Division of Hematology/Oncology, University of Michigan, Ann Arbor, Michigan.
Population Health Sciences, Weill Cornell Medicine, New York, New York.
Cancer. 2021 Apr 15;127(8):1301-1310. doi: 10.1002/cncr.33349. Epub 2020 Dec 8.
In preclinical Ewing sarcoma (ES) models, poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors were identified as a potential therapeutic strategy with synergy in combination with cytotoxic agents. This study evaluated the safety and dosing of the PARP1/2 inhibitor niraparib (NIR) with temozolomide (TMZ; arm 1) or irinotecan (IRN; arm 2) in patients with pretreated ES.
Eligible patients in arm 1 received continuous NIR daily and escalating TMZ (days 2-6 [D2-6]) in cohort A. Subsequent patients received intermittent NIR dosing (cohort B), with TMZ re-escalation in cohort C. In arm 2, patients were assigned to NIR (days 1-7 [D1-7]) and escalating doses of IRN (D2-6).
From July 2014 to May 2018, 29 eligible patients (23 males and 6 females) were enrolled in arms 1 and 2, which had 7 dose levels combined. Five patients experienced at least 1 dose-limiting toxicity (DLT) in arm 1 (grade 4 [G4] neutropenia for >7 days or G4 thrombocytopenia), and 3 patients experienced at least 1 DLT in arm 2 (grade 3 [G3] colitis, G3 anorexia, or G3 alanine aminotransferase elevation). The maximum tolerated dose was NIR at 200 mg every day on D1-7 plus TMZ at 30 mg/m every day on D2-6 (arm 1) or NIR at 100 mg every day on D1-7 plus IRN at 20 mg/m every day on D2-6 (arm 2). One confirmed partial response was observed in arm 2; the median progression-free survival was 9.0 weeks (95% CI, 7.0-10.1 weeks) and 16.3 weeks (95% CI, 5.1-69.7 weeks) in arms 1 and 2, respectively. The median decrease in tumor poly(ADP-ribose) activity was 89% (range, 83%-98%).
The combination of NIR and TMZ or IRN was tolerable, but at lower doses in comparison with conventional cytotoxic combinations. A triple-combination study of NIR, IRN, and TMZ has commenced.
在临床前尤因肉瘤（ES）模型中，聚（二磷酸腺苷核糖）聚合酶（PARP）抑制剂被确定为一种具有协同作用的潜在治疗策略，与细胞毒性药物联合使用。本研究评估了 PARP1/2 抑制剂尼拉帕尼（NIR）与替莫唑胺（TMZ；臂 1）或伊立替康（IRN；臂 2）联合治疗预处理 ES 患者的安全性和剂量。
臂 1 中的合格患者接受连续每日 NIR 和递增 TMZ（第 2-6 天[D2-6]）。随后的患者接受间歇性 NIR 给药（队列 B），在队列 C 中重新递增 TMZ。在臂 2 中，患者接受 NIR（第 1-7 天[D1-7]）和递增剂量的 IRN（D2-6）。
从 2014 年 7 月至 2018 年 5 月，29 名符合条件的患者（23 名男性和 6 名女性）入组臂 1 和 2，共 7 个剂量水平。臂 1 中有 5 名患者发生至少 1 例剂量限制性毒性（DLT）（>7 天的 4 级[G4]中性粒细胞减少或 G4 血小板减少），臂 2 中有 3 名患者发生至少 1 例 DLT（3 级[G3]结肠炎、G3 厌食症或 G3 丙氨酸氨基转移酶升高）。最大耐受剂量为 NIR 每日 200 mg，于 D1-7 时给药，TMZ 每日 30 mg/m，于 D2-6 时给药（臂 1），或 NIR 每日 100 mg，于 D1-7 时给药，IRN 每日 20 mg/m，于 D2-6 时给药（臂 2）。臂 2 中观察到 1 例确认的部分缓解；臂 1 和 2 的中位无进展生存期分别为 9.0 周（95%CI，7.0-10.1 周）和 16.3 周（95%CI，5.1-69.7 周）。肿瘤多聚（ADP-核糖）活性的中位降低率为 89%（范围，83%-98%）。
NIR 与 TMZ 或 IRN 的联合治疗是可以耐受的，但与传统细胞毒性联合治疗相比，剂量较低。目前已经开始了 NIR、IRN 和 TMZ 的三联组合研究。
