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A Dose-Escalation and Pharmacokinetic Study of Subcutaneously Administered Recombinant Human Interleukin 12 and Its Biological Effects in Japanese Patients with Advanced Malignancies

Department of Medicine III, Hamamatsu University School of Medicine, Hamamatsu 431-3192 [R.O., K.O.]; Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-0037 [Y. Y.,T. To.]; Department of Urology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka 537-8511 [T. Ki.,T. Ko.]; First Department of Surgery, Nihon University School of Medicine, Tokyo 157-0065 [M. S.]; Department of Dermatology, Saitama Medical School, Saitama 350-0495 [Y. K., S. I.]; Department of Urology, Cancer Institute Hospital, Tokyo 170-8455 [I. F.]; First Department of Surgery, Okayama University School of Medicine, Okayama 700-0914 [A. G.]; Second Department of Surgery, Gifu University School of Medicine, Gifu 500-8705 [Y. S., S. S.]; Department of Surgery, Yamaguchi University School of Medicine, Yamaguchi 755-8505 [S. H., M. O.]; Department of Epidemiology and Biostatistics, School of Health Sciences and Nursing, Faculty of Medicine, University of Tokyo, Tokyo 113-0033 [Y. O.]; Japanese Foundation for Cancer Research, Cancer Institute, Tokyo 170-8455 [S. T.]; and Japan Society for Cancer Chemotherapy, Osaka 550-0002 [T. Ta.], Japan

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 1-week rest. The same dosage and schedule was repeated for two additional courses. Sixteen previously treated patients were registered, and 15 were evaluated. Common toxicities were fever and leukopenia; the abnormality of laboratory tests included elevations in aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, C-reactive protein, and ß2-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 first course in one patient and after the third course in the other. Leukopenia was observed at all of the dose levels; two of six patients at 300 ng/kg 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 second courses, but the areas under the curve were almost the same in the first and second courses. Biological effects included increases of plasma levels of IFN-, tumor necrosis factor-, IL-6, IL-10, and neopterin. In two patients with renal cell carcinoma, complete response and partial response of metastatic tumors were observed with 50 and 300 ng/kg; the responses lasted for 5 and 3.5 months, respectively. Although immunological response to rhIL-12 varies depending on administration route and schedule and on patients’ physiological conditions, the recommended dose for Phase II studies is 300 ng/kg s.c. three times a week for 2 weeks followed by 1-week rest.

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