<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/NCT04495088</url>
  </required_header>
  <id_info>
    <org_study_id>ACO/ARO/AIO-18.2</org_study_id>
    <secondary_id>2018-001356-35</secondary_id>
    <nct_id>NCT04495088</nct_id>
  </id_info>
  <brief_title>Preoperative FOLFOX Versus Postoperative Risk-adapted Chemotherapy in Patients With Locally Advanced Rectal Cancer</brief_title>
  <official_title>Preoperative FOLFOX Versus Postoperative Risk-adapted Chemotherapy in Patients With Locally Advanced Rectal Cancer and Low Risk for Local Failure: A Randomized Phase III Trial of the German Rectal Cancer Study Group</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Ralf Hofheinz</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Deutsche Krebshilfe e.V., Bonn (Germany)</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>German Rectal Cancer Study Group</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Universitätsmedizin Mannheim</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, prospective, randomized, stratified, controlled, open-label study&#xD;
      comparing preoperative FOLFOX versus postoperative risk-adapted chemotherapy in patients with&#xD;
      locally advanced rectal cancer and low risk for local failure&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Patients with locally advanced rectal cancer are generally treated with preoperative 5-FU- or&#xD;
      capecitabine-based chemo-radiotherapy (CRT) and total mesorectal excision (TME) surgery in&#xD;
      order to decrease the rate of local failure. In patients with low risk for local failure in&#xD;
      the middle third of the rectum (cT3a/b, N-) as determined with quality controlled MRI, the&#xD;
      German S3 guidelines and the ESMO clinical practice guidelines state that neoadjuvant&#xD;
      radiotherapy may be omitted. However, distant failure rate is still substantial in the range&#xD;
      of 20-25% in these patients highlighting the need for more effective systemic treatment.&#xD;
&#xD;
      The hereby proposed ACO/ARO/AIO-18.2 randomized trial incorporates three novel aspects: (1)&#xD;
      patient selection relies on strict and quality controlled MRI features and therefore&#xD;
      identifies a cohort without imminent need for radiotherapy, (2) the sequence of chemotherapy&#xD;
      and surgery is changed in a way that chemotherapy is administered preoperatively to increase&#xD;
      the rate of patients treated with chemotherapy, and (3) three months of neoadjuvant FOLFOX or&#xD;
      XELOX (instead of up to 6 months adjuvant chemotherapy) are used as a sole perioperative&#xD;
      treatment in order to administer effective doses of the presumably most effective&#xD;
      perioperative treatment at an early time point during the course of disease.&#xD;
&#xD;
      Thus, patients with locally advanced rectal cancer but low risk for local failure (cT1/2N+ in&#xD;
      all thirds of the rectum, cT3a/b N- in the middle third, and cT3-4 Nany in the upper third)&#xD;
      will be included and randomized between three months of neoadjuvant FOLFOX/XELOX in Arm A and&#xD;
      primary resection of the tumor followed by risk (i.e. stage) adapted chemotherapy in Arm B.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">September 30, 2020</start_date>
  <completion_date type="Anticipated">August 2030</completion_date>
  <primary_completion_date type="Anticipated">August 2030</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>
    <intervention_model_description>multicenter, randomized, two-armed</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
    <masking_description>open-label</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>disease-free survival</measure>
    <time_frame>up to 3 years</time_frame>
    <description>time from randomisation to one of the following events: no surgery or non-radical (R2) surgery of the primary tumour, locoregional recurrence after R0/1 resection of the primary tumour, second primary colorectal or other cancer, metastatic disease or progression, or death from any cause, whichever occurred first.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Acute and late toxicity</measure>
    <time_frame>From date of informed consent until the End of Treatment or 30 days after the last dose of study treatment</time_frame>
    <description>assessment of acute and late toxicity according to NCI CTCAE version 5.0</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Compliance (completion rate) of chemotherapy</measure>
