<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04503694</url>
  </required_header>
  <id_info>
    <org_study_id>IJB-REGINA-2020</org_study_id>
    <nct_id>NCT04503694</nct_id>
  </id_info>
  <brief_title>Neoadjuvant Regorafenib in Combination With Nivolumab and Short-course Radiotherapy in Stage II-III Rectal Cancer</brief_title>
  <acronym>REGINA</acronym>
  <official_title>A Phase II Trial of Neoadjuvant Regorafenib in Combination With Nivolumab and Short-course Radiotherapy in Stage II-III Rectal Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Jules Bordet Institute</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Jules Bordet Institute</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a multicenter, single-arm, phase II study of nivolumab in combination with&#xD;
      regorafenib in subjects with locally-advanced rectal cancer who are eligible for a curative&#xD;
      treatment including pre-operative SCRT and TME(or watch &amp; wait approach). The study is based&#xD;
      on the Simon's two-stage design and a maximum of 60 subjects will be enrolled. In addition to&#xD;
      the standard efficacy interim analysis according to the statistical design, a safety interim&#xD;
      analysis will be performed on the first 6 subjects who have completed the study treatment to&#xD;
      ensure safe continuation of the study investigation.&#xD;
&#xD;
      Eligible subjects will be treated according to the following sequential treatment plan:&#xD;
&#xD;
        -  Induction treatment: This consists of treatment with nivolumab (240 mg intravenously, on&#xD;
           day 1 and 15) and regorafenib (80 mg/day orally, from day 1 to 14)&#xD;
&#xD;
        -  Standard SCRT: This consists of 25 Gy delivered in 5 fractions (from day 22 to 26)&#xD;
&#xD;
        -  Consolidation treatment: This consists of treatment with nivolumab (240 mg&#xD;
           intravenously, on day 29, 43 and 57) and regorafenib (80 mg/day orally, from day 29 to&#xD;
           49)&#xD;
&#xD;
        -  Surgery: Surgical resection will be performed according to the principles of TME&#xD;
           (between day 74 and 87, i.e., between 7 to 8 weeks after completion of SCRT). As an&#xD;
           alternative to surgery, subjects who achieve cCR can be offered a watch &amp; wait approach.&#xD;
&#xD;
        -  Adjuvant chemotherapy: Administration of adjuvant chemotherapy will be left to the&#xD;
           discretion of the treating physician&#xD;
&#xD;
      The study also includes translational procedures (i.e. collection of tumour biopsies, blood&#xD;
      samples and stool samples at pre-specified time points) for exploratory molecular and immune&#xD;
      contexture analyses. These are mandatory for all study subjects.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">March 25, 2021</start_date>
  <completion_date type="Anticipated">September 2028</completion_date>
  <primary_completion_date type="Anticipated">September 2023</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <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.</measure>
    <time_frame>immediately after the surgery</time_frame>
    <description>Measurement of the pathological response rate. This will be evaluated in the mITT population and defined as the absence of viable tumour cells in the surgical specimens.&#xD;
Rate of pCR will be presented as number of subjects and percentage, along with a 95% confidence interval.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Assessment of the toxicity according to the NCI CTCAE version 5.0.</measure>
    <time_frame>5 months after the last administration of study treatment</time_frame>
    <description>The type, frequency and severity of adverse events will be analysed in the mITT population.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of the proportion of subjects who complete systemic treatment, radiotherapy and surgery according (if perfomed) to the study protocol.</measure>
    <time_frame>immediately after the surgery (if performed)</time_frame>
    <description>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)</description>
  </secondary_outcome>
  <secondary_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.</measure>
    <time_frame>immediately after the surgery (if performed)</time_frame>
    <description>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., &gt;1 mm).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evaluation of the immune activation induced by the investigational treatment regorafenib with nivolumab</measure>
    <time_frame>Before (biopsy at week 3) and immediately after surgery (surgical specimen) (if performed)</time_frame>
    <description>CD3 and CD8 T-cells infiltrate increase in post-treatment tumour tissue samples</description>
  </secondary_outcome>
  <secondary_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.</measure>
