BACKGROUND Relapsed or refractory classical Hodgkin lymphoma could be treated with multiagent salvage chemotherapy followed by autologous haematopoietic stem-cell transplantation. The aim of this study is to establish the safety and activity of dose-dense brentuximab vedotin combined with ifosfamide, carboplatin, and etoposide (BV-ICE) chemotherapy in second-line treatment of classical Hodgkin lymphoma. METHODS We conducted a single-arm, open-label, phase 1/2 study of dose-dense BV-ICE at the Seattle Cancer Care Alliance, University of Washington (Seattle, WA, USA). Eligibility criteria were age 18 years or older; diagnosis of first relapse, primary refractory classical Hodgkin lymphoma after one previous line of therapy; measurable disease of at least 1 cm in the longest axis, CT of chest, abdomen, and pelvis with PET within the past 28 days; Eastern Cooperative Oncology Group performance status of 0-1; and adequate organ function. A 3 + 3 dose escalation study was done for the phase 1 part of the trial to establish the maximum tolerated dose to be used for the phase 2 study. Brentuximab vedotin was delivered on days 1 and 8 at either 1·2 mg/kg (dose level 1) or 1·5 mg/kg (dose level 2) intravenously (capped at 150 mg) with standard dosing of ICE on days 1-3 (ifosfamide 5 g/m2 plus mesna 5 g/m2 intravenously over 24 h on day 2, carboplatin area under the curve 5 on day 2 in one intravenous injection, and etoposide 100 mg/m2 on days 1-3 in one intravenous injection per day) for two 21-day cycles. The primary endpoint was to establish the recommended phase 2 dose (phase 1 part) and complete response rate after two cycles, with a prespecified target of 78% (phase 2 part). Safety analysis was done in all enrolled participants and the primary activity analysis was done in all patients with evaluable response data. This study is registered with ClinicalTrials.gov (NCT02227199); enrolment and study treatment are complete. FINDINGS Between Oct 16, 2014, and Feb 10, 2020, we enrolled 45 patients with a median age of 31 years (IQR 28-45). The recommended phase 2 dose of brentuximab vedotin was established to be 1·5 mg/kg. After a median follow-up of 3·1 years (IQR 1·7-4·1), 32 (74%; 95% CI 58·8-86·5) of 43 evaluable patients had complete responses after two cycles of treatment. Grade 3-4 haematological toxic effects were common, including neutropenia (33 [73%]), anaemia (six [13%]), and thrombocytopenia (36 [80%]). The most common grade 3-4 non-haematological toxic effects were febrile neutropenia (four [9%]), sepsis (six [13%]), increased alanine aminotransferase (five [11%]), hyperglycaemia (three [7%]), pulmonary embolism (two [4%]), and increased aspartate aminotransferase (two [4%]). There was one (2%) on-treatment death due to multisystem organ failure that was considered treatment related. Serious adverse events occurred in 13 (29%) patients. INTERPRETATION Our data suggest that dose-dense BV-ICE is a rapidly administered and active salvage regimen for patients with relapsed or refractory classical Hodgkin lymphoma despite a complete response in this trial lower than the prespecified phase 2 target. Although cross-trial comparisons should be made with caution, activity results seem to be similar to previously presented brentuximab vedotin chemotherapy salvage combinations delivered over much longer durations and can be considered in young (<60 years), transplantation-eligible patients for second-line therapy. FUNDING Seagen, Lymphoma Research Foundation, National Institutes of Health/National Cancer Institute, and generous philanthropic donations to the University of Washington from numerous individuals and families in support of lymphoma research.

中文翻译：

---

剂量密集的 brentuximab vedotin 加异环磷酰胺、卡铂和依托泊苷用于复发或难治性经典霍奇金淋巴瘤的二线治疗：单中心 1/2 期研究。

背景 复发性或难治性经典霍奇金淋巴瘤可通过多药挽救性化疗继以自体造血干细胞移植进行治疗。本研究的目的是确定剂量密集的 brentuximab vedotin 联合异环磷酰胺、卡铂和依托泊苷 (BV-ICE) 化疗在经典霍奇金淋巴瘤二线治疗中的安全性和活性。方法 我们在华盛顿大学西雅图癌症护理联盟（美国华盛顿州西雅图）开展了一项单臂、开放标签、1/2 期剂量密集型 BV-ICE 研究。资格标准为 18 岁或以上；前一次治疗后首次复发、原发性难治性经典霍奇金淋巴瘤的诊断；过去 28 天内可测量最长轴至少 1 cm 的疾病，胸部、腹部和骨盆 CT 与 PET；东部肿瘤协作组绩效状态0-1；和足够的器官功能。对试验的第 1 阶段部分进行了 3 + 3 剂量递增研究，以确定用于第 2 阶段研究的最大耐受剂量。Brentuximab vedotin 在第 1 天和第 8 天以 1·2 mg/kg（剂量水平 1）或 1·5 mg/kg（剂量水平 2）静脉内给药（上限为 150 mg），第 1 天给予 ICE 标准剂量- 3（异环磷酰胺 5 g/m2 加美司钠 5 g/m2 第 2 天静脉注射 24 小时，卡铂曲线下面积第 2 天静脉注射 5 次，依托泊苷 100 mg/m2 第 1-3 天静脉注射一次每天）两个 21 天的周期。主要终点是确定推荐的第 2 阶段剂量（第 1 阶段部分）和两个周期后的完全缓解率，预设目标为 78%（第 2 阶段部分）。对所有登记的参与者进行了安全性分析，并对所有具有可评估反应数据的患者进行了主要活动分析。该研究已在 ClinicalTrials.gov (NCT02227199) 注册；入组和研究治疗已完成。结果 在 2014 年 10 月 16 日至 2020 年 2 月 10 日期间，我们招募了 45 名中位年龄为 31 岁（IQR 28-45）的患者。brentuximab vedotin 的推荐 2 期剂量确定为 1·5 mg/kg。中位随访 3·1 年（IQR 1·7-4·1）后，43 名可评估患者中有 32 名（74%；95% CI 58·8-86·5）在两个治疗周期后完全缓解. 3-4 级血液学毒性作用很常见，包括中性粒细胞减少 (33 [73%])、贫血 (6 [13%]) 和血小板减少 (36 [80%])。最常见的 3-4 级非血液学毒性作用是发热性中性粒细胞减少症（4 [9%]），败血症（6 [13%]）、丙氨酸氨基转移酶升高（5 [11%]）、高血糖（3 [7%]）、肺栓塞（2 [4%]）和天冬氨酸氨基转移酶升高（2 [4%]） . 由于被认为与治疗相关的多系统器官衰竭，有 1 人（2%）在治疗中死亡。13 名 (29%) 患者发生严重不良事件。解释 我们的数据表明，尽管在该试验中的完全缓解低于预先指定的 2 期目标，但剂量密集 BV-ICE 是一种快速给药和积极的补救方案，用于复发或难治性经典霍奇金淋巴瘤患者。尽管应谨慎进行交叉试验比较，但活性结果似乎与之前提出的 brentuximab vedotin 化疗挽救组合相似，且持续时间更长，可考虑用于年轻患者（< 60 岁），符合移植条件的二线治疗患者。资助 Seagen、淋巴瘤研究基金会、美国国立卫生研究院/国家癌症研究所，以及众多个人和家庭向华盛顿大学慷慨捐赠以支持淋巴瘤研究。