Cancer Chemother Pharmacol (1995) 35:496-500 9 Springer-Verlag 1995 Marc Trudeau 9 Alex Zukiwski 9 Adrian Langleben Gerald Boos 9 Gerald Batist A phase I study of recombinant human interferon alpha-2b combined with 541uorouracil and cisplatin in patients with advanced cancer (Received: 1 November 1993/Accepted: 22 September 1994) Abstract To determine the maximum tolerated dose (MTD) of escalating doses of interferon-~-2b (IFN, Intron A) with 5-fluorouracil (5-FU) and cisplatin (DDP) in patients with advanced cancer, 15 patients were accrued between May 1990 and July 1991. Pri- mary sites were unknown (3), colorectal (3), head and neck (2), lung (2), gynecologic (1), gallbladder (1), sar- coma (1), anal canal (1) and pancreas (1). IFN was given s.c. on days 1-5 and then three times weekly with DDP (75 mg/m z, day 1) and 5-FU [750 mg/m 2, days 1-5, continuous infusion (CI) on a 28-day cycle. The first two patients treated at level I (3 x 106 U/m 2 s.c.) experi- enced possible neurotoxic deaths [massive cerebrovas- cular accident (CVA) and metabolic encephalopathy], and patient 3 had a grade 4 toxicity of performance status decline. Analysis of these events led us to exclude the enrollment of patients on i.v. morphine and of those with prior exposure to DDP. This resulted in grade 3 toxicity in terms of nausea, vomiting, fatigue and leukopenia but in no further CNS event. All patients were evaluable for toxicity but only ten were evaluable for response. Only two partial responses were seen, one in a patient with an unknown primary tumour and one in a patient with head and neck cancer. The combina- tion of IFN is possible with 5-FU and DDP. The recommended dose of IFN is 2x 106 U/m2s.c. in Supported in part by a grant from Schering Canada Inc. M. Trudeau 9 A. Zukiwski 1 9 A. Langleben 9 G. Boos 9 G. Batist Section of Experimental Therapeutics, Department of Oncology, McGill University, Montreal, Canada M. Trudeau (1~) Montreal General Hospital, 1650 Cedar Avenue, Room D5-515, Montreal, Quebec, Canada H3G 1A4 Present address: 1 M.D. Anderson Cancer Center, Houston, Texas, USA patients with no prior exposure to DDP or i.v. mor- phine, given together with 5-FU (750 mg/m 2, days 1-5, CI) and DDP (75 mg/m 2, day 1) on a 28-day cycle. Key words Cisplatin 9 5-Fluorouracil 9 Interferon Introduction Interferon (IFN) was characterized in 1957 as a protein elaborated by virus-infected cells that functioned to prevent secondary viral infection [-1]. It is now evident that IFN has direct and indirect cytotoxic, cytostatic and immune effects. Response to treatment with IFN has been observed in hairy-cell leukemia, lymphoma, melanoma, Kaposi's sarcoma, renal-cell carcinoma, myeloma and chronic myelogenous leukemia [2]. 5-Fluorouracil (5-FU) is a structural analogue of the pyrimidines uracil and thymidine that has a fluorine atom substituted in the 5 position and modulates the enzyme thymidylate synthetase, which in turn blocks the synthesis of DNA. 5-FU, has been used successfully in the treatment of gastrointestinal malignancies, carci- noma of the aerodigestive tract, and breast and bladder cancer. Several laboratories have shown an in vitro synergis- tic interaction of IFN and 5-FU [-3-5]. The report of earlier phase I trial of the combination of 5-FU and IFN in colon carcinoma has been published [6]. A recent phase II trial of this combination has been re- ported with very encouraging results [7]. The mecha- nism of the synergistic interaction of 5-FU and 1FN remains unclear. However, evidence indicates that the possible mechanism is an increase in thymidylate syn- thetase inhibition [8]. Cisplatin (DDP) is an inorganic complex of platinum surrounded by chlorine and ammonia atoms in the cis position of the horizontal plane. DDP inhibits DNA synthesis by causing inter- and intra-strand cross-link- ing. The major clinical indication for DDP use has