National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Cancer Med. 2021 Jan;10(1):109-118. doi: 10.1002/cam4.3575. Epub 2020 Oct 31.
The recommended phase 2 dose (RP2D) of pamiparib, an investigational PARP1/2 inhibitor, was established as 60 mg twice daily (BID) in a first-in-human (FIH) study (NCT02361723).
Chinese patients with advanced non-mucinous high-grade ovarian cancer (HGOC) or triple-negative breast cancer (TNBC) whose disease either progressed despite standard therapy, or for which there is no standard therapy were enrolled in the dose-escalation (DE) portion of a phase 1/2 study (NCT03333915). The primary endpoint was safety/tolerability; secondary objectives were pharmacokinetics and antitumor activity. BRCA1/2 mutation status was retrospectively evaluated.
Nine HGOC and six TNBC patients (N = 15; n = 4, 20 mg; n = 4, 40 mg; n = 7, 60 mg) were enrolled; as of 30 September 2019, one HGOC patient remained on treatment. Seven patients (n = 5, HGOC; n = 2, TNBC) had germline BRCA1/2 mutation (gBRCA ); all HGOC patients were resistant/refractory to platinum. Asthenia and nausea (n = 12 each) were the most common treatment-related adverse events (TRAEs). Decreased hemoglobin was the most common grade 3 TRAE (n = 3); no grade ≥4 AEs were observed. No dose-limiting toxicities (DLTs) were reported. Pamiparib plasma exposure was similar to exposure observed in the FIH study after a single-dose administration, albeit slightly higher at steady state. Among 13 RECIST-evaluable patients, two with HGOC (gBRCA , n = 1) achieved a confirmed partial response and six with HGOC (gBRCA , n = 4) achieved stable disease; all TNBC RECIST-evaluable patients (n = 5) reported progressive disease.
Pamiparib was generally well tolerated in Chinese patients, with durable responses observed in patients with HGOC. Based on these results, pamiparib 60 mg BID was confirmed as the RP2D.
在一项首次人体（FIH）研究（NCT02361723）中，作为一种研究性 PARP1/2 抑制剂的帕米帕利的推荐 2 期剂量（RP2D）确定为 60mg 每日两次（BID）。
患有晚期非黏液性高级卵巢癌（HGOC）或三阴性乳腺癌（TNBC）的中国患者，其疾病在标准治疗后进展，或尚无标准治疗方法，这些患者被纳入一项 1/2 期研究的剂量递增（DE）部分（NCT03333915）。主要终点是安全性/耐受性；次要目标是药代动力学和抗肿瘤活性。BRCA1/2 突变状态是回顾性评估的。
9 例 HGOC 和 6 例 TNBC 患者（N=15；n=4，20mg；n=4，40mg；n=7，60mg）被纳入；截至 2019 年 9 月 30 日，1 例 HGOC 患者仍在接受治疗。7 例患者（n=5，HGOC；n=2，TNBC）有胚系 BRCA1/2 突变（gBRCA）；所有 HGOC 患者对铂类药物均耐药/难治。乏力和恶心（n=12 例）是最常见的治疗相关不良事件（TRAEs）。血红蛋白减少是最常见的 3 级 TRAE（n=3）；未观察到 4 级及以上的 AE。未报告剂量限制性毒性（DLTs）。帕米帕利的血浆暴露在单次给药后与 FIH 研究中的暴露相似，尽管在稳态时略高。在 13 例可评估 RECIST 的患者中，2 例 HGOC（gBRCA，n=1）确认部分缓解，6 例 HGOC（gBRCA，n=4）疾病稳定；所有 TNBC 可评估 RECIST 的患者（n=5）报告疾病进展。
帕米帕利在中国患者中总体耐受性良好，HGOC 患者观察到持久反应。基于这些结果，确定帕米帕利 60mg BID 为 RP2D。
