Phase I studies of recombinant interferon-gamma

Area of Science:

• Immunology
• Pharmacology
• Clinical Trials

Background:

• Interferon-gamma (IFN-γ) is a cytokine with diverse biological activities.
• Understanding the optimal dose, schedule, and chronic administration of recombinant IFN-γ is crucial for therapeutic applications.

Purpose of the Study:

• To evaluate the safety, tolerability, and biological effects of intravenous recombinant interferon-gamma in a phase I study.
• To determine the maximum tolerated dose (MTD), dose-limiting toxicities, and effects of different administration schedules and chronic dosing.

Main Methods:

• A phase I clinical trial involving 31 patients.
• Dose-escalation study to determine MTD (0.01-500 MU/m2).
• Evaluation of different infusion schedules (20 min, 4 h, 24 h) and chronic administration (1 or 30 MU/m2).
• Assessment of toxicity, natural killer cell activity, cytotoxicity, 2',5'-oligodenylate synthetase activity, and bone marrow colony formation.

Main Results:

• The MTD of intravenous recombinant IFN-γ was determined to be 400 MU/m2, with hypotension as the dose-limiting toxicity.
• No significant toxicity differences were observed between short (20 min) and prolonged (4 h, 24 h) infusions at 60 MU/m2.
• Chronic administration of 30 MU/m2 twice weekly for 4 weeks resulted in more symptoms (fever, nausea, orthostasis) compared to 1 MU/m2.
• Maximal stimulation of 2',5'-oligodenylate synthetase occurred at low doses (12 MU/m2), while bone marrow colony formation was depressed in vivo.
• No objective antitumor responses were observed.

Conclusions:

• Recombinant interferon-gamma can be safely administered intravenously at doses up to 400 MU/m2.
• Chronic administration appears limited to 30 MU/m2 due to increased toxicity.
• Lower doses may achieve maximal biological responses, suggesting a complex dose-response relationship for IFN-γ.