Randomized multicenter phase II trial of subcutaneous recombinant human interleukin-12 versus interferon-alpha 2a for patients with advanced renal cell carcinoma

Recombinant human interleukin-12 (rHuIL-12) is a pleiotropic cytokine with anticancer activity against renal cell carcinoma (RCC) in preclinical model s and in a phase I trial. A randomized phase LT study of rHuIL-12 compared with interferon-a (IFN-a) evaluated clinical response for patients with pre viously untreated, advanced RCC, Patients were randomly assigned 2:1 to rec eive either rHuIL-12 or IFN-alpha 2a, rHuIL-12 was administered by subcutan eous (s.c.) injection on days 1, 8, and 15 of each 28-day cycle. The dose o f IL-12 was escalated during cycle 1 to a maintenance dose of 1.25 mug/kg. IFN was administered at 9 million units by s.c. injection three times per w eek. Serum concentrations of IL-12, IFN-gamma, IL-10, and neopterin were ob tained in 10 patients treated with rHuIL-12 after the first full dose of 1. 25 mug/kg given on day 15 (dose 3) of cycle 1 and again after multiple dose s on day 15 (dose 6) of cycle 2, Thirty patients were treated with rHuIL-12 , and 16 patients were treated with IFN-alpha. Two (7%) of 30 patients trea ted with rHuIL-12 achieved a partial response, and the trial was closed to accrual based on the low response proportion. IL-12 was absorbed rapidly af ter s.c. drug administration, with the peak serum concentration appearing a t approximately 12 h in both cycles. Serum IL-12 concentrations remained st able on multiple dosing. Levels of IFN-gamma, IL-10, and neopterin increase d with rHuIL-12 and were maintained in cycle 2, rHuIL-12 is a novel cytokin e with unique pharmacologic and pharmacodynamic features under study for th e treatment of malignancy and other medical conditions. The low response pr oportion associated with rHuIL-12 single-agent therapy against metastatic R CC was disappointing, given the preclinical data. Further study of rHuIL-12 for other medical conditions is underway. For RCC, the study of new cytoki nes is of the highest priority.