Weathers Shiao-Pei, Rood-Breithaupt Julie, de Groot John, Thomas Gail, Manfrini Marianna, Penas-Prado Marta, Puduvalli Vinay K, Zwingelstein Christian, Yung W K Alfred
University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Actelion Pharmaceuticals US, Cherry Hill, NJ 08002, USA.
Neurooncol Adv. 2021 Oct 2;3(1):vdab141. doi: 10.1093/noajnl/vdab141. eCollection 2021 Jan-Dec.
There is an urgent need for additional therapies to treat recurrent glioblastoma (GBM). Preclinical studies suggest that high dose macitentan, an oral dual endothelin receptor antagonist, enhances the cytotoxic effects of temozolomide (TMZ) in GBM, improving survival. This phase I trial investigated the maximum tolerated dose of macitentan combined with TMZ in patients with recurrent GBM and assessed the safety and tolerability of high dose macitentan in these patients (NCT01499251).
Adults with recurrent GBM received ascending doses of macitentan from 30 mg once daily concomitantly with TMZ. Safety and tolerability were assessed in addition to exploratory efficacy and pharmacokinetic endpoints. An ancillary study examined biomarker expression following macitentan treatment prior to surgical resection of recurrent GBM.
Thirty-eight patients with recurrent GBM were administered macitentan doses up to 300 mg once daily; no dose-limiting toxicities were observed, and a maximum tolerated dose was not determined. All patients experienced at least one treatment-emergent adverse event (TEAE), the majority associated with GBM or TMZ treatment. TEAEs related to macitentan and TMZ were reported for 16 (42.1%) and 26 (68.4%) patients, respectively, with no serious macitentan-related TEAEs. Macitentan concentrations increased with dose, with no plateau in exposure. Substantial heterogeneity was observed in the expression of efficacy biomarkers within tumors. The Kaplan-Meier estimate of median overall survival across all dose groups was 9.4 (95% CI 8.5, 13.4) months.
High-dose macitentan was well tolerated in recurrent GBM patients concomitantly receiving TMZ. TEAEs were consistent with those seen in patients receiving either drug individually.
治疗复发性胶质母细胞瘤（GBM）迫切需要更多的治疗方法。临床前研究表明，高剂量的马西替坦（一种口服双重内皮素受体拮抗剂）可增强替莫唑胺（TMZ）对GBM的细胞毒性作用，提高生存率。这项I期试验研究了马西替坦联合TMZ在复发性GBM患者中的最大耐受剂量，并评估了高剂量马西替坦在这些患者中的安全性和耐受性（NCT01499251）。
复发性GBM的成人患者接受每日一次剂量递增的马西替坦，剂量从30mg开始，同时服用TMZ。除了探索性疗效和药代动力学终点外，还评估了安全性和耐受性。一项辅助研究检查了复发性GBM手术切除前接受马西替坦治疗后的生物标志物表达。
38例复发性GBM患者接受了每日一次高达300mg的马西替坦剂量；未观察到剂量限制性毒性，也未确定最大耐受剂量。所有患者至少经历了一次治疗中出现的不良事件（TEAE），大多数与GBM或TMZ治疗有关。分别有16例（42.1%）和26例（68.4%）患者报告了与马西替坦和TMZ相关的TEAE，没有严重的与马西替坦相关的TEAE。马西替坦浓度随剂量增加而升高，暴露量无平台期。肿瘤内疗效生物标志物的表达存在显著异质性。所有剂量组的Kaplan-Meier估计中位总生存期为9.4个月（95%CI 8.5，13.4）。
在同时接受TMZ的复发性GBM患者中，高剂量马西替坦耐受性良好。TEAE与单独接受任何一种药物治疗的患者中观察到的情况一致。
