Dose Individualization of Chemotherapy in Patients With Gastrointestinal Cancers Lacking a Specific Liver Enzyme

Official title

Dihydropyrimidine Dehydrogenase (DPD) Phenotype-guided Dose Individualization of Fluoropyrimidine-based Chemotherapy in DPD Deficient Patients With Gastrointestinal Cancers

Overview

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

Detailed description

Multicenter phase II trial evaluating different strategies of pre-specified fluoropyrimidine-dose adjustment according to \[U\] in DPD-deficient patients with gastrointestinal cancer.

Interventions

• Drug FOLFOX regimen
  Oxaliplatin will be administered at a fixed dose of 85 mg/m² by 2h intravenous (IV) infusion concurrently with folinic acid 400 mg/m² (or 200 mg/m² if L-folinic acid) as a 2 h IV infusion on day 1 of each 14-day cycle followed by 5-fluorouracil (5-FU) 400 mg/m² IV bolus on day 1, then continuous IV infusion of 1,200 mg/m² /day × 2 days (total 2400 mg/m² for 46-48 hours)
• Drug CAPOX regimen
  Oxaliplatin will be administered at a fixed dose of 130 mg/m² by 2h IV infusion on day 1 of each 21-day cycle followed by capecitabine (1000 mg/m²) twice a day (BID) during 2 weeks, every 3 weeks

Primary outcome measures

• Proportion of fluoropyrimidine-induced grade ≥ 3 haematological and gastrointestinal toxicity after 2 cycles [Time frame: Throughout the two first cycles of treatment, up to 42 days]

Secondary outcome measures (7)

• Recommended fluoropyrimidine dose [Time frame: Throughout the four first cycles of treatment, up to 3 months]
• Description of fluoropyrimidine dose [Time frame: Throughout the four first cycles of treatment, up to 3 months]
• Percentage of fluoropyrimidine dose modification [Time frame: Throughout the four first cycles of treatment, up to 3 months]
• Fluoropyrimidine toxicity during the study [Time frame: Throughout the four first cycles of treatment, up to 3 months]
• Disease-free survival (DFS) - Stage III Colon Cancer [Time frame: 3 years]
• Overall survival (OS) - Stage III Colon Cancer [Time frame: From randomization to death from any cause, up to 3 years.]
• Progression-free survival (PFS) - Stage IV Colon Cancer [Time frame: From randomization to disease progression or death, up to 1 year.]

Eligibility criteria

Inclusion criteria

• 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.

Exclusion criteria

• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

France · 41 centers

• CHU Amiens — Amiens
• Hopital Henri Mondor — Aurillac
• Institut du Cancer Avignon Provence — Avignon
• CH Aunay Bayeux — Bayeux
• CH Cote Basque — Bayonne
• CHU Besançon — Besançon
• Centre François Baclesse — Caen
• Polyclinique du Parc - Centre d'Oncologie Maurice Tubiana — Caen
• … and 33 more centers

Publications

• Camilleri GM, Loriot MA, Teuff GL, Thuillier F, Bouche O, Narjoz C, Abdelghani MB, Herve C, Corbinais S, Locher C, Lecomte T, Villemin M, Tougeron D, Lepage C, Peytier A, Moussaddaq AS, Dubreuil O, Mabro M, Desrame J, Carvalho NS, Boige V. Dihydropyrimidine dehydrogenase phenotype-guided dose individualization of fluoropyrimidine in gastrointestinal cancers: PRODIGE100-UCGI48-FUDOSE phase II study PMID 42173726

Identifiers

NCT: NCT06475352 · UC-GIG-2311 · 2023-509963-25-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