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Rectal Cancer Stage IIPhase 2REGINANCT04503694

Neoadjuvant Regorafenib in Combination With Nivolumab and Short-course Radiotherapy in Stage II-III Rectal Cancer

A Phase 2 study testing Nivolumab 10 MG/ML Intravenous Solution, Regorafenib 30 MG Oral Tablet and Radiotherapy in people with Rectal Cancer Stage II and Rectal Cancer Stage III, run by Jules Bordet Institute at 9 sites in Belgium.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record
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Trial 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(or watch \& wait approach). Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Nivolumab 10 MG/ML Intravenous Solution, Regorafenib 30 MG Oral Tablet and Radiotherapy
Could I receive a placebo?
No, everyone receives an active treatment
How many people
72 participants
Where
9 sitesBelgium
Study dates
25 Mar 2021to Dec 2032
Phase
Phase 2
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Female or Male
  • Age ≥ 18 years old
  • Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
  • Histologically or cytologically verified adenocarcinoma of the rectum
  • Tumour with distal border below the peritoneal reflection and within 15 cm from the anal verge
  • Stage cT3/T4a and Nany or cT1-2 and N+ as documented by baseline pelvic MRI
Show all 18Show fewer
  • 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
  • Adequate haematological function as defined by absolute neutrophil count (ANC) ≥1.5 × 109/L, platelet count ≥100 × 109/L, and haemoglobin ≥9 g/dL
  • 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 alanine aminotransferase (ALT) levels ≤2.5 × ULN
  • Adequate renal function as defined by an estimated creatinine clearance ≥30 mL/min according to the Cockcroft-Gault or Wright formula
  • Negative serum pregnancy test at screening (up to 7 days before treatment start) for women of childbearing potential
  • 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.
  • 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.
  • 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
  • Absence of clinical conditions that, in the opinion of the investigator, would contraindicate neoadjuvant therapy and/or surgery
  • Life expectancy of at least 3 months
  • Completion of all necessary screening procedures within 28 days prior to enrolment.
  • Signed Informed Consent form (ICF) obtained prior to any study related procedure.

Who cannot join

  • 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.
  • Any contraindication to pelvic irradiation as evaluated by the investigator
  • Prior organ transplantation, including allogeneic stem cell transplantation
  • 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
Show all 19Show fewer
  • 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)
  • 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.
  • Known severe hypersensitivity reactions to the investigational treatments, or any excipients or non-investigational medicinal products or concomitant medications
  • Pregnant and/or lactating women
  • Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke, myocardial infarction, unstable angina, congestive heart failure, uncontrolled arterial hypertension, or serious cardiac arrhythmia requiring medication
  • Prior myocarditis
  • 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
  • Vaccination within 28 days of the first dose of study treatment and while on trial (except for administration of inactivated vaccines)
  • 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.
  • Any investigational anti-cancer therapy other than the protocol specified therapies.
  • 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.
  • Major surgery within 28 days of the first dose of study treatment
  • Presence of gastrointenstinal perforation of fistula

Trial locations and contacts

9 sites in 1 country.

9 sites in 1 country

Belgium9 sites

  • Institut Jules Bordet

    Anderlecht, 1070

  • Chirec Delta

    Brussels, 1160

  • Cliniques Universitaires Saint-Luc

    Brussels, 1200

  • UZAntwerpen

    Edegem, 2650

  • UZ Gent

    Ghent, 9000

  • Grand Hopital de Charleroi

    Gilly, 6060

  • AZ Groeninge

    Kortrijk, 8500

  • CHU Ambroise Paré

    Mons, 7000

  • CHR Namur

    Namur, 5000

Other trials in Belgium

About this study

Official title: A Phase II Trial of Neoadjuvant Regorafenib in Combination With Nivolumab and Short-course Radiotherapy in Stage II-III Rectal Cancer

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(or watch \& wait approach). 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:

Read more
  • Induction treatment: This consists of treatment with nivolumab (240 mg intravenously, on day 1 and 15) and regorafenib (60 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 (60 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). As an alternative to surgery, subjects who achieve cCR can be offered a watch \& wait approach.
  • 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.

