<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/NCT03829462</url>
  </required_header>
  <id_info>
    <org_study_id>PROICM 2018-01 NEX</org_study_id>
    <nct_id>NCT03829462</nct_id>
  </id_info>
  <brief_title>Assessing a Regorafenib-irinotecan Combination Versus Regorafenib Alone in Metastatic Colorectal Cancer Patients</brief_title>
  <acronym>NEXT-REGIRI</acronym>
  <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</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Institut du Cancer de Montpellier - Val d'Aurelle</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Institut du Cancer de Montpellier - Val d'Aurelle</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>
      Patients with metastatic colorectal cancer (mCRC) who have received all approved standard&#xD;
      treatments (except Regorafenib and TAS 102) no longer have treatment options available while&#xD;
      maintaining a good performance status which would allow them to receive a new treatment&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      A Phase III randomized trial that compared Nexiri (Nexavar® + Irinotecan) vs irinotecan or&#xD;
      versus Sorafenib alone showed a progression-free survival at two-months which was favorable&#xD;
      to the NEXIRI combination ; 59% ( IC95% : 39-66 ) versus 23% (IC95% : 10-33) and 22% (IC95%:&#xD;
      8-30) respectively.&#xD;
&#xD;
      The patients treated with Irinotecan or Sorafenib alone could receive NEXIRI combination&#xD;
      after progression and the progression-free survivals were 3,7 months (IC95% : 2,2-4,9) and&#xD;
      3,5 months (IC95% : 2,1-3,7) in patients treated with NEXIRI or after progression and 1,9&#xD;
      months (IC95% : 1,7-2,1) and 2,1 months (IC95% : 1,9-2,5) in patients treated only with&#xD;
      Irinotecan and Sorafenib respectively.&#xD;
&#xD;
      The median overall survival was higher with NEXIRI : 7,2 months (patients treated from the&#xD;
      beginning of the study) and 7,9 months (patients treated after progression and crossover)&#xD;
      versus 3 months in patients treated only with Irinotecan and 3,2 months in patients receiving&#xD;
      only Sorafenib.&#xD;
&#xD;
      The A870A rs603965 polymorphism of cyclin D1, a molecule involved in the initiation of cell&#xD;
      division, was favorable to the NEXIRI combination on overall survival with a median of 19.6&#xD;
      months versus 6.2 months for two other genotypes A/G and G/G.&#xD;
&#xD;
      Regorafenib, which is an oral signal deactivation agent with a chemical structure very&#xD;
      similar to Sorafenib, is a standard treatment in heavily pretreated mCRC patients since the&#xD;
      results of CORRECT study which compared Regorafenib to placebo on overall survival showed a&#xD;
      superiority of Regorafenib : 6,4 months versus 5 months (HR 0,774 [IC95% 0,63, 0,94]).&#xD;
&#xD;
      Sorafenib isn't approved in mCRC so the objective of this NEXT-REGIRI trial is compared&#xD;
      REGIRI combination (Regorafenib-Irinotecan) to Regorafenib alone in a phase III trial in&#xD;
      patients in progression after having received all standard treatments and bearing genotype&#xD;
      A/A of cyclin D1&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">March 28, 2019</start_date>
  <completion_date type="Anticipated">September 2025</completion_date>
  <primary_completion_date type="Anticipated">October 2024</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Overall survival</measure>
    <time_frame>Approximately 36 months</time_frame>
    <description>From randomization of first patient until the datebase cut-off</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival (PFS)</measure>
    <time_frame>Approximately 36 months</time_frame>
    <description>From randomization of first patient until the datebase cut-off,</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disease control rate (DCR)</measure>
    <time_frame>Tumor is assessed every 8 weeks</time_frame>
    <description>From randomization of first patient until the datebase cut-off,</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Objective response rate (OOR)</measure>
    <time_frame>Tumor is assessed at 8 weeks intervals</time_frame>
    <description>From randomization of first patient until the datebase cut-off,</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of adverse events by using the NCI-CTCAE version 5.0 scale</measure>
