Phase I study of subcutaneously administered recombinant human interleukin12 in patients with advanced renal cell cancer

A phase I study was conducted to characterize the maximum tolerated dose (M TD), dose-limiting toxicity (DLT), and pharmacokinetics of a single dose fo llowed by three times weekly s.c. injections of recombinant human interleuk in 12 (rHuIL-12), The study encompassed 28 patients with advanced renal cel l carcinoma. rHuIL-12 was administered on day 1, followed by an observation period of 7 days. Starting on day 8, repeated s.c. injections were adminis tered 3 times a week for 2 weeks. The MTD of the initial injection was eval uated at dose levels of 0.1, 0.5, and 1.0 mu g/kg. DLT was observed at 1.0 mu g/kg and consisted of fever, perivasculitis of the skin, and leukopenia, The MTD of the subsequent repeated injections after 1 week of rest was stu died at dose levels 0.5, 1.0, and 1.25 mu g/kg. DLT at 1.25 mu g/kg compris ed deterioration of performance status, fever, vomiting, mental depression, and leukopenia, Other notable toxicities were oral mucositis and elevation of hepatic enzymes. Fever, leukopenia, and elevation of hepatic enzymes we re more severe after the initial injection than after repeated injections a t the same dose level, At dose level 0.5 mu g/kg, the mean area under the p lasma concentration-time curve decreased from 7.4 ng/h/ml after the first i njection to 3.3 ng . h/ml (P = 0.034) after repeated administrations, and a t dose level 1.0 mu g/kg, it ranged from 31.8 ng/h/ml to 6.0 ng . h/ml (P = 0.041), One patient had a partial response and seven had stable disease, T he MTD of a single s.c. injection of rHuIL-12% was 0.5 mu g/kg, and the MTD of three subsequent administrations per week was 1.0 mu g/kg. In compariso n with a single administration, the three times weekly administrations at t he same dose level was accompanied with a milder pattern of side effects an d a reduction of the area under the plasma concentration-time curve.