Assessing a Regorafenib-irinotecan Combination Versus Regorafenib Alone in Metastatic Colorectal Cancer Patients

NCT ID: NCT03829462

Last Updated: 2025-11-21

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 377 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-03-28
• Study Completion Date: 2026-09-30

Brief Summary

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

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.

Conditions

Metastatic Colorectal Cancer (mCRC)

Study Design

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

Study Groups

Irinotecan + regorafenib (REGIRI)

irinotecan (180 mg/m2) at day1 of each cycle + regorafenib (160 mg/day) from day 2 to day 8

Group Type: EXPERIMENTAL

Regorafenib

Intervention Type: DRUG

regorafenib tab 40 mg i.e 160 mg/day

Irinotecan

Intervention Type: DRUG

irinotecan 120 mg/m2 cycle 1, 150 mg/m2 cycle 2, 180 mg/m2 cycle 3 and more

regorafenib

Regorafenib (160 mg/day) for 3 weeks followed by 1 week off

Group Type: ACTIVE_COMPARATOR

Regorafenib

Intervention Type: DRUG

regorafenib tab 40 mg i.e 160 mg/day

Interventions

Regorafenib

regorafenib tab 40 mg i.e 160 mg/day

Intervention Type: DRUG

Irinotecan

irinotecan 120 mg/m2 cycle 1, 150 mg/m2 cycle 2, 180 mg/m2 cycle 3 and more

Intervention Type: DRUG

Eligibility Criteria

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

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

Sponsors

Institut du Cancer de Montpellier - Val d'Aurelle

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Emmanuelle SAMALIN, MD

Role: STUDY_CHAIR

Institut régional du cancer de Montpellier

Locations

Centre Antoine Lacassagne

Nice, Alpes-Maritimes, France

Centre François Baclesse

Caen, Basse-Normandie, France

Hôpital Pontchaillou

Rennes, Ile Et Vilaine, France

Hôpital Robert Debré

Reims, Marne, France

Institut Godinot

Reims, Marne, France

Hôpital Saint-Jean

Perpignan, Pyrénées-orientales, France

Centre Léon Bérard

Lyon, Rhône, France

Hôpital privé Jean Mermoz

Lyon, Rhône, France

Institut Gustave Roussy

Villejuif, Val De Marne, France

CRLC Val d'Aurelle-Paul Lamarque

Montpellier, , France

Hôpital Européen Georges Pompidou

Paris, , France

Countries

France

References

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.

Reference Type: BACKGROUND

PMID: 24407191 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 14612495 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 11124803 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 23177514 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

PROICM 2018-01 NEX

Identifier Type: -

Identifier Source: org_study_id