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

Phase 3

Active, not recruiting

Conditions: Metastatic Colorectal Cancer (mCRC)

Interventions: Drug: Regorafenib
Drug: Irinotecan

Registration Number: NCT03829462

Lead Sponsor: Institut du Cancer de Montpellier - Val d'Aurelle

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.

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 377

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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Irinotecan + regorafenib (REGIRI)	Regorafenib	irinotecan (180 mg/m2) at day1 of each cycle + regorafenib (160 mg/day) from day 2 to day 8
regorafenib	Regorafenib	Regorafenib (160 mg/day) for 3 weeks followed by 1 week off
Irinotecan + regorafenib (REGIRI)	Irinotecan	irinotecan (180 mg/m2) at day1 of each cycle + regorafenib (160 mg/day) from day 2 to day 8

Primary Outcome Measures

Name	Time	Method
Overall Survival	Up to 36 months

Secondary Outcome Measures

Name	Time	Method
Quality of Life Questionnaire	Questionnaire is assessed until 16 weeks (baseline, 8 weeks and 16 weeks)	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).
Progression-free Survival (PFS)	Up to 36 months
Time to Deterioration	Up to 36 months
Number of Patients With an Objective Response Rate	Through treatment completion, up to 14 months
Number of Participants With Disease Control Rate	Through study 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

Trial Locations

Locations (11): 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
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Centre Antoine Lacassagne
🇫🇷Nice, Alpes-Maritimes, France