Targeting both CD20 and phosphoinositol-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 (U2), was evaluated in patients with chronic lymphocytic lymphoma (CLL) or non-Hodgkin lymphoma (NHL) in this phase I/Ib study. Phase I dose-escalation was performed with a 3+3 design to establish the maximum tolerated dose (MTD). In this portion, ublituximab was given intravenously (NHL, 900 mg; CLL, 600 mg or 900 mg) for 12 cycles. Umbralisib was given orally once daily at 800 mg or 1200 mg (standard formulation) or 400 mg to 1200 mg (micronized formulation) in the Phase I dose-escalation portion, and at 800 mg to 1200 mg in the phase Ib portion until progression, toxicity, or study removal. The MTD was not reached in either CLL or NHL cohort and only one dose-limiting toxicity was observed. U2 had low instances of grade {greater than or equal to}3 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% CI: 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 is registered at www.ClinicalTrials.gov (NCT02006485).

中文翻译：

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Ublituximab 和 Umbralisib 治疗复发/难治性 B 细胞非霍奇金淋巴瘤和慢性淋巴细胞白血病

同时靶向 CD20 和磷酸肌醇 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。在本研究中，在慢性淋巴细胞淋巴瘤 (CLL) 或非霍奇金淋巴瘤 (NHL) 患者中评估了下一代化合物 umbralisib（一种 PI3K-δ 抑制剂）和 ublituximab（一种抗 CD20 单克隆抗体（U2））的安全性I/Ib 期研究。I 期剂量递增采用 3+3 设计，以确定最大耐受剂量 (MTD)。在这部分中，ublituximab 静脉给药（NHL，900 mg；CLL，600 mg 或 900 mg），共 12 个周期。在 I 期剂量递增部分，Umbralisib 每天口服一次，剂量为 800 毫克或 1200 毫克（标准制剂）或 400 毫克至 1200 毫克（微粉化制剂），并且在 Ib 期部分为 800 mg 至 1200 mg，直至进展、毒性或研究移除。CLL 或 NHL 队列均未达到 MTD，仅观察到一种剂量限制性毒性。U2 具有{大于或等于}3 级腹泻 (8%)、肺炎 (8%) 或肝毒性 (4%) 的低实例。13% 的患者因不良事件而中断治疗，15% 的患者出现 umbralisib 剂量减少。所有患者的总体反应率为 46%，完全反应率为 17%。中位反应持续时间为 20 个月（95% CI：11.3，未达到）。U2 耐受性良好，与单药 umbralisib 相比没有观察到新的安全信号。这种组合的初步疗效很有希望，值得进一步研究。该研究已在 www.ClinicalTrials.gov (NCT02006485) 上注册。