A Phase Ib/II Randomized, Open Label Drug Repurposing Trial of Glutamate Signaling Inhibitors in Combination With Chemoradiotherapy in Patients With Newly Diagnosed Glioblastoma
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 120
- 试验地点
- 1
- 主要终点
- PFS-6
研究概览
简要总结
The goal of this 1:1 randomized, multi-center, open-label phase Ib/II clinical trial is to explore the efficacy of the add-on of the anti-glutamatergic drugs gabapentin, sulfasalazine and memantine to standard chemoradiotherapy with temozolomide compared to chemoradiotherapy alone in patients with newly diagnosed glioblastoma.
详细描述
Background: Glioblastoma is the most common and the most aggressive primary malignant brain tumor in adults. The clinical course of glioblastoma is invariably fatal despite multimodal therapy comprising surgical resection followed by chemoradiotherapy. Population-based median overall survival is in the range of only 12 months. Glioblastomas synthesize and secrete large quantities of the excitatory neurotransmitter glutamate, driving epilepsy, neuronal death, tumor growth and invasion.
Rationale: Several brain-penetrating drugs that have obtained clinical approval in other contexts can inhibit glutamate synthesis, secretion and signalling, including (i) the anti-epileptic drug gabapentin, which is a potent inhibitor of the critical glutamate synthesis enzyme branched chain amino acid transaminase 1 (BCAT-1), (ii) the anti-inflammatory drug sulfasalazine, which is a potent inhibitor of glutamate secretion by blocking the cystine-glutamate exchanger system Xc, and (iii) the cognitive enhancer memantine, which can prevent glutamate-driven, calcium-induced neuronal death and tumor cell invasion by blocking N-methyl-D-aspartate (NMDA) type glutamate receptors. The omnipresence and pleiotropic functions of glutamate in glioblastoma lends rationale for a combined anti-glutamatergic therapeutic approach. The well-documented tolerability of these drugs support the feasibility of a repurposing approach in combination with standard chemoradiotherapy. There is limited commercial interest in exploring the activity of these drugs as anti-cancer agents.
Aim: The aim of the herein proposed clinical trial is to explore the tolerability and efficacy of combined anti-glutamatergic treatment as an add-on to standard chemoradiotherapy in newly diagnosed glioblastoma. The trial is designed to explore the efficacy of a triple anti-glutamatergic treatment regimen to justify and statistically plan a subsequent phase III expansion trial.
Methodology: This randomized phase Ib/II, parallel-group, open-label, multicenter trial will be conducted in 120 adult patients with newly diagnosed glioblastoma. Any study treatments will be administered orally in combination with standard chemoradiotherapy and will be continued until tumor progression. The trial design comprises a per-patient dose-escalation approach in the experimental arm, i.e. doses of the study drugs will be increased weekly to pre-specified maximum dose levels and will be reduced if toxicities attributed to either study drug occur. The primary endpoint is progression-free survival at 6 months (PFS-6) and will be analysed by intent-to-treat. After the first 20 events in the experimental study arm, an interim toxicity analysis will be performed to evaluate study discontinuation and maximum target dose level adaptions. Secondary endpoints include estimates of median PFS and overall survival (OS), OS at 12 months, seizure-free survival (SFS) and SFS-6. Secondary objectives include the central review of neuropathological diagnoses, central response assessment on magnetic resonance imaging scans (MRI) utilizing the Response Assessment in Neuro-Oncology (RANO) working group criteria, determination of quality of life of patients and their care givers, symptom burden, cognitive functioning, anti-epileptic drug use, steroid use and exploratory analyses of outcome among molecular glioblastoma subtypes determined by methylome and gene panel sequencing.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Standard of care
Radiotherapy 30 x 2 Gy with concomitant temozolomide followed by maintenance temozolomide
干预措施: Temozolomide (Drug)
Standard of care
Radiotherapy 30 x 2 Gy with concomitant temozolomide followed by maintenance temozolomide
干预措施: Radiotherapy (Radiation)
Standard of care plus glutamate signaling inhibitors
Radiotherapy 30 x 2 Gy with concomitant temozolomide followed by maintenance temozolomide plus combined daily gabapentin, sulfasalazine and memantine
干预措施: Gabapentin (Drug)
Standard of care plus glutamate signaling inhibitors
Radiotherapy 30 x 2 Gy with concomitant temozolomide followed by maintenance temozolomide plus combined daily gabapentin, sulfasalazine and memantine
干预措施: Sulfasalazine (Drug)
Standard of care plus glutamate signaling inhibitors
Radiotherapy 30 x 2 Gy with concomitant temozolomide followed by maintenance temozolomide plus combined daily gabapentin, sulfasalazine and memantine
干预措施: Memantine (Drug)
Standard of care plus glutamate signaling inhibitors
Radiotherapy 30 x 2 Gy with concomitant temozolomide followed by maintenance temozolomide plus combined daily gabapentin, sulfasalazine and memantine
干预措施: Temozolomide (Drug)
Standard of care plus glutamate signaling inhibitors
Radiotherapy 30 x 2 Gy with concomitant temozolomide followed by maintenance temozolomide plus combined daily gabapentin, sulfasalazine and memantine
干预措施: Radiotherapy (Radiation)
结局指标
主要结局
PFS-6
时间窗: 6 months
progression-free survival at 6 months
次要结局
- OS-12(12 months)
- QoL(From date of randomization until the date of first documented tumor progression or date of death from any cause, whichever came first, assessed for a minimum of 6 months and up to 42 months)
- PFS(From date of randomization until the date of first documented tumor progression or date of death from any cause, whichever came first, assessed for a minimum of 6 months and up to 42 months)
- OS(From date of randomization until the date of death from any cause, assessed for at least 6 months and up to 42 months)
- SFS(From date of randomization until the date of first documented seizure or date of death from any cause, whichever came first, assessed for a minimum of 6 months and up to 42 months)
- SFS-6(6 months)
- Cognitive Functioning(From date of randomization until the date of first documented tumor progression or date of death from any cause, whichever came first, assessed for a minimum of 6 months and up to 42 months)
- Symptom burden(From date of randomization until the date of first documented tumor progression or date of death from any cause, whichever came first, assessed for a minimum of 6 months and up to 42 months)
- Quality of life of an informal caregiver(From date of randomization until the date of first documented tumor progression or date of death from any cause, whichever came first, assessed for a minimum of 6 months and up to 42 months)