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

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ClinicalTrials.gov Identifier: NCT03829462
Recruitment Status : Recruiting
First Posted : February 4, 2019
Last Update Posted : May 9, 2019
Sponsor:
Information provided by (Responsible Party):
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 TAS 102) no longer have treatment options available while maintaining a good performance status which would allow them to receive a new treatment

Condition or disease Intervention/treatment Phase
Metastatic Colorectal Cancer (mCRC) Drug: Regorafenib Drug: Irinotecan Phase 3

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


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 78 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : March 28, 2019
Estimated Primary Completion Date : June 2022
Estimated Study Completion Date : June 2023

Resource links provided by the National Library of Medicine


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




Primary Outcome Measures :
  1. Overall survival [ Time Frame: Approximately 36 months ]
    From randomization of first patient until the datebase cut-off


Secondary Outcome Measures :
  1. Progression-free survival (PFS) [ Time Frame: Approximately 36 months ]
    From randomization of first patient until the datebase cut-off,

  2. Disease control rate (DCR) [ Time Frame: Tumor is assessed every 8 weeks ]
    From randomization of first patient until the datebase cut-off,

  3. Objective response rate (OOR) [ Time Frame: Tumor is assessed at 8 weeks intervals ]
    From randomization of first patient until the datebase cut-off,

  4. Assessment of adverse events by using the NCI-CTCAE version 5.0 scale [ Time Frame: Approximately 36 months ]
    From randomization of first patient until the end of treatment,

  5. Quality of life questionnaire [ Time Frame: questionnaire is assessed at 8 weeks intervals ]
    From date of randomization until the date of end of treatment



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Signed informed consent obtained before any study specific procedures
  • Male or female ≥ 18 years of age
  • Histological or cytological 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 8 weeks after the last study drug administration of Regorafenib and 12 weeks 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03829462


Contacts
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Contact: Jean-Pierre BLEUSE, MD 0467613102 ext +33 jean-pierre.bleuse@icm.unicancer.fr

Locations
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France
CRLC Val d'Aurelle-Paul Lamarque Recruiting
Montpellier, France, 34298
Contact: Emmanuelle SAMALIN, MD         
Principal Investigator: Emmanuelle SAMALIN, MD         
Sponsors and Collaborators
Institut du Cancer de Montpellier - Val d'Aurelle
Investigators
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Study Chair: Emmanuelle SAMALIN, MD Institut régional du cancer de Montpellier

Publications:
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Responsible Party: Institut du Cancer de Montpellier - Val d'Aurelle
ClinicalTrials.gov Identifier: NCT03829462     History of Changes
Other Study ID Numbers: PROICM 2018-01 NEX
First Posted: February 4, 2019    Key Record Dates
Last Update Posted: May 9, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Institut du Cancer de Montpellier - Val d'Aurelle:
REGIRI
regorafenib
irinotecan

Additional relevant MeSH terms:
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Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Irinotecan
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents