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Phase I Evaluation of Combination Therapy with Interleukin 2 and -Interferon¹

Department of Medical Oncology and Biostatistics, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111

Recombinant interleukin 2 (IL-2) is a potent inducer of lymphokine-activated killer (LAK) activity directed against autologous and allogeneic tumors; these effects are mediated by CD3-negative, CD56-positive, and CD16-positive lymphocytes. Although IL-2 therapy has been associated with clinical responses, particularly in patients with renal cell carcinoma and melanoma, these responses have occurred with high, toxic doses of this cytokine. Since -interferon (IFN-) potentiates LAK activity in vitro and in animal models, we initiated a dose-escalating Phase I trial of IFN- and IL-2 in patients with advanced cancer. Patients were treated three times weekly (Monday, Wednesday, and Friday) for 6 weeks with bolus injections of IL-2; each dose was preceded 2 h earlier by a s.c. injection of IFN-. Patients were treated with IFN- at 0.01, 0.05, 0.1, or 0.25 mg/m²/dose. At each IFN- dose, cohorts of at least three patients were treated with IL-2 at 1, 2.5, 5.0, or 7.5 x 10⁶ Cetus units/m² dose. Patients with clinical responses continued therapy three times weekly, while those with stable disease at 6 weeks were then treated twice weekly. A total of 41 patients were treated, all with Eastern Cooperative Oncology Group performance status 0 or 1. All patients were evaluable for toxicity. Dose-limiting toxicities were cumulative fatigue and constitutional symptoms. One documented transmural myocardial infarct occurred. The maximally tolerated dose combination, based on analysis of IL-2 dose intensity, was 0.1 mg IFN-/m² and 7.5 x 10⁶ Cetus units IL-2/m² per dose. Two partial responses and two minor responses were observed. Treatment was not associated with dose-associated changes in peripheral blood lymphocyte phenotype, but there was a trend favoring IFN- dose-associated rises in IL-2 induction of natural killer and LAK activity by treated patients' lymphocytes. Analysis of the cumulative effects of therapy on induction of natural killer and LAK activity by measurement of the median area under the curve of activation showed clear evidence of IFN- and IL-2 dose-associated changes. The IL-2 dose effects on cell lysis were monotone, while the optimal IFN- dose appeared to be 0.1 mg/m²/dose, with a bell-shaped dose-response curve described previously for other effects of this cytokine. Using this novel statistical method of evaluating the biological effects of treatment, the optimal biological dose was identical to the maximally tolerated dose. This analytical approach permitted comparison of dose-associated effects of treatment in small patient cohorts and facilitated efforts to identify an optimal biological dose.

¹ This work was supported by the Eastern Cooperative Oncology Group (CA 21115). National Cancer Institute Core Grant CA06927, and National Cancer Institute Clinical Investigator Award CA01130 (L. M. W.). The preclinical data supporting this trial were made possible by an award from the Mary L. Smith Charitable Lead Trust.

² To whom requests for reprints should be addressed, at Fox Chase Cancer Center, 7701 Burholme Avenue, Philadelphia, PA 19111.

³ Present address: Hahnemann University, Philadelphia, PA.

Received 1/16/91. Accepted 5/16/91.