    <time_frame>Approximately 36 months</time_frame>
    <description>From randomization of first patient until the end of treatment,</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of life questionnaire</measure>
    <time_frame>questionnaire is assessed at 8 weeks intervals</time_frame>
    <description>From date of randomization until the date of end of treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to Deterioration</measure>
    <time_frame>Approximately 36 months</time_frame>
    <description>It is defined as the time between the date of randomization and the first time the patient has a WHO ≥ 2 during treatment.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">78</enrollment>
  <condition>Metastatic Colorectal Cancer (mCRC)</condition>
  <arm_group>
    <arm_group_label>Irinotecan + regorafenib (REGIRI)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>irinotecan (180 mg/m2) at day1 of each cycle + regorafenib (160 mg/day) from day 2 to day 8</description>
  </arm_group>
  <arm_group>
    <arm_group_label>regorafenib</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Regorafenib (160 mg/day) for 3 weeks followed by 1 week off</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Regorafenib</intervention_name>
    <description>regorafenib tab 40 mg i.e 160 mg/day</description>
    <arm_group_label>Irinotecan + regorafenib (REGIRI)</arm_group_label>
    <arm_group_label>regorafenib</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Irinotecan</intervention_name>
    <description>irinotecan 120 mg/m2 cycle 1, 150 mg/m2 cycle 2, 180 mg/m2 cycle 3 and more</description>
    <arm_group_label>Irinotecan + regorafenib (REGIRI)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Signed informed consent obtained before any study specific procedures&#xD;
&#xD;
          -  Male or female ≥ 18 years of age&#xD;
&#xD;
          -  Histological documentation of adenocarcinoma of the colon or rectum&#xD;
&#xD;
          -  Patients with metastatic colorectal cancer&#xD;
&#xD;
          -  Progression during or within 3 months following the last administration of approved&#xD;
             standard therapies, which must include a fluoropyrimidine (or raltitrexed),&#xD;
             oxaliplatin, irinotecan, anti VEGF therapy and an anti EGFR therapy (for RAS wild-type&#xD;
             tumors)&#xD;
&#xD;
          -  ECOG performance status ≤1&#xD;
&#xD;
          -  Life expectancy of at least 3 months&#xD;
&#xD;
          -  Patients with A/A CCND1 genotype of rs603965 CCND1&#xD;
&#xD;
          -  Adequate bone marrow, liver and renal function as assessed by the following laboratory&#xD;
             requirements conducted within 7 days of starting study treatment: Amylase and lipase&#xD;
             ≤1.5 x ULN,Total bilirubin ≤ 1.5 x ULN,Alanine aminotransferase (ALT) and aspartate&#xD;
             aminotransferase (AST) ≤ 3.0 x ULN (≤ 5 x ULN for patients with liver involvement of&#xD;
             their cancer), Alkaline phosphatase (ALP) ≤ 2.5 x ULN (≤ 5.0 x ULN for patients with&#xD;
             liver involvement for their cancer and/or have bone metastases), Platelet count ≥&#xD;
             100,000/mm3; Hemoglobin (Hb) ≥ 9 g/dL; Absolute neutrophil count (ANC) ≥ 1,500/ mm3.&#xD;
             Transfusion to meet the inclusion criterion, Serum creatinine ≤ 1.5 x ULN&#xD;
&#xD;
          -  International normalized ratio (INR) ≤ 1.5 x ULN and partialthromboplastin time (PTT)&#xD;
             or activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN unless receiving treatment&#xD;
             with therapeutic anticoagulation. Patients being treated with anticoagulant, e.g.,&#xD;
             heparin, will be allowed to participate provided no prior evidence of an underlying&#xD;
             abnormality in these parameters exists. Close monitoring of at least weekly&#xD;
             evaluations will be performed until INR and PTT are stable based on a pre-dose&#xD;
             measurement as defined by the local standard of care&#xD;
&#xD;
          -  Women of childbearing potential must have a blood or urine pregnancy test performed a&#xD;
             maximum of 7 days before start of study treatment, and a negative result must be&#xD;
