Clinical Cancer Research CTRC-AACR San Antonio Breast Cancer Symposium Translational Cancer Medicine 2008: Cancer Clinical Trials and Personalized Medicine
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Clinical Cancer Research Vol. 10, 2253-2264, April 2004
© 2004 American Association for Cancer Research

Clinical Trials

Phase I Studies of Interleukin (IL)-2 and Rituximab in B-Cell Non-Hodgkin’s Lymphoma

IL-2 Mediated Natural Killer Cell Expansion Correlations with Clinical Response

William Larry Gluck1, Deborah Hurst2, Alan Yuen3, Alexandra M. Levine4, Mark A. Dayton5, Jon P. Gockerman6, Jennifer Lucas7, Kimberly Denis-Mize2, Barbara Tong2, Dawn Navis2, Anita Difrancesco2, Sandra Milan2, Susan E. Wilson2 and Maurice Wolin2

1 Cancer Center of the Carolinas, Greenville, South Carolina; 2 Chiron Corporation, Emeryville, California; 3 Stanford University Medical Center, Stanford, California; 4 Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California; 5 Lousiana State University Health Sciences Center, Shreveport, Louisiana; 6 Duke University Medical Center, Durham, North Carolina; and 7 California Cancer Care, Inc., Greenbrae, California

ABSTRACT

Purpose: Expansion and activation of natural killer (NK) cells with interleukin-2 (IL-2) may enhance antibody-dependent cellular cytotoxicity (ADCC), an important mechanism of rituximab activity. Two parallel Phase I studies evaluated combination therapy with rituximab and IL-2 in relapsed or refractory B-cell non-Hodgkin’s lymphoma (NHL).

Experimental Design: Thirty-four patients with advanced NHL received rituximab (375 mg/m2 i.v. weekly, weeks 1–4) and escalating doses of s.c. IL-2 [2–7.5 MIU daily (n = 19) or 4.5–14 million international units three times weekly (n = 15), weeks 2–5]. Safety, tolerability, clinical responses, NK cell counts, and ADCC activity were evaluated.

Results: Maximally tolerated doses (MTD) of IL-2 were 6 MIU daily and 14 million international units thrice weekly. The most common adverse events were fever, chills, and injection site reactions. Dose-limiting toxicities were fatigue and reversible liver enzyme test elevations. Of the 9 patients enrolled at the daily schedule MTD, 5 showed clinical response. On the thrice-weekly schedule at the MTD, 4 of 5 patients responded. Responders showed median time to progression of 14.9 and 16.1 months, respectively, for the two studies. For the same total weekly dose, thrice-weekly IL-2 administration induced greater increases in NK cell counts than daily dosing, and NK cells correlated with clinical response on the thrice-weekly regimen. ADCC activity was increased and maintained after IL-2 therapy in responding and stable disease patients.

Conclusions: Addition of IL-2 to rituximab therapy is safe and, using thrice-weekly IL-2 dosing, results in NK cell expansion that correlates with response. This combination treatment regimen merits additional evaluation in a randomized clinical trial.




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Copyright © 2004 by the American Association for Cancer Research.