Safety of Trifluridine/Tipiracil in Patients With Dihydropyrimidine Dehydrogenase Deficiency Diagnosed With Metastatic Colorectal or Gastroesophageal Cancer

NCT06245356 | Recruiting Phase 2

• 1 other identifier: PRODIGE 91 - UCGI 46
• Study Type: interventional
• Target: 73
• Locations: 1 country
• Sites: 21

Brief Summary

The goal of this clinical trial is to test the safety of the trifluridine/tipiracil as replacement of fluoropyrimidines based chemotherapy as first line metastatic colorectal or gastroesophageal cancer regimens in patients with dihydropyrimidine dehydrogenase (DPD) deficiency. The main questions it aims to answer are:

• Is this alternative chemotherapy option a better option in term of safety for this type of patients?
• Does the combination of treatments improves the overall safety?
• Does the combination of treatments improves the progression-free survival, overall survival, objective response rate and disease control rate?
• Does the combination of treatment have an effect on quality of life? Participants will:
• Receive the trifluridine/tipiracil with oxaliplatin every 14 days, associated with:
• Panitumumab or bevacizumab for colorectal adenocarcinomas
• Nivolumab or trastuzumab for gastroesophageal adenocarcinomas.
• Have a CT-Scan every 2 months until disease progression
• Complete Health-related quality of life questionnaire every 2 months for a maximum of 6 months
• Participate to the optional translational research: Blood samples fo DPYD genotyping and pharmacokinetic analysis

Conditions

Metastatic Colorectal Cancer; Metastatic Gastroesophageal Adenocarcinoma; DPD Deficiency

Keywords

Metastatic colorectal cancer; Metastatic Gastroesophageal Adenocarcinoma; DPD Deficiency; Trifluridine/Tipiracil

Outcome Measures

Primary Outcomes (1)

• Treatment specific safety

  The percentage of patients without specific toxicities defined as grade 3-4-5 digestive toxicities (diarrhoea and/or stomatitis) and grade 4-5 neutropenia or febrile neutropenia over the first 2 cycles of first-line metastatic treatment. Toxicities will be graded using the National Cancer Institute-Common Terminology Criteria for Adverse Events version 5 (NCI-CTCAE v5), 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.

  1 month

Secondary Outcomes (9)

• Overall Safety

  Throughout study completion, up to 2 years

• Compliance with study treatment

  1 month

• Progression Free Survival

  From baseline until disease progression or death, up to 2 years

• Overall Survival

  From baseline until disease progression or death, up to 2 years

• Objective response rate

  From baseline until disease progression, up to 2 years

Study Arms (2)

Colorectal adenocarcinoma

OTHER

Trifluridine/tipiracil in association with oxaliplatin with or without: * Panitumumab in RAS wild type tumors * Bevacizumab in RAS wild type of right colon or RAS mutated tumors

Drug: Lonsurf; Drug: Oxaliplatin; Drug: Panitumumab; Drug: Bevacizumab

Gastroesophageal adenocarcinoma

OTHER

Trifluridine/tipiracil in association with oxaliplatin with or without: * Trastuzumab in HER2-positive tumors (3+ IHC or 2+/FISH+) * Nivolumab if CPS≥5 and HER2-negative tumors

Drug: Lonsurf; Drug: Oxaliplatin; Drug: Trastuzumab; Drug: Nivolumab

Interventions

Lonsurf DRUG

Trifluridine/tipiracil orally 35 mg/m²/dose (D1-D5 twice daily, D1=D15)

Colorectal adenocarcinoma; Gastroesophageal adenocarcinoma

Oxaliplatin DRUG

Oxaliplatin intravenous injection 85 mg/m² every 2 weeks (D1=D15)

Colorectal adenocarcinoma; Gastroesophageal adenocarcinoma

Panitumumab DRUG

Panitumumab intravenous injection 6 mg/kg (D1=D15)

Colorectal adenocarcinoma

Bevacizumab DRUG

Bevacizumab intravenous injection 5 mg/kg (D1=D15)

Colorectal adenocarcinoma

Trastuzumab DRUG

Trastuzumab intravenous injection 4 mg/kg (D1=D15)

Gastroesophageal adenocarcinoma

Nivolumab DRUG

Nivolumab intravenous injection 240 mg (D1=D15)

