Phase 1 study of the PI3Kδ inhibitor INCB040093 ± JAK1 inhibitor itacitinib in relapsed/refractory B-cell lymphoma
Phase 1 study of the PI3Kδ inhibitor INCB040093 ± JAK1 inhibitor itacitinib in relapsed/refractory B-cell lymphoma
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DOI：
10.1182/blood-2017-10-812701
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发表时间：
2018-07-19
期刊：
影响因子：
20.3
通讯作者：
Barr, Paul M.
中科院分区：
文献类型：
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作者：
Phillips, Tycel J.;Forero-Torres, Andres;Barr, Paul M.
由于磷脂酰肌醇3-激酶δ（PI 3 K δ）和Janus激酶（JAK）-信号转导和转录激活因子途径都有助于B细胞恶性肿瘤中的肿瘤细胞增殖和存活，因此同时抑制它们可能会提供协同治疗功效。这项I期剂量递增/扩展研究评估了INCB 040093（一种选择性PI 3 K δ抑制剂）单药治疗或与伊他替尼（原INCB 039110）（一种选择性JAK 1抑制剂）联合治疗复发性或难治性（R/R）B细胞淋巴瘤成人患者的安全性、疗效、药代动力学和药效学。报告了最终结果。总体而言，114例患者接受了治疗（单药治疗，n = 49;联合治疗，n = 72 [7例患者从单药治疗交叉至联合治疗]）。INCB 040093 100 mg每日两次（单药治疗）和INCB 040093 100 mg每日两次1伊他替尼300 mg每日一次（联合治疗）是推荐的II期剂量。单药治疗发生1例剂量限制性毒性（胃弥漫性大B细胞淋巴瘤[DLBCL]消退继发胃肠道出血）。单药治疗组最常见的严重不良事件为肺炎（n = 5）和发热（n = 4），联合治疗组为耶氏肺孢子虫肺炎（n = 5）、肺炎（与耶氏肺孢子虫无关; n = 5）和发热（n = 4）。3级或3级以上转氨酶升高在联合用药中不太常见。INCB 040093在B细胞淋巴瘤中具有活性; 63%的滤泡性淋巴瘤患者（5/8）对单药治疗有反应。添加伊他替尼在选定的亚型中提供了有希望的活性，经典霍奇金淋巴瘤的缓解率为67%（14/21）（单药治疗为29% [5/17]），非淋巴瘤中心B细胞样DLBCL为31%（4/13）。INCB 040093联合/不联合伊他替尼在本研究中是耐受的和有效的，并且是选择R/R B细胞淋巴瘤患者的有希望的治疗策略。本试验在www.clinicaltrials.gov上注册为#NCT01905813。
Because both phosphatidylinositol 3-kinase delta (PI3K delta) and Janus kinase (JAK)-signal transducer and activator of transcription pathways contribute to tumor cell proliferation and survival in B-cell malignancies, their simultaneous inhibition may provide synergistic treatment efficacy. This phase 1 dose-escalation/expansion study assessed the safety, efficacy, pharmacokinetics, and pharmacodynamics of INCB040093, a selective PI3K delta inhibitor, as monotherapy or combined with itacitinib (formerly INCB039110), a selective JAK1 inhibitor, in adult patients with relapsed or refractory (R/R) B-cell lymphomas. Final results are reported. Overall, 114 patients were treated (monotherapy, n = 49; combination therapy, n = 72 [7 patients crossed over from monotherapy to combination]). INCB040093 100 mg twice daily (monotherapy) and INCB040093 100 mg twice daily 1 itacitinib 300 mg once daily (combination) were the recommended phase 2 doses. One dose-limiting toxicity (gastrointestinal bleed secondary to gastric diffuse large B-cell lymphoma [DLBCL] regression) occurred with monotherapy. The most common serious adverse events with monotherapy were pneumonia (n = 5) and pyrexia (n = 4), and with combination Pneumocystis jiroveci pneumonia (n = 5), pneumonia (unrelated to P jiroveci; n = 5), and pyrexia (n = 4). Grade 3 or higher transaminase elevations were less common with combination. INCB040093 was active across the B-cell lymphomas; 63% of patients (5/8) with follicular lymphoma responded to monotherapy. Adding itacitinib provided promising activity in select subtypes, with responses of 67% (14/21) in classic Hodgkin lymphoma (vs 29% [5/17] with monotherapy) and 31% (4/13) in nongerminal center B-cell-like DLBCL. INCB040093 with/without itacitinib was tolerated and active in this study, and is a promising treatment strategy for patients with select R/R B-cell lymphomas. This trial was registered at www.clinicaltrials.gov as #NCT01905813.