Clinical trial NCT04450836: Sequences Of REGorafenib And Trifluridine/Tipiracil in Patients With Metastatic Colorectal Cancer
Official title: A Randomized, Phase II Study Comparing the Sequences of Regorafenib and Trifluridine/Tipiracil, After Failure of Standard Therapies in Patients With Metastatic Colorectal Cancer
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Metastatic Colorectal Cancer
Keywords: Regorafenib
Trifluridine/Tipiracil
Metastatic colorectal cancer
Lead sponsor: UNICANCER
Sponsor class: OTHER
First posted: 2020-06-30
Enrollment: 234
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: To evaluate the feasibility of treatment sequence (R-TT or TT-R)
timeFrame: Expected duration of 5 months from randomization
Secondary outcomes:
measure: To evaluate the efficacy of treatment sequence (R-TT or TT-R) in terms of Overall Survival rate
timeFrame: Expected duration of 9 months from randomization
measure: To evaluate the efficacy of treatment sequence (R-TT or TT-R) in terms of the progression-free Survival 1 (PFS1)
timeFrame: Expected duration of 3 months from randomization
measure: To evaluate the efficacy of treatment sequence (R-TT or TT-R) in terms of the Progression-free survival 2 (PFS2)
timeFrame: Expected duration of 6 months from randomization
measure: To evaluate the efficacy of treatment sequence (R-TT or TT-R) in terms of the Disease control rate (DCR)
timeFrame: Expected duration of 6 months from randomization
measure: To evaluate the efficacy of treatment sequence (R-TT or TT-R) in terms of the Objective response rate (ORR)
timeFrame: Expected duration of 6 months from randomization
measure: To evaluate the efficacy of treatment sequence (R-TT or TT-R) in terms of the Time-to-treatment failure 1 (TTF1)
timeFrame: Expected duration of 3 months from randomization
measure: To evaluate the efficacy of treatment sequence (R-TT or TT-R) in terms of the Time-to-treatment failure 2 (TTF2)
timeFrame: Expected duration of 6 months from randomization
measure: To evaluate the health-related quality of life of cancer patients during treatment
timeFrame: Expected 30 days after last study treatment administration, up to 5 years
measure: To evaluate the performance status deterioration
timeFrame: Expected 30 days after last study treatment administration, up to 5 years
measure: To evaluate the safety (Treatment-Emergent Adverse Events) during treatment
timeFrame: Expected 30 days after last study treatment administration, up to 5 years
Other outcomes:
Locations:
city: Bouge
country: Belgium
facility: Clinique Saint Luc
city: Libramont
country: Belgium
facility: CH de l'Ardenne
city: Verviers
country: Belgium
facility: CH Verviers
city: Annemasse
country: France
facility: Hôpital Privé Pays de Savoie
city: Auxerre
country: France
facility: Centre hospitalier d'Auxerre
city: Avignon
country: France
facility: Institut Sainte Catherine
city: Bayeux
country: France
facility: Centre Hospitalier de Bayeux
city: Caen
country: France
facility: Centre François Baclesse
city: Caluire-et-Cuire
country: France
facility: Infirmerie Protestante de Lyon
city: Cherbourg
country: France
facility: CH Cotentin
city: Dijon
country: France
facility: Institut de Cancérologie de Bourgogne
city: Lille
country: France
facility: Centre Oscar Lambret
city: Lorient
country: France
facility: Hôpital Scorff
city: Lyon
country: France
facility: Centre Léon Bérard
city: Marseille
country: France
facility: Association Hôpital Saint Joseph de Marseille
city: Nantes
country: France
facility: Hôpital privé du Confluent
city: Nice
country: France
facility: Centre Antoine Lacassagne
city: Paris
country: France
facility: Hôpital Privé des Peupliers
city: Paris
country: France
facility: APHP - Hôpital Européen Georges Pompidou
city: Paris
country: France
facility: Groupe hospitalier Pitié Salpétrière
city: Perigueux
country: France
facility: CH Périgueux
city: Perpignan
country: France
facility: CH Saint Jean
city: Pessac
country: France
facility: CHU de Bordeaux - Hôpital Haut Lévèque
city: Plérin
country: France
facility: Hôpital Privé des Côtes d'Armor - Centre CARIO-HPCA
city: Poitiers
country: France
facility: CHU de Poitiers
city: Reims
country: France
facility: CHU - Robert Debre
city: Reims
country: France
facility: Institut Jean Godinot
city: Rouen
country: France
facility: Hopital Charles Nicolle
city: Saint-Malo
country: France
facility: Centre Hospitalier de Saint Malo
city: Saint-Étienne
country: France
facility: CHU Hôpital Nord
city: Strasbourg
country: France
facility: Centre Paul Strauss (ICANS)
city: Toulouse
country: France
facility: CHU de Toulouse
city: Valence
country: France
facility: Centre Hospitalier de Valence
city: Vandoeuvre Les Nancy
country: France
facility: Institut de Cancérologie de Lorraine
city: Villejuif
country: France
facility: Paul Brousse
city: Villejuif
country: France
facility: Gustave Roussy
Study officials:
affiliation: Gustave Roussy, Cancer Campus, Grand Paris
name: Michel MD DUCREUX, Pr
role: PRINCIPAL_INVESTIGATOR
References: