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Neoadjuvant Regorafenib in Combination With Nivolumab and Short-course Radiotherapy in Intermediate-risk, Stage II-III Rectal Cancer (REGINA)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04503694
Recruitment Status : Recruiting
First Posted : August 7, 2020
Last Update Posted : January 18, 2023
Sponsor:
Information provided by (Responsible Party):
Jules Bordet Institute

Brief Summary:

This is a multicenter, single-arm, phase II study of nivolumab in combination with regorafenib in subjects with locally-advanced rectal cancer who are eligible for a curative treatment including pre-operative SCRT and TME. The study is based on the Simon's two-stage design and a maximum of 60 subjects will be enrolled. In addition to the standard efficacy interim analysis according to the statistical design, a safety interim analysis will be performed on the first 6 subjects who have completed the study treatment to ensure safe continuation of the study investigation.

Eligible subjects will be treated according to the following sequential treatment plan:

  • Induction treatment: This consists of treatment with nivolumab (240 mg intravenously, on day 1 and 15) and regorafenib (80 mg/day orally, from day 1 to 14)
  • Standard SCRT: This consists of 25 Gy delivered in 5 fractions (from day 22 to 26)
  • Consolidation treatment: This consists of treatment with nivolumab (240 mg intravenously, on day 29, 43 and 57) and regorafenib (80 mg/day orally, from day 29 to 49)
  • Surgery: Surgical resection will be performed according to the principles of TME (between day 74 and 87, i.e., between 7 to 8 weeks after completion of SCRT)
  • Adjuvant chemotherapy: Administration of adjuvant chemotherapy will be left to the discretion of the treating physician

The study also includes translational procedures (i.e. collection of tumour biopsies, blood samples and stool samples at pre-specified time points) for exploratory molecular and immune contexture analyses. These are mandatory for all study subjects.


Condition or disease Intervention/treatment Phase
Rectal Cancer Stage II Rectal Cancer Stage III Drug: Nivolumab 10 MG/ML Intravenous Solution Drug: Regorafenib 40 MG Oral Tablet Radiation: Radiotherapy Procedure: Surgery Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Trial of Neoadjuvant Regorafenib in Combination With Nivolumab and Short-course Radiotherapy in Intermediate-risk, Stage II-III Rectal Cancer
Actual Study Start Date : March 25, 2021
Estimated Primary Completion Date : September 2023
Estimated Study Completion Date : September 2028

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Single arm

Eligible subjects will be treated according to the following plan:

  • Induction treatment: Consists of treatment with nivolumab (240 mg intravenously on day 1 and 15) and regorafenib (80 mg/day orally from day 1 to 14)
  • Standard SCRT: Consists of 25 Gy delivered in 5 fractions (from day 22 to 26)
  • Consolidation treatment: Consists of treatment with nivolumab (240 mg intravenously on day 29, 43 and 57) and regorafenib (80 mg/day orally from day 29 to 49)
  • Surgery: Surgical resection will be performed according to the principles of TME (between day 74 and 87, i.e., between 7 to 8 weeks after completion of SCRT)
  • Adjuvant chemotherapy: Administration of adjuvant chemotherapy will be left to the discretion of the treating physician The study also includes translational procedures (collection of tumour biopsies, blood and stool samples at pre-specified time points) for exploratory molecular and immune contexture analyses. These are mandatory for all study subjects.
Drug: Nivolumab 10 MG/ML Intravenous Solution

Nivolumab will be given at a dose of 240 mg during the pre-operative phase only as indicated below:

  • On day 1 and 15, during the "Induction treatment"
  • On day 29, 43 and 57, during the "Consolidation treatment"

Drug: Regorafenib 40 MG Oral Tablet

Regorafenib will be administered orally once a day at a dose of 80 mg/day (2 tablets of 40 mg), during the pre-operative phase only as indicated below:

  • From day 1 to 14, during the "Induction treatment"
  • From day 29 to 49, during the "Consolidation treatment"

Radiation: Radiotherapy
All study subjects will receive 5 daily fractions of radiotherapy. Each fraction will consist of 5 Gy for a total dose of 25 Gy. Radiotherapy is to start on day 22 and to finish on day 26.

