Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Department of Oncology and Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Clin Cancer Res. 2019 Jan 1;25(1):73-79. doi: 10.1158/1078-0432.CCR-18-0110. Epub 2018 Aug 21.
Iniparib is a purported prodrug causing cell death through intracellular conversion to nitro radical ions. We assessed the efficacy and safety of iniparib with standard radiotherapy and temozolomide in patients with newly diagnosed glioblastoma (GBM).
Adults meeting eligibility criteria were enrolled in this prospective, single-arm, open-label multi- institution phase II trial with median overall survival (mOS) compared with a historical control as the primary objective. A safety run-in component of radiotherapy + temozolomide + iniparib ( = 5) was followed by an efficacy study ( = 76) with the recommended phase II doses of iniparib (8.0 mg/kg i.v. twice/week with radiotherapy + daily temozolomide followed by 8.6 mg/kg i.v. twice/week with 5/28-day temozolomide).
The median age of the 81 evaluable participants was 58 years (63% male). Baseline KPS was ≥ 80% in 87% of participants. The mOS was 22 months [95% confidence interval (CI), 17-24] and the HR was 0.44 (95% CI, 0.35-0.55) per-person-year of follow-up. The 2- and 3-year survival rates were 38% and 25%, respectively. Treatment-related grade 3 adverse events (AEs) occurred in 27% of patients; 9 patients had AEs requiring drug discontinuation including infusion-related reaction, rash, gastritis, increased liver enzymes, and thrombocytopenia.
Iniparib is well tolerated with radiotherapy and temozolomide in patients with newly diagnosed GBM at up to 17.2 mg/kg weekly. The primary objective of improved mOS compared with a historical control was met, indicating potential antitumor activity of iniparib in this setting. Dosing optimization (frequency and sequence) is needed prior to additional efficacy studies.
Iniparib 是一种据称的前药，通过细胞内转化为硝自由基离子导致细胞死亡。我们评估了 Iniparib 联合标准放疗和替莫唑胺治疗新诊断的胶质母细胞瘤（GBM）患者的疗效和安全性。
符合入选标准的成年人参加了这项前瞻性、单臂、开放标签的多中心 II 期试验，主要目的是比较中位总生存期（mOS）与历史对照。放疗+替莫唑胺+Iniparib 的安全性预试验（=5）后，进行疗效研究（=76），采用 Iniparib 的推荐 II 期剂量（放疗时静脉注射 8.0mg/kg ，每周两次，随后每日替莫唑胺，5/28 天替莫唑胺时静脉注射 8.6mg/kg ，每周两次）。
81 例可评估参与者的中位年龄为 58 岁（63%为男性）。基线 KPS 为≥80%的参与者占 87%。mOS 为 22 个月[95%置信区间（CI），17-24]，每随访 1 人年的 HR 为 0.44（95%CI，0.35-0.55）。2 年和 3 年生存率分别为 38%和 25%。27%的患者出现治疗相关 3 级不良事件（AE）；9 例患者因 AE 停药，包括输注相关反应、皮疹、胃炎、肝酶升高和血小板减少症。
Iniparib 联合放疗和替莫唑胺治疗新诊断的 GBM 患者的耐受性良好，每周剂量高达 17.2mg/kg。与历史对照相比，mOS 改善的主要目标达到了，表明 Iniparib 在该环境下具有潜在的抗肿瘤活性。在进行额外的疗效研究之前，需要优化（频率和顺序）剂量。
