Department of Medicine, Weill Cornell Medical College, Memorial Sloan Kettering Cancer Center (MSKCC), 1275 York Avenue, New York, NY, USA.
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY, USA.
Invest New Drugs. 2017 Dec;35(6):742-750. doi: 10.1007/s10637-017-0445-0. Epub 2017 Mar 9.
Purpose We previously reported the phase I dose escalation study of buparlisib, a pan-class 1A PI3K inhibitor, combined with platinum/taxane-based chemotherapy in patients with advanced solid tumors. The combination was well tolerated and promising preliminary efficacy was observed in PTEN deficient tumors. This phase I dose expansion study now evaluates buparlisib plus high dose carboplatin and paclitaxel in unselected patients with advanced solid tumors and buparlisib plus standard dose carboplatin and paclitaxel in patients with PTEN deficient tumors (ClinicalTrials.gov, NCT01297452). Methods There were two expansion cohorts: Cohort A received continuous buparlisib (100 mg/daily) orally plus high dose carboplatin AUC 6 and paclitaxel 200 mg/m2; Cohort B treated patients with PTEN deficient tumors only and they received the recommended phase II dose (RP2D) of continuous buparlisib (100 mg/daily) orally plus standard dose carboplatin AUC 5 and paclitaxel 175 mg/m2. Both cohorts received chemotherapy intravenously on day 1 of the 21-day cycle with pegfilgrastim support. Primary endpoint in Cohort A was to evaluate the safety and tolerability of chemotherapy dose intensification with buparlisib and in Cohort B was to describe preliminary efficacy of the combination among patients with tumors harboring a PTEN mutation or homozygous deletion. Results 14 subjects were enrolled, 7 in Cohort A and 7 in Cohort B. Dose reductions were required in 5 (71%) and 3 (43%) patients, in cohort A and B respectively. Grade 3 adverse events in Cohort A included lymphopenia (n = 5 [71%]), hyperglycemia (n = 2, [29%]), diarrhea (n = 2, [29%]) and rash (n = 2, [29%]) and in cohort B included lymphopenia (n = 5 [71%]), hyperglycemia (n = 4 [57%]) and neutropenia (n = 2 [29%]. The mean number of cycles on protocol was 6. The overall objective response rate was 14% (2 /14). No objective responses were observed in the PTEN deficient cohort. Four out of 6 patients with stable disease (SD) had SD or better for ≥6 cycles, 2 of which had PTEN deficient tumors. Conclusion The addition of buparlisib to high dose carboplatin and paclitaxel was not tolerable. The combination did not reveal significant clinical activity amongst a small and heterogenous group of PTEN deficient tumors.
目的 我们先前报告了一种泛 class 1A PI3K 抑制剂 buparlisib 与铂类/紫杉烷类化疗联合治疗晚期实体瘤的 I 期剂量递增研究。该联合治疗耐受性良好，在 PTEN 缺失肿瘤中观察到有初步疗效。本 I 期剂量扩展研究现评估 buparlisib 联合高剂量卡铂和紫杉醇用于未选择的晚期实体瘤患者，以及 buparlisib 联合标准剂量卡铂和紫杉醇用于 PTEN 缺失肿瘤患者（ClinicalTrials.gov，NCT01297452）。
方法 有两个扩展队列：队列 A 接受连续口服 buparlisib（100mg/天）加高剂量卡铂 AUC6 和紫杉醇 200mg/m2；队列 B 仅治疗 PTEN 缺失肿瘤患者，他们接受连续口服 buparlisib（100mg/天）加标准剂量卡铂 AUC5 和紫杉醇 175mg/m2 的推荐 II 期剂量（RP2D）。两个队列均在 21 天周期的第 1 天静脉输注化疗药物，并使用培非格司亭支持。队列 A 的主要终点是评估 buparlisib 联合化疗剂量强化的安全性和耐受性，而队列 B 的主要终点是描述携带 PTEN 突变或纯合缺失的肿瘤患者联合治疗的初步疗效。
结果 共纳入 14 例患者，7 例入队列 A，7 例入队列 B。队列 A 和 B 分别有 5（71%）例和 3（43%）例患者需要减少剂量。队列 A 的 3 级不良事件包括淋巴细胞减少（n=5 [71%]）、高血糖（n=2 [29%]）、腹泻（n=2 [29%]）和皮疹（n=2 [29%]），而队列 B 的 3 级不良事件包括淋巴细胞减少（n=5 [71%]）、高血糖（n=4 [57%]）和中性粒细胞减少（n=2 [29%]）。方案规定的平均周期数为 6 个。总客观缓解率为 14%（2/14）。PTEN 缺失队列未观察到客观缓解。6 例稳定疾病（SD）患者中有 4 例（4/6）SD 或更好持续≥6 个周期，其中 2 例有 PTEN 缺失肿瘤。
结论 buparlisib 联合高剂量卡铂和紫杉醇不耐受。该联合治疗在一小部分异质性 PTEN 缺失肿瘤中并未显示出显著的临床活性。
Int J Mol Sci. 2021-3-27
Biochim Biophys Acta Mol Cell Res. 2020-2-19
Middle East J Dig Dis. 2019-1
Mol Cancer. 2019-2-19
Clin Transl Radiat Oncol. 2018-4-27
Clin Breast Cancer. 2017-10-28
Nat Rev Clin Oncol. 2015-11-10
Curr Drug Targets. 2014-1
Science. 2013-7-26
World J Gastroenterol. 2012-6-7
Zotero 插件