Procedure: Surgery
Subject will undergo surgical resection of the primary tumour in the rectum between day 74 and 87. Surgery must be performed according to the principles of total mesorectal excision as described by Heald et al. The type of surgical approach (low anterior resection or abdominoperineal resection, etc.) will be left to the discretion of the treating surgeon.




Primary Outcome Measures :
  1. Evaluation of the efficacy of the combination of nivolumab and regorafenib when administered before and after standard, pre-operative short-course radiation therapy. [ Time Frame: immediately after the surgery ]

    Measurement of the pathological complete response rate. This will be evaluated in the mITT population and defined as the absence of viable tumour cells in the surgical specimens.

    Rate of pCR will be presented as number of subjects and percentage, along with a 95% confidence interval.



Secondary Outcome Measures :
  1. Assessment of the toxicity according to the NCI CTCAE version 5.0. [ Time Frame: 5 months after the last administration of study treatment ]
    The type, frequency and severity of adverse events will be analysed in the mITT population.

  2. Assessment of the proportion of subjects who complete systemic treatment, radiotherapy and surgery according to the study protocol. [ Time Frame: immediately after the surgery ]
    This is will be evaluated in the Intention to Treat (ITT) population to assess the feasibility of combining regorafenib with nivolumab in the setting of locally-advanced rectal cancer as demonstrated by subject compliance with the investigational strategy, SCRT and surgery

  3. Evaluation of the efficacy of the combination of nivolumab and regorafenib when administered before and after standard, pre-operative short-course radiation therapy. [ Time Frame: immediately after the surgery ]
    RO resection rate will be analysed in the mITT population and defined as the proportion of subjects who undergo surgical resection of the tumour with clear margins (i.e., >1 mm).

  4. Evaluation of the immune activation induced by the investigational treatment regorafenib with nivolumab [ Time Frame: Before (biopsy at week 3) and immediately after surgery (surgical specimen) ]
    CD3 and CD8 T-cells infiltrate increase in post-treatment tumour tissue samples

  5. Evaluation of the efficacy of the combination of nivolumab and regorafenib when administered before and after standard, pre-operative short-course radiation therapy. [ Time Frame: immediately after the surgery ]
    The rate of complete/near complete pathological tumour regression will be evaluated in the mITT population and defined as the proportion of subjects who achieve pathological tumour regression grade (pTRG) 3 or 4 according to the Dworak pTRG score.

  6. Evaluation of the efficacy of the combination of nivolumab and regorafenib when administered before and after standard, pre-operative short-course radiation therapy. [ Time Frame: Before surgery ]
    The Objective tumour response (ORR) will be evaluated in the mITT population and defined as the proportion of subjects who achieve a partial or complete response according to RECIST criteria version 1.1 and based on the pre-surgery, pelvic MRI.

  7. Evaluation of the efficacy of the combination of nivolumab and regorafenib when administered before and after standard, pre-operative short-course radiation therapy. [ Time Frame: 5 years after end of treatment ]
    The Event-free survival (EFS) will be evaluated in the mITT population and calculated from the date of registration to the date of occurrence of any of the following events: progression of disease that precludes surgery, local or distant recurrence, or death due to any cause. Kaplan Meier methods will be used to calculate EFS rates along with 95% confidence intervals.