             documented before start of study treatment&#xD;
&#xD;
          -  Women of childbearing potential and men must agree to use adequate contraception&#xD;
             before entering the study until at least respectively 7 months and 4 months after the&#xD;
             last study drug administration of Regorafenib and respectively 6 months and 3 months&#xD;
             after the last study drug administration of Irinotecan. The investigator or a&#xD;
             designated associate is requested to advise the patient on how to achieve an adequate&#xD;
             birth control. Adequate contraception is defined in the study as any medically&#xD;
             recommended method (or combination of methods) as per standard of care.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients with A/G or G/G CCND1 genotype of rs603965 CCND1&#xD;
&#xD;
          -  Prior treatment with regorafenib or sorafenib&#xD;
&#xD;
          -  Prior treatment with TAS 102&#xD;
&#xD;
          -  Major surgical procedure, open biopsy, or significant traumatic injury within 28 days&#xD;
             before start of study drug&#xD;
&#xD;
          -  Pregnant or breast-feeding subjects. Women of childbearing potential must have a&#xD;
             pregnancy test performed a maximum of 7 days before start of treatment, and a negative&#xD;
             result must be documented before start of study drug&#xD;
&#xD;
          -  Congestive heart failure ≥ New York Heart Association (NYHA) class 2&#xD;
&#xD;
          -  Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3&#xD;
             months)&#xD;
&#xD;
          -  Myocardial infarction less than 6 months before start of study drug&#xD;
&#xD;
          -  Cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are&#xD;
             permitted)&#xD;
&#xD;
          -  Uncontrolled hypertension. (Systolic blood pressure &gt; 140 mmHg or diastolic pressure &gt;&#xD;
             90 mmHg despite optimal medical management)&#xD;
&#xD;
          -  Pleural effusion or ascites that causes respiratory compromise (≥ NCI-CTCAE V5.0 Grade&#xD;
             2 dyspnea)&#xD;
&#xD;
          -  Ongoing infection &gt; Grade 2 NCI-CTCAE V5.0&#xD;
&#xD;
          -  Known history of human immunodeficiency virus (HIV) infection&#xD;
&#xD;
          -  Active hepatitis B or C, or chronic hepatitis B or C requiring treatment with&#xD;
             antiviral therapy&#xD;
&#xD;
          -  Patients with seizure disorder requiring medication&#xD;
&#xD;
          -  History of organ allograft&#xD;
&#xD;
          -  Patients with evidence or history of any bleeding diathesis, irrespective of severity&#xD;
&#xD;
          -  Any hemorrhage or bleeding event ≥ NCI-CTC V5.0 Grade 3 within 4 weeks prior to the&#xD;
             start of study medication&#xD;
&#xD;
          -  Non-healing wound, ulcer, or bone fracture&#xD;
&#xD;
          -  Dehydration NCI-CTCAE V5.0 Grade ≥ 1&#xD;
&#xD;
          -  Substance abuse, medical, psychological or social conditions that may interfere with&#xD;
             the subject's participation in the study or evaluation of the study results&#xD;
&#xD;
          -  Known hypersensitivity to any of the study drugs, study drug classes, or excipients in&#xD;
             the formulation&#xD;
&#xD;
          -  Any illness or medical conditions that are unstable or could&#xD;
&#xD;
          -  jeopardize the safety of the subject and his/her compliance in the study&#xD;
&#xD;
          -  Persistent proteinuria of NCI-CTCAE V5.0 Grade 3 (&gt; 3.5g/24 hours)&#xD;
&#xD;
          -  Patients unable to swallow oral medications&#xD;
&#xD;
          -  Any malabsorption condition&#xD;
&#xD;
          -  Chronic inflammatory bowel disease and / or bowel obstruction&#xD;
&#xD;
          -  Unresolved toxicity higher than NCI-CTCAE V.5.0 Grade 1 attributed to any prior&#xD;
             therapy/procedure excluding alopecia, hypothyroidism and oxaliplatin induced&#xD;
             neurotoxicity ≤ Grade 2&#xD;
&#xD;
          -  Concomitant participation or participation within the last 30 days in another clinical&#xD;
             trial&#xD;
&#xD;
          -  Systemic anticancer therapy during this trial or within 4 weeks before randomization&#xD;
&#xD;
          -  Concomitant intake of st John's wort&#xD;
&#xD;
