Phase I study of sequentially administered recombinant tumor necrosis factor and recombinant interleukin-2.
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 micrograms/ml rTNF by rapid i.v. infusion for 5 days, followed by rIL-2 therapy daily at doses up to 18 x 10(6) IU/m2/day for 5 days and 6 x 10(6) 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 x 10(6) 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.
Krigel
R L
RL
Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Padavic-Shaller
K
K
Toomey
C
C
Comis
R L
RL
Weiner
L M
LM
D000328:Adult; D000368:Aged; D003602:Cytotoxicity, Immunologic; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology; D009369:Neoplasms / Q000628:therapy*; D011994:Recombinant Proteins / Q000008:administration & dosage; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage* / Q000009:adverse effects
D007376:Interleukin-2; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha