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Phase I Trial of Toll-Like Receptor 9 Agonist PF-3512676 with and Following Rituximab in Patients with Recurrent Indolent and Aggressive Non–Hodgkin's Lymphoma

Authors' Affiliations: ¹ Weill Medical College of Cornell University and New York Presbyterian Hospital, New York, New York; ² University of Iowa, Iowa City, Iowa; ³ University of California at Los Angeles Medical Center, Los Angeles, California; ⁴ Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois; ⁵ University of Minnesota, Minneapolis, Minnesota; ⁶ Scripps Clinic, La Jolla, California; ⁷ Sarah Cannon Cancer Center, Nashville, Tennessee; ⁸ Montefiore-Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, New York; ⁹ University of Pennsylvania Medical Center, Philadelphia, Pennsylvania; ¹⁰ Stanford University Medical Center, Palo Alto, California; and ¹¹ Coley Pharmaceutical Group, Inc., Wellesley, Massachusetts

Requests for reprints: George J. Weiner, Holden Comprehensive Cancer Center at the University of Iowa, 5970Z JPP, 200 Hawkins Drive, University of Iowa, Iowa City, IA 52242. Phone: 319-353-8620; Fax: 319-353-8988; E-mail: george-weiner{at}uiowa.edu.

Purpose: PF-3512676 (formerly CpG 7909) is a novel Toll-like receptor 9–activating oligonucleotide with single-agent antitumor activity that augments preclinical rituximab efficacy. This Phase I trial was designed to investigate the safety, tolerability, and preliminary antitumor activity of PF-3512676 in combination with rituximab.

Experimental Design: Patients with relapsed/refractory CD20⁺ B cell non–Hodgkin's lymphoma received i.v. rituximab (375 mg/m²/week for 4 weeks) and PF-3512676 weekly for 4 weeks either i.v. (0.04, 0.16, 0.32, or 0.48 mg/kg) or s.c. (0.01, 0.04, 0.08, or 0.16 mg/kg). An additional extended-treatment cohort received 4 weeks of 0.24 mg/kg s.c. PF-3512676 in combination with rituximab followed by s.c. PF-3512676 alone weekly for 20 weeks.

Results: Patients (N = 50) had received a median of three prior therapies (range, 1-11) including rituximab in 80% of patients. Treatment-related adverse events occurred in 11 of 19 (58%) i.v. patients, 15 of 19 (79%) s.c. patients, and all 12 patients in the extended-treatment cohort. Most common adverse events were mild to moderate systemic flu-like symptoms and injection-site reactions (s.c. cohorts only). Grade 3/4 neutropenia occurred in four patients. Objective responses occurred in 12 of 50 (24%) patients overall and in 6 of 12 (50%) patients in the extended-treatment cohort, including 2 patients with rituximab-refractory disease.

Conclusion: Brief or extended-duration PF-3512676 can be safely administered in combination with rituximab in patients with relapsed/refractory non–Hodgkin's lymphoma.

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