■利妥昔单抗和来那度胺是复发性惰性B细胞非霍奇金淋巴瘤的首选选择。与利妥昔单抗相比,奥比妥珠单抗可能是来那度胺的优异组合伴侣,其抗体依赖性细胞毒性和吞噬作用增强。我们的目的是确定推荐的2期剂量,安全,来那度胺联合固定剂量的奥比努珠单抗治疗复发和难治性惰性B细胞非霍奇金淋巴瘤的活性。
■在此单臂中,开放标签,1/2期试验,我们纳入了复发或难治性WHO1-3A级滤泡性淋巴瘤患者,MDAnderson癌症中心的边缘区淋巴瘤和小淋巴细胞淋巴瘤以及适当的表现状态(ECOG0-2)。我们排除了有证据表明正在向侵袭性淋巴瘤转化的患者。在1期期间,以3+3剂量递增设计给予1000mg静脉内奥比妥珠单抗和三种预定水平的口服来那度胺,以建立来那度胺20mg作为推荐的2期剂量。在第2阶段,患者接受了六个28天周期的来那度胺20mg和静脉内奥比妥珠单抗1000mg的诱导治疗。根据我们先前使用来那度胺加利妥昔单抗的经验,对联合治疗有反应的患者可接受多达6个额外周期(总共多达12个周期)的联合治疗.在治疗开始后每2个月的第6周期后,所有有反应的患者继续服用奥比努珠单抗,共30个月。超过6个联合治疗周期数的决定由研究者自行决定,并包括在内,以允许治疗的个性化,以最大程度地提高反应,同时最大程度地减少暴露。共同的主要目标是评估安全性和总体反应,定义为在诱导治疗结束时复发和难治性惰性非霍奇金淋巴瘤获得完全或部分缓解的患者比例,根据切森及其同事(2007年标准)。次要终点是诱导治疗后完全缓解和事件终点时间,包括进展时间,无进展生存期,和总体生存率。分析旨在在所有接受至少一个剂量的任一研究药物的患者中,在疗效队列中进行治疗,并在安全性人群中进行治疗。该试验已在ClinicalTrials.gov注册,NCT01995669。
■在2014年6月03日至2019年3月07日之间,我们完成了计划的注册,66例患者开始治疗,其中9例患者为1期,57例患者为2期.对所有患者进行安全性评估,以推荐的2期剂量20mg来那度胺治疗的60名患者的活性可评估。3-4级血液毒性包括中性粒细胞减少21%(14/66)和血小板减少11%(7/66),无发热性中性粒细胞减少病例。3-4级非血液毒性包括肺部感染8%(5/66),疲劳8%(5/66)和皮疹6%(4/66)。根据切森2007年的标准,90%(54/60,95%CI:79-96)在诱导结束时达到满足预定活性终点的总体响应。在诱导结束时,在33%(20/60,95%CI:22-47)中观察到完全应答。中位无进展生存期,中位随访时间41.7个月后仍未达到进展时间和总生存期.估计的4年无进展生存率为55%(95%CI:42-73),至进展时间为56%(95%CI:43-74),总生存率为84%(95%CI:74-95)。
■我们的研究结果表明,口服来那度胺联合奥比努珠单抗在复发和难治性惰性B细胞非霍奇金淋巴瘤患者中是安全且活跃的,并且与延长的缓解持续时间相关。该研究受到缺乏控制臂的限制,导致进行跨试验比较以评估活动。未来的随机试验将该方案与利妥昔单抗和来那度胺进行比较是必要的。
■基因泰克和MD安德森核心资助。
UNASSIGNED: Rituximab and lenalidomide is a preferred option for relapsed indolent B cell non-Hodgkin lymphoma. Obinutuzumab may be a superior combination partner with lenalidomide given enhanced antibody dependent cellular cytotoxicity and phagocytosis compared to rituximab. Our aim was to determine the recommended phase 2 dose, safety, and activity of lenalidomide in combination with fixed dose of obinutuzumab in relapsed and refractory indolent B cell non-Hodgkin lymphoma.
UNASSIGNED: In this single-arm, open-label, phase 1/2 trial, we enrolled patients with relapsed or refractory WHO Grade 1-3A follicular lymphoma, marginal zone lymphoma and small lymphocytic lymphoma and adequate performance status (ECOG 0-2) at the MD Anderson Cancer Center. We excluded patients with evidence of ongoing transformation to aggressive lymphoma. During phase 1, 1000 mg intravenous obinutuzumab was administered with three predefined levels of oral lenalidomide in a 3 + 3 dose escalation design to establish lenalidomide 20 mg as the recommended phase 2 dose. During phase 2, patients received induction therapy with six 28-day cycles of lenalidomide 20 mg with intravenous obinutuzumab 1000 mg. In accordance with our prior experience with lenalidomide plus rituximab, patients who were responding to the combination could receive up to 6 additional cycles (up to 12 cycles in total) of combination therapy. Dosing of obinutuzumab was continued in all responding patients after cycle 6 every 2 months for a total of 30 months from the start of therapy. The decision of number of cycles of combination therapy beyond 6 was at discretion of the investigator and was included to allow individualisation of therapy to maximise response while minimising exposure. The co-primary objectives were to evaluate the safety and overall response, defined as the proportion of patients who achieved a complete or partial response in relapsed and refractory indolent non-Hodgkin lymphoma at the end of induction therapy, according to Cheson and colleagues (2007 criteria). The secondary endpoints were complete response after induction therapy and time to event endpoints including time to progression, progression free survival, and overall survival. Analyses were intent to treat in the efficacy cohort and per-treated in the safety population in all patients who received at least one dose of either investigational agent. This trial is registered with ClinicalTrials.gov, NCT01995669.
UNASSIGNED: Between June 03, 2014, and 07 March 2019, we completed planned enrolment, and 66 patients started therapy including 9 patients in phase 1 and 57 patients in phase 2. All patients were evaluated for safety and the 60 patients treated at the recommended phase 2 dose of lenalidomide 20 mg were evaluable for activity. Grade 3-4 haematological toxicities included neutropenia 21% (14/66) and thrombocytopenia 11% (7/66) with no cases of febrile neutropenia. Grade 3-4 non-haematological toxicities included lung infection 8% (5/66), fatigue 8% (5/66) and rash 6% (4/66). By Cheson 2007 criteria, 90% (54/60, 95% CI: 79-96) achieved an overall response at the end of induction meeting the prespecified activity endpoint. Complete responses were seen in 33% (20/60, 95% CI: 22-47) at the end of induction. Median progression free survival, time to progression and overall survival have not been reached after median follow-up of 41.7 months. Estimated 4-year progression free survival rates were 55% (95% CI: 42-73), time to progression of 56% (95% CI: 43-74) and overall survival of 84% (95% CI: 74-95).
UNASSIGNED: Our findings suggest that oral lenalidomide with obinutuzumab is safe and highly active in patients with relapsed and refractory indolent B cell non-Hodgkin lymphoma and is associated with prolonged remission duration. The study is limited by the lack of a control arm leading to cross-trial comparisons to evaluate activity. Future randomised trials comparing this regime to rituximab and lenalidomide are warranted.
UNASSIGNED: Genentech and an MD Anderson Core grant.