title: 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.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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 [(90)Y]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 [(90)Y]ibritumomab tiuxetan/motexafin gadolinium were prompt with a high rate of CRs, especially in rituximab-refractory follicular lymphoma.
authors.affiliation: Lymphoma Program, Division of Hematology/Oncology, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, 676 North St. Clair Street, Chicago, IL 60611, USA. a-evens@northwestern.edu
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Evens
authors.forename: William G
authors.initials: WG
authors.lastname: Spies
authors.forename: Irene B
authors.initials: IB
authors.lastname: Helenowski
authors.forename: David
authors.initials: D
authors.lastname: Patton
authors.forename: Stewart
authors.initials: S
authors.lastname: Spies
authors.forename: Borko D
authors.initials: BD
authors.lastname: Jovanovic
authors.forename: Sarah
authors.initials: S
authors.lastname: Miyata
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hamilton
authors.forename: Daina
authors.initials: D
authors.lastname: Variakojis
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.forename: Louie
authors.initials: L
authors.lastname: Naumovski
authors.forename: Steven T
authors.initials: ST
authors.lastname: Rosen
authors.forename: Jane N
authors.initials: JN
authors.lastname: Winter
authors.forename: Richard A
authors.initials: RA
authors.lastname: Miller
authors.forename: Leo I
authors.initials: LI
authors.lastname: Gordon
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000532:radiotherapy*; D008297:Male; D008665:Metalloporphyrins / Q000008:administration & dosage* / Q000009:adverse effects; D008875:Middle Aged; D011166:Porphyrins; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage*; D016499:Radioimmunotherapy; D012008:Recurrence; D016896:Treatment Outcome; D015021:Yttrium Radioisotopes / Q000008:administration & dosage*
chemical_list: D000911:Antibodies, Monoclonal; D008665:Metalloporphyrins; D011166:Porphyrins; D011838:Radiation-Sensitizing Agents; D015021:Yttrium Radioisotopes; C422802:ibritumomab tiuxetan; C437683:motexafin gadolinium