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Phase I Study of Subcutaneously Administered Recombinant Human Interleukin 12 in Patients with Advanced Renal Cell Cancer

Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital Rotterdam, The Netherlands; Departments of Medical Oncology [J. E. A. P., W. H. J. K., G. S., M. de B-D.] and Medical and Tumor Immunology [C. H. J. L., R. L. H. B.], Johannes Gutenberg-Universität Mainz, Mainz, Germany; Department of Medicine III [M. S., J. B., C. H., W. E. A.]; and Hoffmann-La Roche Inc., Nutley, New Jersey [A. R.]

A phase I study was conducted to characterize the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics of a single dose followed by three times weekly s.c. injections of recombinant human interleukin 12 (rHuIL-12). The study encompassed 28 patients with advanced renal cell 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 administered 3 times a week for 2 weeks. The MTD of the initial injection was evaluated at dose levels of 0.1, 0.5, and 1.0 µg/kg. DLT was observed at 1.0 µg/kg and consisted of fever, perivasculitis of the skin, and leukopenia. The MTD of the subsequent repeated injections after 1 week of rest was studied at dose levels 0.5, 1.0, and 1.25 µg/kg. DLT at 1.25 µg/kg comprised 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 were more severe after the initial injection than after repeated injections at the same dose level. At dose level 0.5 µg/kg, the mean area under the plasma concentration-time curve decreased from 7.4 ng/h/ml after the first injection to 3.3 ng·h/ml (P = 0.034) after repeated administrations, and at dose level 1.0 µg/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. The MTD of a single s.c. injection of rHuIL-12 was 0.5 µg/kg, and the MTD of three subsequent administrations per week was 1.0 µg/kg. In comparison with a single administration, the three times weekly administrations at the same dose level was accompanied with a milder pattern of side effects and a reduction of the area under the plasma concentration-time curve.

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