AN EASTERN-COOPERATIVE-ONCOLOGY-GROUP PHASE-I TRIAL OF ALL-TRANS-RETINOIC ACID AND INTERFERON-ALPHA - E2Y92

The Eastern Cooperative Oncology Group conducted a Phase I trial to de termine the maximally tolerated doses of combination therapy with alph a interferon (IFN-alpha) and all-trans-retinoic acid (tRA). Fifty pati ents with incurable malignancies received IFN-alpha administered subcu taneously three times weekly, and tRA administered by mouth at bedtime . Doses were escalated between patient groups, starting at tRA dose le vel of 45 mg/m(2) and 3 million units of IFN-alpha. Major, dose-limiti ng toxicities were attributable to either the tRA (rash, chelitis) or IFN (constitutional symptoms), and were observed only at tRA dose leve ls of 224 mg/m(2) and 291 mg/m(2), or 6 million units of IFN-alpha. Th e maximally tolerated dose level of 172.5 mg/m(2) of tRA and 3 million units of IFN alpha was well-tolerated, with no grade 3 or 4 toxicitie s attributable to therapy. One patient at the third dose level (75 mg/ m(2) of tRA and 3 million units of IFN-alpha) developed acute hepatic and renal failure and a metabolic encephalopathy of unclear etiology. We conclude that tRA and IFN-alpha may be safely administered together at the maximally tolerated dose of tRA as a single agent without unex pected side effects. The recommended doses of IFN-alpha and tRA for Ph ase II trials are 3 million units of IFN-alpha and 172.5 mg/m(2) of tR A.