Cancer Therapy: Clinical The Novel Expanded Porphyrin, Motexafin Gadolinium, Combined with [Y]Ibritumomab Tiuxetan for Relapsed/Refractory Non-Hodgkin's Lymphoma: Preclinical Findings and Results of a Phase I Trial

Purpose: Therapeutic strategies to enhance the efficacy of radioimmunotherapy have not been explored. Motexafin gadolinium is a novel anticancer agent that targets redox-dependent pathways and enhances sensitivity of tumor cells to ionizing radiation. Experimental Design:We did preclinical studies examining motexafin gadolinium combined with rituximab and/or radiation in lymphoma cells. We subsequently completed a phase I clinical trial combining escalating doses of motexafin gadolinium concurrently with standard [Y]ibritumomab tiuxetan for patients with relapsed/refractory nonHodgkin's lymphoma. Results: In HF1 lymphoma cells, motexafin gadolinium and rituximab resulted in synergistic cytotoxicity (combination index, 0.757) through amitochondrial-mediated caspasedependent pathway, whereas cell death in Ramos and SUDHL4 cells was additive. Motexafin gadolinium/rituximab combined with radiation (1-3 Gy) resulted in additive apoptosis. Twenty-eight of 30 patients were evaluable on the phase I clinical trial. Median age was 65 years (47-87 years), and histologies were marginal-zone (n = 1), mantle-cell (n = 3), diffuse large cell (n = 6), and follicular lymphoma (n = 18). Of all patients, 86% were rituximab refractory. Therapy was well tolerated, and no dose-limiting toxicity was seen. Overall response rate was 57% [complete remission (CR), 43%], with median time–to–treatment failure of 10months (1-48+months) andmedian duration-of-response of 17 months. Of note, all responses were documented at 4 weeks. Furthermore, in rituximab-refractory follicular lymphoma (n = 14), overall response rate was 86% (CR, 64%), with a median time–to–treatment failure of 14 months (2-48+ months). Conclusions: This represents the first report of a novel agent to be combined safely concurrently with radioimmunotherapy. Furthermore, tumor responses with [Y]ibritumomab tiuxetan/motexafin gadolinium were prompt with a high rate of CRs, especially in rituximab-refractory follicular lymphoma. (Clin Cancer Res 2009; 15(20):6462–71) Authors' Affiliations: Lymphoma Program, Division of Hematology/ Oncology, The Robert H. Lurie Comprehensive Cancer Center; Departments of Radiology/Nuclear Medicine, Preventive Medicine, and Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois; and Pharmacyclics, Inc., Sunnyvale, California Received 4/9/09; revised 7/20/09; accepted 7/22/09; published OnlineFirst 10/13/09. Grant support: National Cancer Institute K23 CA109613-A1 for translational research/clinical trial (A.M. Evens) and M01 RR-00048 National Center for Research Resources, NIH (clinical trial). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Presented in part at the American Society of Hematology 47th Annual Meeting, December 11th, 2005, Atlanta, Georgia; the American Society of Hematology 49th Annual Meeting, December 9th, 2007, Atlanta, Georgia; and the 10th International Conference on Malignant Lymphoma, June 4th, 2008, Lugano, Switzerland. The radioimmunoconjugate [Y]ibritumomab tiuxetan is currently Food and Drug Administration approved for treatment of patients with relapsed or refractory, low-grade, or follicular B-cell non-Hodgkin's lymphoma, including patients with follicular non-Hodgkin's lymphoma who are refractory to rituximab. Motexafin gadolinium is not a Food and Drug Administration–approved treatment agent. Requests for reprints: AndrewM. Evens, Division of Hematology/Oncology, The Robert H. Lurie Comprehensive Cancer Center, Suite 850, 676 North St. Clair Street, Chicago, IL, 60611. Phone: 312-695-4537; Fax: 1-312-695-6189; E-mail: [email protected]. F 2009 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-09-0905 6462 Clin Cancer Res 2009;15(20) October 15, 2009 www.aacrjournals.org Research. on July 17, 2017. © 2009 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Published OnlineFirst October 14, 2009; DOI: 10.1158/1078-0432.CCR-09-0905