Improving the Safety of Fluoropyrimidine-based Chemotherapy by Combined DPYD Genotype-guided and DPD Phenotype-guided Dose Individualization: The ALPE2U Study
试验速览
- 阶段
- 不适用
- 入组人数
- 1,440
- 试验地点
- 1
- 主要终点
- Safety: incidence of severe fluoropyrimidine-related toxicity (CTCAE grade 3 to 5) in wild type patients
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 phenotypic assessment of dihydropyrimidine dehydrogenase (DPD) deficiency.
详细描述
In this study a phenotypic approach will be studied to determine the additional value of pretreatment uracil level-guided dose individualization in wildtype patients. Patients with a pretreatment serum uracil concentration above 16 ng/ml will be treated with a 50% reduced fluoropyrimidine starting dose. The pretreatment serum uracil levels in DPYD variant carriers will be assessed retrospectively and non-interventional. Additionally, the effect of a higher dose reduction in c.1236G>A and c.2846A>T DPYD variants carriers (50% instead of 25%) will be studied.
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
- •Patient need to be of Western descent
- •Able and willing to give written informed consent
- •WHO performance status of 0, 1 or 2
- •Able and willing to undergo extra blood sampling for study related analysis
- •Adequate baseline patient characteristics, in the opinion of the treating physician (complete blood count, hepatic function which involves serum bilirubin, AST, ALT, and renal function)
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 in the opinion of the treating physician
- •Patients treated with the combination of a fluoropyrimidine and irinotecan
研究组 & 干预措施
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)
heterozygous carrier of c.1236G>A or c.2846A>T 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 c.1236G>A or c.2846A>T of these SNPs
干预措施: Fluoropyrimidine (capecitabine or 5-fluorouracil) (Drug)
Homozygous or compound heterozygous carrier of DPYD variants
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 homozygous or compound heterozygous 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 fluoropyrimidine-related toxicity (CTCAE grade 3 to 5) in wild type patients
时间窗: Patients with a pre-treatment uracil concentration above 16 ng/ml will be followed until end of treatment (expected average of 1 year). Otherwise, patients will be followed for the first 2 cycles (each cycle is 28 days).
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)
- Safety: incidence of severe treatment-related toxicity (CTCAE grade 3 to 5) in heterozygous carriers of c.1236G>A or c.2846A>T DPYD variants(Patients will be followed during fluoropyrimidine treatment, expected average of 1 year)
- Assessment of pharmacokinetics: Such profile parameters will include Cmax, Tmax, AUC and elimination half-life(During the first administration of fluoropyrimidine treatment)
- Assessment of feasibility of dose titration following an initial dose reduction(During fluoropyrimidine treatment, expected average of 1 year)
- Assessment of geriatric parameters for grade 3-5 toxicity and/or treatment discontinuation(During fluoropyrimidine treatment, expected average of 1 year)