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A Phase I Study of Recombinant Interleukin 2 plus Recombinant ß-Interferon

Departments of Medicine and Biostatistics, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111 [R. L. K., K. A. P-S., S. L., R. L. C.], and Cetus Corporation, Emeryville, California 94608 [A. R. R., M. K., E. C. B.]

Interleukin 2 (IL-2) therapies have antitumor activities against several neoplasms. In vitro these activities are enhanced by ß-interferon (IFN-ß). Therefore, we initiated a Phase I trial with a combination of IL-2 and IFN-ß three times weekly. The IFN-ß was administered i.v. Initially, the IL-2 was administered s.c. However, neutralizing antibody to the IL-2 developed in five patients, and the route of administration of the IL-2 was changed to i.v.

Forty-seven patients were entered on the study. The maximum tolerated doses for the combination given i.v. were 5 x 10⁶ units/m² of IL-2 and 10 x 10⁶ units/m² of IFN-ß. Dose-limiting toxicities were profound fatigue/decreased performance status, anorexia/weight loss, depression, and arthralgias. Hypotension, exfoliative skin rash, thrombocytopenia, diarrhea, temperature >40.6°C, and peripheral edema were rarely dose limiting.

Thirty-two patients were evaluable for response. After 4 weeks of treatment, 21 patients had stable disease, three patients had a minor response, and one patient had a partial response. Significant lymphokine-activated killer cell (LAK) activity was seen in seven patients (22%) and required 5 x 10⁶ units/m² of IL-2. Those who had progressive disease had significantly less LAK activity than those with either stable disease or a response. This therapy also induced more than 60 units/ml of endogenous -interferon 4 h after the i.v. IL-2 administration.

This study demonstrates that (a) intermittent i.v. bolus IL-2 therapy can generate LAK activity, (b) LAK activity may be associated with an antitumor response, (c) significant levels of -interferon are induced by this therapy, and (d) IL-2 and IFN-ß given three times weekly i.v. is both tolerable and biologically active. The recommended Phase II dose is 5 x 10⁶ units/m² of IL-2 plus 6 x 10⁶ units/m² of IFN-ß.

¹ To whom requests for reprints should be addressed, at Department of Medicine, Fox Chase Cancer Center, Philadelphia, PA 19111.

Received 11/24/87. Revised 3/16/88. Accepted 3/31/88.