Abstract：
Parsaclisib is a potent and highly selective PI3Kδ inhibitor that has shown clinical benefit with monotherapy in a phase 2 study in relapsed or refractory (R/R) follicular lymphoma (FL). CITADEL-102 (NCT03039114), a phase 1, multicenter study, assessed the efficacy of parsaclisib in combination with obinutuzumab and bendamustine in patients with R/R FL. Patients were ≥18 years of age with histologically confirmed and documented CD20-positive FL, and R/R to previous rituximab-containing treatment regimens. Part one (safety run-in) determined the maximum tolerated dose of parsaclisib in combination with standard dosage regimens of obinutuzumab and bendamustine. Part two (dose expansion) was an open-label, single-group design evaluating safety, tolerability (primary endpoint), and efficacy (secondary endpoint) of parsaclisib combination therapy. Twenty-six patients were enrolled in CITADEL-102 and all patients received parsaclisib 20 mg once daily for 8 weeks, followed by 20 mg once weekly thereafter, in combination with obinutuzumab and bendamustine. One patient in safety run-in experienced a dose-limiting toxicity of grade 4 QT interval prolongation that was considered related to parsaclisib. Eight patients (30.8%) discontinued treatment due to treatment-emergent adverse events (TEAEs) of colitis (2 [7.7%]), alanine aminotransferase and aspartate aminotransferase increase (both in one patient [3.8%]), neutropenia, thrombocytopenia, QT prolongation, tonsil cancer, and maculopapular rash (each 1 [3.8%]). The most common reported TEAEs were pyrexia (53.8%), neutropenia (50.0%), and diarrhea (46.2%). Twenty-three patients (88.5%) experienced grade 3 or 4 TEAEs; the most common were neutropenia (34.6%), febrile neutropenia (23.1%), and thrombocytopenia (19.2%). Seventeen patients (65.4%) had a complete response and 3 patients (11.5%) had a partial response, for an objective response rate of 76.9%. Overall, results from CITADEL-102 suggest that the combination of parsaclisib with obinutuzumab and bendamustine did not result in unexpected safety events, with little evidence of synergistic toxicity, and demonstrated preliminary efficacy in patients with R/R FL who progressed following prior rituximab-containing regimens.
摘要：
Parsaclisib是一种有效且高度选择性的PI3Kδ抑制剂，在复发性或难治性（R/R）滤泡性淋巴瘤（FL）的2期研究中，单药治疗已显示出临床益处。CITADEL-102(NCT03039114),第一阶段，多中心研究，评估了帕沙利布联合奥比妥珠单抗和苯达莫司汀在R/RFL患者中的疗效。患者年龄≥18岁，经组织学证实并记录CD20阳性FL，和R/R以前含利妥昔单抗的治疗方案。第一部分（安全性试验）确定了帕沙利布与奥比妥珠单抗和苯达莫司汀的标准剂量方案联合使用的最大耐受剂量。第二部分（剂量扩大）是一个开放标签，单组设计评估安全性，耐受性（主要终点），Parsaclisib联合治疗的疗效（次要终点）。26例患者被纳入CITADEL-102，所有患者接受parsaclisib20mg每日一次，持续8周，此后每周一次20毫克，联合奥比妥珠单抗和苯达莫司汀。一名安全磨合患者经历了4级QT间期延长的剂量限制性毒性，这被认为与parsaclisib有关。8名患者（30.8%）因治疗引起的结肠炎不良事件（TEAE）而停止治疗（2[7.7%]），丙氨酸氨基转移酶和天冬氨酸氨基转移酶增加（均在一名患者中[3.8％]），中性粒细胞减少症,血小板减少症,QT延长,扁桃体癌,和斑丘疹（各1例[3.8%]）。最常见的TEAE是发热（53.8%），中性粒细胞减少症（50.0%），腹泻（46.2%）。23例患者（88.5%）经历了3级或4级TEAE；最常见的是中性粒细胞减少症（34.6%）。发热性中性粒细胞减少症（23.1％），和血小板减少（19.2%）。17例患者（65.4%）完全缓解，3例患者（11.5%）部分缓解，客观反应率为76.9%。总的来说,来自CITADEL-102的结果表明，帕沙利布与奥比努珠单抗和苯达莫司汀的组合没有导致意外的安全事件，几乎没有协同毒性的证据，并证明了在先前含利妥昔单抗方案后进展的R/RFL患者的初步疗效。
