title: An Eastern Cooperative Oncology Group phase I trial of all-trans-retinoic acid and interferon-alpha: E2Y92.
abstract: The Eastern Cooperative Oncology Group conducted a Phase I trial to determine the maximally tolerated doses of combination therapy with alpha interferon (IFN-alpha) and all-trans-retinoic acid (tRA). Fifty patients with incurable malignancies received IFN-alpha administered subcutaneously three times weekly, and tRA administered by mouth at bedtime. Doses were escalated between patient groups, starting at tRA dose level of 45 mg/m2 and 3 million units of IFN-alpha. Major, dose-limiting toxicities were attributable to either the tRA (rash, chelitis) or IFN (constitutional symptoms), and were observed only at tRA dose levels of 224 mg/m2 and 291 mg/m2, or 6 million units of IFN-alpha. The maximally tolerated dose level of 172.5 mg/m2 of tRA and 3 million units of IFN-alpha was well-tolerated, with no grade 3 or 4 toxicities attributable to therapy. One patient at the third dose level (75 mg/m2 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 unexpected side effects. The recommended doses of IFN-alpha and tRA for Phase II trials are 3 million units of IFN-alpha and 172.5 mg/m2 of tRA.
authors.affiliation: University of Wisconsin Comprehensive Cancer Center, Madison, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Schiller
authors.forename: D
authors.initials: D
authors.lastname: Neuberg
authors.forename: D
authors.initials: D
authors.lastname: Burns
authors.forename: P
authors.initials: P
authors.lastname: Ritch
authors.forename: M
authors.initials: M
authors.lastname: Larson
authors.forename: M
authors.initials: M
authors.lastname: Levitt
authors.forename: J
authors.initials: J
authors.lastname: Dutcher
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007370:Interferon Type I / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011994:Recombinant Proteins; D014212:Tretinoin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D007370:Interferon Type I; D011994:Recombinant Proteins; D014212:Tretinoin