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Clinical and Immunologic Effects of Subcutaneously Administered Interleukin-12 and Interferon Alfa-2b: Phase I Trial of Patients With Metastatic Renal Cell Carcinoma or Malignant Melanoma

From the Experimental Therapeutics Program, Cleveland Clinic Taussig Cancer Center, and Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH

Address reprint requests to Ronald M. Bukowski, MD, Experimental Therapeutics Program, Department of Hematology and Medical Oncology, Taussig Cancer Center, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195; e-mail: bukowsr{at}cc.ccf.org

PURPOSE: Interleukin-12 (IL-12) and interferon alfa-2b (IFN--2b) are pleiotropic cytokines with activity in renal cell carcinoma (RCC) and malignant melanoma (MM) as single agents. Preclinical studies suggest concurrent administration may have synergistic antitumor effects. We conducted a phase I trial of concurrent subcutaneous (SC) administration of IL-12 and IFN--2b in patients with metastatic RCC or MM to determine toxicity, maximum-tolerated dose, preliminary efficacy, and effects on chemokine/cytokine gene expression in peripheral blood mononuclear cells (PBMCs).

PATIENTS AND METHODS: Cohorts of three to six patients were treated with escalating doses of IL-12 (dose I, 100 ng/kg; dose II, 300 ng/kg; dose III, 500 ng/kg; dose IV, 500 ng/kg SC) given twice weekly and IFN--2b (dose I, 1.0 MU/m²; dose II, 1.0 MU/m²; dose III, 1.0 MU/m²; dose IV, 3.0 MU/m² SC) three times weekly in 4-week cycles. Effects on gene expression were assessed by reverse transcriptase polymerase chain reaction.

RESULTS: Twenty-six patients (19 with RCC, seven with MM) were accrued at dose levels I (n = 3), II (n = 3), III (n = 13), and IV (n = 7). Dose-limiting toxicity included grades 3 and 4 hepatotoxicity and neutropenia/leukopenia. Patients received a median of three cycles of treatment. Two patients with RCC and one patient with MM had partial responses. Median survival was 13.8 months. Reverse transcriptase polymerase chain reaction on PBMCs revealed induction of IP-10, Mig, B7.1 (CD80), interleukin-5, and interferon gamma in selected patients.

CONCLUSION: Concurrent SC administration of IL-12 and IFN--2b is possible at the dose levels utilized. Recommended doses for phase II trials are 500 ng/kg IL-12 and 1.0 MU/m² IFN--2b. Consistent induction of IP-10 and Mig, as well as variable induction of B7.1, interleukin-5, and interferon gamma expression was noted in PBMCs.

Supported by a grant from Schering- Plough and the Zito Chair for Cancer Research.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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