A Phase I/II Study of Evofosfamide, A Hypoxia-activated Prodrug with or without Bortezomib in Subjects with Relapsed/Refractory Multiple Myeloma.
A Phase I/II Study of Evofosfamide, A Hypoxia-activated Prodrug with or without Bortezomib in Subjects with Relapsed/Refractory Multiple Myeloma.
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DOI：
10.1158/1078-0432.ccr-18-1325
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发表时间：
2019-01-15
期刊：
影响因子：
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通讯作者：
Ghobrial IM
中科院分区：
文献类型：
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作者：
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
在患病骨髓中缺氧的存在为多发性骨髓瘤（MM）提供了一个新的治疗靶点。Evofosfamide（以前称为TH-302）是DNA烷基化剂溴异磷酰胺氮芥的2-硝基咪唑前药，在缺氧条件下选择性活化。一项研究evofosfamide联合地塞米松（EvoD）和联合硼替佐米和地塞米松（EvoBorD）治疗复发性/难治性MM的1/2期研究。59例患者开始治疗，31例接受EvoD治疗，28例接受EvoBorD治疗。患者接受了大量预治疗，既往治疗的中位数为7（范围：2-15）。所有患者既往均接受过硼替佐米和免疫调节剂治疗。测定最大耐受剂量（MTD）、治疗毒性和疗效。MTD确定为340 mg/m2 Evo+D，在较高剂量下会出现剂量限制性粘膜炎。对于EVOBord，没有患者出现剂量限制性毒性，推荐的II期剂量确定为340 mg/m2。最常见的≥ 3级不良事件为血小板减少（25例患者）、贫血（24例患者）、中性粒细胞减少（15例患者）和白细胞减少（9例患者）。42例（71%）报告皮肤毒性。缓解包括EvoD的1例VGPR、3例PR、2例MR、20例SD和4例PD，EvoBord的1例CR、2例PR、1例MR、18例SD和5例PD。在超过80%的患者中观察到疾病稳定，这反映了11.2个月的延长的总生存期。Evofosfamide可以以340 mg/m2每周两次与或不与硼替佐米一起施用。在接受过大量预治疗的复发性难治性MM患者中观察到临床活性。
The presence of hypoxia in the diseased bone marrow presents a new therapeutic target for multiple myeloma (MM). Evofosfamide (formerly TH-302) is a 2-nitroimidazole prodrug of the DNA alkylator bromo-isophosphoramide mustard that is selectively activated under hypoxia. A phase 1/2 study investigating evofosfamide in combination with dexamethasone (EvoD) and in combination with bortezomib and dexamethasone (EvoBorD) in relapsed/refractory MM. 59 patients initiated therapy, 31 received EvoD and 28 received EvoBorD. Pts were heavily pre-treated with a median number of prior therapies of 7 (range: 2–15). All had previously received bortezomib and immunomodulators. The maximum tolerated dose (MTD), treatment toxicity, and efficacy were determined. The MTD was established at 340 mg/m2 Evo+D with dose limiting mucositis at higher doses. For EVOBorD, no patient had a dose limiting toxicity and the recommended phase 2 dose was established at 340 mg/m2. The most common ≥ Gr 3 adverse events were thrombocytopenia (25 patients), anemia (24 patients), neutropenia (15 patients) and leukopenia (9 patients). Skin toxicity was reported in 42 (71%). Responses included 1 VGPR, 3 PR, 2 MR, 20 SD and 4 PD for EvoD and 1 CR, 2 PR, 1 MR, 18 SD and 5 PD for EvoBorD. 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 pre-treated relapsed refractory MM.