Phase II Trial of Interleukin-12 Followed by Interferon Alfa-2b in Patients with Metastatic Malignant Melanoma: Results from CALGB 500001 (Alliance).

The ability of IL12 to stimulate production of IFNγ suggested it might improve the efficacy of low-dose IFNα. In this phase II trial, patients with metastatic malignant melanoma were administered recombinant human (rh) IL12 followed by IFNα2b. Primary endpoints were clinical response and progression-free survival. Secondary objectives were to evaluate the effect of endogenous IFNγ on JAK-STAT signaling and IFN-regulated genes in peripheral blood mononuclear cells (PBMC). Patients with advanced melanoma received rhIL12 on day 1 and IFNα2b on days 2 to 6 of a 14-day cycle. rhIL12 was given intravenously at 300 ng/kg. IFNα2b was dosed at 3 × 106 units subcutaneously. Plasma IFNγ was assayed by ELISA; JAK-STAT signaling was measured in PBMCs by flow cytometry. The proportion of responders was assessed via Simon two-stage design. Thirty-eight patients were enrolled. The regimen was well-tolerated. Two patients achieved a partial response lasting 6 months or longer (5.3%). IL12 administration led to an increase in mean plasma IFNγ from 33.57 pg/mL at baseline to a maximum of 564.86 pg/mL and increased expression of STAT1 and STAT2 in PBMCs. Generation of phosphorylated STAT1 and IFN-simulated gene product 15 in response to IFNα was enhanced following IL12. rhIL12 given prior to IFNα2b stimulated production of IFNγ, which led to increased levels of JAK-STAT signaling intermediates in patient PBMCs. Combination therapy was reasonably well-tolerated but conferred marginal benefit in patients with metastatic melanoma. These results can inform future studies that use recombinant IL12 or novel IL12 constructs.