Phase I and pharmacokinetic study of bendamustine hydrochloride in relapsed or refractory indolent B-cell non-Hodgkin lymphoma and mantle cell lymphoma
Phase I and pharmacokinetic study of bendamustine hydrochloride in relapsed or refractory indolent B-cell non-Hodgkin lymphoma and mantle cell lymphoma
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DOI：
10.1111/j.1349-7006.2010.01633.x
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发表时间：
2010-09-01
期刊：
影响因子：
5.7
通讯作者：
Tobinai, Kensei
中科院分区：
文献类型：
--
作者：
Ogura, Michinori;Uchida, Toshiki;Tobinai, Kensei
苯达莫司汀是一种具有新颖作用机制的细胞毒剂。这项 I 期剂量递增研究评估了苯达莫司汀在日本无主要器官功能障碍的复发/难治性惰性 B 细胞非霍奇金淋巴瘤 (B-NHL) 或套细胞淋巴瘤 (MCL) 患者中的安全性、耐受性、有效性和药代动力学。每 3 周在第 1 天和第 2 天静脉注射 90 或 120 mg/m2（剂量递增）60 分钟内的苯达莫司汀，最多三个周期。 9 名患者（8 名惰性 B-NHL 和 1 名 MCL）接受了符合方案的治疗，其中 3 名患者接受 90 mg/m2 治疗，6 名患者接受 120 mg/m2 治疗。未观察到剂量限制性毒性；因此，未达到最大耐受剂量。 3/4 级血液学毒性为中性粒细胞减少症 (33%) 和白细胞减少症 (33%)。非血液学毒性为 1/2 级，包括胃肠道事件和疲劳。两个剂量组的苯达莫司汀血浆浓度峰值均出现在输注结束时，相当于体外观察到的治疗浓度。苯达莫司汀被迅速消除，平均消除半衰期 (t(1/2)) 为 29 分钟。活性代谢物 M3 和 M4 的血浆浓度约为母体分子血浆浓度的 4% 和 < 1%，t(1/2) 分别为 42 和 33 分钟。观察到 2 例未经确认的完全缓解和 6 例部分缓解，总体缓解率 (ORR) 为 89%。 II 期试验中该方案的推荐剂量为 120 mg/m2。可接受的安全性和高 ORR 值得进一步研究苯达莫司汀治疗复发或难治性惰性 B-NHL 和 MCL。 （ClinicalTrials.gov ID：NCT00389051）。 （癌症科学 2010）。
Bendamustine is a cytotoxic agent with a novel mechanism of action. This phase I, dose-escalation study evaluated the safety, tolerability, efficacy, and pharmacokinetics of bendamustine in Japanese patients with relapsed/refractory indolent B-cell non-Hodgkin lymphoma (B-NHL) or mantle cell lymphoma (MCL) without major organ dysfunction. Bendamustine 90 or 120 mg/m2 (dose escalation) was administered intravenously over 60 min on days 1 and 2 every 3 weeks for up to three cycles. Nine patients (eight indolent B-NHL and one MCL) received per-protocol treatment, three at 90 mg/m2 and six at 120 mg/m2. No dose-limiting toxicities were observed; thus, the maximum-tolerated dose was not reached. Grade 3/4 hematologic toxicities were neutropenia (33%) and leukopenia (33%). Non-hematologic toxicities were grade 1/2 and included gastrointestinal events and fatigue. Peak plasma concentrations of bendamustine occurred near the end of infusion in both dose groups and were equivalent to therapeutic concentrations observed in vitro. Bendamustine was rapidly eliminated, with a mean elimination half-life (t(1/2)) of 29 min. Plasma concentrations of active metabolites M3 and M4 were approximately 4 and < 1% of the plasma concentration of the parent molecule, with t(1/2) of 42 and 33 min, respectively. Two unconfirmed complete responses and six partial responses were observed for an overall response rate (ORR) of 89%. The recommended dose for this schedule in phase II trials is 120 mg/m2. The acceptable safety profile and high ORR warrant further investigation of bendamustine in relapsed or refractory indolent B-NHL and MCL. (ClinicalTrials.gov ID: NCT00389051). (Cancer Sci 2010).