  8. Evaluation of the efficacy of the combination of nivolumab and regorafenib when administered before and after standard, pre-operative short-course radiation therapy. [ Time Frame: 5 years after end of treatment ]
    The Overall survival (OS) will be evaluated in the mITT population and calculated from the date of registration to the date of death from any cause. Kaplan Meier methods will be used to calculate OS rates along with 95% confidence intervals.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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:

  1. Female or Male
  2. Age ≥ 18 years old
  3. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
  4. Histologically or cytologically verified adenocarcinoma of the rectum
  5. Tumour with distal border below the peritoneal reflection and within 15 cm from the anal verge
  6. Stage cT3/T4a and Nany or cT1-2 and N+ as documented by baseline pelvic MRI
  7. Absence of distant metastases as shown by baseline computed tomography (CT) of the thorax-abdomen or CT scan of the thorax and MRI of the abdomen
  8. Adequate haematological function as defined by absolute neutrophil count (ANC) ≥1.5 × 109/L, platelet count ≥100 × 109/L, and haemoglobin ≥9 g/dL
  9. Adequate hepatic function as defined by a total bilirubin level ≤1.5 × the upper limit of normal (ULN) range (excluding subjects with known Gilbert's syndrome), and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels ≤2.5 × ULN
  10. Adequate renal function as defined by an estimated creatinine clearance ≥30 mL/min according to the Cockcroft-Gault or Wright formula
  11. Negative serum pregnancy test at screening (up to 28 days before treatment start) for women of childbearing potential
  12. Women of childbearing potential must agree to use of one highly effective method of contraception prior study entry, during the course of the study and at least 5 months after the last administration of study treatment.
  13. Men with childbearing potential partner must agree to use condom during the course of this study and for at least 5 months after the last administration of the study treatment.
  14. Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
  15. Absence of clinical conditions that, in the opinion of the investigator, would contraindicate neoadjuvant therapy and/or surgery
  16. Life expectancy of at least 3 months
  17. Completion of all necessary screening procedures within 28 days prior to enrolment.
  18. Signed Informed Consent form (ICF) obtained prior to any study related procedure.

Exclusion Criteria:

  1. Any prior or concurrent surgery, chemotherapy, radiotherapy, immunotherapy, biologic or hormonal therapy for rectal cancer. Concurrent use of hormones for noncancer-related conditions (i.e., insulin for diabetes and hormone replacement therapy) is acceptable.
  2. Any contraindication to pelvic irradiation as evaluated by the investigator
  3. Prior organ transplantation, including allogeneic stem cell transplantation
  4. Clinically significant acute or chronic infections including, among others:

    • known history of testing positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
    • known history of testing positive for hepatitis B virus (HBV) surface antigen or anti-hepatitis C virus (HCV) antibody and confirmatory HCV ribonucleic acid (RNA) test
  5. Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent (subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible)
  6. Systemic corticosteroids administered as hormone replacement or as immunosuppressants at doses exceeding 10 mg/day of prednisone or equivalent. Other immunosuppressive medications including, but not limited to methotrexate, azathioprine, and TNF-α blockers. Use of immunosuppressive medications for the management of treatment-related AEs or in subjects with contrast allergies is acceptable. A temporary period of steroids is allowed for different indications, at the discretion of the investigator (i.e., chronic obstructive pulmonary disease, radiation, nausea, etc.). Administration of steroids through a route known to result in a minimal systemic exposure [topical, intranasal, intro-ocular, or inhalation] is acceptable.
  7. Known severe hypersensitivity reactions to the investigational treatments, or any excipients or non-investigational medicinal products or concomitant medications
  8. Pregnant and/or lactating women
  9. Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke, myocardial infarction, unstable angina, congestive heart failure, or serious cardiac arrhythmia requiring medication
  10. Prior myocarditis
  11. Known history of immune colitis, immune pneumonitis, pulmonary fibrosis or other medical conditions (for example, inflammatory bowel disease, uncontrolled asthma), which, in the opinion of the Investigator, might impair the subject's tolerance of trial treatment
  12. Vaccination within 28 days of the first dose of study treatment and while on trial (except for administration of inactivated vaccines)
  13. Other invasive malignancy within 2 years except for non-invasive malignancies such as cervical carcinoma in situ, non-melanomatous carcinoma of the skin or ductal carcinoma in situ of the breast that has/have been surgically cured. Anti-neoplastic treatment received in the past for malignancies cured 2 or more years before enrolment are permitted.
  14. Any investigational anti-cancer therapy other than the protocol specified therapies.
  15. Strong inhibitors of CYP3A4 activity (e.g. clarithromycin, grapefruit juice, itraconazole, ketoconazole, posaconazole, telithromycin and voriconazole), strong UGT1A9 inhibitors (e.g. mefenamic acid, diflunisal, and niflumic acid), and strong inducers of CYP3A4 (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital and St. John's wort) from 28 days before study enrolment up to the end of study treatment.