          -  Live attenuated vaccines are prohibited 10 days before the treatment, during the&#xD;
             treatment and 6 months after the termination of treatment&#xD;
&#xD;
          -  History of gastrointestinal fistula or perforation&#xD;
&#xD;
          -  Previous or concurrent cancer that is distinct in primary site or histology from&#xD;
             colorectal cancer within 5 years prior to study inclusion, except for curatively&#xD;
             treated cervical cancer in situ, non-melanoma skin cancer and superficial&#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>Emmanuelle SAMALIN, MD</last_name>
    <role>Study Chair</role>
    <affiliation>Institut régional du cancer de Montpellier</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Jean-Pierre BLEUSE, MD</last_name>
    <phone>0467613102</phone>
    <phone_ext>+33</phone_ext>
    <email>jean-pierre.bleuse@icm.unicancer.fr</email>
  </overall_contact>
  <location>
    <facility>
      <name>Centre Antoine Lacassagne</name>
      <address>
        <city>Nice</city>
        <state>Alpes-Maritimes</state>
        <zip>06189</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ludovic Evesque, MD</last_name>
    </contact>
    <investigator>
      <last_name>Ludovic Evesque, MS</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Centre François Baclesse</name>
      <address>
        <city>Caen</city>
        <state>Basse-Normandie</state>
        <zip>14000</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Mélanie Dos Santos, MD</last_name>
    </contact>
    <investigator>
      <last_name>Mélanie Dos Santos, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Hôpital Pontchaillou</name>
      <address>
        <city>Rennes</city>
        <state>Ile Et Vilaine</state>
        <zip>35000</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Astrid Lièvre, MD</last_name>
    </contact>
    <investigator>
      <last_name>Astrid Lièvre, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Hôpital Robert Debré</name>
      <address>
        <city>Reims</city>
        <state>Marne</state>
        <zip>51100</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Olivier Bouché, MD</last_name>
    </contact>
    <investigator>
      <last_name>Olivier Bouché, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Institut Godinot</name>
      <address>
        <city>Reims</city>
        <state>Marne</state>
        <zip>51100</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Damien Botsen, MD</last_name>
    </contact>
    <investigator>
      <last_name>Damien Botsen, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Hôpital Saint-Jean</name>
      <address>
        <city>Perpignan</city>
        <state>Pyrénées-orientales</state>
        <zip>66000</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Faiza Khemissa, MD</last_name>
    </contact>
    <investigator>
      <last_name>Faiza Khemissa, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Centre Léon Bérard</name>
      <address>
        <city>Lyon</city>
        <state>Rhône</state>
        <zip>69008</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Christelle De La Fouchardiere, MD</last_name>
    </contact>
    <investigator>
      <last_name>Christelle De La Fouchardiere, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Hôpital privé Jean Mermoz</name>
      <address>
        <city>Lyon</city>
        <state>Rhône</state>
        <zip>69008</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Léa Clavel, MD</last_name>
    </contact>
    <investigator>
      <last_name>Léa Clavel, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Institut Gustave Roussy</name>
      <address>
        <city>Villejuif</city>
        <state>Val De Marne</state>
        <zip>94800</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Valérie Boige, MD</last_name>
    </contact>
    <investigator>
      <last_name>Valérie Boige, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>CRLC Val d'Aurelle-Paul Lamarque</name>
      <address>
        <city>Montpellier</city>
        <zip>34298</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Emmanuelle SAMALIN, MD</last_name>
    </contact>
    <investigator>
      <last_name>Emmanuelle SAMALIN, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Hôpital Européen Georges Pompidou</name>
      <address>
        <city>Paris</city>