    <time_frame>immediately after the surgery (if performed)</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_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.</measure>
    <time_frame>Before surgery</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_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.</measure>
    <time_frame>5 years after end of treatment</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_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.</measure>
    <time_frame>5 years after end of treatment</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">60</enrollment>
  <condition>Rectal Cancer Stage II</condition>
  <condition>Rectal Cancer Stage III</condition>
  <arm_group>
    <arm_group_label>Single arm</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Induction treatment: treatment with nivolumab (240 mg intravenously on day 1 and 15) and regorafenib (80 mg/day orally from day 1 to 14)&#xD;
Standard SCRT: consists of 25 Gy delivered in 5 fractions (from day 22 to 26)&#xD;
Consolidation treatment: treatment with nivolumab (240 mg intravenously on day 29, 43 and 57) and regorafenib (80 mg/day orally from day 29 to 49)&#xD;
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 &amp; wait approach.&#xD;
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.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nivolumab 10 MG/ML Intravenous Solution</intervention_name>
    <description>Nivolumab will be given at a dose of 240 mg during the pre-operative phase only as indicated below:&#xD;
On day 1 and 15, during the &quot;Induction treatment&quot;&#xD;
On day 29, 43 and 57, during the &quot;Consolidation treatment&quot;</description>
    <arm_group_label>Single arm</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Regorafenib 40 MG Oral Tablet</intervention_name>
    <description>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:&#xD;
From day 1 to 14, during the &quot;Induction treatment&quot;&#xD;
From day 29 to 49, during the &quot;Consolidation treatment&quot;</description>
    <arm_group_label>Single arm</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>Radiotherapy</intervention_name>
    <description>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.</description>
    <arm_group_label>Single arm</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Surgery</intervention_name>
    <description>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.</description>
    <arm_group_label>Single arm</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Non-operative Management</intervention_name>
    <description>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:&#xD;
Digital rectal examination&#xD;
Rectal endoscopy&#xD;
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 &amp; wait, otherwise they would need to undergo surgical resection.&#xD;
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</description>
    <arm_group_label>Single arm</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Female or Male&#xD;
&#xD;
          2. Age ≥ 18 years old&#xD;
&#xD;
          3. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1&#xD;
&#xD;
          4. Histologically or cytologically verified adenocarcinoma of the rectum&#xD;
&#xD;
          5. Tumour with distal border below the peritoneal reflection and within 15 cm from the&#xD;
             anal verge&#xD;
&#xD;
          6. Stage cT3/T4a and Nany or cT1-2 and N+ as documented by baseline pelvic MRI&#xD;
&#xD;
          7. Absence of distant metastases as shown by baseline computed tomography (CT) of the&#xD;
             thorax-abdomen or CT scan of the thorax and MRI of the abdomen&#xD;
&#xD;
          8. Adequate haematological function as defined by absolute neutrophil count (ANC) ≥1.5 ×&#xD;
             109/L, platelet count ≥100 × 109/L, and haemoglobin ≥9 g/dL&#xD;
&#xD;
          9. Adequate hepatic function as defined by a total bilirubin level ≤1.5 × the upper limit&#xD;
             of normal (ULN) range (excluding subjects with known Gilbert's syndrome), and&#xD;
             aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels ≤2.5 × ULN&#xD;
&#xD;
         10. Adequate renal function as defined by an estimated creatinine clearance ≥30 mL/min&#xD;
             according to the Cockcroft-Gault or Wright formula&#xD;
&#xD;
         11. Negative serum pregnancy test at screening (up to 28 days before treatment start) for&#xD;
             women of childbearing potential&#xD;
&#xD;
         12. Women of childbearing potential must agree to use of one highly effective method of&#xD;
             contraception prior study entry, during the course of the study and at least 5 months&#xD;
             after the last administration of study treatment.&#xD;
&#xD;
         13. Men with childbearing potential partner must agree to use condom during the course of&#xD;
             this study and for at least 5 months after the last administration of the study&#xD;
             treatment.&#xD;
