Jacob P Laubach 1,2 , Chia-Jen Liu 1 , Noopur S Raje 3 , Andrew J Yee 3 , Philippe Armand 1,2 , Robert L Schlossman 1,2 , Jacalyn Rosenblatt 2,4 , Jacquelyn Hedlund 2,5 , Michael Martin 2,6 , Craig Reynolds 2,7 , Kenneth H Shain 8 , Ira Zackon 2,9 , Laura Stampleman 2,10 , Patrick Henrick 1,2 , Bradley Rivotto 1 , Kalvis T V Hornburg 1 , Henry J Dumke 1 , Stacey Chuma 1,2 , Alexandra Savell 1,2 , Damian R Handisides 11 , Stew Kroll 11 , Kenneth C Anderson 1,2 , Paul G Richardson 12,2 , Irene M Ghobrial 12,2 Show Affiliations »
Abstract
PURPOSE: The presence of hypoxia in the diseased bone marrow presents a new therapeutic target for multiple myeloma. Evofosfamide (formerly TH-302) is a 2-nitroimidazole prodrug of the DNA alkylator, bromo-isophosphoramide mustard, which is selectively activated under hypoxia. This trial was designed as a phase I/II study investigating evofosfamide in combination with dexamethasone, and in combination with bortezomib and dexamethasone in relapsed/refractory multiple myeloma. PATIENTS AND METHODS: Fifty-nine patients initiated therapy, 31 received the combination of evofosfamide and dexamethasone, and 28 received the combination of evofosfamide, bortezomib, and dexamethasone. Patients were heavily pretreated with a median number of prior therapies of 7 (range: 2-15). All had previously received bortezomib and immunomodulators. The MTD, treatment toxicity, and efficacy were determined. RESULTS: The MTD was established at 340 mg/m2 evofosfamide + dexamethasone with dose-limiting mucositis at higher doses. For the combination of evofosfamide, bortezomib, and dexamethasone, no patient had a dose-limiting toxicity (DLT) and the recommended phase II dose was established at 340 mg/m2. The most common ≥grade 3 adverse events (AE) were thrombocytopenia (25 patients), anemia (24 patients), neutropenia (15 patients), and leukopenia (9 patients). Skin toxicity was reported in 42 (71%) patients. Responses included 1 very good partial response (VGPR), 3 partial response (PR), 2 minor response (MR), 20 stable disease (SD), and 4 progressive disease (PD) for evofosfamide + dexamethasone and 1 complete response (CR), 2 PR, 1 MR, 18 SD, and 5 PD for evofosfamide + bortezomib + dexamethasone. Disease stabilization was observed in over 80% and this was reflective of the prolonged overall survival of 11.2 months. CONCLUSIONS: Evofosfamide can be administered at 340 mg/m2 twice a week with or without bortezomib. Clinical activity has been noted in patients with heavily pretreated relapsed refractory multiple myeloma. ©2018 American Association for Cancer Research.
PURPOSE: The presence of hypoxia in the diseased bone marrow presents a new therapeutic target for multiple myeloma . Evofosfamide (formerly TH-302 ) is a 2-nitroimidazole prodrug of the DNA alkylator, bromo-isophosphoramide mustard, which is selectively activated under hypoxia . This trial was designed as a phase I/II study investigating evofosfamide in combination with dexamethasone , and in combination with bortezomib and dexamethasone in relapsed/refractory multiple myeloma . PATIENTS AND METHODS: Fifty-nine patients initiated therapy, 31 received the combination of evofosfamide and dexamethasone , and 28 received the combination of evofosfamide , bortezomib , and dexamethasone . Patients were heavily pretreated with a median number of prior therapies of 7 (range: 2-15). All had previously received bortezomib and immunomodulators. The MTD , treatment toxicity , and efficacy were determined. RESULTS: The MTD was established at 340 mg/m2 evofosfamide + dexamethasone with dose-limiting mucositis at higher doses. For the combination of evofosfamide , bortezomib , and dexamethasone , no patient had a dose-limiting toxicity (DLT) and the recommended phase II dose was established at 340 mg/m2. The most common ≥grade 3 adverse events (AE) were thrombocytopenia (25 patients ), anemia (24 patients ), neutropenia (15 patients ), and leukopenia (9 patients ). Skin toxicity was reported in 42 (71%) patients . Responses included 1 very good partial response (VGPR), 3 partial response (PR), 2 minor response (MR ), 20 stable disease (SD ), and 4 progressive disease (PD ) for evofosfamide + dexamethasone and 1 complete response (CR), 2 PR, 1 MR , 18 SD , and 5 PD for evofosfamide + bortezomib + dexamethasone . Disease stabilization was observed in over 80% and this was reflective of the prolonged overall survival of 11.2 months. CONCLUSIONS: Evofosfamide can be administered at 340 mg/m2 twice a week with or without bortezomib . Clinical activity has been noted in patients with heavily pretreated relapsed refractory multiple myeloma . ©2018 American Association for Cancer Research.
Entities: Chemical
Disease
Gene
Species
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Year: 2018
PMID： 30279233 PMCID： PMC6335171 DOI： 10.1158/1078-0432.CCR-18-1325
Source DB: PubMed Journal: Clin Cancer Res ISSN： 1078-0432 Impact factor: 12.531