Phase I trial of orally administered CEP-701, a novel neurotrophin receptor-linked tyrosine kinase inhibitor

A phase I clinical trial in patients with advanced carcinomas was conducted using the orally available neurotrophin receptor-linked tyrosine kinase receptor inhibitor, CEP-701. The objectives were to determine the maximum tolerated dose (MTD), dose-limiting toxicities, and pharmacokinetic profile of this orally administered agent. A total of 30 patients were accrued to receive escalating BID doses of CEP-701 in cycles lasting 28 days. Between 3 and 6 patients were enrolled at each dose level. Once the MTD was determined, nine de novo patients were recruited to receive that level of drug. Pharmacokinetic studies were performed after the first dose, with additional sampling to assess intraindividual variability. The dosages ranged from 5 mg BID to 160 mg BID. While the criteria for MTD were not met at the dose levels administered, DLTs were observed at 80 and 120 mg BID. Treatment related adverse events, especially of the gastrointestinal system, made CEP-701 poorly tolerated at dosages above 40 mg BID. While CEP-701 did not produce an objective tumor response in any patient, 7 of the 30 patients received treatment for 3 months or more, including 3 who were on study with stable disease for more than 6 months. Orally administered CEP-701 was rapidly absorbed, with a mean t(max) between 1 and 3 hours. At higher dose levels, serum drug levels showed greater than dose-proportional increases by Day 28 versus Day 1. CEP-701 40 mg BID was well tolerated by patients with advanced malignancy and is the recommended dose level for planned phase II trials. Further study is necessary to determine the clinical efficacy of this novel new chemotherapeutic agent.