Being tested
Nivolumab 10 MG/ML Intravenous Solution, Regorafenib 30 MG Oral Tablet, Radiotherapy, Surgery, Non-operative Management
Medical subject headings
Rectal Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Nivolumab 10 MG/ML Intravenous SolutionDrug

    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"

  • Regorafenib 30 MG Oral TabletDrug

    Regorafenib will be administered orally once a day at a dose of 60 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"

  • RadiotherapyRadiation

    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.

  • SurgeryProcedure or 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.

  • Non-operative ManagementProcedure or surgery

    Subjects who achieve cCR after pre-operative treatment can, after discussion with the local investigator, decline surgery and opt for a non-operative management. cCR will need to be confirmed between day 67 and 74 by the following procedures per local practise:

    • Digital rectal examination
    • Rectal endoscopy
    • Rectal MRI Subjects who achieve near cCR at the first assessment time point after pre-operative treatment, can be re-assessed 6 to 8 weeks later with the same procedures. If cCR is diagnosed, they can opt for watch \& wait, otherwise they would need to undergo surgical resection.

    Subjects who opt for a non-operative management will be followed for tumour recurrence and survival for 5 years after end of treatment visit. Follow-up for these subjects will be more intensive than that for subjects undergoing surgery

Study groups in NCT04503694
Study groupRoleWhat they receive
Single armExperimental* Induction treatment: treatment with nivolumab (240 mg intravenously on day 1 and 14) and regorafenib (60 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: treatment with nivolumab (240 mg intravenously on day 29, 43 and 57) and regorafenib (60 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). As an alternative to surgery, subjects who achieve cCR can be offered a watch \& wait approach. * 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.
Receives: Drug: Nivolumab 10 MG/ML Intravenous Solution; Drug: Regorafenib 30 MG Oral Tablet; Radiation: Radiotherapy; Procedure: Surgery; Procedure: Non-operative Management

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Evaluation of the efficacy of the combination of nivolumab and regorafenib when administered before and after standard, pre-operative short-course radiation therapy.

    Measurement of the clinical (cCR) and pathological complete response (pCR) rate in subjects with pMMR/MSS tumours 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.

    Measured: immediately after the surgery

Secondary outcomes (7)

  1. Assessment of the toxicity according to the NCI CTCAE version 5.0.

    The type, frequency and severity of adverse events will be analysed in the mITT population.

    Measured: 5 months after the last administration of study treatment

  2. Assessment of the proportion of subjects who complete systemic treatment, radiotherapy and surgery according (if perfomed) to the study protocol.

    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 (if performed)

    Measured: immediately after the surgery (if performed)

  3. Evaluation of the efficacy of the combination of nivolumab and regorafenib when administered before and after standard, pre-operative short-course radiation therapy.

    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).

    Measured: immediately after the surgery (if performed)

  4. Evaluation of the immune activation induced by the investigational treatment regorafenib with nivolumab

    CD3 and CD8 T-cells infiltrate increase in post-treatment tumour tissue samples

    Measured: Before (biopsy at week 3) and immediately after surgery (surgical specimen) (if performed)

  5. Evaluation of the efficacy of the combination of nivolumab and regorafenib when administered before and after standard, pre-operative short-course radiation therapy.

    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.

    Measured: immediately after the surgery (if performed)

  6. Evaluation of the efficacy of the combination of nivolumab and regorafenib when administered before and after standard, pre-operative short-course radiation therapy.

    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.

    Measured: 5 years after end of treatment

  7. Evaluation of the efficacy of the combination of nivolumab and regorafenib when administered before and after standard, pre-operative short-course radiation therapy.

    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.

    Measured: 5 years after end of treatment

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted7 Aug 2020
  2. Study start25 Mar 2021
  3. Primary completion31 Dec 2026 (estimated)
  4. Study completionDec 2032 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
72 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04503694
Sponsor's protocol ID
IJB-REGINA-2020
Other IDs
2024-516554-22-00
Acronym
REGINA
Status last verified
May 2026
First submitted
28 Jul 2020
Last updated
22 May 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Undecided

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Nivolumab 10 MG/ML Intravenous Solution, Regorafenib 30 MG Oral Tablet and Radiotherapy in people with Rectal Cancer Stage II and Rectal Cancer Stage III, run by Jules Bordet Institute at 9 sites in Belgium.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 18 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: under way, not looking for participants, as of the sponsor's last update on 22 May 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 9 sites in Belgium. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04503694.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 May 2026.

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