Assessing a Regorafenib-irinotecan Combination Versus Regorafenib Alone in Metastatic Colorectal Cancer Patients (NEXT-REGIRI)

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

Patients with metastatic colorectal cancer (mCRC) who have received all approved standard treatments (except Regorafenib and Lonsurf) no longer have treatment options available while maintaining a good performance status which would allow them to receive a new treatment

Study Overview

• Status: Active, not recruiting
• Conditions: Metastatic Colorectal Cancer (mCRC)
• Intervention / Treatment: Drug: Regorafenib; Drug: Irinotecan

Detailed Description

A Phase II randomized trial compared Nexiri (Nexavar® + Irinotecan) vs irinotecan or versus Sorafenib (Nexavar®). The patients treated with Irinotecan or Sorafenib alone could receive NEXIRI combination after progression (crossover to Nexiri).

Regorafenib, which is an oral signal deactivation agent with a chemical structure very similar to Sorafenib, is a standard treatment in heavily pretreated mCRC patients since the results of CORRECT study which compared Regorafenib to placebo on overall survival.

Sorafenib isn't approved in mCRC so the objective of this NEXT-REGIRI trial is compared REGIRI combination (Regorafenib-Irinotecan) to Regorafenib alone in a phase III trial in patients in progression after having received all standard treatments and bearing genotype A/A of cyclin D1. The study's hypothesis is that regorafenib could have effects similar to those of sorafenib.

• Study Type: Interventional
• Enrollment (Actual): 377
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Montpellier, France, 34298
    • CRLC Val d'Aurelle-Paul Lamarque
  • Paris, France, 75015
    • Hopital Europeen Georges Pompidou
  • Alpes-Maritimes
    • Nice, Alpes-Maritimes, France, 06189
      • Centre Antoine Lacassagne
  • Basse-Normandie
    • Caen, Basse-Normandie, France, 14000
      • Centre Francois Baclesse
  • Ile Et Vilaine
    • Rennes, Ile Et Vilaine, France, 35000
      • Hôpital Pontchaillou
  • Marne
    • Reims, Marne, France, 51100
      • Institut Godinot
    • Reims, Marne, France, 51100
      • Hôpital Robert Debré
  • Pyrénées-orientales
    • Perpignan, Pyrénées-orientales, France, 66000
      • Hôpital Saint-Jean
  • Rhône
    • Lyon, Rhône, France, 69008
      • Centre Leon Berard
    • Lyon, Rhône, France, 69008
      • Hopital Prive Jean Mermoz
  • Val De Marne
    • Villejuif, Val De Marne, France, 94800
      • Institut Gustave Roussy

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Signed informed consent obtained before any study specific procedures
• Male or female ≥ 18 years of age
• Histological documentation of adenocarcinoma of the colon or rectum
• Patients with metastatic colorectal cancer
• Progression during or within 3 months following the last administration of approved standard therapies, which must include a fluoropyrimidine (or raltitrexed), oxaliplatin, irinotecan, anti Vascular endothelial growth factor (VEGF) therapy and an anti Epithelial Growth Factor Receptor (EGFR) therapy (for RAS wild-type tumors)
• Eastern Cooperative Oncology Group (ECOG) performance status ≤1
• Life expectancy of at least 3 months
• Patients with A/A cycline D1 (CCND1) genotype of rs603965 CCND1
• 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 Upper Limit Normal (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
• 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
• 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
• Women of childbearing potential and men must agree to use adequate contraception before entering the study until at least respectively 7 months and 4 months after the last study drug administration of Regorafenib and respectively 6 months and 3 months 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.

Exclusion Criteria:

• Patients with A/G or G/G cycline d1 (CCND1) genotype of rs603965 CCND1
• Prior treatment with regorafenib or sorafenib
• Prior treatment with TAS 102
• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before start of study drug
• 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
• Congestive heart failure ≥ New York Heart Association (NYHA) class 2
• Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months)
• Myocardial infarction less than 6 months before start of study drug
• Cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted)
• Uncontrolled hypertension. (Systolic blood pressure > 140 mmHg or diastolic pressure > 90 mmHg despite optimal medical management)
• Pleural effusion or ascites that causes respiratory compromise (≥ NCI-CTCAE V5.0 Grade 2 dyspnea)
• Ongoing infection > Grade 2 NCI-CTCAE V5.0
• Known history of human immunodeficiency virus (HIV) infection
• Active hepatitis B or C, or chronic hepatitis B or C requiring treatment with antiviral therapy
• Patients with seizure disorder requiring medication
• History of organ allograft
• Patients with evidence or history of any bleeding diathesis, irrespective of severity
• Any hemorrhage or bleeding event ≥ NCI-CTC V5.0 Grade 3 within 4 weeks prior to the start of study medication
• Non-healing wound, ulcer, or bone fracture
• Dehydration NCI-CTCAE V5.0 Grade ≥ 1
• Substance abuse, medical, psychological or social conditions that may interfere with the subject's participation in the study or evaluation of the study results
• Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation
• Any illness or medical conditions that are unstable or could
• jeopardize the safety of the subject and his/her compliance in the study
• Persistent proteinuria of NCI-CTCAE V5.0 Grade 3 (> 3.5g/24 hours)
• Patients unable to swallow oral medications
• Any malabsorption condition
• Chronic inflammatory bowel disease and / or bowel obstruction
• 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
• Concomitant participation or participation within the last 30 days in another clinical trial
• Systemic anticancer therapy during this trial or within 4 weeks before randomization
• Concomitant intake of st John's wort
• Live attenuated vaccines are prohibited 10 days before the treatment, during the treatment and 6 months after the termination of treatment
• History of gastrointestinal fistula or perforation
• 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 cervical cancer in situ, non-melanoma skin cancer and superficial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Irinotecan + regorafenib (REGIRI); irinotecan (180 mg/m2) at day1 of each cycle + regorafenib (160 mg/day) from day 2 to day 8	Drug: Regorafenib; regorafenib tab 40 mg i.e 160 mg/day; Drug: Irinotecan; irinotecan 120 mg/m2 cycle 1, 150 mg/m2 cycle 2, 180 mg/m2 cycle 3 and more
Active Comparator: regorafenib; Regorafenib (160 mg/day) for 3 weeks followed by 1 week off	Drug: Regorafenib; regorafenib tab 40 mg i.e 160 mg/day

