Clinical trial NCT03829462: Assessing a Regorafenib-irinotecan Combination Versus Regorafenib Alone in Metastatic Colorectal Cancer Patients
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Metastatic Colorectal Cancer (mCRC)
Keywords: REGIRI
regorafenib
irinotecan
Lead sponsor: Institut du Cancer de Montpellier - Val d'Aurelle
Sponsor class: OTHER
First posted: 2019-02-04
Enrollment: 66
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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

Detailed 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

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 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

Primary outcomes:
measure: Overall survival
timeFrame: Approximately 36 months
Secondary outcomes:
measure: Progression-free survival (PFS)
timeFrame: Approximately 36 months
measure: Disease control rate (DCR)
timeFrame: Tumor is assessed every 8 weeks
measure: Objective response rate (OOR)
timeFrame: Tumor is assessed at 8 weeks intervals
measure: Assessment of adverse events by using the NCI-CTCAE version 5.0 scale
timeFrame: Approximately 36 months
measure: Quality of life questionnaire
timeFrame: questionnaire is assessed at 8 weeks intervals
measure: Time to Deterioration
timeFrame: Approximately 36 months
Other outcomes:
Locations:
city: Nice
country: France
facility: Centre Antoine Lacassagne
state: Alpes-Maritimes
city: Caen
country: France
facility: Centre François Baclesse
state: Basse-Normandie
city: Rennes
country: France
facility: Hôpital Pontchaillou
state: Ile Et Vilaine
city: Reims
country: France
facility: Hôpital Robert Debré
state: Marne
city: Reims
country: France
facility: Institut Godinot
state: Marne
city: Perpignan
country: France
facility: Hôpital Saint-Jean
state: Pyrénées-orientales
city: Lyon
country: France
facility: Centre Léon Bérard
state: Rhône
city: Lyon
country: France
facility: Hôpital privé Jean Mermoz
state: Rhône
city: Villejuif
country: France
facility: Institut Gustave Roussy
state: Val De Marne
city: Montpellier
country: France
facility: CRLC Val d'Aurelle-Paul Lamarque
city: Paris
country: France
facility: Hôpital Européen Georges Pompidou
Study officials:
affiliation: Institut régional du cancer de Montpellier
name: Emmanuelle SAMALIN, MD
role: STUDY_CHAIR
References:
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.
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.
citation: 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.
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.