Dihydropyrimidine Dehydrogenase (DPD) Phenotype-guided Dose Individualization of Fluoropyrimidine-based Chemotherapy in DPD Deficient Patients With Gastrointestinal Cancers
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- UNICANCER
- 入组人数
- 400
- 试验地点
- 79
- 主要终点
- Proportion of fluoropyrimidine-induced grade ≥ 3 haematological and gastrointestinal toxicity after 2 cycles
研究概览
简要总结
The goal of this clinical trial is to establish guidelines for fluoropyrimidine dose reduction according to uracilemia in patients with DPD deficiency in the treatment of digestive cancers. The main question it aims to answer is:
- Which reduction dose of fluoropyrimidine is needed for patient with DPD deficiency?
Participants will:
- Take the treatment with the reduction of dose stated by the protocol
- Visit the clinic once every 2-3 weeks for checkups and tests for collection of adverse events
详细描述
Multicenter phase II trial evaluating different strategies of pre-specified fluoropyrimidine-dose adjustment according to [U] in DPD-deficient patients with gastrointestinal cancer.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65+ years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients with pre-treatment screening based on [U] value according to INCa/HAS recommendations.
- •Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2
- •Fluoropyrimidine-naïve patients with gastrointestinal cancer starting chemotherapy combining fluoropyrimidine (5-FU or capecitabine) and oxaliplatin whatever the context (adjuvant, neoadjuvant, palliative) including the following regimens (the most frequently prescribed in gastrointestinal cancers):
- •biweekly 5-FU and oxaliplatin (FOLFOX) +/- targeted therapy (TT)
- •three-weekly capecitabine and oxaliplatin (CAPOX) +/- TT
- •Age ≥ 18 years
- •Patients eligible for full standard fluoropyrimidine and oxaliplatin doses regardless of DPD deficiency
- •Adequate bone marrow function (cell blood count (CBC)), estimated glomerular filtration rate (DFG) ≥ 50 ml/min, alkaline phosphatase (ALP) / aspartate aminotransferase (ASAT) / alanine aminotransferase (ALAT) ≤ 5 upper limit of normal (ULN), and bilirubin ≤ 50 micromol/L
- •Patient must have signed and dated a written informed consent form prior to any trial specific procedures. When the patient is physically unable to give their written consent, a trusted person of their choice, independent from the investigator or the sponsor, can confirm in writing the patient's consent.
- •Women of childbearing potential must have a negative serum or urine pregnancy test.
- •Patients must agree to remain abstinent or use contraceptive methods with a failure rate of < 1% per year for the duration of study treatment and within 6 months after completing treatment.
- •Patients must be affiliated to a Social Security System (or equivalent).
- •Patient is willing and able to comply with the protocol for the duration of the trial including undergoing treatment and scheduled visits, and examinations including follow-up.
排除标准
- •Patients with complete DPD deficiency based on [U] ≥150 ng/mL
- •Any prior treatment including a fluoropyrimidine
- •Patients with any contraindication to treatment with fluoropyrimidine or oxaliplatin regardless of DPD deficiency
- •Patients not eligible for full standard dose fluoropyrimidine and oxaliplatin for clinical reasons including older age and/or comorbidity regardless of a DPD deficiency
- •Patients unwilling or unable to comply with trial obligations for geographic, social, or physical reasons, or who are unable to understand the purpose and procedures of the trial
- •Recent or concomitant treatment with brivudine
- •Pregnant or breastfeeding woman.
- •Participation in another therapeutic trial within 30 days prior to inclusion.
- •Persons deprived of their liberty or under protective custody or guardianship.