Gastroesophageal adenocarcinoma

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• Histological or cytological documentation of adenocarcinoma of the colon or rectum or gastroesophageal cancer (lower oesophagus, gastroesophageal junction and gastric)
• Synchronous or metachronous metastatic colorectal or gastroesophageal cancer
• Presence of at least one measurable lesion according to RECIST v1.1
• No prior therapy for metastatic disease
• known DPD deficiency defined as plasma uracil concentration≥16 ng/ml For plasma uracil concentration \[16-20\[ ng/ml, plasma uracil dosage must be repeated in the 7 days to confirm that plasma uracil concentration ≥16 ng/ml. If the second result is different (i.e; uracil concentration \<16 ng/ml), keep the favourable result, and do not include the patient if only the first plasma uracil concentration≥16 ng/ml.
• Age ≥18 years
• Eastern Cooperative Oncology Group (ECOG) performance status ≤1
• Adequate bone marrow, renal and liver functions as evidenced by the following laboratory requirements within 7 days prior to study treatment initiation:
• Absolute neutrophil count (ANC) ≥ 1,500/ mm³ without biologic response modifiers such as granulocyte colony-stimulating factor (G-CSF), within 21 days before the start of study treatment
• Platelet count ≥100,000/mm³, without platelet transfusion within 21 days before the start of study treatment
• Hemoglobin (Hb) ≥9 g/dL, without blood transfusion or erythropoietin within 21 days before the start of study treatment
• Serum creatinine ≤1.5 x upper limit of normal (ULN)
• Glomerular filtration rate as assessed by the estimated glomerular filtration rate (eGFR) ≥50 mL/min per 1.73 m² calculated by the Modification of Diet in Renal Disease (MDRD) abbreviated formula
• Total bilirubin ≤ 1.5 x ULN

You may not qualify if:

• Radiotherapy within 28 days prior to first dose of treatment
• Active cardiac disease including any of the following:
• Symptomatic Congestive heart failure ≥New York Heart Association (NYHA) class 3 or 4
• Severe Unstable angina (angina symptoms at rest)
• Myocardial infarction less than 12 months before first dose of treatment
• Uncontrolled hypertension (Systolic blood pressure ≥140 mmHg or diastolic pressure ≥ 90 mmHg) despite optimal medical management.
• Ongoing infection ≥Grade 2 (NCI CTCAE v.5.0)
• Known history of human immunodeficiency virus (HIV) infection
• Chronic hepatitis B or C infection (if hepatitis status cannot be obtained from medical records, re-testing is required)
• Seizure disorder requiring medication
• Symptomatic metastatic brain or meningeal tumours
• History of organ allograft
• Known hypersensitivity to any of the study drugs, study drug classes, or any constituent of the products
• In case of planned treatment with oxaliplatin: Peripheral neuropathy \>Grade 1 (NCI CTCAE v.5.0)
• In case of planned treatment with bevacizumab: Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to first dose of treatment

Sponsors & Collaborators

• UNICANCER: lead
• Servier: collaborator

Study Sites (21)

CHU Amiens

Amiens, 80054, France

NOT YET RECRUITING

Institut de Cancérologie de l'Ouest

Angers, 49055, France

NOT YET RECRUITING

Institut du Cancer d'Avignon

Avignon, 84918, France

ACTIVE NOT RECRUITING

CHU Jean Minjoz

Besançon, 25000, France

ACTIVE NOT RECRUITING

Centre Hospitalier de Cholet

Cholet, 49300, France

ACTIVE NOT RECRUITING

Centre Georges François Leclerc

Dijon, 21079, France

WITHDRAWN

Hôpital Privé Jean Mermoz

Lyon, 69008, France

ACTIVE NOT RECRUITING

Institut Régional du Cancer de Montpellier - ICM Val d'Aurelle

Montpellier, 34298, France

RECRUITING

Hôpital Saint Louis

Paris, 75010, France

ACTIVE NOT RECRUITING

Hôpital Saint Antoine

Paris, 75012, France

RECRUITING

Hôpital Cochin

Paris, 75014, France

ACTIVE NOT RECRUITING

Hôpital des Diaconesses Croix Saint Simon

Paris, 75960, France

ACTIVE NOT RECRUITING

Hospices Civils de Lyon

Pierre-Bénite, 69495, France

ACTIVE NOT RECRUITING

CHU de Poitiers

Poitiers, 86000, France

ACTIVE NOT RECRUITING

CHU de REIMS

Reims, 51092, France

ACTIVE NOT RECRUITING

Institut Godinot

Reims, 51100, France

RECRUITING

Institut de Cancérologie de l'Ouest - Site René Gauducheau

Saint-Herblain, France

WITHDRAWN

CHU Saint-Etienne

Saint-Priest-en-Jarez, 42270, France

ACTIVE NOT RECRUITING

CH de Saint-Malo

St-Malo, 35403, France

ACTIVE NOT RECRUITING

Hôpital Nord Franche-Comté / Site du Mittan

Trévenans, 90400, France

ACTIVE NOT RECRUITING

Institut de Cancérologie de Lorraine

Vandœuvre-lès-Nancy, 54519, France

ACTIVE NOT RECRUITING

MeSH Terms

Conditions

Colorectal Neoplasms; Dihydropyrimidine Dehydrogenase Deficiency

Interventions

trifluridine tipiracil drug combination; Oxaliplatin; Panitumumab; Bevacizumab; Trastuzumab; Nivolumab

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Purine-Pyrimidine Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Coordination Complexes; Organic Chemicals; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Emmanuelle SAMALIN, MD

  Institut du Cancer de Montepllier

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Emilie BRUMENT

CONTACT

+33(0)6 68 32 03 59; e-brument@unicancer.fr

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 29, 2024
• First Posted: February 7, 2024
• Study Start: March 21, 2025
• Primary Completion (Estimated): October 22, 2026
• Study Completion (Estimated): October 21, 2028
• Last Updated: December 10, 2025

Record last verified: 2025-12

Locations

FR (21)