DIRECT (DIsulfiram REsponse as add-on to ChemoTherapy in Recurrent) Glioblastoma: A Randomized Controlled Trial
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 88
- 试验地点
- 8
- 主要终点
- Survival 6 mo
研究概览
简要总结
Disulfiram (Antabuse®) is a well-tolerated, cheap, generic drug that has been in use since the 1950s to treat alcoholism. There is now an increasing amount of independent preclinical data to support disulfiram as an anticancer agent. The potency of disulfiram as an anticancer agent seems strengthened by copper.
The investigators aim is to investigate disulfiram and copper-supplement as add-on treatment in glioblastoma patients with recurrence receiving alkylating chemotherapy.
详细描述
Disulfiram (Antabuse®) is a well-tolerated, cheap, generic drug that has been in use since the 1950s to treat alcoholism. There is now an increasing amount of independent preclinical data to support disulfiram as an anticancer agent. The potency of disulfiram as an anticancer agent seems strengthened by copper. There is now anecdotal clinical evidence of disulfiram as an anticancer agent. So far no clinical studies have been published in glioma patients, but two small, uncontrolled studies are planned according to clinicaltrials.gov. with search 1st November 2015.
The investigators aim to investigate disulfiram and copper-supplement as add-on treatment in glioblastoma patients with recurrence receiving alkylating chemotherapy. The study will be performed as a multicenter RCT including patients in Norway and Sweden. This will serve as a proof-of concept study.
The primary end-point is survival at 6 months
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
- Single (Outcomes Assessor)
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
- •A previous diagnosis of glioblastoma (histologically verified) and presenting with a first progression/recurrence documented by MRI.
- •Indication for treatment with chemotherapeutic alkylating agents (i.e. temozolomide OR lomustine including PCV treatment).
- •Age 18 years or older.
- •Karnofsky performance status of 60 - 100 .
- •Not receiving another experimental treatment for glioblastoma at the moment of inclusion or during active treatment within the assigned group (i.e. control or disulfiram group).
- •Able to take oral medications.
- •No known allergy to disulfiram or copper.
- •Absolute neutrophil count ≥ 1,500/mcL and platelets ≥ 100,000/mcL
- •Serum/plasma copper and serum ceruloplasmin within institutional limits.
- •a. However increased levels are seen together with ongoing acute phase reaction as determined by elevated C-reactive protein (ceruloplasmin is elevated as part of the same process) it is possible to retest after normalization of C-reactive protein.
- •Willing to refrain from ingestion of alcoholic beverages while on the study is a criteria to be randomized. However, once randomized alcohol abstinence only affects the group treated with disulfiram, and in this group it includes the entire period and one month after last dosage of disulfiram.
排除标准
- •Earlier treatment for progression (e.g. "rescue therapy")
- •History of idiopathic seizure disorder, psychosis or schizophrenia.
- •History of uncontrolled hypertension (i.e. systolic BP > 180 mmHg) and a diagnosis of congestive heart failure
- •Received radiotherapy within the 3 months before the diagnosis of progression .
- •Addiction to alcohol or drugs.
- •Pregnant and/or breastfeeding.
- •Women of childbearing potential who do not have negative pregnancy test not older than 14 days before enrollment.
- •History of active liver disease, including chronic active hepatitis, viral hepatitis (hepatitis B, C and CMV), cholestatic jaundice of any etiology or toxic hepatitis or inadequate hepatic function, defined as baseline ASAT and ALAT > 2.5 X upper institutional limit and/or bilirubin > 2.0 X upper institutional limit.
- •History of Wilson's disease or family member with Wilson's disease (unless excluded as a carrier by genetic test).
- •History of hemochromatosis or family member with hemochromatosis (unless excluded as a carrier by genetic test).
- •Nickel hypersensitivity (disulfiram mobilize nickel causing a brief increase in nickel concentrations before excretion. The initial increase may lead to hepatitis and predisposed patients).
- •Need for metronidazole, warfarin and/or theophylline medication (the metabolism may be influenced by disulfiram).
- •Patients who are taking medications metabolized by cytochrome P450 2E1, including chlorzoxazone or halothane and its derivatives (phenytoin, phenobarbital, chlordiazepoxide, imipramine, diazepam, isoniazid, metronidazole, warfarin, amitriptyline within 14 days prior to the first dose of disulfiram. Of note, lorazepam and oxazepam are not affected by the P450 system and are not contraindicated with disulfiram).
- •Unfit for participation for any other reason judged by the including physician.
研究组 & 干预措施
Control
Alkylating chemotherapy
干预措施: Alkylating Agents (Drug)
Experimental
Alkylating chemotherapy + disulfiram + copper
干预措施: Disulfiram (Drug)
Experimental
Alkylating chemotherapy + disulfiram + copper
干预措施: Copper (Dietary Supplement)
Experimental
Alkylating chemotherapy + disulfiram + copper
干预措施: Alkylating Agents (Drug)
结局指标
主要结局
Survival 6 mo
时间窗: Proportion of alive participants at 6 months
次要结局
- Number of participants with treatment-related adverse events as assessed by CTCAE v4.0(Assessed month 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 18, 21, 24, but analyzed as cumulative burden at 6 and 24 months)
- Health related quality of life(Assessed at baseline and month 3, 6, 9, 12, 15, 18, 21, 24)
- Median overall survival(Median overall survival assessed at 6 months and 24 months after last included participant)
- Survival 12 and 24 mo(Proportion of alive participants at 12 and 24 months)
- Volumetric tumor assessment(Baseline and first follow-up scan being scheduled at 3 months post-inclusion)
- Progression free survival(Proportion without progression at 6 and 12 months)
研究者
Asgeir S. Jakola
MD, PhD
Sahlgrenska University Hospital, Sweden