    <time_frame>From date of randomization until end of chemotherapy, approx. 12 (arm A) respectively up to 34 (arm B) weeks after randomization</time_frame>
    <description>Rate of completion of administered chemotherapy</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Surgical morbidity and complications</measure>
    <time_frame>After surgery, approx. 2 (arm B) respectively 20 (arm A) weeks after randomization</time_frame>
    <description>Surgical morbidity and complications if surgery is performed and events occur</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pathological UICC-staging, including pCR (ypT0N0) rate</measure>
    <time_frame>After surgery, approx. 2 (arm B) respectively 20 (arm A) weeks after randomization</time_frame>
    <description>Pathological staging according UICC criteria, including detailed information about pathologically assessed complete response rate (ypT0N0)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>R0 resection rate, Negative circumferential resection rate (CRM &gt; 1mm)</measure>
    <time_frame>After surgery, approx. 2 (arm B) respectively 20 (arm A) weeks after randomization</time_frame>
    <description>defined as microscopically margin negative resection with no gross or microscopic tumor remains in the area of the primary tumor and/or samples regional lymph nodes based on evaluation by the local pathologist</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Tumor regression grading according to Dworak in the experimental arm</measure>
    <time_frame>After surgery, approx. 2 (arm B) respectively 20 (arm A) weeks after randomization</time_frame>
    <description>Grading of tumor regression according to Dworak in the experimental arm</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of sphincter-sparing surgery</measure>
    <time_frame>After surgery, approx. 2 (arm B) respectively 20 (arm A) weeks after randomization</time_frame>
    <description>Rate of sphincter-sparing surgery if surgery is performed</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of W&amp;W with or without local regrowth</measure>
    <time_frame>Up to 5 years after end of treatment</time_frame>
    <description>Number of performed watch&amp;wait approaches with or without local regrowth compared to planned and performed surgery</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cumulative incidence of local and distant recurrences</measure>
    <time_frame>Up to 5 years after end of treatment</time_frame>
    <description>Total number of local and distant recurrences, if they occur</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival</measure>
    <time_frame>Up to at least 3 years and until 5 years</time_frame>
    <description>Overall survival is defined as the time interval between the date of randomization and the date of death of any cause. Patients who are still alive when last traced will be censored at the date of last follow-up</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Patient reported outcome: Quality of life according to questionnaire EORTC-QLQ-C30</measure>
    <time_frame>From date of randomization until the date of first documented progression or date of death from any cause, whichever occured first, assessed up to approximately 68 months</time_frame>
    <description>Quality of life scores according to validated questionnaires EORTC-QLQ-C30, based on treatment arm, and surgical procedures. 30 questions; score values from 1 (not at all) to 4 (very much) respectively from 1 (very poor) to 7 (excellent). Score outcome depends on score type.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Patient reported outcome: Quality of life according to questionnaire EORTC-QLQ-CR29</measure>
    <time_frame>From date of randomization until the date of first documented progression or date of death from any cause, whichever occured first, assessed up to approximately 68 months</time_frame>
    <description>Quality of life scores according to validated questionnaires EORTC-QLQ-CR29, based on treatment arm, and surgical procedures. 29 questions; score values from 1 (not at all) to 4 (very much). Score outcome depends on score type.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Patient reported outcome: Functional outcome according to Wexner score</measure>
