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Phase I Study of the Sequential Combination of Interleukin-12 and Interferon Alfa-2b in Advanced Cancer: Evidence for Modulation of Interferon Signaling Pathways by Interleukin-12

From the Divisions of Hematology and Oncology and Surgical Oncology, Human Cancer Genetics, and Center for Biostatistics, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Columbus, OH; and Yale University, New Haven, CT

Address reprint requests to William E. Carson III, MD, Department of Surgery, Division of Surgical Oncology, N924 Doan Hall, 410 W 10th Ave, Columbus, OH 43210; e-mail: william.carson{at}osumc.edu

PURPOSE: To evaluate the safety of sequentially administered recombinant (r) human (h) interleukin-12 (IL-12) and interferon alfa-2b (IFN--2b) in patients with advanced cancer and to determine the effects of endogenously produced IFN- on Janus kinase-signal transducer and activator of transcription (Jak-STAT) signal transduction in patient peripheral-blood mononuclear cells (PBMCs).

PATIENTS AND METHODS: Forty-nine patients with metastatic cancer received rhIL-12 on day 1 and IFN--2b on days 2 to 6 of either a 14-day (n = 43) or a 7-day treatment cycle (n = 6). rhIL-12 was initially administered subcutaneously at a dose of 100 ng/kg, whereas IFN--2b was escalated from 1 to 10 million units (MU) in cohorts of three patients (1, 3, 5, 7, or 10 MU). rhIL-12 was subsequently administered intravenously (IV) in escalating doses (100 to 500 ng/kg) to achieve greater IFN- production. Peripheral blood was drawn for measurement of plasma IFN- and the induction of Jak-STAT signal transduction in PBMCs.

RESULTS: No IL-12–or IFN-–related dose-limiting toxicities were observed. There were no responses in 41 assessable patients. Five patients exhibited stable disease lasting 6 months or longer while on therapy. Optimal induction of IFN- by IL-12 occurred after an IV dose of 250 ng/kg. Patient PBMCs exhibited increased levels of STAT1 after IL-12 administration. The peak level of IFN- achieved with IL-12 therapy correlated with the peak level of intracellular STAT1 in patient PBMCs (r = 0.38, P = .021).

CONCLUSION: The combination of rhIL-12 and IFN--2b can be administered sequentially with minimal toxicity. IV administration of rhIL-12 modulates IFN-–induced Jak-STAT signal transduction in patient PBMCs.

Supported by National Institutes of Health Grant Nos. CA84402, P30-CA16058, 2-UO1 CA-076576-06, K08 CA93518 (C.F.E.), and K24 CA93670 (W.E.C.), The Valvano Foundation for Cancer Research Award, and The Ohio State University Department of Surgery Clinical Science Seed Grant. G.B.L. is a National Research Service Award T32 fellow (5 T32 CA90223-02).

C.F.E. and G.B.L. contributed equally to this work.

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

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