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.

摘要

PURPOSE: To evaluate the safety of sequentially administered recombinant (r) human (h) interleukin-12 (IL-12) and interferon alfa-2b (IFN-alpha-2b) in patients with advanced cancer and to determine the effects of endogenously produced IFN-gamma 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-alpha-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-alpha-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-gamma production. Peripheral blood was drawn for measurement of plasma IFN-gamma and the induction of Jak-STAT signal transduction in PBMCs. RESULTS: No IL-12-or IFN-alpha-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-gamma 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-gamma 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-alpha-2b can be administered sequentially with minimal toxicity. IV administration of rhIL-12 modulates IFN-alpha-induced Jak-STAT signal transduction in patient PBMCs.