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Phase I Study of Sequentially Administered Recombinant Tumor Necrosis Factor and Recombinant Interleukin‐2

Summary: The purposes of this study were to determine the maximally tolerated dose (MTD) of IL-2 when sequentially administered following TNF (at its MTD), to identify any unique toxicities, and determine the immunomodulatory effects of this combination. Patients with metastatic cancer were treated with 160 üg/ml rTNF by rapid i.v. infusion for 5 days, followed by rIL-2 therapy daily at doses up to 18 × 106 IU/m2/day for 5 days and 6 × 106 IU/m2/day for 7 days. Cycles were repeated at 3− or 4-week intervals until progressive disease or unacceptable toxicity developed. Fifteen patients received 46 cycles of therapy (range 1–8, median 3). Major toxicities included hypotension, weight loss, and decreased performance status comparable to that reported with rIL-2 alone. No novel toxicities were identified. Two of 14 patients who received two cycles of therapy had objective responses (1 complete, 1 partial). Both occurred in patients with malignant melanoma, lasted 30 and 75 weeks, respectively, and included a complete response in liver metastasis. Dosage reductions of IL-2 were necessary for 3 patients over 11 treatment cycles (23%), and rTNF in 1 patient for 1 cycle (2%). The MTD of 5-day infusional rIL-2 was determined at 18 × 106 IU/m2/day. rTNF did not augment natural killer/lymphokine-activated killer activities beyond that commonly seen with IL-2 infusions. We conclude that full doses of rTNF can be combined with escalating rIL-2 infusions in an outpatient setting without additive toxicity and with clinical activity in patients with malignant melanoma.