The novel expanded porphyrin, motexafin gadolinium, combined with [ 90Y]ibritumomab tiuxetan for relapsed/refractory non-Hodgkin's lymphoma: Preclinical findings and results of a phase I trial

Andrew M. Evens, William G. Spies, Irene B. Helenowski, David Patton, Stewart Spies, Borko D. Jovanovic, Sarah Miyata, Elizabeth Hamilton, Daina Variakojis, Jun Chen, Louie Naumovski, Steven T. Rosen, Jane N. Winter, Richard A. Miller, Leo I. Gordon

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

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 [ 90Y]ibritumomab tiuxetan for patients with relapsed/refractory non-Hodgkin's lymphoma. Results: In HF1 lymphoma cells, motexafin gadolinium and rituximab resulted in synergistic cytotoxicity (combination index, 0.757) through a mitochondrial-mediated caspase-dependent 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 10 months (1-48+ months) and median 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 [90Y]ibritumomab tiuxetan/motexafin gadolinium were prompt with a high rate of CRs, especially in rituximab-refractory follicular lymphoma.

Original languageEnglish (US)
Pages (from-to)6462-6471
Number of pages10
JournalClinical Cancer Research
Volume15
Issue number20
DOIs
StatePublished - Oct 15 2009

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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