Results From The First-In-Human Phase I Trials Of Recombinant Human Interleukin 15 (Rhil-15) Administered As A Daily 30 Minute Intravenous Infusion (Ivb) For 12 Consecutive Days Or As Continuous Intravenous Infusion (Civ) For 240 Hours In Patients With Refractory Metastatic Cancers

Preclinical laboratory experiments with Interleukin 15 (IL-15) have demonstrated significant immunotherapeutic potential for recombinant human IL-15 (rhIL-15) in cancer patients. We have completed a first-in-human (FIH), phase I dose escalation trial of E. coli produced rhIL-15 administered as a 30 minute intravenous bolus (IVB) infusion given daily for 12 consecutive days to patients with metastatic melanoma (MM) or renal cell carcinoma (mRCC). rhIL-15 treatment produced up to an 8-fold expansion of circulating NK cells, approximately 2 fold expansion of CD8+ CD45RO+ memory T-cells and up to 50 fold increases in serum level for multiple cytokines. Characteristic toxicities associated with cytokine treatment such as fever, rigors or chills, capillary leak, myalgias and blood pressure changes occurred at frequency and severity proportional to the dose of rhIL-15. Laboratory results showed early course transient leukopenia, lymphopenia, modest neutropenia, occasional thrombocytopenia and significant elevations of alanine and asparagine transaminase (ALT, AST) in a number of patients. Antibodies to rhIL-15 antibodies were not detected in any patient. The maximum tolerated dose for this schedule was 0.3 μg/kg/day with dose-limiting toxicities (DLTs) of grade 3 hypotension, thrombocytopenia, grade 3 or 4 ALT and AST elevation. There were no documented objective responses by RECIST criteria, but decreases in the sum of diameters for the marker lesions between 10 and 30% and improvement or clearance of parenchymal lung metastases were observed in several patients suggesting some antitumor activity. A phase I dose escalation trial evaluating a 10 day (240 hour) continuous intravenous infusion (CIV) of rhIL-15 which is expected to produce greater expansion of CD8 effector cells and immune activation has been initiated. Patients treated at the first two dose levels have demonstrated improved clinical tolerability, immune activation; fewer laboratory abnormalities and no DLTs. Patient accrual and dose escalation to the third dose level are ongoing. Citation Format: Kevin C. Conlon, Enrico Lugli, Steven A. Rosenberg, John C. Morris, Thomas Fleisher, Hugh Welles, Sigrid Dubois, Liyanage Perera, Carolyn Goldman, Bonita Bryant, Jean Decker, Joanna Shih, Tat9Yana Worthy, William Figg, Cody Peer, Michael Sneller, H. Clifford Lane, Jason Yovandich, Stephen Creekmore, Mario Roederer, Thomas A. Waldmann. Results from the first-in-human phase I trials of recombinant human Interleukin 15 (rhIL-15) administered as a daily 30 minute intravenous infusion (IVB) for 12 consecutive days or as continuous intravenous infusion (CIV) for 240 hours in patients with refractory metastatic cancers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2575. doi:10.1158/1538-7445.AM2014-2575