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Overall Survival	Up to 36 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival (PFS)		Up to 36 months
Time to Deterioration		Up to 36 months
Number of Participants With Disease Control Rate		Through study completion, up to 14 months
Number of Patients With an Objective Response Rate		Through treatment completion, up to 14 months
Assessment of Adverse Events by Using the NCI-CTCAE Version 5.0 Scale (Grade Max Per Patient)		Up to 36 months
Quality of Life Questionnaire	The Quality of Life questionnaire (QLQ-C30) is a 30-item instrument designed to measure quality of life in all cancer patients. The QLQ-C30 incorporates five functional scales (physical, role, cognitive, emotional, and social), three symptom scales (fatigue, pain, and nausea and vomiting), a global health status, and a number of single items assessing additional symptoms commonly reported by cancer patients (dyspnea, loss of appetite, insomnia and diarrhea) and perceived financial impact of the disease. Score 0 to 100 for all subscales.; Functional scale : 0 the worst outcome, 100 is the best outcome,; Symptomatic scale : 0 the best outcome, 100 is the worst outcome Global functioning measures how much a person's symptoms affect their day-to-day life and role functioning assesses a patient's ability to perform daily activities, leisure time activities, and work on a scale of 0 to 100 (0 the worst outcome and 100 the best outcome).	Questionnaire is assessed until 16 weeks (baseline, 8 weeks and 16 weeks)

Collaborators and Investigators

• Sponsor: Institut du Cancer de Montpellier - Val d'Aurelle
• Investigators: Study Chair: Emmanuelle SAMALIN, MD, Institut régional du Cancer de Montpellier

Publications and helpful links

General Publications

• Samalin E, Bouche O, Thezenas S, Francois E, Adenis A, Bennouna J, Taieb J, Desseigne F, Seitz JF, Conroy T, Galais MP, Assenat E, Crapez E, Poujol S, Bibeau F, Boissiere F, Laurent-Puig P, Ychou M, Mazard T. Sorafenib and irinotecan (NEXIRI) as second- or later-line treatment for patients with metastatic colorectal cancer and KRAS-mutated tumours: a multicentre Phase I/II trial. Br J Cancer. 2014 Mar 4;110(5):1148-54. doi: 10.1038/bjc.2013.813. Epub 2014 Jan 9.
• Lu F, Gladden AB, Diehl JA. An alternatively spliced cyclin D1 isoform, cyclin D1b, is a nuclear oncogene. Cancer Res. 2003 Nov 1;63(21):7056-61.
• Alt JR, Cleveland JL, Hannink M, Diehl JA. Phosphorylation-dependent regulation of cyclin D1 nuclear export and cyclin D1-dependent cellular transformation. Genes Dev. 2000 Dec 15;14(24):3102-14. doi: 10.1101/gad.854900.
• Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, Humblet Y, Bouche O, Mineur L, Barone C, Adenis A, Tabernero J, Yoshino T, Lenz HJ, Goldberg RM, Sargent DJ, Cihon F, Cupit L, Wagner A, Laurent D; CORRECT Study Group. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013 Jan 26;381(9863):303-12. doi: 10.1016/S0140-6736(12)61900-X. Epub 2012 Nov 22.

Study record dates

Study Major Dates

• Study Start (Actual): March 28, 2019
• Primary Completion (Actual): September 4, 2024
• Study Completion (Estimated): September 1, 2026

Study Registration Dates

• First Submitted: January 23, 2019
• First Submitted That Met QC Criteria: February 1, 2019
• First Posted (Actual): February 4, 2019

Study Record Updates

• Last Update Posted (Estimated): November 21, 2025
• Last Update Submitted That Met QC Criteria: November 14, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Keywords: irinotecan; regorafenib; REGIRI
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colonic Diseases; Colorectal Neoplasms; Heterocyclic Compounds; Camptothecin; Alkaloids; Irinotecan; regorafenib
• Other Study ID Numbers: PROICM 2018-01 NEX

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All data will be available after publication of the results in peer-reviewed revues, and in national and international meetings. It includes all disidentified participants' data, the study protocol, the statistical analysis plan, the clinical study report and the analytic code. The corresponding author will provide data and datasets generated and/or analyzed during the study upon reasonable request.
• IPD Sharing Time Frame: Access to study data upon written detailed request sent to Institute of Montpellier Cancer after publication.
• IPD Sharing Access Criteria: The data shared will be limited to that required for independent mandated verification of the published results, the applicant will need authorization from ICM for personal access, and data will only be transferred after signing of a data access agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No