Background

Preclinical studies have shown synergistic antitumour effects between ibrutinib and immune-checkpoint blockade. The aim of this study was to assess the safety and activity of ibrutinib in combination with nivolumab in patients with relapsed or refractory B-cell malignant diseases.

Methods

We did a two-part, open-label, phase 1/2a study at 21 hospitals in Australia, Israel, Poland, Spain, Turkey, and the USA. The primary objective of part A (dose escalation) was to assess the safety of daily oral ibrutinib (420 mg or 560 mg) in combination with intravenous nivolumab (3 mg/kg every 2 weeks) to ascertain a recommended phase 2 dose in patients with relapsed or refractory high-risk chronic lymphocytic leukaemia or small lymphocytic lymphoma (del17p or del11q), follicular lymphoma, or diffuse large B-cell lymphoma. Dose optimisation was investigated using a modified toxicity probability interval design. The primary objective of the part B expansion phase was to establish the preliminary activity (the proportion of patients who achieved an overall response) of the combination of ibrutinib and nivolumab in four cohorts: relapsed or refractory high-risk chronic lymphocytic leukaemia or small lymphocytic lymphoma (del17p or del11q), follicular lymphoma, diffuse large B-cell lymphoma, and Richter's transformation. All participants who received at least one dose of treatment were included in the primary analysis and analyses were done by disease cohort. This trial is registered with ClinicalTrials.gov, number NCT02329847. The trial is ongoing.

Findings

Between March 12, 2015, and April 11, 2017, 144 patients were enrolled in the study. Three patients died before receiving study treatment; thus, 141 patients were included in the analysis, 14 in part A and 127 in part B. One dose-limiting toxicity (grade 3 hyperbilirubinaemia) was reported at the 420 mg dose in the diffuse large B-cell lymphoma cohort, which resolved after 5 days. The combination of ibrutinib and nivolumab led to overall responses in 22 (61%) of 36 patients with high-risk chronic lymphocytic leukaemia or small lymphocytic lymphoma, 13 (33%) of 40 patients with follicular lymphoma, 16 (36%) of 45 patients with diffuse large B-cell lymphoma, and 13 (65%) of 20 patients with Richter's transformation. The most common all-grade adverse events were diarrhoea (47 [33%] of 141 patients), neutropenia (44 [31%]), and fatigue (37 [26%]). 11 (8%) of 141 patients had adverse events leading to death; none were reported as drug-related. The most common grade 3–4 adverse events were neutropenia (40 [28%] of 141 patients) and anaemia (32 [23%]). The incidence of grade 3–4 neutropenia ranged from eight (18%) of 45 patients with diffuse large B-cell lymphoma to 19 (53%) of 36 patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma; incidence of grade 3–4 anaemia ranged from five (13%) of 40 patients with follicular lymphoma to seven (35%) of 20 patients with Richter's transformation. The most common serious adverse events included anaemia (six [4%] of 141 patients) and pneumonia (five [4%]). The most common grade 3–4 immune-related adverse events were rash (11 [8%] of 141 patients) and increased alanine aminotransferase (three [2%]).

Interpretation

The combination of ibrutinib and nivolumab had an acceptable safety profile and preliminary activity was similar to that reported with single-agent ibrutinib in chronic lymphocytic leukaemia or small lymphocytic lymphoma, follicular lymphoma, and diffuse large B-cell lymphoma. The clinical response in patients with Richter's transformation was promising and supports further clinical assessment.

Funding

Janssen R&D.

中文翻译：

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1 / 2a期研究显示，依鲁替尼联合尼古拉单抗治疗非霍奇金淋巴瘤或慢性淋巴细胞性白血病复发性患者的安全性和活性

背景

临床前研究表明，依鲁替尼和免疫检查点阻滞之间具有协同的抗肿瘤作用。这项研究的目的是评估依鲁替尼联合尼古鲁单抗在复发或难治性B细胞恶性疾病患者中的安全性和活性。

方法

我们在澳大利亚，以色列，波兰，西班牙，土耳其和美国的21家医院进行了两部分，开放标签的1 / 2a期研究。A部分（剂量递增）的主要目的是评估每日口服依鲁替尼（420 mg或560 mg）与静脉内尼古鲁单抗（每2周3 mg / kg）结合的安全性，以确定推荐的2期肝硬化患者的剂量复发或难治的高危慢性淋巴细胞白血病或小淋巴细胞淋巴瘤（del17p或del11q），滤泡性淋巴瘤或弥漫性大B细胞淋巴瘤。使用改良的毒性概率区间设计研究剂量优化。B部分扩展阶段的主要目标是确定ibrutinib和nivolumab组合在以下四个队列中的初步活动（达到总体缓解的患者比例）：复发或难治的高危慢性淋巴细胞白血病或小淋巴细胞淋巴瘤（del17p或del11q），滤泡性淋巴瘤，弥漫性大B细胞淋巴瘤和Richter转化。所有接受至少一剂治疗的参与者都包括在主要分析中，并按疾病队列进行了分析。该试验已在ClinicalTrials.gov上注册，编号为NCT02329847。审判正在进行中。

发现

在2015年3月12日至2017年4月11日之间，共有144名患者参加了研究。三名患者在接受研究治疗前死亡；因此，分析中包括了141例患者，A部分14例，B部分127例。据报道，在420 mg剂量的弥漫性大B细胞淋巴瘤队列中有一种剂量限制性毒性（3级高胆红素血症），在5天。依鲁替尼和尼古鲁单抗的组合导致36例高危慢性淋巴细胞性白血病或小淋巴细胞性淋巴瘤患者的总体缓解（61％），40例滤泡性淋巴瘤患者13例（33％），45例中的16例（36％）弥漫性大B细胞淋巴瘤患者和20例Richter转化患者中的13例（65％）。最常见的全等级不良事件为腹泻（141名患者中的47名[33％]），中性粒细胞减少症（44名[31％]）和疲劳（37名[26％]）。141名患者中有11名（8％）发生了导致死亡的不良事件；没有人被报告与毒品有关。最常见的3-4级不良事件是中性粒细胞减少（141名患者中的40 [28％]）和贫血（32 [23％]）。3-4级中性粒细胞减少的发生率从4​​5例弥漫性大B细胞淋巴瘤患者中的8例（18％）到36例慢性淋巴细胞白血病或小淋巴细胞淋巴瘤患者中的19例（53％）不等。3-4级贫血的发生率从4​​0例滤泡性淋巴瘤患者中的五例（13％）到20例Richter转化患者中的七例（35％）不等。最常见的严重不良事件包括贫血（141名患者中的6名[4％]）和肺炎（5名[4％]）。最常见的3-4级免疫相关不良事件为皮疹（141例患者中的11例[8％]）和丙氨酸转氨酶升高（3例[2％]）。

解释

ibrutinib和nivolumab的组合具有可接受的安全性，初步活性与单药ibrutinib在慢性淋巴细胞性白血病或小淋巴细胞性淋巴瘤，滤泡性淋巴瘤和弥漫性大B细胞淋巴瘤中报道的相似。Richter转化患者的临床反应是有希望的，并支持进一步的临床评估。

资金

Janssen研发。