Phase I clinical trial of CEP-2563 dihydrochloride, a receptor tyrosine kinase inhibitor, in patients with refractory solid tumors.
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.
Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA.
Samir D
SD
Undevia
Nicholas J
NJ
Vogelzang
Ann M
AM
Mauer
Linda
L
Janisch
Sridhar
S
Mani
Mark J
MJ
Ratain
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000633:toxicity*; D002227:Carbazoles / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D015331:Cohort Studies; D004151:Dipeptides / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004342:Drug Hypersensitivity / Q000209:etiology; D005260:Female; D006801:Humans; D007022:Hypotension / Q000139:chemically induced; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011355:Prodrugs / Q000493:pharmacokinetics* / Q000633:toxicity; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013997:Time Factors
D000970:Antineoplastic Agents; C503409:CEP 2563; D002227:Carbazoles; D004151:Dipeptides; D011355:Prodrugs; D020794:Receptor Protein-Tyrosine Kinases