研究动态
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DTRMWXHS-12,一种新型的布鲁顿酪氨酸激酶抑制剂,在复发/难治型淋巴瘤患者中与依维莫司和泊马利莫德联合应用:一项开放标签、多中心、1a/1b期研究。

DTRMWXHS-12, a novel Bruton tyrosine kinase inhibitor, in combination with everolimus and pomalidomide in patients with relapsed/refractory lymphomas: an open-label, multicenter, phase 1a/1b study.

发表日期:2023 Feb 21
作者: Scott F Huntington, Stephen J Schuster, Wei Ding, Amber B Koehler, Danielle M Brander, Allison C Rosenthal, Jose F Leis, Han W Tun, Muhamad Alhaj Moustafa, Madiha Iqbal, Wei He, Albert S Kearney, Timothy P McKinlay, Min Gui, Anthony R Mato
来源: AMERICAN JOURNAL OF HEMATOLOGY

摘要:

临床前研究表明,在Bruton酪氨酸激酶抑制剂(BTKi)与哺乳动物雷帕霉素靶(mTOR)抑制剂和免疫调节药物(IMiD)联合应用时,活性增强。我们在美国的5个中心进行了一项一期开放标签研究,以评估三联疗法BTKi/mTOR/IMiD的安全性。符合条件的患者为18岁或以上、复发/难治性CLL、B细胞NHL或霍奇金淋巴瘤的成年人。我们的剂量递增研究采用加速滴定设计,从单药BTKi(DTRMWXHS-12)开始,逐步转化到双联疗法(DTRMWXHS-12 + 依维莫司),然后是三联疗法(DTRMWXHS-12 + 依维莫司 + 泊马度胺)。所有药物每个28天周期的第1-21天单次剂量。主要目标是确定三联组合的建议2期剂量。从2016年9月27日至2019年7月24日,共招募了32名年龄中位数为70岁(范围为46至94岁)的患者。没有发现单药治疗和双联疗法的最大耐受剂量。三联疗法的最大耐受剂量确定为DTRMWXHS-12 200mg + 依维莫司5mg + 泊马度胺2mg。在所有研究组中,13/32(41.9%)看到了反应。将DTRMWXHS-12与依维莫司和泊马度胺结合使用是可耐受的,并显示出临床活性。进一步的试验可能会确认这种口服联合治疗难治性/复发性淋巴瘤的益处。本文受版权保护,所有权利已保留。
Preclinical studies have shown augmented activity when combining Bruton tyrosine kinase inhibitors (BTKi) with inhibitors of mammalian target of rapamycin (mTOR) and immunomodulatory agents (IMiD). We conducted a phase 1, open-label study at 5 centers in USA to evaluate the safety of triplet BTKi/mTOR/IMiD therapy. Eligible patients were adults aged 18 years or older with relapsed/refractory CLL, B cell NHL, or Hodgkin lymphoma. Our dose escalation study used an accelerated titration design and moved sequentially from single agent BTKi (DTRMWXHS-12), doublet (DTRMWXHS-12 + everolimus), and then to triplet therapy (DTRMWXHS-12 + everolimus + pomalidomide). All drugs were dosed once daily on days 1-21 of each 28-day cycle. The primary goal was to establish the recommended phase 2 dose of the triplet combination. Between September 27, 2016, and July 24, 2019, a total of 32 patients with a median age of 70 years (range 46 to 94 years) were enrolled. No MTD was identified for monotherapy and the doublet combination. The MTD for the triplet combination was determined to be DTRMWXHS-12 200 mg + everolimus 5 mg + pomalidomide 2 mg. Responses across all studied cohorts were seen in 13 of 32 (41.9%). Combining DTRMWXHS-12 with everolimus and pomalidomide is tolerable and shows clinical activity. Additional trials could confirm benefit of this all-oral combination therapy for relapsed/refractory lymphomas. This article is protected by copyright. All rights reserved.This article is protected by copyright. All rights reserved.