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): NCT04503694


Contacts
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Contact: Francesco Sclafani, MD 0032 2 541 7397 francesco.sclafani@bordet.be
Contact: Chloé Velghe 0032 2 541 7366 ctsu.regina@bordet.be

Locations
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Belgium
Institut Jules Bordet Recruiting
Brussels, Belgium, 1000
Contact: Alain Hendlisz, MD    0032 2 541 31 11    alain.hendlisz@bordet.be   
Erasme Recruiting
Brussels, Belgium, 1070
Contact: Jean-Luc Van Laethem, MD    0032 2 555 3714    jean-luc.van.laethem@ulb.ac.be   
Chirec Delta Recruiting
Bruxelles, Belgium, 1160
Contact: Francesco Puleo, MD    0032 24 34 81 05    francesco.puleo@chirec.be   
Cliniques Universitaires Saint-Luc Recruiting
Bruxelles, Belgium, 1200
Contact: Marc Van Den Eynde, MD    0032 2 764 51 06    marc.vandeneynde@uclouvain.be   
Grand Hopital de Charleroi Recruiting
Charleroi, Belgium, 6000
Contact: Javier Carasco, MD    0032 7 10 47 32    javier.carrasco@ghdc.be   
UZAntwerpen Recruiting
Edegem, Belgium, 2650
Contact: Hans Prenen, MD    0032 3 821 43 66      
UZ Gent Recruiting
Gent, Belgium, 9000
Contact: Karen Geboes, MD    0032 9 332 23 71    KAREN.GEBOES@uzGent.be   
AZ Groeninge Recruiting
Kortrijk, Belgium, 8500
Contact: Philippe Vergauwe, MD    0032 56 63 33 00    philippe.vergauwe@azgroeninge.be   
CHU Ambroise Paré Recruiting
Mons, Belgium, 7000
Contact: Marie Diaz, MD    0032 65 41 37 38    marie.diaz@hap.be   
CHR Namur Recruiting
Namur, Belgium, 5000
Contact: Yeter Gökburun, MD    +32 81 72 78 30    yeter.gokburun@chrsm.be   
France
Centre Hospitalier Regional Universitaire de Besancon - Hopital Jean Minjoz Not yet recruiting
Besancon, France, 25030
Contact: Christophe BORG         
Centre de Lutte Contre le Cancer Georges Francois Leclerc Not yet recruiting
Dijon, France, 21079
Contact: Francois GHIRINGHELLI         
Centre Hospitalier Universitaire de Rouen - Hôpital Charles Nicolle Not yet recruiting
Rouen, France, 76031
Contact: Frederic DI FIORE         
Sponsors and Collaborators
Jules Bordet Institute
Investigators
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Study Chair: Francesco Sclafani, MD Jules Bordet Institute
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Responsible Party: Jules Bordet Institute
ClinicalTrials.gov Identifier: NCT04503694    
Other Study ID Numbers: IJB-REGINA-2020
First Posted: August 7, 2020    Key Record Dates
Last Update Posted: January 18, 2023
Last Verified: July 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Rectal Neoplasms
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Intestinal Diseases
Rectal Diseases
Nivolumab
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action