Venetoclax, bendamustine, and rituximab in patients with relapsed or refractory NHL: a phase 1b dose-finding study
Venetoclax, bendamustine, and rituximab in patients with relapsed or refractory NHL: a phase 1b dose-finding study
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DOI：
10.1093/annonc/mdy256
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发表时间：
2018-09-01
影响因子：
50.5
通讯作者：
Flowers, C. R.
中科院分区：
文献类型：
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作者：
de Vos, S.;Swinnen, L. J.;Flowers, C. R.
工作背景：维奈托克是一种抗凋亡B细胞白血病/淋巴瘤-2蛋白的选择性强效抑制剂，获批用于治疗慢性淋巴细胞白血病。我们进行了一项剂量探索研究维奈托克与苯达莫司汀-利妥昔单抗（BR）联合治疗复发/难治性非霍奇金淋巴瘤（NHL）患者。患者和方法：BR以标准剂量给药6个周期。以50-1200 mg每日剂量探索了间歇和连续口服维奈托克给药。共同主要目标包括安全性、药代动力学（PK）、最大耐受剂量（MD）和推荐阶段。II剂量（RP 2D）;结果：60例患者中，滤泡性淋巴瘤32例，弥漫性大B细胞淋巴瘤22例，边缘区淋巴瘤6例。恶心（70%）、中性粒细胞减少（68%）、腹泻（55%）和血小板减少（52%）是最常见的不良事件（AE）。最常见的3/4级AE为中性粒细胞减少症（60%）和淋巴细胞减少症（38%）。24例患者报告了严重AE;最常见的是发热性中性粒细胞减少和疾病进展（各8%）。5例患者死于疾病进展（n = 4）或呼吸衰竭（n = 1）。未达到MTD;确定维奈托克-BR复方制剂的RP 2D为800 mg/天，连续给药。联合和不联合BR的维奈托克PK暴露相当。对于所有患者，总有效率为65%。中位持续时间的总体反应，总生存期，无进展生存期为383个月[95%置信区间（CI）10.4-NR），尚未达到，和10.7个月（95%CI 4.3-21.0），分别。结论：这项研究建立了安全性的维奈托克与BR组合，结果表明，耐受性和初步疗效的组合。需要额外的随访，以更好地确定BR加维奈托克在复发性/难治性B细胞NHL治疗中的未来作用。
Background: Venetoclax is a selective, potent inhibitor of the anti-apoptotic B-cell leukemia/lymphoma-2 protein approved for treatment of chronic lymphocytic leukemia. We conducted a dose-finding study of venetoclax in combination with bendamustine-rituximab (BR) in patients with relapsed/refractory non Hodgkin's lymphoma (NHL).Patients and methods: BR was given for six cycles at standard doses. Intermittent and continuous oral venetoclax administration was explored at 50-1200 mg daily doses. Co primary objectives included safety, pharmacokinetics (PKs), maximum-tolerated dose (MD), and recommended phase. II dose (RP2D); secondary objective was preliminary efficacy.Results: Sixty patients were enrolled: 32 with follicular lymphoma, 22 with diffuse large B-cell lymphoma, and 6 with marginal zone lymphoma. Nausea (70%), neutropenia (68%), diarrhea (55%, and thrombocytopenia (52%) were the most frequent adverse events (AEs). Most common grade 3/4 AEs were neutropenia (60%) and lymphopenia (38%). Serious AEs were reported in 24 patients; the most frequent were febrile neutropenia and disease progression (8% each). Five patients died from either disease progression (n = 4) or respiratory failure (n = 1). MTD was not reached; RP2D for venetoclax-BR combination was established as 800 mg daily continuously. Venetoclax PK exposure with and without BR was comparable. For all patients, overall response rate was 65%. Median duration of overall response, overall survival, and progression-free survival was 383 months [95% confidence interval (CI) 10.4-NR), not yet reached, and 10.7 months (95% CI 4.3-21.0), respectively.Conclusions: This study established the safety profile of venetoclax in combination with BR, and results demonstrated tolerability and preliminary efficacy of the combination. Additional follow-up is needed to better determine the future role of BR plus venetoclax in the treatment of relapsed/refractory B-cell NHL.