期刊
CLINICAL CANCER RESEARCH
卷 25, 期 2, 页码 478-486出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-18-1325
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类别
资金
- Threshold Pharmaceuticals
- Merck KGaA, Darmstadt, Germany
- Leukemia and Lymphoma Society
- [R01 CA181683-01A1]
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 pre-treated 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/m(2) evofosfamide thorn 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(2). 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 thorn dexamethasone and 1 complete response (CR), 2 PR, 1 MR, 18 SD, and 5 PD for evofosfamide thorn bortezomib thorn 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/m(2) twice a week with or without bortezomib. Clinical activity has been noted in patients with heavily pretreated relapsed refractory multiple myeloma.
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