目的:在临床前和早期临床研究中,口服Bcl-2抑制剂navitoclax作为单药治疗以及与其他细胞毒性药物联合治疗在实体和血液系统恶性肿瘤中具有活性。我们评估了安全性,药代动力学(PK),navitoclax和伊立替康的抗肿瘤活性。
方法:在这个多中心中,开放标签,第一阶段剂量递增研究,在21天的周期内,患有晚期实体瘤的成人接受navitoclax(起始剂量为150mg/天)联合伊立替康方案1/2:每3周一次的方案(Q3W180,250或350mg/m(2))或每周一次的方案(QW75或100mg/m(2)).直到达到最大耐受剂量(MTD)和/或推荐的2期剂量(RPTD)。
结果:所有患者(Q3W,n=14;QW,n=17)可评估安全性,PK,和功效。两组中最常见的不良事件是腹泻(Q3W92.9%;QW76.5%),这是最常见的3级/4级不良事件(Q3W42.9%;QW29.4%).该研究被修改为排除4名UGT1A1*287/7纯合子患者,因为频繁的伊立替康相关3级/4级腹泻和/或发热性中性粒细胞减少症。在navitoclax和伊立替康之间没有观察到明显的PK相互作用。在施用的最低剂量下,在Q3W组中超过组合的MTD。在QW组中,navitoclax联合伊立替康75mg/m时的MTD和RPTD为150mg(2)。每组中的一名患者获得部分响应。
结论:navitoclax联合伊立替康75mg/m(2)QW在21天周期内的RPTD为150mg。
OBJECTIVE: The oral Bcl-2 inhibitor navitoclax demonstrated activity in solid and hematologic malignancies as monotherapy and in combination with other cytotoxic agents in preclinical and early clinical studies. We evaluated the safety, pharmacokinetics (PK), and antitumor activity of navitoclax plus irinotecan.
METHODS: In this multicenter, open-label, phase 1 dose escalation
study, adults with advanced solid tumors received navitoclax (starting dose 150 mg/day) in combination with 1 of 2 irinotecan schedules during a 21-day cycle: a once-every-3-week regimen (Q3W 180, 250, or 350 mg/m(2)) or a once-weekly regimen (QW 75 or 100 mg/m(2)). Enrollment occurred until a maximum tolerated dose (MTD) and/or recommended phase 2 dose (RPTD) was reached.
RESULTS: All patients (Q3W, n = 14; QW, n = 17) were evaluable for safety, PK, and efficacy. The most common adverse event in both groups was diarrhea (Q3W 92.9 %; QW 76.5 %), which was the most frequent grade 3/grade 4 adverse event (Q3W 42.9 %; QW 29.4 %). The
study was amended to exclude 4 UGT1A1*28 7/7 homozygous patients due to frequent irinotecan-related grade 3/grade 4 diarrhea and/or febrile neutropenia. No apparent PK interactions between navitoclax and irinotecan were observed. The MTD of the combination was exceeded in the Q3W group at the lowest dose administered. In the QW group, the MTD and RPTD for navitoclax were 150 mg when combined with irinotecan 75 mg/m(2). One patient in each group achieved a partial response.
CONCLUSIONS: The RPTD of navitoclax in combination with irinotecan 75 mg/m(2) QW during a 21-day cycle was 150 mg in these heavily pretreated patients.