Sequences Of REGorafenib And Trifluridine/Tipiracil in Patients With Metastatic Colorectal Cancer

NCT ID: NCT04450836

Last Updated: 2025-03-30

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 234 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-11-23
• Study Completion Date: 2024-12-31

Brief Summary

A randomized, phase II study comparing the sequences of regorafenib and trifluridine/tipiracil, after failure of standard therapies in patients with metastatic colorectal cancer

Detailed Description

Multicenter, international, comparative, randomized, open-label, phase II study conducted in two parallel groups.

The study population will consist of male and female patients aged ≥18 years old with metastatic colorectal cancer after failure of fluoropyrimidine-, irinotecan-, and oxaliplatin-based chemotherapies, as well as epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) inhibitors in patients eligible for these treatments.

Patients will be randomized according to a 1:1 ratio to treatment arms A and B.

• Arm A: regorafenib until disease progression or unacceptable toxicity occurs, followed by trifluridine/tipiracil until disease progression or unacceptable toxicity occurs.
• Arm B: trifluridine/tipiracil until disease progression or unacceptable toxicity occurs, followed by regorafenib until disease progression or unacceptable toxicity occurs.

Conditions

Metastatic Colorectal Cancer

Study Design

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

Study Groups

Arm A (R-TT)

Regorafenib followed by trifluridine-tipiracil.

Group Type: EXPERIMENTAL

Regorafenib then Trifluridine/Tipiracil

Intervention Type: DRUG

REGORAFENIB 160 mg per day during 3 weeks followed by 1 week off of each 4-week cycle except for cycle 1.

During first cycle: dose is started at 80 mg per day at week 1, 120 mg per day at week 2, 160 mg per day at week 3, followed by 1 week off.

Then TRIFLURIDINE/TIPIRACIL 35 mg/m² Dose administered orally twice daily on Days 1 to 5 and Days 8 to 12 of each 4-week cycle.

Arm B (TT-R)

Trifluridine-tipiracil followed by Regorafenib.

Group Type: EXPERIMENTAL

Trifluridine/Tipiracil then Regorafenib

Intervention Type: DRUG

TRIFLURIDINE/TIPIRACIL 35 mg/m² Dose administered orally twice daily on Days 1 to 5 and Days 8 to 12 of each 4-week cycle.

Then REGORAFENIB 160 mg per day during 3 weeks followed by 1 week off of each 4-week cycle except for cycle 1.

During first cycle: dose is started at 80 mg per day at week 1, 120 mg per day at week 2, 160 mg per day at week 3, followed by 1 week off.

Interventions

Regorafenib then Trifluridine/Tipiracil

REGORAFENIB 160 mg per day during 3 weeks followed by 1 week off of each 4-week cycle except for cycle 1.

During first cycle: dose is started at 80 mg per day at week 1, 120 mg per day at week 2, 160 mg per day at week 3, followed by 1 week off.

Then TRIFLURIDINE/TIPIRACIL 35 mg/m² Dose administered orally twice daily on Days 1 to 5 and Days 8 to 12 of each 4-week cycle.

Intervention Type: DRUG

Trifluridine/Tipiracil then Regorafenib

TRIFLURIDINE/TIPIRACIL 35 mg/m² Dose administered orally twice daily on Days 1 to 5 and Days 8 to 12 of each 4-week cycle.

Then REGORAFENIB 160 mg per day during 3 weeks followed by 1 week off of each 4-week cycle except for cycle 1.

During first cycle: dose is started at 80 mg per day at week 1, 120 mg per day at week 2, 160 mg per day at week 3, followed by 1 week off.

Intervention Type: DRUG

Other Intervention Names

STIVARGA; LONSURF; LONSURF; STIVARGA

Eligibility Criteria

Inclusion Criteria

1. Patients must have provided informed consent before performing any study specific procedures.

2. Histological or cytological documented adenocarcinoma of the colon or rectum.

3. Patients with metastatic colorectal cancer (stage IV).

4. Measurable disease, defined as at least one unidimensional measurable lesion on a computed tomography (CT) scan according to RECIST v1.1.

5. The patient must have progressed following exposure of all the following agents : one fluoropyrimidine-based chemotherapy (capecitabine or fluorouracil [5-FU], combined with oxaliplatin and/or irinotecan (including FOLFOX, FOLFIRI or FOLFOXIRI) as well as EGFR and/or VEGF inhibitors in patients eligible for these treatments.

6. Patients considered eligible for treatment with both regorafenib and trifluridine-tipiracil.

7. Male or female patients aged ≥18 years.

8. ECOG performance status of ≤1.

9. Adequate bone marrow, liver and renal functions as assessed by the following laboratory requirements:

• Total bilirubin ≤1.5 x upper limit of normal (ULN).
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x ULN (≤5 x ULN for patients with liver metastasis).
• Alkaline phosphatase limit ≤2.5 x ULN (≤5 x ULN for patients with liver metastasis).
• Serum creatinine ≤1.5 x ULN.
• International normalized ratio (INR) and partial thromboplastin time (PTT) ≤1.5 x ULN. Patients receiving anticoagulants, such as warfarin or heparin are eligible if there is no prior evidence of an underlying abnormality with coagulation.
• Platelet count ≥75000 /mm³, hemoglobin (Hb) ≥9 g/dL, absolute neutrophil count (ANC) ≥1500/mm³. Blood transfusions to meet this inclusion criterion are not allowed.