&#xD;
         14. Absence of any psychological, familial, sociological or geographical condition&#xD;
             potentially hampering compliance with the study protocol and follow-up schedule; those&#xD;
             conditions should be discussed with the patient before registration in the trial&#xD;
&#xD;
         15. Absence of clinical conditions that, in the opinion of the investigator, would&#xD;
             contraindicate neoadjuvant therapy and/or surgery&#xD;
&#xD;
         16. Life expectancy of at least 3 months&#xD;
&#xD;
         17. Completion of all necessary screening procedures within 28 days prior to enrolment.&#xD;
&#xD;
         18. Signed Informed Consent form (ICF) obtained prior to any study related procedure.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Any prior or concurrent surgery, chemotherapy, radiotherapy, immunotherapy, biologic&#xD;
             or hormonal therapy for rectal cancer. Concurrent use of hormones for&#xD;
             noncancer-related conditions (i.e., insulin for diabetes and hormone replacement&#xD;
             therapy) is acceptable.&#xD;
&#xD;
          2. Any contraindication to pelvic irradiation as evaluated by the investigator&#xD;
&#xD;
          3. Prior organ transplantation, including allogeneic stem cell transplantation&#xD;
&#xD;
          4. Clinically significant acute or chronic infections including, among others:&#xD;
&#xD;
               -  known history of testing positive test for human immunodeficiency virus (HIV) or&#xD;
                  known acquired immunodeficiency syndrome (AIDS)&#xD;
&#xD;
               -  known history of testing positive for hepatitis B virus (HBV) surface antigen or&#xD;
                  anti-hepatitis C virus (HCV) antibody and confirmatory HCV ribonucleic acid (RNA)&#xD;
                  test&#xD;
&#xD;
          5. Active autoimmune disease that might deteriorate when receiving an immunostimulatory&#xD;
             agent (subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid&#xD;
             disease not requiring immunosuppressive treatment are eligible)&#xD;
&#xD;
          6. Systemic corticosteroids administered as hormone replacement or as immunosuppressants&#xD;
             at doses exceeding 10 mg/day of prednisone or equivalent. Other immunosuppressive&#xD;
             medications including, but not limited to methotrexate, azathioprine, and TNF-α&#xD;
             blockers. Use of immunosuppressive medications for the management of treatment-related&#xD;
             AEs or in subjects with contrast allergies is acceptable. A temporary period of&#xD;
             steroids is allowed for different indications, at the discretion of the investigator&#xD;
             (i.e., chronic obstructive pulmonary disease, radiation, nausea, etc.). Administration&#xD;
             of steroids through a route known to result in a minimal systemic exposure [topical,&#xD;
             intranasal, intro-ocular, or inhalation] is acceptable.&#xD;
&#xD;
          7. Known severe hypersensitivity reactions to the investigational treatments, or any&#xD;
             excipients or non-investigational medicinal products or concomitant medications&#xD;
&#xD;
          8. Pregnant and/or lactating women&#xD;
&#xD;
          9. Clinically significant (i.e., active) cardiovascular disease: cerebral vascular&#xD;
             accident/stroke, myocardial infarction, unstable angina, congestive heart failure, or&#xD;
             serious cardiac arrhythmia requiring medication&#xD;
&#xD;
         10. Prior myocarditis&#xD;
&#xD;
         11. Known history of immune colitis, immune pneumonitis, pulmonary fibrosis or other&#xD;
             medical conditions (for example, inflammatory bowel disease, uncontrolled asthma),&#xD;
             which, in the opinion of the Investigator, might impair the subject's tolerance of&#xD;
             trial treatment&#xD;
&#xD;
         12. Vaccination within 28 days of the first dose of study treatment and while on trial&#xD;
             (except for administration of inactivated vaccines)&#xD;
&#xD;
         13. Other invasive malignancy within 2 years except for non-invasive malignancies such as&#xD;
             cervical carcinoma in situ, non-melanomatous carcinoma of the skin or ductal carcinoma&#xD;
             in situ of the breast that has/have been surgically cured. Anti-neoplastic treatment&#xD;
             received in the past for malignancies cured 2 or more years before enrolment are&#xD;
             permitted.&#xD;
&#xD;
         14. Any investigational anti-cancer therapy other than the protocol specified therapies.&#xD;
&#xD;
         15. Strong inhibitors of CYP3A4 activity (e.g. clarithromycin, grapefruit juice,&#xD;
             itraconazole, ketoconazole, posaconazole, telithromycin and voriconazole), strong&#xD;
             UGT1A9 inhibitors (e.g. mefenamic acid, diflunisal, and niflumic acid), and strong&#xD;
