摘要

Targeting both CD20 and phosphatidylinositol 3-kinase (PI3K), a protein that is critically involved in B-cell maturation, could be an efficacious strategy for treating B-cell malignancies. The safety of the next-generation compounds umbralisib, a PI3K-δ inhibitor, plus ublituximab, an anti-CD20 monoclonal antibody (combination referred to as U2), was evaluated in patients with chronic lymphocytic lymphoma (CLL) or non-Hodgkin lymphoma (NHL) in this phase 1/1b study. Phase 1 dose escalation was performed with a 3 + 3 design to establish the maximum tolerated dose. In this portion, ublituximab was given intravenously (NHL, 900 mg; CLL, 600 or 900 mg) for 12 cycles. Umbralisib was given orally once daily at 800 or 1200 mg (initial formulation) or 400 to 1200 mg (micronized formulation) in the phase 1 dose escalation portion, and at 800 to 1200 mg in the phase 1b portion until progression, toxicity, or study removal. The maximum tolerated dose was not reached in either the CLL or NHL cohort, and only 1 dose-limiting toxicity was observed. U2 had low instances of grade 3 or higher diarrhea (8%), pneumonia (8%), or hepatic toxicity (4%). Treatment discontinuation due to adverse events occurred in 13% of patients, and umbralisib dose reductions occurred in 15% of patients. The overall response rate for all patients was 46% with 17% complete responses. The median duration of response was 20 months (95% confidence interval, 11.3-not reached). U2 was well tolerated, and no new safety signals were observed over single-agent umbralisib. Preliminary efficacy with this combination is promising and warrants further investigation. This study was registered at www.clinicaltrials.gov as #NCT02006485.

译文

靶向 CD20 和磷脂酰肌醇 3-激酶 (PI3K)，一种与 b细胞成熟密切相关的蛋白质，可能是治疗 b细胞恶性肿瘤的有效策略。下一代化合物 umbralisib，一种 PI3K-δ 抑制剂，加上 ublituximab，一种 anti-CD20 单克隆抗体 (组合称为 U2) 的安全性, 在本 1/1b 期研究中对慢性淋巴细胞淋巴瘤 (CLL) 或非霍奇金淋巴瘤 (NHL) 患者进行了评估。1 期剂量递增采用 3 3 设计，以确定最大耐受剂量。在这一部分，静脉注射乌布里妥昔单抗 (NHL，900 毫克; CLL，600 或 900 毫克) 12 个周期。Umbralisib 在第一阶段剂量递增部分以 800 或 1200 毫克 (初始配方) 或 400 至 1200 毫克 (微粉化配方) 口服每日一次, 在 1b 阶段的 800 到 1200 毫克，直到进展、毒性或研究移除。CLL 或 NHL 队列均未达到最大耐受剂量，仅观察到 1 次剂量限制性毒性。U2 有 3 级或以上腹泻 (8%) 、肺炎 (8%) 或肝毒性 (4%) 的低病例。13% 的患者因不良事件而中断治疗，15% 的患者因 umbralisib 剂量减少。所有患者的总反应率为 46%，完全反应率为 17%。反应的中位持续时间为 20 个月 (95% 置信区间，11.3-未达到)。U2 耐受性良好，在单药 umbralisib 上没有观察到新的安全信号。这种组合的初步疗效是有希望的，值得进一步研究。这项研究在 www.clinicaltrials.gov 注册为 # nct02006485。