A phase I trial involving continuous infusion of both β- and γ-interferon (IFN-β and IFN-γ) was conducted in 20 patients in order to determine whether combinations of high doses of IFN-β and IFN-γ were tolerable when administered under conditions which mimic conditions of in vitro antiproliferative studies. Patients received a 5-day continuous infusion of IFN-β/IFN-γ, followed by a 9-day rest period. Two cycles were administered. Doses of IFN-β/IFN-γ were escalated between 4 dose levels, with 5 patients per dose level.

Dose-dependent side effects, consisting primarily of constitutional symptoms typical of those experienced with IFN, were observed. The maximally tolerated dose of continuous IFN-β/IFN-γ infusion was 3 × 106 units of IFN-β and 200 µg of IFN-γ. Dose-limiting side effects consisted of severe headache, fatigue, fever, and hepatic toxicity. No clinical responses were observed.

Serum IFN was measurable only at the highest 3 dose levels. Only 5 patients (4 at the highest dose level) had total serum levels which exceeded 50 laboratory units/ml (55, 63, 800, 800, and 550 laboratory units/ml, respectively).

In order to confirm the biological effectiveness of this schedule, we measured IFN-inducible proteins prior to therapy, 24 h after the initiation of the infusion, and at the completion of the 5-day infusion. 2′-5′-Oligoadenylate synthetase, serum β2-microglobulin, neopterin, and p78 levels all increased significantly, and serum tryptophan decreased significantly within 24 h after the initiation of treatment (P < 0.0001). A dose-response effect was observed for serum β2-microglobulin, neopterin, and p78 (P < 0.02).

We retrospectively compared the results of this trial with those of another IFN-β/IFN-γ trial in which IFN-β and IFN-γ were administered by i.v. bolus. Within the limitations of a retrospective comparison, continuous infusion was less well tolerated than our previous schedule of bolus administration 3 times/week. However, the continuous infusion schedule appeared to be more effective in enhancing 2′-5′-oligoadenylate synthetase levels in mononuclear cells. We conclude that tolerable doses of IFN-β and IFN-γ do not result in serum IFN levels which produce significant synergistic antiproliferative responses in vitro. This study and other findings suggest that, unless higher doses can be achieved, combinations of IFN-β and IFN-γ are unlikely to have significant therapeutic activity.

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This work was partially supported by NIH contract CM47669, and NIH grant RR03186 from the Division of Research Resources to the University of Wisconsin Medical School.

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