             inducers of CYP3A4 (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital and St.&#xD;
             John's wort) from 28 days before study enrolment up to the end of study treatment.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Francesco Sclafani, MD</last_name>
    <role>Study Chair</role>
    <affiliation>Jules Bordet Institute</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Francesco Sclafani, MD</last_name>
    <phone>0032 2 541 7397</phone>
    <email>francesco.sclafani@bordet.be</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Chloé Velghe</last_name>
    <phone>0032 2 541 7366</phone>
    <email>ctsu.regina@bordet.be</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Institut Jules Bordet</name>
      <address>
        <city>Brussels</city>
        <zip>1000</zip>
        <country>Belgium</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Alain Hendlisz, MD</last_name>
      <phone>0032 2 541 31 11</phone>
      <email>alain.hendlisz@bordet.be</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Erasme</name>
      <address>
        <city>Brussels</city>
        <zip>1070</zip>
        <country>Belgium</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Jean-Luc Van Laethem, MD</last_name>
      <phone>0032 2 555 3714</phone>
      <email>jean-luc.van.laethem@ulb.ac.be</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Chirec Delta</name>
      <address>
        <city>Bruxelles</city>
        <zip>1160</zip>
        <country>Belgium</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Francesco Puleo, MD</last_name>
      <phone>0032 24 34 81 05</phone>
      <email>francesco.puleo@chirec.be</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Cliniques Universitaires Saint-Luc</name>
      <address>
        <city>Bruxelles</city>
        <zip>1200</zip>
        <country>Belgium</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Marc Van Den Eynde, MD</last_name>
      <phone>0032 2 764 51 06</phone>
      <email>marc.vandeneynde@uclouvain.be</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Grand Hopital de Charleroi</name>
      <address>
        <city>Charleroi</city>
        <zip>6000</zip>
        <country>Belgium</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Javier Carasco, MD</last_name>
      <phone>0032 7 10 47 32</phone>
      <email>javier.carrasco@ghdc.be</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>UZAntwerpen</name>
      <address>
        <city>Edegem</city>
        <zip>2650</zip>
        <country>Belgium</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Hans Prenen, MD</last_name>
      <phone>0032 3 821 43 66</phone>
    </contact>
  </location>
  <location>
    <facility>
      <name>UZ Gent</name>
      <address>
        <city>Gent</city>
        <zip>9000</zip>
        <country>Belgium</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Karen Geboes, MD</last_name>
      <phone>0032 9 332 23 71</phone>
      <email>KAREN.GEBOES@uzGent.be</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>AZ Groeninge</name>
      <address>
        <city>Kortrijk</city>
        <zip>8500</zip>
        <country>Belgium</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Philippe Vergauwe, MD</last_name>
      <phone>0032 56 63 33 00</phone>
      <email>philippe.vergauwe@azgroeninge.be</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>CHU Ambroise Paré</name>
      <address>
        <city>Mons</city>
        <zip>7000</zip>
        <country>Belgium</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Marie Diaz, MD</last_name>
      <phone>0032 65 41 37 38</phone>
      <email>marie.diaz@hap.be</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>CHR Namur</name>
      <address>
        <city>Namur</city>
        <zip>5000</zip>
        <country>Belgium</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Yeter Gökburun, MD</last_name>
      <phone>+32 81 72 78 30</phone>
      <email>yeter.gokburun@chrsm.be</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Centre Hospitalier Regional Universitaire de Besancon - Hopital Jean Minjoz</name>
      <address>
        <city>Besancon</city>
        <zip>25030</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Christophe BORG</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Centre de Lutte Contre le Cancer Georges Francois Leclerc</name>
      <address>
        <city>Dijon</city>
        <zip>21079</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Francois GHIRINGHELLI</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Centre Hospitalier Universitaire de Rouen - Hôpital Charles Nicolle</name>
      <address>
        <city>Rouen</city>
        <zip>76031</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Frederic DI FIORE</last_name>
    </contact>
  </location>
  <location_countries>
    <country>Belgium</country>
    <country>France</country>
  </location_countries>