    <time_frame>From date of randomization until the date of first documented progression or date of death from any cause, whichever occured first, assessed up to approximately 68 months</time_frame>
    <description>Functional score according to validated Wexner score, based on treatment arm, and surgical procedures. 5 questions; five score values from &quot;never&quot; to &quot;1 per day or more often&quot;. The more often the worse the outcome.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">818</enrollment>
  <condition>Rectal Cancer</condition>
  <arm_group>
    <arm_group_label>A (experimental arm)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The experimental arm A starts with 6 cycles of mFOLFOX or 4 cycles of XELOX. Surgery is scheduled four or six weeks after day 1 of the last mFOLFOX or XELOX cycle, respectively. No postoperative chemotherapy is planned</description>
  </arm_group>
  <arm_group>
    <arm_group_label>B (control arm)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>In the standard arm B, patients undergo surgical resection of the primary tumor followed by stage- (risk-)adapted adjuvant chemotherapy 4-8 weeks after surgery according to recommendations of the S3 guidelines in analogy to colon cancer. Details of the recommended protocols are provided in the protocol.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>mFOLFOX (neoadjuvant)</intervention_name>
    <description>neoadjuvant application Folinic acid: 400 mg/m2, 2h i.v., on day 1 Oxaliplatin: 85 mg/m2, 2-6h i.v., on day 1 5-FU: 2400 mg/m2, 46-48h i.v., on day 1. Cycles are repeated on day 15. A total of 6 cycles are administered.</description>
    <arm_group_label>A (experimental arm)</arm_group_label>
    <other_name>Folinic acid, Oxaliplatin, 5-FU</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>XELOX (neoadjuvant)</intervention_name>
    <description>neoadjuvant application Capecitabine: 1,000 mg/m2 bid, po, on days 1-14 Oxaliplatin: 130 mg/m2, 2-6h i.v. day 1 Cycles are repeated on day 22. A total of 4 cycles are administered.</description>
    <arm_group_label>A (experimental arm)</arm_group_label>
    <other_name>Capecitabine, Oxaliplatin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>mFOLFOX (adjuvant)</intervention_name>
    <description>adjuvant application Folinic acid: 400 mg/m2, 2h i.v., on day 1 Oxaliplatin: 85 mg/m2, 2-6h i.v., on day 1 5-FU: 2400 mg/m2, 46-48h i.v., on day 1. Cycles are repeated on day 15. A total of 6 cycles are administered.</description>
    <arm_group_label>B (control arm)</arm_group_label>
    <other_name>Folinic acid, Oxaliplatin, 5-FU</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>XELOX (adjuvant)</intervention_name>
    <description>adjuvant application Capecitabine: 1,000 mg/m2 bid, po, on days 1-14 Oxaliplatin: 130 mg/m2, 2-6h i.v. day 1 Cycles are repeated on day 22. A total of 4 cycles are administered.</description>
    <arm_group_label>B (control arm)</arm_group_label>
    <other_name>Capecitabine, Oxaliplatin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Capecitabine (adjuvant)</intervention_name>
    <description>adjuvant application Capecitabine: 1,250 mg/m2 bid, po, on days 1-14 Cycles are repeated on day 22. A total of 8 cycles are administered.</description>
    <arm_group_label>B (control arm)</arm_group_label>
    <other_name>Capecitabine</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>infusional 5-FU/FA &quot;AIO&quot; regimen (adjuvant)</intervention_name>
    <description>adjuvant application Folinic acid 2h i.v. 500 mg/m² 5-FU 2,600mg/m² (24h infusion) Days 1, 8, 15, 22, 29, 36; cycle is repeated day 57 (representing one cycle); a total of 3 cycles should be administered.</description>
    <arm_group_label>B (control arm)</arm_group_label>
    <other_name>5-FU, Folinic acid</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>infusional 5-FU/FA &quot;de Gramont&quot; (adjuvant)</intervention_name>
    <description>adjuvant application Folinic acid 2h i.v. 200 mg/m² days 1 and 2 5-FU 400mg/m² bolus followed by 600mg/m² 22h infusion days 1 and 2 The cycle is repeated day 15; a total of 12 cycles should be administered.</description>
    <arm_group_label>B (control arm)</arm_group_label>
    <other_name>5-FU, Folinic acid</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Male and female patients with histologically confirmed diagnosis of rectal&#xD;
             adenocarcinoma localised 0 - 16 cm from the anocutaneous line as measured by rigid&#xD;
