PHASE-I TRIAL OF HIGH-DOSE BOLUS INTERLEUKIN-2 AND INTERFERON-ALFA-2A IN PATIENTS WITH METASTATIC MALIGNANCY

Purpose: Based on preclinical evidence that the antitumor effects of the combination of interleukin-2 (IL-2) and interferon alfa (IFNα) are greater than those of either cytokine alone, we have performed a phase I trial of recombinant IL-2 (rIL-2) and recombinant human IFNα2a (rHuIFNα2a) in patients with refractory malignancies. This study was an extension of an earlier trial that identified reversible myelosuppression as the dose- limiting toxicity of this combination. The present trial used modified definitions of unacceptable toxicity to allow exploration of higher doses of rIL-2. Patients and Methods: Both rHuIFNα2a 10.0 x 106 U/m2 intramuscularly (IM) and rIL-2 were administered three times weekly for 4 consecutive weeks. IL-2 was given by intravenous (IV) bolus injection at doses that were escalated in successive cohorts of four to six patients, provided that toxicity at the preceding dose level was acceptable. Unacceptable toxicity was defined as an elevation of the serum creatinine level to greater than 5 mg/dL, an elevation of the serum bilirubin level to greater than 5 mg/dL, dyspnea at rest, hypotension refractory to pressors, altered mental status, or other toxicities of grade 3 to 4, using the National Cancer Institute (NCI) Common Toxicity Criteria. The doses of rIL-2 administered were 4.0 x 106, 6.0 x 106, 8.0 x 106, 10.0 x 106, 12.0 x 106, 14.0 x 106, 18.0 x 106, 22.0 x 106, and 26.0 x 106 BRMP (Hoffman- LaRoche) U/m2. At a dose of rIL-2 10.0 x 106 BRMP U/m2, patients were also treated with doses of rHuIFNα2a of 1.0 x 106 and 0.1 x 106 U/m2. Results: A total of 57 patients were treated. Intolerable side effects (hypotension, pulmonary, and CNS toxicity) were produced by rIL-2 26.0 x 106 BRMP U/m2 and rHuIFNα2a 10.0 x 106 U/m2. Two of 21 patients with renal cell carcinoma showed objective responses, and five of 17 patients with malignant melanoma responded. Two of these responses in melanoma were complete and continue to be longlasting. Conclusions: When given with rHuIFNα2a 10.0 x 106 U/m2 as described above, the maximum-tolerated dose of rIL-2 is 22.0 x 106 BRMP U/m2. This dose of rIL-2 is equivalent to 50 to 60 MIU/m2, depending on the conversion factor used. Based on this experience and other trials, we favor phase II trials in renal cell carcinoma using an alternative dose schedule of this cytokine combination, in which rIL-2 is administered by continuous infusion. We suggest that phase II trials of this combination in patients with melanoma use an rIL-2 dose of 8.0 x 106 BRMP U/m2 by IV bolus injection three times weekly in combination with rHuIFNα2a 10.0 x 106 U/m2 IM three times weekly.