Abstract LB-015: Phase I trial of recombinant human interleukin 15 (rhIL-15) in combination with nivolumab and ipilimumab in refractory cancers
Authors: Coyne Geraldine OSullivan , Khan Sabrina S. , Conlon Kevin , Streicher Howard , Bruns Ashley , Piekarz Richard , Takebe Naoko , Juwara Lamin , Parchment Ralph , Navas Tony , Fino Kirstin , Fung King L. , Sharon Elad , Doroshow James H. , Waldmann Thomas A. , Chen Alice P. 
Published: August 2019

Abstract
Introduction: Treatment with rhIL-15 has been reported to significantly increase levels of circulating CD8+ T cells, NK cells, and inflammatory cytokines. In vivo administration of rhIL-15 with immune checkpoints inhibitors of CTLA-4 and PD-L1 resulted in increased tumor antigen-specific CD8+ T-cells, enhanced CD8+ tumor lytic activity, and improved mouse survival. This combination is therefore expected to enhance the anti-tumor immune response in patients by promoting T-cell expansion and cytotoxic activity. The primary objective of this trial is to determine the safety, dose-limiting toxicity (DLT), and maximum tolerated dose (MTD) of rhIL-15 with nivolumab (N) and ipilimumab (Ipi) in refractory tumors. Prior to initiating treatment with all three drugs, we treated a cohort of patients (pts) with doublet combinations (rhIL-15+Ipi; rhIL-15+N) to establish safety. Here we report results for the doublets.
Methods: This is an open-label, 3+3 design, phase I trial with a pharmacodynamic expansion cohort at the MTD (NCT03388632). Pts with prior immunotherapy are eligible unless they experienced a prior grade ≥ 3 immune-related toxicity. The doses for the doublets are rhIL-15 0.5 mcg/kg/day SC and N 240 mg IV or Ipi 1 mg/kg IV. rhIL-15 is given on days 1-8 & 22-29 (first 4 cycles only), followed by N on days 8, 22, & 36 or Ipi on day 8, every 6 weeks until disease progression. No dose reductions are permitted. Response is assessed by RECIST 1.1 and iRECIST after every cycle. Blood is collected at baseline and throughout the study to assess PD-L1 levels, T-cell phenotypic markers, and markers of T-cell activation/inhibition (Zap70 pY493 and SHP2 pY580).
Results: Five patients were treated on the doublet arms, three with N and two with Ipi. Histologies were pancreatic, colon, rectal, cervical and thyroid cancers. The median age was 50 (range 33-70). All patients had at least 1 prior therapy (range 1-6). Two had prior immunotherapy (pembrolizumab & brachyury vaccine). There were no DLTs in the first cycle. The most common adverse events possibly related to treatment were all grade 1: injection site reaction post rhIL-15 (n=4), leukopenia (n=3), anemia (n=3), and AST/ALT increase (n=3). One pt on N experienced a grade 3 immune colitis at week 13, which resolved with steroids. Best response was stable disease in both the rhIL-15+N arm (median 18 wks, range 8-30) and rhIL-15+Ipi arm (median 14 wks, range 12-16).
Conclusions: The doublet arms met safety endpoints, and the trial is currently enrolling pts for the triplet combination. In addition to the biomarker studies in blood, tumor biopsies will be collected at the MTD to assess the tumor immune microenvironment, including the proximity of T-cells to tumor cells, and the expression of intrinsic apoptosis biomarkers. Funded in part by NCI Contract HHSN261200800001E.
Citation Format: Geraldine OSullivan Coyne, Sabrina S. Khan, Kevin Conlon, Howard Streicher, Ashley Bruns, Richard Piekarz, Naoko Takebe, Lamin Juwara, Ralph Parchment, Tony Navas, Kirstin Fino, King L. Fung, Elad Sharon, James H. Doroshow, Thomas A. Waldmann, Alice P. Chen. Phase I trial of recombinant human interleukin 15 (rhIL-15) in combination with nivolumab and ipilimumab in refractory cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-015.