Background

Therapeutic approaches for B-cell malignancies continue to evolve, especially with regard to combination approaches. We assessed the safety and efficacy of the triplet ublituximab, umbralisib, and ibrutinib in patients with advanced B-cell malignancies.

Methods

We did an open-label, phase 1 study with dose-escalation and dose-expansion phases, at five centres in the USA. Eligible patients were aged 18 years or older with histologically confirmed lymphocytic leukaemia or relapsed or refractory B-cell non-Hodgkin lymphoma, had measurable disease, adequate organ function, and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less. Patients with known CNS lymphoma, active hepatitis B or C infection, or HIV were excluded. In the dose-escalation cohort, patients were treated in cycles of 28 days with escalating doses of oral umbralisib (400, 600, or 800 mg) and fixed doses of intravenous ublituximab (900 mg) and oral ibrutinib (420 mg for patients with chronic lymphocytic leukaemia; 560 mg for patients with B-cell non-Hodgkin lymphoma) in a standard 3 × 3 design until disease progression or intolerance. In the dose-expansion phase, patients were given the recommended dose of the drug combination as determined from the dose-escalation phase. The primary endpoints were safety, dose-limiting toxicities, and the maximum tolerated dose of umbralisib, when given in combination with ublituximab and ibrutinib. Safety was assessed in patients who received at least one dose of study drug; activity was assessed in all patients who had at least one post-treatment efficacy measurement. The study is ongoing but no longer recruiting patients. This trial is registered with ClinicalTrials.gov, number NCT02006485.

Findings

Between Sept 2, 2014, and Nov 6, 2017, we enrolled 46 patients: 24 in the dose-escalation cohort (n=14 chronic lymphocytic leukaemia or small lymphocytic lymphoma; n=10 B-cell non-Hodgkin lymphoma) and 22 in the dose-expansion cohort (n=9 chronic lymphocytic leukaemia or small lymphocytic lymphoma; n=13 B-cell non-Hodgkin lymphoma). 46 patients received at least one dose of study drug. The maximum tolerated dose of umbralisib was not reached. The recommended dose for the dose-expansion phase was umbralisib 800 mg orally once daily plus ibrutinib orally once daily and intravenous ublituximab 900 mg administered on days 1, 8, and 15 of cycle 1, day 1 of cycles 2–6, and on day 1 of cycles 9 and 12. 37 (84%) of 44 patients achieved an overall response (complete or partial response). The most common any-grade adverse events were diarrhoea (n=27 [59%]), fatigue (n=23 [50%]), infusion-related reaction (n=20 [43%]), dizziness (n=17 [37%]), nausea (n=17 [37%]), and cough (n=16 [35%]). Grade 3–4 adverse events were manageable with the most common being neutropenia (n=10 [22%]) and cellulitis (n=6 [13%]). Serious adverse events occurred in 11 (24%) of 46 patients and included rash (n=2 [4%]), pneumonia (n=2 [4%]), atrial fibrillation (n=2 [4%]), sepsis (n=2 [4%]), abdominal pain (n=1 [2%]), syncope (n=1 [2%]), cellulitis (n=1 [2%]), pneumonitis (n=1 [2%]), headache (n=1 [2%]), lung infection (n=1 [2%]), skin infection (n=1 [2%]), pleural effusion (n=1 [2%]), pericardial infusion (n=1 [2%]), upper gastrointestinal bleeding (n=1 [2%]), diarrhoea (n=1 [2%]), and weakness (n=1 [2%]). No deaths related to adverse events occurred.

Interpretation

The combination of ublituximab, umbralisib, and ibrutinib seems to be tolerable and is associated with encouraging activity in advanced chronic lymphocytic leukaemia and B-cell non-Hodgkin lymphoma. This triplet combination will require further investigation in future studies to improve understanding of this novel, chemotherapy-free triplet combination in the management of these cancers.

Funding

TG Therapeutics.

