A Phase 1-2 Study of 6-Thioguanine in Combination With Methotrexate and 6-Mercaptopurine During Maintenance Therapy of Childhood Non-Hodgkin's Lymphoma
试验速览
- 阶段
- 1 期
- 状态
- 撤回
- 发起方
- 试验地点
- 1
- 主要终点
- Change in median thiopurine metabolite index
研究概览
简要总结
The purpose of this phase 1-2 study is to explore the applicability of supplementing standard methotrexate/6-mercaptopurine (MTX/6MP) maintenance therapy of children with non-Hodgkin lymphoma with 6-thioguanine (6TG).
The investigators hypothesize that addition of 6TG to 6MP-based maintenance therapy of patients with high TPMT activity will mimic the more favourable thiopurine metabolism of patients with low TPMT activity and ultimately reduce relapse rates.
详细描述
MTX/6MP maintenance therapy is challenged by treatment related liver toxicity, failure to achieve the target treatment parameter in all patients, and lack of direct parameters for monitoring treatment efficacy or even intensity. Patients with low activity of thiopurine methyltransferase (TPMT), an enzyme involved in the metabolism of 6MP, have lower levels of liver toxic metabolites (MeMPs), higher levels of the major active metabolites (TGNs), and reduced relapse rates. Most patients (90%) have high TPMT activity. Nearly all patients with high TPMT activity and high MeMP levels experience elevated liver enzymes. Increasing the 6MP dose in patients with high TPMT activity, to intensify therapy, will mainly lead to further increase in the MeMP level. A novel approach compensating the adverse thiopurine metabolism of the majority of patients is warranted.
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
- 2 Years 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Confirmed histomorphological or cytomorphological diagnosis of NHL or ALL.
- •Meets just one of the following:
- •Patient with NHL treated after the EURO-LB 02 protocol with at least 3.5 months of 6MP/MTX maintenance therapy remaining or
- •Patient with ALL or NHL not achieving the target WBC (patients with a WBC > 3.0 x10^9/L) and/or experience elevated liver enzymes (ALAT > UNL) attributed to a simultaneous high Ery-MeMP level on standard MTX/6MP maintenance therapy.
- •TPMT wild-type genotype or TPMT high activity phenotype (TPMT activity above 14 IU/mL or during maintenance therapy TPMT above 8 IU/mL measured in erythrocytes).
- •Bilirubin < 35 micromol/L, factor 2-7-10 > 0.5 or INR < 1.5 and normal hepatic blood flow (verified by ultrasound) within 1 week prior to inclusion.
- •WBC > 1.5 x10^9/L, ANC > 0.5 x10^9/L and TBC > 50 x10^9/L within 1 week prior to inclusion.
- •Pubertal females, Tanner stage B3/PH3 or higher, must present with a negative pregnancy test.
- •Sexually active females must use accepted safe contraception (OCPs, IUD, transdermal hormonal patch, vaginal hormonal ring or subdermal hormonal implants) during therapy and until a month after completion of therapy.
- •Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
- •Oral and written informed consent to participate have been provided by both the parents (and when appropriate by the patient) according to the ICH/GCP guidelines and the Helsinki II Declaration.
- •Patients with acute lymphoblastic lymphoma (0-17.9 yrs) not achieving the target WBC (patients with a WBC > 3.0 x10^9/L) and/or experience elevated liver enzymes (ALAT > UNL) attributed to a simultaneous high Ery-MeMP level on standard MTX/6MP maintenance therapy.
排除标准
- •Any clinical suspicion of relapse or disease progression on routine imaging or in laboratory results.
- •Previous veno-occlusive disease (VOD).
- •Allergy towards any of the ingredients in the three medicinal products used in the study.
研究组 & 干预措施
6-thioguanine, 6-mercaptopurine and methotrexate
This is the only treatment arm; all eligible patients will receive standard methotrexate/6-mercaptopurine (6MP/MTX) maintenance therapy supplemented with 6-thioguanine (6TG).
Patients are enrolled when they have 12 to 3.5 months remaining of their maintenance therapy. After dose reduction in 6MP to 2/3 of the current dose 6TG therapy is initiated with a starting dose of 2.5 mg/m2/day. The 6TG dose will hereafter be increased at 2.5 mg/m2/day every 14 days until a max. of 12.5 mg/m2/day is reached or until the thiopurine metabolite profile (Ery-TGN/Ery-MeMP) has been increased by at least a factor 5.
干预措施: 6-thioguanine (Drug)
结局指标
主要结局
Change in median thiopurine metabolite index
时间窗: Every 2 weeks up to the max. trial period of 12 months
Change in Ery-TGN/Ery-MeMP after addition of 6-thioguanine to therapy. The thiopurine metabolites will be measured every 2 weeks during the trial period. The trial period is max. 12 months.
次要结局
- Change in median DNA-TG(Every 2 weeks, up to 12 months)
- Toxicities(Minimum every 2 weeks, up to 12 months)
研究者
Kjeld Schmiegelow
MD, DMSc
Rigshospitalet, Denmark