  <verification_date>July 2022</verification_date>
  <study_first_submitted>July 28, 2020</study_first_submitted>
  <study_first_submitted_qc>August 6, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">August 7, 2020</study_first_posted>
  <last_update_submitted>February 24, 2023</last_update_submitted>
  <last_update_submitted_qc>February 24, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 27, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Rectal Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Nivolumab</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04503694
org study id: IJB-REGINA-2020
nct id: NCT04503694
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
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:

        -  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). 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.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
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
description: Measurement of the pathological 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.
measure: Assessment of the toxicity according to the NCI CTCAE version 5.0.
time frame: 5 months after the last administration of study treatment
description: The type, frequency and severity of adverse events will be analysed in the mITT population.
measure: Assessment of the proportion of subjects who complete systemic treatment, radiotherapy and surgery according (if perfomed) to the study protocol.
time frame: immediately after the surgery (if performed)
description: 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)
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 (if performed)
description: 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).
measure: 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) (if performed)
description: CD3 and CD8 T-cells infiltrate increase in post-treatment tumour tissue samples
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 (if performed)
description: 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.
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: Before surgery
description: 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.
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: 5 years after end of treatment
description: 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.
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: 5 years after end of treatment
description: 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.
arm group label: Single arm
arm group type: Experimental
description: Induction treatment: 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: 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). 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.
intervention type: Drug
intervention name: Nivolumab 10 MG/ML Intravenous Solution
description: 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"
arm group label: Single arm
intervention type: Drug
intervention name: Regorafenib 40 MG Oral Tablet
description: 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"
arm group label: Single arm
intervention type: Radiation
intervention name: Radiotherapy
description: 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.
arm group label: Single arm
intervention type: Procedure
intervention name: Surgery
description: 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.
arm group label: Single arm
intervention type: Procedure
intervention name: Non-operative Management
description: 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
arm group label: Single arm
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Francesco Sclafani, MD
role: Study Chair
affiliation: Jules Bordet Institute
last name: Francesco Sclafani, MD
phone: 0032 2 541 7397
email: francesco.sclafani@bordet.be
last name: Chloé Velghe
phone: 0032 2 541 7366
email: ctsu.regina@bordet.be
facility: 
status: Recruiting
contact: 
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status: Recruiting
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status: Recruiting
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status: Recruiting
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status: Recruiting
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status: Recruiting
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status: Recruiting
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status: Recruiting
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status: Recruiting
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status: Recruiting
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status: Not yet recruiting
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status: Not yet recruiting
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status: Not yet recruiting
contact: 
country: Belgium
country: France
responsible party type: Sponsor
mesh term: Rectal Neoplasms
mesh term: Nivolumab
sharing ipd: Undecided