A Phase I/II Study of Evofosfamide, A Hypoxia-activated Prodrug with or without Bortezomib in Subjects with Relapsed/Refractory Multiple Myeloma

• Published in: Clinical cancer research Vol. 25; no. 2; pp. 478 - 486
• Main Authors: Laubach, Jacob P., Liu, Chia-Jen, Raje, Noopur S., Yee, Andrew J., Armand, Philippe, Schlossman, Robert L., Rosenblatt, Jacalyn, Hedlund, Jacquelyn, Martin, Michael, Reynolds, Craig, Shain, Kenneth H., Zackon, Ira, Stampleman, Laura, Henrick, Patrick, Rivotto, Bradley, Hornburg, Kalvis T.V., Dumke, Henry J., Chuma, Stacey, Savell, Alexandra, Handisides, Damian R., Kroll, Stew, Anderson, Kenneth C., Richardson, Paul G., Ghobrial, Irene M.
• Format: Journal Article
• Language: English
• Published: United States 15.01.2019
• Subjects: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Bortezomib - administration & dosage; Disease Progression; Drug Resistance, Neoplasm; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Multiple Myeloma - diagnosis; Multiple Myeloma - drug therapy; Multiple Myeloma - etiology; Multiple Myeloma - mortality; Neoplasm Recurrence, Local; Neoplasm Staging; Nitroimidazoles - administration & dosage; Nitroimidazoles - adverse effects; Nitroimidazoles - therapeutic use; Phosphoramide Mustards - administration & dosage; Phosphoramide Mustards - adverse effects; Phosphoramide Mustards - therapeutic use; Retreatment; Treatment Outcome
• ISSN: 1078-0432; 1557-3265; 1557-3265
• DOI: 10.1158/1078-0432.CCR-18-1325

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. 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. The MTD was established at 340 mg/m 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/m . 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. Evofosfamide can be administered at 340 mg/m twice a week with or without bortezomib. Clinical activity has been noted in patients with heavily pretreated relapsed refractory multiple myeloma.