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

NCT ID: NCT06245356

Last Updated: 2025-12-10

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 73 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-03-21
• Study Completion Date: 2028-10-21

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

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Colorectal adenocarcinoma

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

Group Type: OTHER

Lonsurf

Intervention Type: DRUG

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

Oxaliplatin

Intervention Type: DRUG

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

Panitumumab

Intervention Type: DRUG

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

Bevacizumab

Intervention Type: DRUG

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

Gastroesophageal adenocarcinoma

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

Group Type: OTHER

Lonsurf

Intervention Type: DRUG

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

Oxaliplatin

Intervention Type: DRUG

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

Trastuzumab

Intervention Type: DRUG

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

Nivolumab

Intervention Type: DRUG

Nivolumab intravenous injection 240 mg (D1=D15)

Interventions

Lonsurf

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

Intervention Type: DRUG

Oxaliplatin

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

Intervention Type: DRUG

Panitumumab

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

Intervention Type: DRUG

Bevacizumab

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

Intervention Type: DRUG

Trastuzumab

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

Intervention Type: DRUG

Nivolumab

Nivolumab intravenous injection 240 mg (D1=D15)

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. 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.

2. Histological or cytological documentation of adenocarcinoma of the colon or rectum or gastroesophageal cancer (lower oesophagus, gastroesophageal junction and gastric)

3. Synchronous or metachronous metastatic colorectal or gastroesophageal cancer

4. Presence of at least one measurable lesion according to RECIST v1.1

5. No prior therapy for metastatic disease

6. 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.

7. Age ≥18 years

8. Eastern Cooperative Oncology Group (ECOG) performance status ≤1

9. Adequate bone marrow, renal and liver functions as evidenced by the following laboratory requirements within 7 days prior to study treatment initiation:

1. 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

2. Platelet count ≥100,000/mm³, without platelet transfusion within 21 days before the start of study treatment

3. Hemoglobin (Hb) ≥9 g/dL, without blood transfusion or erythropoietin within 21 days before the start of study treatment

4. Serum creatinine ≤1.5 x upper limit of normal (ULN)

5. 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

6. Total bilirubin ≤ 1.5 x ULN

7. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN (≤ 5 x ULN for patients with liver involvement of their cancer)

8. Alkaline phosphatase (ALP) ≤ 2.5 x ULN (≤ 5.0 x ULN for patients with liver involvement for their cancer and/or bone metastases)

9. International normalized ratio (INR) ≤1.5 or prothrombin time (PT) ≤1.5 x ULN Note: Patients on stable dose (dose has not been changed in at least 28 days) of anticoagulation therapy will be allowed to participate if they have no sign of bleeding or clotting and INR / PT and PTT / aPTT test results are compatible with the acceptable benefit-risk ratio at the investigator's discretion. In such case, limits as noted would not apply

10. For women of reproductive potential, negative serum beta human chorionic gonadotropin (β-HCG) pregnancy test obtained within 7 days before the start of study treatment. Women not of reproductive potential are female patients who are postmenopausal or permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy)

11. For women of childbearing potential and men, agreement to use an adequate contraception for the duration of study participation and up to 7 months following completion of therapy.

12. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests and other study procedures

13. Affiliation to the Social Security System (or equivalent).

Exclusion Criteria

1. Previous or concurrent cancer that is distinct in primary site or histology from colorectal or gastroesophageal cancer within 5 years prior to study inclusion, except for curatively treated cervical cancer in situ, non-melanoma skin cancer and superficial bladder tumors [Ta (non invasive tumor), Tis (carcinoma in situ) and T1 (lamina propria invasion)]

2. Radiotherapy within 28 days prior to first dose of treatment

3. Active cardiac disease including any of the following:

1. Symptomatic Congestive heart failure ≥New York Heart Association (NYHA) class 3 or 4

2. Severe Unstable angina (angina symptoms at rest)

3. Myocardial infarction less than 12 months before first dose of treatment

4. Uncontrolled hypertension (Systolic blood pressure ≥140 mmHg or diastolic pressure ≥ 90 mmHg) despite optimal medical management.

5. Ongoing infection ≥Grade 2 (NCI CTCAE v.5.0)

6. Known history of human immunodeficiency virus (HIV) infection

7. Chronic hepatitis B or C infection (if hepatitis status cannot be obtained from medical records, re-testing is required)

8. Seizure disorder requiring medication

9. Symptomatic metastatic brain or meningeal tumours

10. History of organ allograft

11. Known hypersensitivity to any of the study drugs, study drug classes, or any constituent of the products

12. In case of planned treatment with oxaliplatin: Peripheral neuropathy >Grade 1 (NCI CTCAE v.5.0)

13. 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

14. In case of planned treatment with bevacizumab: Evidence or history of any bleeding diathesis, irrespective of severity. Any hemorrhage or bleeding event ≥CTCAE v 5.0 Grade 3 within 4 weeks prior to the start of study medication

15. In case of planned treatment with trastuzumab or panitumumab or bevacizumab: Interstitial lung disease with ongoing signs and symptoms

16. Inability to swallow oral medication

17. Any uncontrolled malabsorption condition

18. Pregnant or breast-feeding subjects. Women of childbearing potential must have a serum pregnancy test performed a maximum of 7 days before start of treatment, and a negative result must be documented before start of study drug

19. Patients unwilling or unable to comply with the medical follow-up required by the trial because of geographic, familial, social, substance abuse, medical or psychological reasons, or any condition that, in the opinion of the investigator, would interfere with the patient's participation in the study or evaluation of study treatment or interpretation of patient safety or study results

20. Participation in another clinical study with an investigational product during the last 30 days before inclusion

21. Patients who might be interconnected with or dependent on the sponsor site or the investigator

22. Persons deprived of their liberty or under protective custody or guardianship, or legal incapacity or limited legal capacity

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Servier

INDUSTRY

Sponsor Role: collaborator

UNICANCER

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Emmanuelle SAMALIN, MD

Role: PRINCIPAL_INVESTIGATOR

Institut du Cancer de Montepllier

Locations

CHU Amiens

Amiens, , France

Site Status: NOT_YET_RECRUITING

Institut de Cancérologie de l'Ouest

Angers, , France

Site Status: NOT_YET_RECRUITING

Institut du Cancer d'Avignon

Avignon, , France

Site Status: ACTIVE_NOT_RECRUITING

CHU Jean Minjoz

Besançon, , France

Site Status: ACTIVE_NOT_RECRUITING

Centre Hospitalier de Cholet

Cholet, , France

Site Status: ACTIVE_NOT_RECRUITING

Centre Georges François Leclerc

Dijon, , France

Site Status: WITHDRAWN

Hôpital Privé Jean Mermoz

Lyon, , France

Site Status: ACTIVE_NOT_RECRUITING

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

Montpellier, , France

Site Status: RECRUITING

Hôpital Saint Louis

Paris, , France

Site Status: ACTIVE_NOT_RECRUITING

Hôpital Saint Antoine

Paris, , France

Site Status: RECRUITING

Hôpital Cochin

Paris, , France

Site Status: ACTIVE_NOT_RECRUITING

Hôpital des Diaconesses Croix Saint Simon

Paris, , France

Site Status: ACTIVE_NOT_RECRUITING

Hospices Civils de Lyon

Pierre-Bénite, , France

Site Status: ACTIVE_NOT_RECRUITING

CHU de Poitiers

Poitiers, , France

Site Status: ACTIVE_NOT_RECRUITING

CHU de REIMS

Reims, , France

Site Status: ACTIVE_NOT_RECRUITING

Institut Godinot

Reims, , France

Site Status: RECRUITING

Institut de Cancérologie de l'Ouest - Site René Gauducheau

Saint-Herblain, , France

Site Status: WITHDRAWN

CHU Saint-Etienne

Saint-Priest-en-Jarez, , France

Site Status: ACTIVE_NOT_RECRUITING

CH de Saint-Malo

St-Malo, , France

Site Status: ACTIVE_NOT_RECRUITING

Hôpital Nord Franche-Comté / Site du Mittan

Trévenans, , France

Site Status: ACTIVE_NOT_RECRUITING

Institut de Cancérologie de Lorraine

Vandœuvre-lès-Nancy, , France

Site Status: ACTIVE_NOT_RECRUITING

Countries

France

Central Contacts

Emilie BRUMENT

Role: CONTACT

e-brument@unicancer.fr

+33(0)6 68 32 03 59

Facility Contacts

Vincent HAUTEFEUILLE, MD

Role: primary

Victor SIMMET, MD

Role: primary

Emmanuelle SAMALIN, MD

Role: primary

Daniel LOPEZ, MD

Role: primary

Damien BOTSEN, MD

Role: primary

Other Identifiers

PRODIGE 91 - UCGI 46

Identifier Type: -

Identifier Source: org_study_id