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

A Randomized, Phase II Study Comparing the Sequences of Regorafenib and Trifluridine/Tipiracil, After Failure of Standard Therapies in Patients With Metastatic Colorectal Cancer

Sponsors

Lead Sponsor: UNICANCER

Source UNICANCER
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.

Overall Status Not yet recruiting
Start Date September 30, 2020
Completion Date March 30, 2028
Primary Completion Date September 30, 2023
Phase Phase 2
Study Type Interventional
Primary Outcome
Measure Time Frame
To evaluate the feasibility of treatment sequence (R-TT or TT-R) Expected duration of 5 months from randomization
Secondary Outcome
Measure Time Frame
To evaluate the efficacy of treatment sequence (R-TT or TT-R) in terms of Overall Survival rate Expected duration of 9 months from randomization
To evaluate the efficacy of treatment sequence (R-TT or TT-R) in terms of the progression-free Survival 1 (PFS1) Expected duration of 3 months from randomization
To evaluate the efficacy of treatment sequence (R-TT or TT-R) in terms of the Progression-free survival 2 (PFS2) Expected duration of 6 months from randomization
To evaluate the efficacy of treatment sequence (R-TT or TT-R) in terms of the Disease control rate (DCR) Expected duration of 6 months from randomization
To evaluate the efficacy of treatment sequence (R-TT or TT-R) in terms of the Objective response rate (ORR) Expected duration of 6 months from randomization
To evaluate the efficacy of treatment sequence (R-TT or TT-R) in terms of the Time-to-treatment failure 1 (TTF1) Expected duration of 3 months from randomization
To evaluate the efficacy of treatment sequence (R-TT or TT-R) in terms of the Time-to-treatment failure 2 (TTF2) Expected duration of 6 months from randomization
To evaluate the health-related quality of life of cancer patients during treatment Expected 30 days after last study treatment administration, up to 5 years
To evaluate the performance status deterioration Expected 30 days after last study treatment administration, up to 5 years
To evaluate the safety (Treatment-Emergent Adverse Events) during treatment Expected 30 days after last study treatment administration, up to 5 years
Enrollment 340
Condition
Intervention

Intervention Type: Drug

Intervention Name: Regorafenib then Trifluridine/Tipiracil

Description: 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 Group Label: Arm A (R-TT)

Intervention Type: Drug

Intervention Name: Trifluridine/Tipiracil then Regorafenib

Description: 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.

Arm Group Label: Arm B (TT-R)

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 received two or more previous lines of treatment for metastatic disease. The prior treatment lines must include at least one fluoropyrimidine-based chemotherapy 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 ≥100000 /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 severe hepatic impairment (Child-Pugh C).

8. Known UGT1A1 and/or UGT1A9 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.

Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No

Overall Official
Last Name Role Affiliation
Michel MD DUCREUX, Pr Principal Investigator Gustave Roussy, Cancer Campus, Grand Paris
Overall Contact

Last Name: Laure MONARD

Phone: 0033173797309

Email: [email protected]

Location
Facility: Investigator:
Hôpital Privé Pays de Savoie | Annemasse, France Wulfran CACHEUX, Dr Principal Investigator
Centre hospitalier d'Auxerre | Auxerre, France Anne-Laure VILLING, Dr Principal Investigator
Centre Hospitalier de Bayeux | Bayeux, France Annie PEYTIER, Dr Principal Investigator
Centre François Baclesse | Caen, France Aurélie PARZY, Dr Principal Investigator
Hôpital Trousseau | Chambray-les-tours, France Thierry LECOMTE, Dr Principal Investigator
Centre Oscar Lambret | Lille, France Diane Pannier, Dr Principal Investigator
Centre Léon Bérard | Lyon, France Clélia COUTZAC, Dr Principal Investigator
Institut Paoli Calmettes | Marseille, France Slimane DERMECHE, Dr Principal Investigator
APHP - Hôpital Européen Georges Pompidou | Paris, France Julien TAIEB, Pr Principal Investigator
Groupe hospitalier Pitié Salpétrière | Paris, France Jean-Baptiste BACHET, Pr Principal Investigator
CH Saint Jean | Perpignan, France Faiza KHEMISSA, Dr Principal Investigator
CHU de Bordeaux - Hôpital Haut Lévèque | Pessac, France Denis SMITH, Dr Principal Investigator
Hôpital Privé des Côtes d'Armor - Centre CARIO-HPCA | Plérin, France Jérôme MARIN BABAU, Dr Principal Investigator
CHU de Poitiers | Poitiers, France David TOUGERON
CHU - Robert Debre | Reims, 51092, France
Institut Jean Godinot | Reims, France Damien BOTSEN Principal Investigator
Hopital Charles Nicolle | Rouen, France David SEFRIOUI Principal Investigator
Centre Hospitalier de Saint Malo | Saint-Malo, France Juliette VIAUD, Dr Principal Investigator
Centre Paul Strass | Strasbourg, France Meher BEN ABDELGHANI, Dr Principal Investigator
Institut de Cancérologie de Lorraine | Vandoeuvre Les Nancy, 54519, France Pierre LEHAIR, Dr Principal Investigator
Gustave Roussy | Villejuif, France Michel DUCREUX, Pr Principal Investigator
Location Countries

France

Verification Date

June 2020

Responsible Party

Type: Sponsor

Keywords
Has Expanded Access No
Condition Browse
Number Of Arms 2
Arm Group

Label: Arm A (R-TT)

Type: Experimental

Description: Regorafenib followed by trifluridine-tipiracil.

Label: Arm B (TT-R)

Type: Experimental

Description: Trifluridine-tipiracil followed by Regorafenib.

Acronym SOREGATT
Study Design Info

Allocation: Randomized

Intervention Model: Parallel Assignment

Primary Purpose: Treatment

Masking: None (Open Label)

Source: ClinicalTrials.gov