             rectoscopy (i.e. lower, middle and upper third of the rectum), depending on&#xD;
             MRI-defined inclusion criteria (see below).&#xD;
&#xD;
          2. Staging requirements: High-resolution magnetic resonance imaging (MRI) of the pelvis&#xD;
             is the mandatory local staging procedure.&#xD;
&#xD;
          3. Transrectal endoscopic ultrasound (EUS) is used to help discriminate between T1/2 and&#xD;
             early T3 tumors.&#xD;
&#xD;
          4. MRI-defined inclusion criteria:&#xD;
&#xD;
               -  Lower third (0-6 cm): cT1/2 with clear cN+ based on MRI-criteria (see SOP in&#xD;
                  chapter 13.3 of the appendix), provided CRM- and EMVI- (defined as MRI-EMVI score&#xD;
                  0-3; see SOP in chapter 13.3 of the appendix)&#xD;
&#xD;
               -  Middle third (≥ 6-12 cm): cT1/2 with clear cN+ provided CRM- and EMVI-; cT3a/b,&#xD;
                  i.e. evidence of extramural tumor spread into the mesorectal fat of ≤ 5 mm&#xD;
                  provided N-, CRM-, and EMVI-&#xD;
&#xD;
               -  Upper third (≥ 12-16 cm): cT1/2 with clear cN+ provided CRM- and EMVI-; any cT3-4&#xD;
                  irrespective of nodal status.&#xD;
&#xD;
          5. Spiral-CT of the abdomen and chest to exclude distant metastases.&#xD;
&#xD;
          6. Aged at least 18 years. No upper age limit.&#xD;
&#xD;
          7. WHO/ECOG Performance Status ≤1.&#xD;
&#xD;
          8. Adequate haematological, hepatic, renal and metabolic function parameters:&#xD;
&#xD;
          9. Leukocytes ≥ 3.000/mm³, ANC ≥ 2.000/mm³, platelets ≥ 100.000/mm³, Hb &gt; 9 g/dl&#xD;
&#xD;
         10. Serum creatinine ≤ 1.5 x upper limit of normal&#xD;
&#xD;
         11. Bilirubin ≤ 2.0 mg/dl, SGOT-SGPT, and AP ≤ 3 x upper limit of normal.&#xD;
&#xD;
         12. QTc interval (Bazett**) ≤ 440 ms&#xD;
&#xD;
         13. Informed consent of the patient.&#xD;
&#xD;
        &quot;**&quot; Formula for QTc interval calculation (Bazett): QTc= ((QT) ̅&quot; (ms)&quot; )/√(RR (sec))=&#xD;
        ((QT) ̅&quot; (ms)&quot; )/√(60/(frequency (1/min)))&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Distant metastases (to be excluded by CT scan of the thorax and abdomen).&#xD;
&#xD;
          2. Prior antineoplastic therapy for rectal cancer.&#xD;
&#xD;
          3. Prior radiotherapy of the pelvic region.&#xD;
&#xD;
          4. Major surgery within the last 4 weeks prior to inclusion.&#xD;
&#xD;
          5. Subject pregnant or breast feeding, or planning to become pregnant within 6 months&#xD;
             after the end of treatment.&#xD;
&#xD;
          6. Subject (male or female) is not willing to use highly effective*** methods of&#xD;
             contraception during treatment and for 6 months (male or female) after the end of&#xD;
             treatment Male patients treated with Oxaliplatin should take legal advice concerning&#xD;
             sperm conservation before start of therapy and should additionally use a condom during&#xD;
             treatment period. Their female partner of childbearing potential should also use an&#xD;
             appropriate contraceptive measure.&#xD;
&#xD;
          7. On-treatment participation in a clinical study in the period 30 days prior to&#xD;
             inclusion.&#xD;
&#xD;
          8. Previous or current drug abuse.&#xD;
&#xD;
          9. Other concomitant antineoplastic therapy.&#xD;
&#xD;
         10. Serious concurrent diseases, including neurologic or psychiatric disorders (incl.&#xD;
             dementia and uncontrolled seizures), active, uncontrolled infections, active,&#xD;
             disseminated coagulation disorder.&#xD;
&#xD;
         11. Clinically significant cardiovascular disease in (incl. myocardial infarction,&#xD;
             unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac&#xD;
             arrhythmia) ≤ 6 months before enrolment.&#xD;
&#xD;
         12. Chronic diarrhea (&gt; grade 1 according NCI CTCAE).&#xD;
&#xD;
         13. Prior or concurrent malignancy ≤ 3 years prior to enrolment in study (Exception:&#xD;
             non-melanoma skin cancer or cervical carcinoma FIGO stage 0-1), if the patient is&#xD;
             continuously disease-free.&#xD;
&#xD;
         14. Known allergic reactions or hypersensitivity on study medication or to any of the&#xD;
             other excipients.&#xD;
&#xD;
         15. Evidence of peripheral sensory neuropathy &gt; grade 1 according to CTCAE version 5.0&#xD;
