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

Metastatic Colorectal Cancer (mCRC) Clinical Trial

— NEXT-REGIRI  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03829462
• Other study ID #: PROICM 2018-01 NEX
• Status: Recruiting
• Phase: Phase 3
• Start date: March 28, 2019
• Est. completion date: September 2025

Study information

• Verified date: September 2023
• Source: Institut du Cancer de Montpellier - Val d'Aurelle
• Contact: Jean-Pierre BLEUSE, MD
• Phone: 0467613102
• Email: jean-pierre.bleuse[@]icm.unicancer.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Patients with metastatic colorectal cancer (mCRC) who have received all approved standard treatments (except Regorafenib and TAS 102) no longer have treatment options available while maintaining a good performance status which would allow them to receive a new treatment

Description:

A Phase III randomized trial that compared Nexiri (Nexavar® + Irinotecan) vs irinotecan or versus Sorafenib alone showed a progression-free survival at two-months which was favorable to the NEXIRI combination ; 59% ( IC95% : 39-66 ) versus 23% (IC95% : 10-33) and 22% (IC95%: 8-30) respectively.

The patients treated with Irinotecan or Sorafenib alone could receive NEXIRI combination after progression and the progression-free survivals were 3,7 months (IC95% : 2,2-4,9) and 3,5 months (IC95% : 2,1-3,7) in patients treated with NEXIRI or after progression and 1,9 months (IC95% : 1,7-2,1) and 2,1 months (IC95% : 1,9-2,5) in patients treated only with Irinotecan and Sorafenib respectively.

The median overall survival was higher with NEXIRI : 7,2 months (patients treated from the beginning of the study) and 7,9 months (patients treated after progression and crossover) versus 3 months in patients treated only with Irinotecan and 3,2 months in patients receiving only Sorafenib.

The A870A rs603965 polymorphism of cyclin D1, a molecule involved in the initiation of cell division, was favorable to the NEXIRI combination on overall survival with a median of 19.6 months versus 6.2 months for two other genotypes A/G and G/G.

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 showed a superiority of Regorafenib : 6,4 months versus 5 months (HR 0,774 [IC95% 0,63, 0,94]).

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

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 78
• Est. completion date: September 2025
• Est. primary completion date: October 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 VEGF therapy and an anti EGFR therapy (for RAS wild-type tumors)

• ECOG performance status =1

• Life expectancy of at least 3 months

• Patients with A/A 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 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 partialthromboplastin 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 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

Related Conditions & MeSH terms

• Colorectal Neoplasms
• Metastatic Colorectal Cancer (mCRC)

Intervention

Drug:
• Regorafenib
regorafenib tab 40 mg i.e 160 mg/day
• Irinotecan
irinotecan 120 mg/m2 cycle 1, 150 mg/m2 cycle 2, 180 mg/m2 cycle 3 and more

Locations

Country	Name	City	State
France	Centre François Baclesse	Caen	Basse-Normandie
France	Centre Léon Bérard	Lyon	Rhône
France	Hôpital privé Jean Mermoz	Lyon	Rhône
France	CRLC Val d'Aurelle-Paul Lamarque	Montpellier
France	Centre Antoine Lacassagne	Nice	Alpes-Maritimes
France	Hôpital Européen Georges Pompidou	Paris
France	Hôpital Saint-Jean	Perpignan	Pyrénées-orientales
France	Hôpital Robert Debré	Reims	Marne
France	Institut Godinot	Reims	Marne
France	Hôpital Pontchaillou	Rennes	Ile Et Vilaine
France	Institut Gustave Roussy	Villejuif	Val De Marne

Sponsors (1)

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

Country where clinical trial is conducted

France, 

References & Publications (4)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall survival	From randomization of first patient until the datebase cut-off	Approximately 36 months
Secondary	Progression-free survival (PFS)	From randomization of first patient until the datebase cut-off,	Approximately 36 months
Secondary	Disease control rate (DCR)	From randomization of first patient until the datebase cut-off,	Tumor is assessed every 8 weeks
Secondary	Objective response rate (OOR)	From randomization of first patient until the datebase cut-off,	Tumor is assessed at 8 weeks intervals
Secondary	Assessment of adverse events by using the NCI-CTCAE version 5.0 scale	From randomization of first patient until the end of treatment,	Approximately 36 months
Secondary	Quality of life questionnaire	From date of randomization until the date of end of treatment	questionnaire is assessed at 8 weeks intervals
Secondary	Time to Deterioration	It is defined as the time between the date of randomization and the first time the patient has a WHO = 2 during treatment.	Approximately 36 months