Safety, Feasibility and Cost-effectiveness of Genotype-directed Individualized Dosing of Fluoropyrimidines
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 1,103
- 试验地点
- 17
- 主要终点
- Safety: incidence of severe treatment-related toxicity (CTC grade 3 to 5)
研究概览
简要总结
In this study it will be determined whether the rate of severe toxicity associated with fluoropyrimidine treatment (capecitabine or 5-fluorouracil) can be significantly diminished by individualized dosing of fluoropyrimidines based on upfront genotypic assessment of dihydropyrimidine dehydrogenase (DPD) deficiency.
In addition to the genotyping, the DPD phenotype of all patients will be determined by measuring the baseline dihydrouracil/uracil (DHU/U) ratio, in order to investigate whether phenotype-guided treatment can further improve patient safety. In a subgroup of patients, other phenotyping methods will be tested: measuring the plasma levels of uracil after a uracil test dose and a uracil breath test after a dose of [2-13C] -labeled uracil. To validate these tests, these phenotyping results will be compared with the results of a DPD activity assay (which measures DPD enzyme activity in peripheral blood mononuclear cells), which is considered the gold standard in measuring DPD phenotype.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 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
- •Pathologically confirmed malignancy for which treatment with a fluoropyrimidine is considered to be in the patient's best interest
- •Age ≥ 18 years
- •Able and willing to give written informed consent
- •WHO performance status of 0, 1 or 2
- •Life expectancy of at least 12 weeks
- •Able to swallow and retain oral medication
- •Able and willing to undergo blood sampling for pharmacogenetic and phenotyping analysis
- •Minimal acceptable safety laboratory values (ANC, platelet count, hepatic function, renal function)
- •Additional inclusion criteria for patients in subgroup of study:
- •Able and willing to undergo blood sampling and breath sampling at several time points
- •Able and willing to receive uracil for the test dose assay
- •Able and willing to receive [2-13C] -labeled uracil for the breath test
排除标准
- •Prior treatment with fluoropyrimidines
- •Patients with known substance abuse, psychotic disorders, and/or other diseases expected to interfere with study or the patient's safety
- •Women who are pregnant or breast feeding
- •Both men and women who refuse to use reliable contraceptive methods throughout the study (adequate contraceptive methods are: condom, sterilization, other barrier contraceptive measures preferably in combination with condoms)
- •Patients with a homozygous polymorphic genotype or compound heterozygous genotype for DPYD
研究组 & 干预措施
heterozygous carrier of DPYD variant
Patients screened for four single nucleotide polymorphisms (SNPs) in DPYD (DPYD*2A, c.2846A>T, c.1236G>A/HapB3 and DPYD*13) that are found to be heterozygous for one of these SNPs
干预措施: Fluoropyrimidine (capecitabine or 5-fluorouracil) (Drug)
wild type for DPYD
Patients screened for four single nucleotide polymorphisms (SNPs) in DPYD (DPYD*2A, c.2846A>T, c.1236G>A/HapB3 and DPYD*13) that are found to be wild type for these SNPs
干预措施: Fluoropyrimidine (capecitabine or 5-fluorouracil) (Drug)
结局指标
主要结局
Safety: incidence of severe treatment-related toxicity (CTC grade 3 to 5)
时间窗: patients will be followed during fluoropyrimidine treatment, expected average of 1 year
The incidence of severe treatment-related toxicity (CTC grade 3 to 5) in patients carrying DPYD variants compared to wild type patients and compared to a historical cohort of DPYD heterozygous patients treated with a full dose of fluoropyrimidines
次要结局
- Cost-effectiveness: medical costs that are made during fluoropyrimidine treatment seen from a health care perspective(patients will be followed during fluoropyrimidine treatment, expected average of 1 year)
- DPD phenotype, defined as deficient or not deficient(Prior to start of fluoropyrimidine treatment of the patient (pre dose))
- Assessment of pharmacokinetics: Such profile parameters will include Cmax, Tmax, AUC and elimination half-life(At first week of start of fluoropyrimidine treatment of the patient)