评估顺铂、吉西他滨和维利帕利在 2 个患者队列中的 1 期临床试验：种系 BRCA 突变携带者和野生型 BRCA 胰腺导管腺癌。
Phase 1 trial evaluating cisplatin, gemcitabine, and veliparib in 2 patient cohorts: Germline BRCA mutation carriers and wild-type BRCA pancreatic ductal adenocarcinoma.
机构信息
Memorial Sloan Kettering Cancer Center, New York, New York.
Weill Cornell Medicine, New York, New York.
出版信息
Cancer. 2018 Apr 1;124(7):1374-1382. doi: 10.1002/cncr.31218. Epub 2018 Jan 16.
BACKGROUND
A phase 1 trial was used to evaluate a combination of cisplatin, gemcitabine, and escalating doses of veliparib in patients with untreated advanced pancreatic ductal adenocarcinoma (PDAC) in 2 cohorts: a germline BRCA1/2-mutated (BRCA+) cohort and a wild-type BRCA (BRCA-) cohort. The aims were to determine the safety, dose-limiting toxicities (DLTs), maximum tolerated dose, and recommended phase 2 dose (RP2D) of veliparib combined with cisplatin and gemcitabine and to assess the antitumor efficacy (Response Evaluation Criteria in Solid Tumors, version 1.1) and overall survival.
METHODS
Gemcitabine and cisplatin were dosed at 600 and 25 mg/m , respectively, over 30 minutes on days 3 and 10 of a 21-day cycle. Four dose levels of veliparib were evaluated: 20 (dose level 0), 40 (dose level 1), and 80 mg (dose level 2) given orally twice daily on days 1 to 12 and 80 mg given twice daily on days 1 to 21 (dose level 2A [DL2A]).
RESULTS
Seventeen patients were enrolled: 9 BRCA+ patients, 7 BRCA- patients, and 1 patient with an unknown status. DLTs were reached at DL2A (80 mg twice daily on days 1 to 21). Two of the 5 patients in this cohort (40%) experienced grade 4 neutropenia and thrombocytopenia. Two grade 5 events occurred on protocol. The objective response rate in the BRCA+ cohort was 7 of 9 (77.8%). The median overall survival for BRCA+ patients was 23.3 months (95% confidence interval [CI], 3.8-30.2 months). The median overall survival for BRCA- patients was 11 months (95% CI, 1.5-12.1 months).
CONCLUSIONS
The RP2D of veliparib was 80 mg by mouth twice daily on days 1 to 12 in combination with cisplatin and gemcitabine; the DLT was myelosuppression. Substantial antitumor activity was seen in BRCA+ PDAC. A randomized phase 2 trial is currently evaluating cisplatin and gemcitabine with and without veliparib for BRCA+ PDAC (NCT01585805). Cancer 2018;124:1374-82. © 2018 American Cancer Society.
背景
一项 1 期临床试验用于评估顺铂、吉西他滨联合递增剂量维利帕尼治疗未经治疗的晚期胰腺导管腺癌（PDAC）患者，共入组 2 个队列：胚系 BRCA1/2 突变（BRCA+）队列和野生型 BRCA（BRCA-）队列。目的是确定维利帕尼联合顺铂和吉西他滨的安全性、剂量限制性毒性（DLTs）、最大耐受剂量和推荐的 2 期剂量（RP2D），并评估抗肿瘤疗效（实体瘤反应评价标准，第 1.1 版）和总生存期。
方法
吉西他滨和顺铂的剂量分别为 600 和 25 mg/m2，在 21 天周期的第 3 和第 10 天静脉滴注 30 分钟。评估了维利帕尼 4 个剂量水平：20（剂量水平 0）、40（剂量水平 1）和 80 mg（剂量水平 2），每日口服 2 次，第 1 至 12 天；80 mg 每日口服 2 次，第 1 至 21 天（剂量水平 2A[DL2A]）。
结果
共入组 17 例患者：9 例 BRCA+患者，7 例 BRCA-患者，1 例患者 BRCA 状态未知。DL2A（80 mg 每日口服 2 次，第 1 至 21 天）组达到 DLT。该队列 5 例患者中的 2 例（40%）发生 4 级中性粒细胞减少和血小板减少。2 例发生 5 级事件。BRCA+队列的客观缓解率为 7 例（77.8%）。BRCA+患者的中位总生存期为 23.3 个月（95%置信区间[CI]，3.8-30.2 个月）。BRCA-患者的中位总生存期为 11 个月（95%CI，1.5-12.1 个月）。
结论
维利帕尼的 RP2D 为顺铂和吉西他滨联合治疗时口服 80 mg，每日 2 次，第 1 至 12 天；DLT 为骨髓抑制。BRCA+ PDAC 患者有明显的抗肿瘤活性。目前正在进行一项随机 2 期临床试验，评估 BRCA+ PDAC 患者中顺铂和吉西他滨联合或不联合维利帕尼的疗效（NCT01585805）。癌症 2018；124:1374-82。© 2018 美国癌症协会。
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