        <zip>75015</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Julien Taïeb, MD</last_name>
    </contact>
    <investigator>
      <last_name>Julien Taïeb, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <reference>
    <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>
    <PMID>24407191</PMID>
  </reference>
  <reference>
    <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>
    <PMID>14612495</PMID>
  </reference>
  <reference>
    <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>
    <PMID>11124803</PMID>
  </reference>
  <reference>
    <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.</citation>
    <PMID>23177514</PMID>
  </reference>
  <verification_date>July 2023</verification_date>
  <study_first_submitted>January 23, 2019</study_first_submitted>
  <study_first_submitted_qc>February 1, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 4, 2019</study_first_posted>
  <last_update_submitted>July 6, 2023</last_update_submitted>
  <last_update_submitted_qc>July 6, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">July 7, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>REGIRI</keyword>
  <keyword>regorafenib</keyword>
  <keyword>irinotecan</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Colorectal Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Irinotecan</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</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/NCT03829462
org study id: PROICM 2018-01 NEX
nct id: NCT03829462
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
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
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
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Overall survival
time frame: Approximately 36 months
description: From randomization of first patient until the datebase cut-off
measure: Progression-free survival (PFS)
time frame: Approximately 36 months
description: From randomization of first patient until the datebase cut-off,
measure: Disease control rate (DCR)
time frame: Tumor is assessed every 8 weeks
description: From randomization of first patient until the datebase cut-off,
measure: Objective response rate (OOR)
time frame: Tumor is assessed at 8 weeks intervals
description: From randomization of first patient until the datebase cut-off,
measure: Assessment of adverse events by using the NCI-CTCAE version 5.0 scale
time frame: Approximately 36 months
description: From randomization of first patient until the end of treatment,
measure: Quality of life questionnaire
time frame: questionnaire is assessed at 8 weeks intervals
description: From date of randomization until the date of end of treatment
measure: Time to Deterioration
time frame: Approximately 36 months
description: It is defined as the time between the date of randomization and the first time the patient has a WHO ≥ 2 during treatment.
arm group label: Irinotecan + regorafenib (REGIRI)
arm group type: Experimental
description: irinotecan (180 mg/m2) at day1 of each cycle + regorafenib (160 mg/day) from day 2 to day 8
arm group label: regorafenib
arm group type: Active Comparator
description: Regorafenib (160 mg/day) for 3 weeks followed by 1 week off
intervention type: Drug
intervention name: Regorafenib
description: regorafenib tab 40 mg i.e 160 mg/day
arm group label: Irinotecan + regorafenib (REGIRI)
arm group label: regorafenib
intervention type: Drug
intervention name: Irinotecan
description: irinotecan 120 mg/m2 cycle 1, 150 mg/m2 cycle 2, 180 mg/m2 cycle 3 and more
arm group label: Irinotecan + regorafenib (REGIRI)
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Emmanuelle SAMALIN, MD
role: Study Chair
affiliation: Institut régional du cancer de Montpellier
last name: Jean-Pierre BLEUSE, MD
phone: 0467613102
phone ext: +33
email: jean-pierre.bleuse@icm.unicancer.fr
facility: 
status: Recruiting
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country: France
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.
PMID: 24407191
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.
PMID: 14612495
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.
PMID: 11124803
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.
PMID: 23177514
responsible party type: Sponsor
mesh term: Colorectal Neoplasms
mesh term: Irinotecan
sharing ipd: No