目的:胶质母细胞瘤(GBM)患者预后不良。虽然DNA烷化剂替莫唑胺(TMZ)是化疗的主要药物,治疗抗性在患者中发展迅速。碱基切除修复抑制剂TRC102(甲氧胺)逆转临床前神经胶质瘤模型中的TMZ抗性。我们试图研究口服TRC102+TMZ治疗复发性GBM(rGBM)的疗效和安全性。
方法:A预注册(NCT02395692),非随机化,多中心,计划并通过成人脑肿瘤协会(ABTC-1402)进行2期临床试验(BERT).第1组包括首次复发的贝伐单抗初治GBM患者,与主要终点的反应率。如果确定了足够的活动,计划在贝伐单抗难治性患者中设立第二组.次要终点是总生存期(OS),无进展生存期(PFS),六个月时的PFS(PFS-6),和毒性。
结果:第1组纳入了19名患者,中位数为两个治疗周期。没有观察到客观反应,因此,手臂2没有打开。中位OS为11.1个月(95CI8.2-17.9)。PFS中位数为1.9个月(95CI1.8-3.7)。PFS-6为10.5%(95CI1.3-33.1%)。大多数毒性为1-2级,有2例3级淋巴细胞减少和1例4级血小板减少。两名PFS≥17个月和OS>32个月的患者被视为“延长幸存者”。肿瘤组织的RNA测序,在诊断时获得的,表现出显著丰富的DNA损伤反应(DDR)特征,染色体不稳定性(CIN70,CIN25),和“延长幸存者”中的细胞增殖(PCNA25)。
结论:这些发现证实了TRC102+TMZ治疗rGBM患者的安全性和可行性。他们还保证在富含生物标志物的试验中对联合治疗进行进一步评估,这些试验招募具有基线高度激活DDR通路的GBM患者。
UNASSIGNED: Patients with glioblastoma (GBM) have a dismal prognosis. Although the DNA alkylating agent temozolomide (TMZ) is the mainstay of chemotherapy, therapeutic resistance rapidly develops in patients. Base excision repair inhibitor TRC102 (methoxyamine) reverses TMZ resistance in preclinical glioma models. We aimed to investigate the efficacy and safety of oral TRC102+TMZ in recurrent GBM (rGBM).
UNASSIGNED: A preregistered (NCT02395692), nonrandomized, multicenter, phase 2 clinical
trial (BERT) was planned and conducted through the Adult Brain Tumor Consortium (ABTC-1402). Arm 1 included patients with bevacizumab-naïve GBM at the first recurrence, with the primary endpoint of response rates. If sufficient activity was identified, a second arm was planned for the bevacizumab-refractory patients. The secondary endpoints were overall survival (OS), progression-free survival (PFS), PFS at 6 months (PFS6), and toxicity.
UNASSIGNED: Arm 1 enrolled 19 patients with a median of two treatment cycles. Objective responses were not observed; hence, arm 2 did not open. The median OS was 11.1 months [95% confidence interval (CI), 8.2-17.9]. The median PFS was 1.9 months (95% CI, 1.8-3.7). The PFS6 was 10.5% (95% CI, 1.3%-33.1%). Most toxicities were grades 1 and 2, with two grade 3 lymphopenias and one grade 4 thrombocytopenia. Two patients with PFS ≥ 17 months and OS > 32 months were deemed \"extended survivors.\" RNA sequencing of tumor tissue, obtained at diagnosis, demonstrated significantly enriched signatures of DNA damage response (DDR), chromosomal instability (CIN70, CIN25), and cellular proliferation (PCNA25) in \"extended survivors.\"
UNASSIGNED: These findings confirm the safety and feasibility of TRC102+TMZ in patients with rGBM. They also warrant further evaluation of combination therapy in biomarker-enriched trials enrolling GBM patients with baseline hyperactivated DDR pathways.