A phase 1 study of romidepsin and pralatrexate reveals marked activity in relapsed and refractory T-cell lymphoma
A phase 1 study of romidepsin and pralatrexate reveals marked activity in relapsed and refractory T-cell lymphoma
复制标题
DOI：
10.1182/blood-2017-09-806737
复制
发表时间：
2018-01-25
期刊：
影响因子：
20.3
通讯作者：
O'Connor, Owen A.
中科院分区：
文献类型：
--
作者：
Amengual, Jennifer E.;Lichtenstein, Renee;O'Connor, Owen A.
外周T细胞淋巴瘤（PTCL）是一组罕见的恶性肿瘤，其特点是化疗耐药和预后差。罗米地辛和普拉曲沙已被美国食品药品监督管理局批准用于复发性/难治性PTCL患者，缓解率分别为25%和29%。基于PTCL临床前模型的协同作用，我们在复发性/难治性淋巴瘤患者中启动了普拉曲沙+罗米地辛的I期研究。这是一项普拉曲沙+罗米地辛的单机构剂量递增研究，旨在确定剂量限制性毒性（DLT）、最大耐受剂量、药代动力学特征和缓解率。患者接受普拉曲沙（10 - 25 mg/m2）和罗米地辛（12 - 14 mg/m2）治疗，治疗方案为3种方案之一：每周x每28天3次，每周x每21天2次，每隔一周每28天1次。治疗持续至疾病进展、撤回知情同意或医疗需要。29例患者入组并可评价毒性。普拉曲沙和罗米地辛联合给药安全、耐受性良好，所有给药方案均发生3例DLT（3级口腔粘膜炎x 2; 4级脓毒症x 1）。推荐的II期剂量定义为普拉曲沙25 mg/m2和罗米地辛12 mg/m2，每隔一周一次。23例患者可评价缓解。所有患者的总体缓解率为57%（13/23），PTCL为71%（10/14）。普拉曲沙联合罗米地辛的I期研究在既往接受过治疗的PTCL患者中产生了较高的缓解率。PTCL的II期研究将确定联合治疗的疗效。本试验在www.clinicaltrials.gov上注册为#NCT 01947140。
Peripheral T-cell lymphomas (PTCL) are a group of rare malignancies characterized by chemotherapy resistance and poor prognosis. Romidepsin and pralatrexate were approved by the US Food and Drug Administration for patients with relapsed/refractory PTCL, exhibiting response rates of 25% and 29% respectively. Based on synergy in preclinical models of PTCL, we initiated a phase 1 study of pralatrexate plus romidepsin in patients with relapsed/refractory lymphoma. This was a single institution dose-escalation study of pralatrexate plus romidepsin designed to determine the dose-limiting toxicities (DLTs), maximum tolerated dose, pharmacokinetic profile, and response rates. Patients were treated with pralatrexate (10 to 25 mg/m(2)) and romidepsin (12 to 14 mg/m(2)) on 1 of 3 schedules: every week x 3 every 28 days, every week x 2 every 21 days, and every other week every 28 days. Treatment continued until progression, withdrawal of consent, or medical necessity. Twenty-nine patients were enrolled and evaluable for toxicity. Co-administration of pralatrexate and romidepsin was safe, well tolerated, with 3 DLTs across all schedules (grade 3 oral mucositis x 2; grade 4 sepsis x 1). The recommended phase 2 dose was defined as pralatrexate 25 mg/m(2) and romidepsin 12 mg/m(2) every other week. Twenty-three patients were evaluable for response. The overall response rate was 57% (13/23) across all patients and 71% (10/14) in PTCL. The phase 1 study of pralatrexate plus romidepsin resulted in a high response rate in patients with previously treated PTCL. A phase 2 study in PTCL will determine the efficacy of the combination. This trial was registered at www.clinicaltrials.gov as # NCT01947140.