A First-in-Human Phase I Study of Subcutaneous Outpatient Recombinant Human IL15 (rhIL15) in Adults with Advanced Solid Tumors
Jeffrey S Miller, Chihiro Morishima, Douglas G McNeel, Manish R Patel, Holbrook E K Kohrt, John A Thompson, Paul M Sondel, Heather A Wakelee, Mary L Disis, Judith C Kaiser, Martin A Cheever, Howard Streicher, Steven P Creekmore, Thomas A Waldmann, Kevin C Conlon, Jeffrey S Miller, Chihiro Morishima, Douglas G McNeel, Manish R Patel, Holbrook E K Kohrt, John A Thompson, Paul M Sondel, Heather A Wakelee, Mary L Disis, Judith C Kaiser, Martin A Cheever, Howard Streicher, Steven P Creekmore, Thomas A Waldmann, Kevin C Conlon
Abstract
Purpose: Preclinical data established IL15 as a homeostatic factor and powerful stimulator of NK and CD8+ T-cell function, the basis for clinical testing.Experimental Design: A first-in-human outpatient phase I dose escalation trial of subcutaneous (SC) rhIL15 was conducted in refractory solid tumor cancer patients. Therapy consisted of daily (Monday-Friday) subcutaneous injections of rhIL15 for two consecutive weeks (10 total doses/cycle). Clinical response was assessed by RECIST. Pharmacokinetics of rhIL15 and immune biomarkers were evaluated.Results: Nineteen patients were treated with rhIL15 at dose levels of 0.25, 0.5, 1, 2, and 3 mcg/kg/day. Fourteen patients completed ≥ 2 cycles of therapy that was well tolerated. One serious adverse event (SAE), grade 2 pancreatitis, required overnight hospitalization. Enrollment was halted after a patient receiving 3 mcg/kg/day developed a dose-limiting SAE of grade 3 cardiac chest pain associated with hypotension and increased troponin. No objective responses were observed; however, several patients had disease stabilization including a renal cell carcinoma patient who continued protocol treatment for 2 years. The treatment induced profound expansion of circulating NK cells, especially among the CD56bright subset. A proportional but less dramatic increase was found among circulating CD8+ T cells with maximal 3-fold expansion for the 2 and 3 mcg/kg patients.Conclusions: SC rhIL15 treatment was well tolerated, producing substantial increases in circulating NK and CD8+ T cells. This protocol establishes a safe outpatient SC rhIL15 regimen of 2 mcg/kg/day dosing amenable to self-injection and with potential as a combination immunotherapeutic agent. Clin Cancer Res; 24(7); 1525-35. ©2017 AACR.
Trial registration: ClinicalTrials.gov NCT01727076.
Conflict of interest statement
Conflict of Interest Statement: DG McNeel reported holding ownership interest (including patents) in and being a consultant/advisory board member for Madison Vaccines Inc. No potential conflicts of interest were disclosed by other authors.
©2017 American Association for Cancer Research.
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Source: PubMed