Investigational New Drugs 15: 319–324, 1997. 319 c 1997 Kluwer Academic Publishers. Printed in the Netherlands. An Eastern Cooperative Oncology Group phase I trial of all-trans-retinoic acid and interferon-alpha: E2Y92 Joan H. Schiller 12 , Donna Neuberg 3 , Dan Burns 1 , Paul Ritch 4 , Marilyn Larson 1 , Mark Levitt 5 and Janice Dutcher 6 1 University of Wisconsin Comprehensive Cancer Center, Madison, Wisconsin; 2 William S. Middleton VA Hospital, Madison, Wisconsin; 3 Dana Farber Cancer Institute, Boston, Massachusetts; 4 Medical College of Wisconsin, Milwaukee, Wisconsin; 5 Allegheny Singer Research Institute, Pittsburgh, Pennsylvania; 6 Albert Einstein College of Medicine, Bronx, New York, USA Key words: interferon-alpha, trans-retinoic acid, Phase I trial Summary The Eastern Cooperative Oncology Group conducted a Phase I trial to determine the maximally tolerated doses of combination therapy with alpha interferon (IFN- ) and all-trans-retinoic acid (tRA). Fifty patients with incurable malignancies received IFN- 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/m 2 and 3 million units of IFN- . Major, dose-limiting toxicities were attributable to either the tRA (rash, chelitis) or IFN (constitutional symp- toms), and were observed only at tRA dose levels of 224 mg/m 2 and 291 mg/m 2 , or 6 million units of IFN- . The maximally tolerated dose level of 172.5 mg/m 2 of tRA and 3 million units of IFN- was well-tolerated, with no grade 3 or 4 toxicities attributable to therapy. One patient at the third dose level (75 mg/m 2 of tRA and 3 million units of IFN- ) developed acute hepatic and renal failure and a metabolic encephalopathy of unclear etiology. We conclude that tRA and IFN- 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- and tRA for Phase II trials are 3 million units of IFN- and 172.5 mg/m 2 of tRA. A large proportion of epithelial malignancies (which compromise approximately 85–90% of all cancers in adults) are diagnosed at a stage when local modality treatment with curative intent is not feasible. Unfortu- nately, systemic therapy with cytotoxic agents, which have been the mainstay for treatment of advanced malignancies, has been largely ineffective despite con- siderable toxicity. Thus, investigation of new para- digms and therapeutic approaches for the systemic treatment of epithelial malignancies has become an urgent priority for the oncology community. Newer therapeutic strategies currently under inves- tigation include modulation of aspects of cellular homeostasis [1–6]. One of the critical aspects of cel- lular homeostasis is the dynamic equilibrium between growth and differentiation. Differentiated epithelial cells expressing a normal phenotype and under physi- ological conditions neither invade nor metastasize [7]. Well differentiated tumors have more indolent natural histories and metastasize later than more anaplastic tumors of similar origin. Thus, induction of differ- entiation may have a role in either the prevention or treatment of cancer [8–11]. Retinoids play a major role in differentiation including control of squamous metaplasia (in both nor- mal and malignant tissue) and maintenance of nor- mal mucinous and squamous epithelia [12–27]. In vit- ro, they induce differentiation and/or growth inhibi- tion in a variety of tumor cell lines [27]. Clinical- ly, all-trans-retinoic acid (RA) induces differentiation