 therapy is feasible with acceptable toxicities. The recommended phase II dose is 256 mg/m 2/d. Rapid dose escalation with single patient cohorts was a safe and efficient method of conducting this phase I trial.

Original languageEnglish (US)
Pages (from-to)449-458
Number of pages10
JournalInvestigational New Drugs
Issue number4
StatePublished - Nov 2004
Externally publishedYes


  • CEP-2563
  • maximum tolerated dose
  • pharmacokinetics
  • phase I clinical trial
  • toxicity

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)


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