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

Abstract

CEP-2563 dihydrochloride (CEP-2563) is a soluble lysinyl-beta-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.

• Authors: Samir D Undevia, Nicholas J Vogelzang, Ann M Mauer, Linda Janisch, Sridhar Mani, Mark J Ratain
• Journal: Investigational new drugs (Invest New Drugs) Vol. 22 Issue 4 Pg. 449-58 (Nov 2004) ISSN: 0167-6997 [Print] United States
• PMID: 15292715 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article)

Chemical References

• Antineoplastic Agents
• CEP 2563
• Carbazoles
• Dipeptides
• Prodrugs
• Receptor Protein-Tyrosine Kinases

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (pharmacokinetics, toxicity)
• Carbazoles (pharmacokinetics, therapeutic use)
• Cohort Studies
• Dipeptides (pharmacokinetics, therapeutic use)
• Dose-Response Relationship, Drug
• Drug Hypersensitivity (etiology)
• Female
• Humans
• Hypotension (chemically induced)
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasms (drug therapy)
• Prodrugs (pharmacokinetics, toxicity)
• Receptor Protein-Tyrosine Kinases (antagonists & inhibitors)
• Time Factors