Phase I study combining tumor necrosis factor with interferon-alpha and interleukin-2

Area of Science:

• Immunotherapy
• Oncology
• Pharmacology

Background:

• Combination immunotherapy using cytokines like IL-2 and IFN-alpha is a strategy for cancer treatment.
• The role of TNF in combination with IL-2 and IFN-alpha for metastatic cancer requires further investigation to establish optimal dosing and feasibility.

Purpose of the Study:

• To determine the maximum tolerated dose (MTD) of a three-cytokine combination therapy including tumor necrosis factor (TNF), interleukin-2 (IL-2), and interferon-alpha (IFN-alpha).
• To evaluate the feasibility of this combination as an outpatient regimen for patients with metastatic cancer.

Main Methods:

• Eighteen patients with metastatic cancer received escalating doses of TNF combined with fixed doses of IL-2 and IFN-alpha.
• Treatment involved 3-week cycles with IFN-alpha administered intramuscularly or subcutaneously, IL-2 via continuous infusion, and TNF intravenously during the first week.
• TNF dose escalation (40, 80, 120 µg/m²) was performed in cohorts of 3 patients.

Main Results:

• The most frequent side effects were fever, chills, and fatigue.
• Grade 3-4 toxicities included anemia, thrombocytopenia, arrhythmia, pulmonary edema, and weight loss.
• Five patients discontinued the study due to toxicity.

Conclusions:

• The combination of TNF, IL-2, and IFN-alpha is feasible as an outpatient regimen.
• Two specific dosing regimens were identified as feasible: (a) TNF 80 µg/m², IL-2 1x10⁶ IU/m²/day, IFN-alpha 9x10⁶ IU/m²/day; or (b) TNF 40 µg/m², IL-2 3x10⁶ IU/m²/day, IFN-alpha 9x10⁶ IU/m²/day.