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|Ref Type||Journal Article|
|Authors||Laubach JP, Liu CJ, Raje NS, Yee AJ, Armand P, Schlossman RL, Rosenblatt J, Hedlund J, Martin M, Reynolds C, Shain KH, Zackon I, Stampleman L, Henrick P, Rivotto B, Hornburg KTV, Dumke HJ, Chuma S, Savell A, Handisides DR, Kroll S, Anderson KC, Richardson PG, Ghobrial IM|
|Title||A Phase I/II Study of Evofosfamide, A Hypoxia-activated Prodrug with or without Bortezomib in Subjects with Relapsed/Refractory Multiple Myeloma.|
|Journal||Clinical cancer research : an official journal of the American Association for Cancer Research|
|Date||2019 Jan 15|
|Abstract Text||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/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.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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||multiple myeloma||not applicable||Dexamethasone + Evofosfamide||Phase Ib/II||Actionable||In a Phase I/II trial, Evofosfamide (TH-302) therapy plus Adexone (dexamethasone) was well tolerated in patients with relapsed/refractory multiple myeloma and resulted in a disease control rate of 83.9% (26/31, stable disease or better), 3.3% (1/31) very good partial responses and 9.7% (3/31) partial responses, a 40% 6-month progression-free survival rate, a median progression-free survival of 4.4 months, and a median overall survival of 12.8 months (PMID: 30279233; NCT01522872).||30279233|
|Unknown unknown||multiple myeloma||not applicable||Bevacizumab + Dexamethasone + Evofosfamide||Phase Ib/II||Actionable||In a Phase I/II trial, treatment with combined Avastin (bevacizumab), Evofosfamide (TH-302) therapy, and Adexone (dexamethasone) was well tolerated in patients with relapsed/refractory multiple myeloma and resulted in a disease control rate of 78.6% (22/28, stable disease or better), 3.6% (1/28) complete and 7.1% (2/28) partial responses, a 25% 6-month progression-free survival rate, a median progression-free survival of 2.2 months, and a median overall survival of 9.0 months (PMID: 30279233; NCT01522872).||30279233|