Immune monitoring of phase II trial of hu14.18-IL2 for patients with metastatic melanoma.

Abstract

e19047 Background: Phase I testing of the hu14.18-IL2 immunocytokine (IC) in patients (pts) with melanoma showed immune activation, reversible toxicities, and a maximal tolerated dose (MTD) of 7.5 mg/m2/day. Methods: In this phase II study, 14 metastatic melanoma pts were scheduled to receive hu14.18-IL2 at 6 mg/m2/day as 4-hour intravenous infusions on days 1, 2 and 3 of each 28 day cycle. Pts with stable disease (SD) or regression following cycle 2 could receive 2 additional treatment cycles. The primary objective was to evaluate anti-tumor activity and response duration. Secondary objectives evaluated adverse events and immunologic activation. Results: All pts received 2 cycles of treatment. One pt had a partial response (PR) [1 PR of 14 pts = response rate of 7.1%; confidence interval 0.2%-33.9%] and 4 pts had SD and received cycles 3 and 4. The PR and SD responses lasted 3-4 months. All toxicities were reversible. Analysis of serum IC for all pts showed a mean value of 1.42 ug/ml on C1D1 and 1.38 ug/ml on C1D3. Pts had a peripheral blood lymphocytosis on day 8 and increased C-reactive protein (CRP). A significant increase in sIL2R levels was seen in all courses from baseline to day 3 (p<0.001 for both courses 1 and 2). Infusion of the IC into these pts enabled their serum to mediate antibody dependent cell-mediated cytotoxicity using the circulating IC. Eight pts developed a “positive” anti-idiotype antibody against hu14.18-IL2 based on a bridging assay, and 13 developed a detectible anti-idiotypic antibody based on a binding inhibition assay. There was no significant effect of this anti-idiotypic antibody response on the in vivo level of hu14.18-IL2. While one PR in 14 pts met protocol criteria to proceed to stage 2 and enter 16 additional pts, we suspended stage 2 due to limited availability of hu14.18-IL2 at that time and the brief duration of PR and SD. Conclusions: We conclude that subsequent testing of hu14.18-IL2 should involve melanoma pts with minimal residual disease based on compelling preclinical data as well as the confirmed immune activation with some antitumor activity in this study. In addition, the demonstrated immunological activation of hu14.18-IL2 with manageable toxicities suggests the potential for combination treatments.