PDF(Pubmed)
Abstract：
UNASSIGNED: A significant unmet need exists for the treatment of glioblastoma, IDH-wildtype (GBM). Preclinical work shows that acetazolamide sensitizes GBM to temozolomide (TMZ) by overcoming TMZ resistance due to BCL-3-dependent upregulation of carbonic anhydrase. Acetazolamide is Food and Drug Administration-approved for the treatment of altitude sickness. Drug repurposing enables the application of drugs to diseases beyond initial indications. This multi-institutional, open-label, phase I trial examined a combination of acetazolamide and TMZ in patients with MGMT promoter-methylated high-grade glioma.
UNASSIGNED: A total of 24 patients (GBM, IDH-wildtype = 22; Grade 4 astrocytoma, IDH-mutant = 1; Grade 3 astrocytoma, IDH-mutant = 1) were accrued over 17 months. All patients received oral acetazolamide (250 mg BID for 7 days increased to 500 mg BID for Days 8-21 of each 28-day cycle) during the adjuvant phase of TMZ for up to 6 cycles.
UNASSIGNED: No patient had a dose-limiting toxicity. Adverse events were consistent with known sequelae of acetazolamide and TMZ. In the 23 WHO Grade 4 patients, the median overall survival (OS) was 30.1 months and the median progression-free survival was 16.0 months. The 2-year OS was 60.9%. In total 37% of the study population had high BCL-3 staining and trended toward shorter OS (17.2 months vs N.R., P = .06).
UNASSIGNED: The addition of acetazolamide is safe and tolerable in GBM patients receiving standard TMZ. Survival results compare favorably to historical data from randomized trials in patients with MGMT promoter-methylated GBM and support examination of acetazolamide in a randomized trial. BCL-3 expression is a potential biomarker for prognosis in GBM or for patients more likely to benefit from TMZ.
UNASSIGNED: A total of 24 patients (GBM, IDH-wildtype = 22; Grade 4 astrocytoma, IDH-mutant = 1; Grade 3 astrocytoma, IDH-mutant = 1) were accrued over 17 months. All patients received oral acetazolamide (250 mg BID for 7 days increased to 500 mg BID for Days 8-21 of each 28-day cycle) during the adjuvant phase of TMZ for up to 6 cycles.
UNASSIGNED: No patient had a dose-limiting toxicity. Adverse events were consistent with known sequelae of acetazolamide and TMZ. In the 23 WHO Grade 4 patients, the median overall survival (OS) was 30.1 months and the median progression-free survival was 16.0 months. The 2-year OS was 60.9%. In total 37% of the study population had high BCL-3 staining and trended toward shorter OS (17.2 months vs N.R., P = .06).
UNASSIGNED: The addition of acetazolamide is safe and tolerable in GBM patients receiving standard TMZ. Survival results compare favorably to historical data from randomized trials in patients with MGMT promoter-methylated GBM and support examination of acetazolamide in a randomized trial. BCL-3 expression is a potential biomarker for prognosis in GBM or for patients more likely to benefit from TMZ.
摘要：
■胶质母细胞瘤的治疗存在显著的未满足的需求，IDH-野生型(GBM)。临床前工作表明，乙酰唑胺通过克服由BCL-3依赖性碳酸酐酶上调引起的TMZ抗性，使GBM对替莫唑胺（TMZ）敏感。乙酰唑胺被食品和药物管理局批准用于治疗高原反应。药物再利用使药物能够应用于超出初始适应症的疾病。这种多机构，开放标签，I期试验在MGMT启动子甲基化的高级别神经胶质瘤患者中检查了乙酰唑胺和TMZ的组合.
■总共24名患者（GBM，IDH-野生型=22；4级星形细胞瘤，IDH突变体=1；3级星形细胞瘤，IDH-突变体=1)积累超过17个月。在TMZ的辅助阶段，所有患者都接受口服乙酰唑胺（每个28天周期的第8-21天，250mgBID持续7天，增加到500mgBID），最多6个周期。
■没有患者具有剂量限制性毒性。不良事件与已知的乙酰唑胺和TMZ后遗症一致。在23名世卫组织4级患者中，中位总生存期(OS)为30.1个月,中位无进展生存期为16.0个月.2年OS为60.9%。总共37%的研究人群有较高的BCL-3染色，并倾向于较短的OS（17.2个月vsN.R.，P=.06）。
■在接受标准TMZ的GBM患者中，添加乙酰唑胺是安全且可耐受的。生存结果与来自MGMT启动子甲基化GBM患者的随机试验的历史数据相比是有利的，并且在随机试验中支持乙酰唑胺的检查。BCL-3表达是GBM预后或更可能受益于TMZ的患者的潜在生物标志物。
■总共24名患者（GBM，IDH-野生型=22；4级星形细胞瘤，IDH突变体=1；3级星形细胞瘤，IDH-突变体=1)积累超过17个月。在TMZ的辅助阶段，所有患者都接受口服乙酰唑胺（每个28天周期的第8-21天，250mgBID持续7天，增加到500mgBID），最多6个周期。
■没有患者具有剂量限制性毒性。不良事件与已知的乙酰唑胺和TMZ后遗症一致。在23名世卫组织4级患者中，中位总生存期(OS)为30.1个月,中位无进展生存期为16.0个月.2年OS为60.9%。总共37%的研究人群有较高的BCL-3染色，并倾向于较短的OS（17.2个月vsN.R.，P=.06）。
■在接受标准TMZ的GBM患者中，添加乙酰唑胺是安全且可耐受的。生存结果与来自MGMT启动子甲基化GBM患者的随机试验的历史数据相比是有利的，并且在随机试验中支持乙酰唑胺的检查。BCL-3表达是GBM预后或更可能受益于TMZ的患者的潜在生物标志物。
