NCI 7977: A Phase I Dose-Escalation Study of Intermittent Oral ABT-888 (Veliparib) plus Intravenous Irinotecan Administered in Patients with Advanced Solid Tumors.
NCI 7977: A Phase I Dose-Escalation Study of Intermittent Oral ABT-888 (Veliparib) plus Intravenous Irinotecan Administered in Patients with Advanced Solid Tumors.
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DOI：
10.1158/2767-9764.crc-22-0485
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发表时间：
2023-06
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Veliparib 是一种 PARP 抑制剂 (PARPi)，对 BRCA 1/2/PALB2 缺陷型肿瘤具有活性。临床前观察表明，无论同源重组缺陷 (HRD) 如何，伊立替康等拓扑异构酶抑制剂都与 PARPi 具有协同作用，这可能会扩大 PARPi 的作用。 NCI 7977 是一项多队列 I 期临床试验，评估 veliparib 联合伊立替康多剂量方案治疗实体瘤的安全性和有效性。在间歇性 veliparib 队列中，在第 1-4 天和第 8-11 天以剂量水平 (DL) 1 (50 mg) 和 DL 2 (100 mg) 每天两次递增剂量的 veliparib，并在第 3 天和第 10 天给予伊立替康 100 mg/m2，周期为 21 天。纳入 15 名患者，15 名患者中有 8 名 (53%) 接受过≥4 次既往全身治疗。在 DL1 时，6 名患者中的 1 名经历了腹泻的剂量限制性毒性 (DLT)。在 DL2 时，9 名患者接受了治疗，其中 3 名患者的 DLT 无法评估，6 名可评估患者中的 2 名经历了 3 级中性粒细胞减少症的 DLT。伊立替康 100 mg/m2 和维利帕尼 50 mg 每日两次是 MTD。尽管 4 名患者的无进展生存期 > 6 个月，但未观察到客观反应。间歇性 veliparib 的 MTD 为 50 mg，每天两次，第 1-4 天和第 8-11 天，每周伊立替康 100 mg/m2 第 3 天和第 10 天，每 21 天一次。无论 HRD 和既往是否服用伊立替康，多名患者都经历了长期稳定的疾病。然而，由于较高剂量间歇性维利帕利和伊立替康的毒性，该方案被确定毒性太大，不适合进一步开发，因此提前关闭了该试验组。间歇性维利帕尼与每周一次伊立替康的组合被认为毒性太大，不适合进一步开发。未来的 PARPi 组合应侧重于具有非重叠毒性的药物，以提高耐受性。在多名接受过大量治疗的患者中观察到，联合治疗的疗效有限，疾病长期稳定，但没有看到客观反应。
Veliparib is a PARP inhibitor (PARPi) with activity in BRCA 1/2/PALB2-deficient tumors. Preclinical observations reveal topoisomerase inhibitors like irinotecan are synergistic with PARPi irrespective of homologous recombination deficiency (HRD), potentially expanding the role for PARPi. NCI 7977 was a multicohort phase I clinical trial evaluating the safety and efficacy of multiple dose schedules of veliparib with irinotecan for solid tumors. In the intermittent veliparib cohort, escalating doses of veliparib were given twice daily at dose level (DL) 1 (50 mg) and DL 2 (100 mg) days 1–4 and 8–11 with irinotecan 100 mg/m2 days 3 and 10 in 21-day cycles. Fifteen patients enrolled, 8 of 15 (53%) received ≥4 prior systemic treatments. At DL1, 1 of 6 patients experienced a dose-limiting toxicity (DLT) of diarrhea. At DL2, 9 patients were treated, with 3 unevaluable for DLT, and 2 of 6 evaluable patients experienced a DLT of grade 3 neutropenia. Irinotecan 100 mg/m2 and veliparib 50 mg twice daily was the MTD. No objective responses were observed, although 4 patients had progression-free survival >6 months. The MTD of intermittent veliparib is 50 mg twice daily days 1–4 and 8–11 with weekly irinotecan 100 mg/m2 days 3 and 10 every 21 days. Multiple patients experienced prolonged stable disease irrespective of HRD and prior irinotecan. However, due to the toxicities with higher dose intermittent veliparib and irinotecan, this schedule was determined too toxic for further development and the arm was closed prematurely. The combination of intermittent veliparib with weekly irinotecan was deemed too toxic for further development. Future PARPi combinations should focus on agents with nonoverlapping toxicities to improve tolerability. The treatment combination showed limited efficacy with prolonged stable disease observed in multiple heavily pretreated patients, but no objective responses were seen.