A dose-escalation and pharmacokinetic study of subcutaneously administeredrecombinant human interleukin 12 and its biological effects in Japanese patients with advanced malignancies

A pilot dose-escalation study of recombinant human interleukin 12 (rhIL-12) was conducted in Japanese patients with advanced malignancies. Cohorts of three patients received escalating doses of rhIL-12 that increased from 50 to 300 ng/kg/day s,c. three times a week for 2 weeks followed by I-week res t. The same dosage and schedule was repeated for two additional courses. Si xteen previously treated patients were registered, and 15 were evaluated. C ommon toxicities were fever and leukopenia; the abnormality of laboratory t ests included elevations in aspartate aminotransferase, ala-nine aminotrans ferase, alkaline phosphatase, C-reactive protein, and beta 2-microglobrin. Dose-limiting toxicity was the grade 3 elevation of aminotransferases, and was observed in two of six patients at the 300-ng/kg dose level after the f irst course in one patient and after the third course in the other, Leukope nia was observed at all of the dose levels; two of six patients at 300 ng/k g experienced grade 3 leukopenia, Thus, 300 ng/kg was determined to be the maximum acceptable dose. Peak plasma levels of rhIL-12 decreased in the sec ond courses, but the areas under the curve were almost the same in the firs t and second courses. Biological effects included increases of plasma level s of IFN-gamma, tumor necrosis factor-or, IL-6, IL-IO, and neopterin. In tw o patients with renal cell carcinoma, complete response and partial respons e of metastatic tumors were observed with 50 and 300 ng/kg; the responses l asted for 5 and 3.5 months, respectively. Although immunological response t o rhIL-12 varies depending on administration route and schedule and on pati ents' physiological conditions, the recommended dose for Phase II studies i s 300 ng/kg s,c, three times a week for 2 weeks followed by I-week rest.