研究组 & 干预措施
Uracilemia <16
Patient with uracilemia <16 ng/mL will receive a full standard fluoropyrimidine dose
干预措施: FOLFOX regimen (Drug)
Uracilemia <16
Patient with uracilemia <16 ng/mL will receive a full standard fluoropyrimidine dose
干预措施: CAPOX regimen (Drug)
Uracilemia [16-20[
Patients with uracilemia between [16-20[ ng/mL will receive a full standard fluoropyrimidine dose -dose
干预措施: FOLFOX regimen (Drug)
Uracilemia [16-20[
Patients with uracilemia between [16-20[ ng/mL will receive a full standard fluoropyrimidine dose -dose
干预措施: CAPOX regimen (Drug)
Uracilemia [20-50[ - 25%
Patients with uracilemia between [20-50[ ng/mL will be randomized to receive a 25% fluoropyrimidine dose reduction
干预措施: FOLFOX regimen (Drug)
Uracilemia [20-50[ - 25%
Patients with uracilemia between [20-50[ ng/mL will be randomized to receive a 25% fluoropyrimidine dose reduction
干预措施: CAPOX regimen (Drug)
Uracilemia [20-50[ - 50%
Patients with uracilemia between [20-50[ ng/mL will be randomized to receive a 50% fluoropyrimidine dose reduction
干预措施: FOLFOX regimen (Drug)
Uracilemia [20-50[ - 50%
Patients with uracilemia between [20-50[ ng/mL will be randomized to receive a 50% fluoropyrimidine dose reduction
干预措施: CAPOX regimen (Drug)
Uracilemia [50-100[
Patients with uracilemia between [50-100[ ng/mL will receive a 50% fluoropyrimidine dose reduction
干预措施: FOLFOX regimen (Drug)
Uracilemia [50-100[
Patients with uracilemia between [50-100[ ng/mL will receive a 50% fluoropyrimidine dose reduction
干预措施: CAPOX regimen (Drug)
Uracilemia [100-150[
Patients with uracilemia between [100-150[ ng/mL will receive a 75% fluoropyrimidine dose reduction
干预措施: FOLFOX regimen (Drug)
Uracilemia [100-150[
Patients with uracilemia between [100-150[ ng/mL will receive a 75% fluoropyrimidine dose reduction
干预措施: CAPOX regimen (Drug)
结局指标
主要结局
Proportion of fluoropyrimidine-induced grade ≥ 3 haematological and gastrointestinal toxicity after 2 cycles
时间窗: Throughout the two first cycles of treatment, up to 42 days
The National Cancer Institute-Common Terminology Criteria for Adverse Events version 5 (NCI-CTCAE v5) is widely accepted in the community of oncology research as the leading rating scale for adverse events. This scale, divided into 5 grades (1 = "mild", 2 = "moderate", 3 = "severe", 4 = "life-threatening", and 5 = "death") determined by the investigator, will make it possible to assess the severity of the disorders.
Proportion of FP-induced grade ≥ 3 haematological and gastrointestinal toxicity after 2 cycles (4 weeks for FOLFOX +/- TT or 6 weeks for 2 CAPOX +/- TT) according to the National Cancer Institute - common terminology criteria for adverse events (NCI CTCAE) version 5.0 in patients treated for a GI cancer in the (neo-)adjuvant or the metastatic setting.
Proportion of FP-induced grade ≥ 3 haematological and gastrointestinal toxicity after 2 cycles (4 weeks for FOLFOX +/- TT or 6 weeks for 2 CAPOX +/- TT) according to the National Cancer Institute - common terminology criteria for adverse events (NCI CTCAE) version 5.0 in patients treated for a GI cancer in the (neo-)adjuvant or the metastatic setting.
次要结局
- Recommended fluoropyrimidine dose(Throughout the four first cycles of treatment, up to 3 months)
- Description of fluoropyrimidine dose(Throughout the four first cycles of treatment, up to 3 months)
- Percentage of fluoropyrimidine dose modification(Throughout the four first cycles of treatment, up to 3 months)
- Fluoropyrimidine toxicity during the study(Throughout the four first cycles of treatment, up to 3 months)
- Disease-free survival (DFS) - Stage III Colon Cancer(3 years)
- Overall survival (OS) - Stage III Colon Cancer(From randomization to death from any cause, up to 3 years.)
- Progression-free survival (PFS) - Stage IV Colon Cancer(From randomization to disease progression or death, up to 1 year.)
- The recommended FP dose will be estimated by comparing the rate of FP-induced grade ≥ 3 haematological and gastrointestinal toxicity in each [U]-based group of DPD-deficient patients (according to [U] level) to the one observed in non DPD-deficient patients (control arm) during the first 4 cycles of chemotherapy
- Description of FP doses administered during the first 4 chemotherapy cycles in all patients, along with reasons of dose-modifications or treatment discontinuation for limiting toxicity
- Percentage of patients in whom FP dose is increased or decreased during the first 4 cycles of chemotherapy
- All grade FP-induced toxicities at each cycle 1 to 4, related (neutropenia, febrile neutropenia, anemia, thrombocytopenia, diarrhea, mucositis) or not including (hand-foot syndrome, central neurotoxicity, cardiotoxicity) to DPD-deficiency (NCI CTC-AE). All other FP induced toxicity related or not will be also described.
- Treatment efficacy will be evaluate in terms of: o DFS defined as the time from surgery to disease recurrence (radiological or clinical) in the subgroup of patients with stage III colon cancer and especially the 3-year DFS.
- Treatment efficacy will be evaluate in terms of: o OS defined as the time from surgery until death from any cause in the subgroup of patients with stage III colon cancer
- Treatment efficacy will be evaluate in terms of: o PFS defined as the time from inclusion to disease progression (radiological or clinical) or death of any cause, whichever occurs first, in the subgroup of patients with stage IV colorectal cancer