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

Interleukin-12 (IL-12) and interferon alfa-2b (IFN-alpha-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...

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Bibliographic Details
Published in:	Journal of clinical oncology Vol. 22; no. 14; pp. 2891 - 2900
Main Authors:	ALATRASH, Gheath, HUTSON, Thomas E, BUKOWSKI, Ronald M, MOLTO, Luis, RICHMOND, Amy, NERNEC, Cheryl, MEKHAIL, Tarek, ELSON, Paul, TANNENBAUM, Charles, OLENCKI, Thomas, FINKE, James
Format:	Journal Article
Language:	English
Published:	Baltimore, MD American Society of Clinical Oncology 15-07-2004 Lippincott Williams & Wilkins
Subjects:	Adult Aged Antineoplastic Agents - administration & dosage Biological and medical sciences Carcinoma, Renal Cell - drug therapy Carcinoma, Renal Cell - immunology Cytokines - genetics Cytokines - immunology Drug Administration Schedule Female Gene Expression Humans Injections, Subcutaneous Interferon-alpha - administration & dosage Interleukin-12 - administration & dosage Kidney Neoplasms - drug therapy Kidney Neoplasms - immunology Kidneys Male Maximum Tolerated Dose Medical sciences Melanoma - drug therapy Melanoma - immunology Middle Aged Nephrology. Urinary tract diseases Recombinant Proteins Skin Neoplasms - drug therapy Skin Neoplasms - immunology Treatment Outcome Tumors Tumors of the urinary system Kidney disease Human Urinary system disease Carcinoma Alpha interferon Cytokine Interleukin 12 Malignant tumor Metastasis Cancerology Malignant melanoma Phase I trial Grawitz tumor Advanced stage
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Summary:	Interleukin-12 (IL-12) and interferon alfa-2b (IFN-alpha-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-alpha-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). 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-alpha-2b (dose I, 1.0 MU/m(2); dose II, 1.0 MU/m(2); dose III, 1.0 MU/m(2); dose IV, 3.0 MU/m(2) SC) three times weekly in 4-week cycles. Effects on gene expression were assessed by reverse transcriptase polymerase chain reaction. 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. Concurrent SC administration of IL-12 and IFN-alpha-2b is possible at the dose levels utilized. Recommended doses for phase II trials are 500 ng/kg IL-12 and 1.0 MU/m(2) IFN-alpha-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.
ISSN:	0732-183X 1527-7755
DOI:	10.1200/JCO.2004.10.045