中文翻译：

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ublituximab，umbralisib和ibrutinib在慢性淋巴细胞性白血病和非霍奇金淋巴瘤患者中的耐受性和活性：1期剂量递增和扩展试验

背景

B细胞恶性肿瘤的治疗方法不断发展，特别是在联合治疗方面。我们评估了三联体ublituximab，umbralisib和ibrutinib在晚期B细胞恶性肿瘤患者中的安全性和有效性。

方法

我们在美国的五个中心进行了一个开放标签的1期研究，包括剂量递增和剂量扩展两个阶段。符合条件的患者年龄在18岁以上，经组织学证实为淋巴细胞性白血病或复发或难治性B细胞非霍奇金淋巴瘤，可测量的疾病，适当的器官功能，并且东部合作肿瘤小组（ECOG）的表现状态为2以下。排除患有已知中枢神经系统淋巴瘤，活动性乙型或丙型肝炎感染或艾滋病毒的患者。在剂量递增队列中，以递增剂量的口服umbralisib（400、600或800 mg）和固定剂量的静脉注射ublituximab（900 mg）和口服ibrutinib（420 mg对于患有以下疾病的患者）进行为期28天的治疗慢性淋巴细胞性白血病 对于B细胞非霍奇金淋巴瘤患者，标准3×3设计为560 mg，直到疾病进展或不耐受为止。在剂量增加阶段，根据剂量增加阶段确定的推荐剂量的药物组合给予患者。与ublituximab和ibrutinib并用时，主要终点是安全性，剂量限制性毒性和umbralisib的最大耐受剂量。评估接受至少一剂研究药物的患者的安全性；在所有接受过至少一项治疗后功效测量的患者中评估其活性。研究正在进行中，但不再招募患者。该试验已在ClinicalTrials.gov上注册，编号为NCT02006485。

发现

在2014年9月2日至2017年11月6日之间，我们招募了46名患者：剂量递增研究队列中的24名患者（n = 14慢性淋巴细胞性白血病或小淋巴细胞性淋巴瘤）; 在剂量增加队列中，n = 10 B细胞非霍奇金淋巴瘤）和剂量增加队列中的22（n = 9慢性淋巴细胞白血病或小淋巴细胞淋巴瘤； n = 13 B细胞非霍奇金淋巴瘤）。46名患者接受了至少一剂研究药物。未达到umbralisib的最大耐受剂量。剂量增加阶段的推荐剂量为：每天umbralisib 800 mg口服一次，加上ibrutinib每天口服1次，以及在第1周期的第1、8、15天，第2-6周期的第1天以及第2天静脉给予ublituximab 900 mg第9和第12周期中的1例达到44例，其中37例（84％）总体缓解（完全或部分缓解）。最常见的任何等级的不良事件为腹泻（n = 27 [59％]），疲劳（n = 23 [50％]），输液相关反应（n = 20 [43％]），头晕（n = 17） [37％]），恶心（n = 17 [37％]）和咳嗽（n = 16 [35％]）。3-4级不良事件是可以控制的，最常见的是中性粒细胞减少症（n = 10 [22％]）和蜂窝织炎（n = 6 [13％]）。46名患者中有11名（24％）发生了严重的不良事件，包括皮疹（n = 2 [4％]），肺炎（n = 2 [4％]），房颤（n = 2 [4％]），败血症（n = 2 [4％]），腹痛（n = 1 [2％]），晕厥（n = 1 [2％]），蜂窝织炎（n = 1 [2％]），肺炎（n = 1 [2] 2％]），头痛（n = 1 [2％]），肺部感染（n = 1 [2％]），皮肤感染（n = 1 [2％]），胸腔积液（n = 1 [2％] ），心包输液（n = 1 [2％]），上消化道出血（n = 1 [2％]），腹泻（n = 1 [2％]）和无力（n = 1 [2％]）。没有发生与不良事件有关的死亡。

解释

ublituximab，umbralisib和ibrutinib的组合似乎是可以耐受的，并且与晚期慢性淋巴细胞性白血病和B细胞非霍奇金淋巴瘤的令人鼓舞的活性有关。这种三联体组合将需要在未来的研究中进一步研究，以增进对这种新型无化疗三联体组合在这些癌症治疗中的了解。

资金

TG治疗学。