A nonrandomized phase I and biomarker trial of regorafenib in advanced myeloid malignancies.
A nonrandomized phase I and biomarker trial of regorafenib in advanced myeloid malignancies.
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DOI：
10.1002/jha2.408
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发表时间：
2022-05
期刊：
影响因子：
--
通讯作者：
Hobbs, Gabriela S.
中科院分区：
文献类型：
--
作者：
How, Joan;Ren, Siyang;Lombardi-Story, Jennifer;Bergeron, Meghan;Foster, Julia;Amrein, Phillip C.;Brunner, Andrew M.;Fathi, Amir T.;Hock, Hanno;Khachatryan, Anna;Kikuchi, Hiroto;Ng, Mei Rosa;Moran, Jenna;Narayan, Rupa;Neuberg, Donna;Ramos, Aura;Som, Tina;Vartanian, Meghan;Chen, Yi-Bin;Duda, Dan G.;Hobbs, Gabriela S.
我们针对晚期髓系肿瘤患者开展了一项单中心、开放标签、剂量递增及扩展的I期试验，使用抗血管生成多激酶抑制剂瑞戈非尼。我们招募了16名复发/难治性急性髓系白血病（AML）、骨髓增殖性肿瘤（MPN）、慢性粒单核细胞白血病（CMML）或骨髓增生异常综合征（MDS）患者。采用3 + 3剂量递增设计，有两个计划剂量水平（每日120毫克或160毫克）以及一个剂量递减水平（每日80毫克）。另有10名患者在扩展队列中接受治疗。瑞戈非尼的推荐II期剂量为每日160毫克，未出现剂量限制性毒性。按照国际工作组标准，最佳总体疾病反应包括11名患者中有1名部分缓解和病情稳定。组织研究表明，应答者中Ras/丝裂原活化蛋白激酶（MAPK）通路激活无变化。在治疗过程中检测到血浆血管内皮生长因子（VEGF）、胎盘生长因子（PlGF）和可溶性血管内皮生长因子受体2（sVEGFR2）的药效学变化。基线促炎和血管生成细胞因子水平与临床反应无关。单药瑞戈非尼在复发/难治性髓系恶性肿瘤患者中显示出可接受的安全性。大多数患者病情稳定，一些MDS患者的细胞计数有适度改善。生物标志物研究与瑞戈非尼对血管生成的靶向作用一致。未来的研究应探讨瑞戈非尼在联合治疗方法中的作用。
We conducted a single‐center, open‐label, dose escalation, and expansion phase I trial of the antiangiogenic multikinase inhibitor regorafenib in patients with advanced myeloid neoplasms. We enrolled 16 patients with relapsed/refractory acute myeloid leukemia (AML), myeloproliferative neoplasms (MPN), chronic myelomonocytic leukemia (CMML), or myelodysplastic syndrome (MDS). A 3 + 3 dose escalation design was used with two planned dose levels (120 or 160 mg daily) and one de‐escalation level (80 mg daily). An additional 10 patients were treated on an expansion cohort. The recommended phase two dose of regorafenib was 160 mg daily, with no dose‐limiting toxicities. The best overall disease response by International Working Group criteria included one partial and stable disease in 11 patients. Tissue studies indicated no change in Ras/mitogen‐activated protein kinase (MAPK) pathway activation in responders. Pharmacodynamic changes in plasma VEGF, PlGF, and sVEGFR2 were detected during treatment. Baseline proinflammatory and angiogenic cytokine levels were not associated with clinical response. Single‐agent regorafenib demonstrated an acceptable safety profile in relapsed/refractory myeloid malignancy patients. Most patients achieved stable disease, with modest improvements in cell counts in some MDS patients. Biomarker studies were consistent with on‐target effects of regorafenib on angiogenesis. Future studies should investigate the role of regorafenib in combination therapy approaches.
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