A Phase II, Open-Label Study to Evaluate the Safety, Tolerability, and Efficacy of Disulfiram and Copper Gluconate When Added to Standard Temozolomide Treatment in Patients With Newly Diagnosed Resected Unmethylated Glioblastoma Multiforme
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 15
- 试验地点
- 1
- 主要终点
- 6 Months Progression Free Survival (PFS)
研究概览
简要总结
One of Disulfiram antitumor effects suggested in preclinical studies is MGMT (methyl-guanine-methyl-transferase) inhibition. Disulfiram MGMT inhibitory effect is enhanced by addition of Copper. This study evaluates the impact of Disulfiram (DSF) + Copper (Cu) combination when added to standard Temozolomide in the treatment of unmethylated Glioblastoma Multiforme (GBM) patients.
详细描述
Glioblastoma is the most common malignant primary brain tumor and one of the most devastating cancers. The current standard of care for glioblastoma includes maximal safe resection followed by radiotherapy and temozolomide, which results in a median progression-free survival of less than 7 months, and median overall survival (OS) of less than 15 months. Moreover, patients with unmethylated glioblastoma respond poorly to this current standard treatment. This clinical trial evaluates the potential role of continuous, upfront use of Disulfiram in combination with Copper gluconate in enhancing temozolomide effect in the treatment of unmethylated Glioblastoma multiforme (GBM) patients.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 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
- •Age 18 or older
- •Diagnosis of histologically confirmed glioblastoma (WHO grade IV). Subjects with an original histologic diagnosis of low grade glioma or anaplastic glioma (WHO grade II or III) are eligible if a subsequent histological diagnosis of glioblastoma is made
- •Patients whose tumor is determined to be unmethylated
- •Patients with incomplete resection as determined by residual, measurable gadolinium or contrast-enhancing lesion or lesions
- •Recent resection of glioblastoma within 4 weeks of study entry. Patients who have only had a tumor biopsy and who are considered unresectable are eligible (but based on the study accrual this subset of patients with unresectable tumor may be considered for separate analysis)
- •Eastern Cooperative Oncology Group Performance Status (ECOG PS) of ≤ 2 (see appendix A)
- •Willing to remain abstinent from consuming alcohol while on DSF
- •No prior radiation or chemotherapy
- •Meets the following laboratory criteria:
- •Absolute neutrophil count ≥ 1,500/mcL (microliter)
- •Platelets ≥ 100,000/mcL
- •Hemoglobin > 10.0 g/dL (grams/deciliter) (transfusion and/or ESA (erythropoiesis-stimulating agent) allowed)
- •Total bilirubin and alkaline phosphatase ≤ 2x institutional upper limit of normal (ULN)
- •Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x ULN
- •Blood urea nitrogen (BUN) and creatinine < 1.5 x ULN
- •Able to take oral medication
- •Able to understand and willing to sign an institutional review board (IRB)-approved written informed consent document (legally authorized representative permitted)
排除标准
- •Radiographic evidence of leptomeningeal dissemination, extensive intraparenchymal dissemination, infratentorial tumor, or metastatic disease to sites remote from the supratentorial brain
- •Enrolled in another clinical trial testing a novel therapy or drug
- •Received prior radiation therapy or chemotherapy for glioblastoma
- •History of allergic reaction/hypersensitivity to DSF (without alcohol) or copper.
- •Treatment with the following medications that may interfere with metabolism of DSF: warfarin (unless otherwise chosen by the study PI who will actively adjust Coumadin dose to consistently maintain a safe, therapeutic international normalized ratio (INR) < 3, theophylline, amitriptyline, isoniazid, metronidazole, phenytoin, phenobarbital, chlorzoxazone, halothane, imipramine, chlordiazepoxide, diazepam. (Note: lorazepam and oxazepam are not affected by the P450 system and are not contraindicated with DSF).
- •Active severe hepatic or renal disease
- •Grade 2 or higher peripheral neuropathy or ataxia per NCI CTCAE version 4.0 (2009)
- •History of idiopathic seizure disorder schizophrenia, or psychosis unrelated to glioblastoma, corticosteroid, or anti-epileptic medications
- •History of Wilson's or Gilbert's disease
- •Current excessive use of alcohol
研究组 & 干预措施
DSF-Cu with temozolomide and radiation
Disulfiram (DSF; oral) / copper gluconate (Cu; oral) dosed at 125 mg / 2 mg, twice daily. Temozolomide will be administered following the standard Stupp protocol at a dose of 75 mg/m2 for 42 days with concurrent radiation therapy. Temozolomide maintenance dose will be 150 mg/m2 once daily on Days 1-5 of every 28-day cycle while DSF-Cu is continued twice daily, as tolerated, for the duration of the Temozolomide adjuvant treatment. Patients demonstrating continued benefit from the adjuvant temozolomide after 6 cycles can continue treatment to a maximum of 12 cycles
干预措施: Disulfiram (Drug)
DSF-Cu with temozolomide and radiation
Disulfiram (DSF; oral) / copper gluconate (Cu; oral) dosed at 125 mg / 2 mg, twice daily. Temozolomide will be administered following the standard Stupp protocol at a dose of 75 mg/m2 for 42 days with concurrent radiation therapy. Temozolomide maintenance dose will be 150 mg/m2 once daily on Days 1-5 of every 28-day cycle while DSF-Cu is continued twice daily, as tolerated, for the duration of the Temozolomide adjuvant treatment. Patients demonstrating continued benefit from the adjuvant temozolomide after 6 cycles can continue treatment to a maximum of 12 cycles
干预措施: Copper gluconate (Dietary Supplement)
DSF-Cu with temozolomide and radiation
Disulfiram (DSF; oral) / copper gluconate (Cu; oral) dosed at 125 mg / 2 mg, twice daily. Temozolomide will be administered following the standard Stupp protocol at a dose of 75 mg/m2 for 42 days with concurrent radiation therapy. Temozolomide maintenance dose will be 150 mg/m2 once daily on Days 1-5 of every 28-day cycle while DSF-Cu is continued twice daily, as tolerated, for the duration of the Temozolomide adjuvant treatment. Patients demonstrating continued benefit from the adjuvant temozolomide after 6 cycles can continue treatment to a maximum of 12 cycles
干预措施: Temozolomide (Drug)
结局指标
主要结局
6 Months Progression Free Survival (PFS)
时间窗: 6 months
To determine 6 month PFS of patients with unmethylated glioblastoma treated with DSF-Cu in combination with concurrent radiation and temozolomide. This was assessed by the number of participants who did not have disease progression and were alive at 6 months.
Overall Survival
时间窗: 1 and 2 years
Overall Survival will be assessed as a number of participants alive at 1 and 2 years.
次要结局
- Quality of Life (QOL)(1 year)