A randomized phase III trial assessing a regorafenib-irinotecan combination (REGIRI) versus regorafenib alone in metastatic colorectal cancer patients after failure of standard therapies, according to the A/A genotype of Cyclin D1

Phase 1

• Conditions: Metastatic colorectal cancer; MedDRA version: 21.0Level: PTClassification code 10052358Term: Colorectal cancer metastaticSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2018-002231-24-FR
• Lead Sponsor: Institut régional du Cancer de Montpellier

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2018-06-22
• Last Update Posted: 8 July 2024

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 312

Inclusion Criteria

1.Signed informed consent obtained before any study specific procedures
2.Male or female = 18 years of age
3.Histological or cytological documentation of adenocarcinoma of the colon or rectum
4.Patients with metastatic colorectal cancer
5.Progression during or within 3 months following the last administration of approved standard therapies, which must include a fluoropyrimidine (or raltitrexed), oxaliplatin, irinotecan, anti VEGF therapy and an anti EGFR therapy (for RAS wild-type tumors)
6.ECOG performance status =1
7.Life expectancy of at least 3 months
8.Patients with A/A CCND1 genotype of rs603965 CCND1
9.Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements conducted within 7 days of starting study treatment:Amylase and lipase =1.5 x ULN, Total bilirubin = 1.5 x ULN, Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) = 3.0 x ULN (= 5 x ULN for patients with liver involvement of their cancer), Alkaline phosphatase (ALP) = 2.5 x ULN (= 5.0 x ULN for patients with liver involvement for their cancer and/or have bone metastases), Platelet count = 100,000/mm3; Hemoglobin (Hb) = 9 g/dL; Absolute neutrophil count (ANC) = 1,500/ mm3. Transfusion to meet the inclusion criterion, Serum creatinine = 1.5 x ULN
10.International normalized ratio (INR) = 1.5 x ULN and partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) = 1.5 x ULN unless receiving treatment with therapeutic anticoagulation. Patients being treated with anticoagulant, e.g., heparin, will be allowed to participate provided no prior evidence of an underlying abnormality in these parameters exists. Close monitoring of at least weekly evaluations will be performed until INR and PTT are stable based on a pre-dose measurement as defined by the local standard of care
11.Women of childbearing potential must have a blood or urine pregnancy test performed a maximum of 7 days before start of study treatment, and a negative result must be documented before start of study treatment
12.Women of childbearing potential and men must agree to use adequate contraception before entering the study until at least 8 weeks after the last study drug administration of Regorafenib and 12 weeks after the last study drug administration of Irinotecan. The investigator or a designated associate is requested to advise the patient on how to achieve an adequate birth control. Adequate contraception is defined in the study as any medically recommended method (or combination of methods) as per standard of care.

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 312
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 312

Exclusion Criteria

1.Patients with A/G or G/G CCND1 genotype of rs603965 CCND1
2.Prior treatment with regorafenib or sorafenib
3.Prior treatment with TAS 102
4.Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before start of study drug
5.Pregnant or breast-feeding subjects. Women of childbearing potential must have a pregnancy test performed a maximum of 7 days before start of treatment, and a negative result must be documented before start of study drug
6.Congestive heart failure = New York Heart Association (NYHA) class 2
7.Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months)
8.Myocardial infarction less than 6 months before start of study drug
9.Cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted)
10.Uncontrolled hypertension. (Systolic blood pressure > 140 mmHg or diastolic pressure > 90 mmHg despite optimal medical management)
11.Pleural effusion or ascites that causes respiratory compromise (= NCI-CTCAE V5.0 Grade 2 dyspnea)
12.Ongoing infection > Grade 2 NCI-CTCAE V5.0
13.Known history of human immunodeficiency virus (HIV) infection
14.Active hepatitis B or C, or chronic hepatitis B or C requiring treatment with antiviral therapy
15.Patients with seizure disorder requiring medication
16.History of organ allograft
17.Patients with evidence or history of any bleeding diathesis, irrespective of severity
18.Any hemorrhage or bleeding event = NCI-CTC V5.0 Grade 3 within 4 weeks prior to the start of study medication
19.Non-healing wound, ulcer, or bone fracture
20.Dehydration NCI-CTCAE V5.0 Grade = 1
21.Substance abuse, medical, psychological or social conditions that may interfere with the subject’s participation in the study or evaluation of the study results
22.Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation
23.Any illness or medical conditions that are unstable or could
jeopardize the safety of the subject and his/her compliance in the study
24.Persistent proteinuria of NCI-CTCAE V5.0 Grade 3 (> 3.5g/24 hours)
25.Patients unable to swallow oral medications
26.Any malabsorption condition
27.Chronic inflammatory bowel disease and / or bowel obstruction
28.Unresolved toxicity higher than NCI-CTCAE V.5.0 Grade 1 attributed to any prior therapy/procedure excluding alopecia, hypothyroidism and oxaliplatin induced neurotoxicity = Grade 2
29.Concomitant participation or participation within the last 30 days in another clinical trial
30.Systemic anticancer therapy during this trial or within 4 weeks before randomization

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: Comparison of overall survival in the Regorafenib and REGIRI combination (Regorafenib + Irinotecan) arms in mCRC patients of Cyclin D1 A/A genotype. ;Secondary Objective: Study of:<br>-Progression-free survival<br>-Objective response rate<br>-Disease control rate according to Recist criteria (version 1.1)<br>-Toxicity (according to the NCI-CTCAE v5.0)<br>-Quality of life (EORTC QLQ-C30)<br> <br>;Primary end point(s): Overall survival presented with its median and confidence interval at 95%, estimated from randomization date to the date of death, whatever the cause, using the Kaplan-Meier method;Timepoint(s) of evaluation of this end point: At the end of the study