10. Women of childbearing potential and men must agree to use a highly effective contraception (1% failure rate) from the signing of the informed consent form until at least 6 months after the last study drug administration. Women using hormonal contraceptive must also use a barrier method.

11. Women of childbearing potential must have a negative pregnancy test within 7 days before starting study treatment.

12. Patients affiliated to the social security system.

13. Patient willing and able to comply with the protocol for the duration of the study including treatment, scheduled visits, and examinations throughout the study, including follow up.

Exclusion Criteria

1. Patients with symptomatic brain or meningeal metastasis, unless definitive therapy occurred more than 6 months ago and with a confirmation of tumoral control within 4 weeks of starting study treatment.

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

3. Prior treatment with regorafenib or any other tyrosine kinase inhibitor.

4. Prior treatment with trifluridine/tipiracil.

5. Known hypersensitivity to any of the study drugs, study drug classes, or study drug excipients.

6. Unresolved toxicity grade >1 (by CTCAE v5.0) caused by prior therapy/procedure, excluding alopecia, hypothyroidism, and oxaliplatin-induced neurotoxicity grade ≤2.

7. Patient with moderate or severe hepatic impairment (Child-Pugh C).

8. Known UGT1A1 polymorphisms. History of Gilbert's syndrome.

9. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before starting study treatment.

10. Chemotherapy within 21 days of starting study treatment.

11. Radiotherapy within 4 weeks of starting study treatment, except for palliative radiotherapy within 2 weeks.

12. Active cardiac disease including any of the Following:

• Congestive heart Failure: New York Heart Association (NYHA) class ≥2.
• Unstable angina (angina symptoms at rest), or a new-onset angina (within the 3 months before enrolment).
• Myocardial infarction that occurred less than 6 months before enrolment.
• Cardiac arrhythmias requiring anti-arrhythmic therapy (treatment with beta blockers or digoxin are permitted)
• Uncontrolled hypertension (systolic blood pressure >140 mmHg or diastolic pressure >90 mmHg despite treatment).

13. Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis, or pulmonary embolism within 6 months of starting study treatment.

14. Ongoing infection grade 2 (CTCAE v5.0).

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

16. Active hepatitis B or C, or chronic hepatitis B or C requiring treatment with antiviral therapy.

17. Patients with seizure disorder requiring medication.

18. Patients with a history of any bleeding diathesis, irrespective of the severity.

19. Any hemorrhage or bleeding event grade ≥3 (CTCAE v5.0) within 4 weeks before starting study treatment.

20. Presence of a wound, ulcer, or bone fracture that is not healing.

21. Patients unable to swallow oral medications.

22. Bowel malabsorption or extended bowel resection that could affect the absorption of regorafenib, occlusive syndrome.

23. Presence of gastro-intestinal fistula or perforation.

24. Any illness or medical conditions that are unstable or could jeopardize the safety of the patient and their compliance in the study.

25. Patients participating in another therapeutic study within the 30 days before enrolment.

26. Pregnant or breast feeding women.

27. Person deprived of their liberty or under protective custody or guardianship.

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

Sponsors

UNICANCER

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Michel MD DUCREUX, Pr

Role: PRINCIPAL_INVESTIGATOR

Gustave Roussy, Cancer Campus, Grand Paris

Locations

Clinique Saint Luc

Bouge, , Belgium

CH de l'Ardenne

Libramont, , Belgium

CH Verviers

Verviers, , Belgium

Hôpital Privé Pays de Savoie

Annemasse, , France

Centre hospitalier d'Auxerre

Auxerre, , France

Institut Sainte Catherine

Avignon, , France

Centre Hospitalier de Bayeux

Bayeux, , France

Centre François Baclesse

Caen, , France

Infirmerie Protestante de Lyon

Caluire-et-Cuire, , France

CH Cotentin

Cherbourg, , France

Institut de Cancérologie de Bourgogne

Dijon, , France

Centre Oscar Lambret

Lille, , France

Hôpital Scorff

Lorient, , France

Centre Léon Bérard

Lyon, , France

Association Hôpital Saint Joseph de Marseille

Marseille, , France

Hôpital privé du Confluent

Nantes, , France

Centre Antoine Lacassagne

Nice, , France

Hôpital Privé des Peupliers

Paris, , France

APHP - Hôpital Européen Georges Pompidou

Paris, , France

Groupe hospitalier Pitié Salpétrière

Paris, , France

CH Saint Jean

Perpignan, , France

CHU de Bordeaux - Hôpital Haut Lévèque

Pessac, , France

CH Périgueux

Périgueux, , France

Hôpital Privé des Côtes d'Armor - Centre CARIO-HPCA

Plérin, , France

CHU de Poitiers

Poitiers, , France

CHU - Robert Debre

Reims, , France

Institut Jean Godinot

Reims, , France

Hopital Charles Nicolle

Rouen, , France

CHU Hôpital Nord

Saint-Etienne, , France

Centre Hospitalier de Saint Malo

St-Malo, , France

Centre Paul Strauss (ICANS)

Strasbourg, , France

CHU de Toulouse

Toulouse, , France

Centre Hospitalier de Valence

Valence, , France

Institut de Cancérologie de Lorraine

Vandœuvre-lès-Nancy, , France

Paul Brousse

Villejuif, , France

Gustave Roussy

Villejuif, , France

Countries

Belgium; France

Other Identifiers

2019-004196-39

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

PRODIGE 68 - UCGI 38

Identifier Type: OTHER

Identifier Source: secondary_id

UC-GIG-1910

Identifier Type: -

Identifier Source: org_study_id