             (see appendix).&#xD;
&#xD;
         16. Severe kidney dysfunction (creatinine clearance &lt; 30 ml/min).&#xD;
&#xD;
         17. Recent or concurrent treatment with brivudine.&#xD;
&#xD;
         18. Pernicious or other megaloblastic anaemia caused by vitamin B12 deficiency.&#xD;
&#xD;
         19. Known dihydropyrimidine dehydrogenase deficiency.&#xD;
&#xD;
         20. Psychological, familial, sociological or geographical condition potentially hampering&#xD;
             compliance with the study protocol and follow-up schedule (these conditions should be&#xD;
             discussed with the patient before registration in the trial).&#xD;
&#xD;
        &quot;***&quot;highly effective (i.e. failure rate of &lt;1% per year when used consistently and&#xD;
        correctly) methods: intravaginal and transdermal combined (estrogen and progestogen&#xD;
        containing) hormonal contraception; injectable and implantable progestogen-only hormonal&#xD;
        contraception; intrauterine device (IUD); intrauterine hormone-releasing system (IUS);&#xD;
        bilateral tubal occlusion; vasectomized partner; sexual abstinence (complete abstinence is&#xD;
        defined as refraining from heterosexual intercourse during the entire period of risk&#xD;
        associated with the study treatments).&#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>Ralf-Dieter Hofheinz, Prof. Dr.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Universitätsmedizin Mannheim</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Ralf-Dieter Hofheinz, Prof. Dr.</last_name>
    <phone>+49 621 383</phone>
    <phone_ext>2855</phone_ext>
    <email>ralf.hofheinz@umm.de</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Benedict Atzler</last_name>
    <phone>+49 69 7601</phone>
    <phone_ext>7052</phone_ext>
    <email>atzler.benedict@ikf-khnw.de</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Unversity Hospital Mannheim</name>
      <address>
        <city>Mannheim</city>
        <zip>68167</zip>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ralf Hofheinz, Prof.</last_name>
      <phone>+49 621 383 2855</phone>
      <email>Ralf.Hofheinz@umm.de</email>
    </contact>
  </location>
  <location_countries>
    <country>Germany</country>
  </location_countries>
  <verification_date>August 2022</verification_date>
  <study_first_submitted>July 28, 2020</study_first_submitted>
  <study_first_submitted_qc>July 28, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 31, 2020</study_first_posted>
  <last_update_submitted>August 12, 2022</last_update_submitted>
  <last_update_submitted_qc>August 12, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">August 15, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Universitätsmedizin Mannheim</investigator_affiliation>
    <investigator_full_name>Ralf Hofheinz</investigator_full_name>
    <investigator_title>Prof. Dr.</investigator_title>
  </responsible_party>
  <keyword>Rectal Cancer</keyword>
  <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>Leucovorin</mesh_term>
    <mesh_term>Folic Acid</mesh_term>
    <mesh_term>Capecitabine</mesh_term>
    <mesh_term>Fluorouracil</mesh_term>
    <mesh_term>Oxaliplatin</mesh_term>
    <mesh_term>Levoleucovorin</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/NCT04495088
org study id: ACO/ARO/AIO-18.2
secondary id: 2018-001356-35
nct id: NCT04495088
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
This is a multicenter, prospective, randomized, stratified, controlled, open-label study
      comparing preoperative FOLFOX versus postoperative risk-adapted chemotherapy in patients with
      locally advanced rectal cancer and low risk for local failure
Patients with locally advanced rectal cancer are generally treated with preoperative 5-FU- or
      capecitabine-based chemo-radiotherapy (CRT) and total mesorectal excision (TME) surgery in
      order to decrease the rate of local failure. In patients with low risk for local failure in
      the middle third of the rectum (cT3a/b, N-) as determined with quality controlled MRI, the
      German S3 guidelines and the ESMO clinical practice guidelines state that neoadjuvant
      radiotherapy may be omitted. However, distant failure rate is still substantial in the range
      of 20-25% in these patients highlighting the need for more effective systemic treatment.

      The hereby proposed ACO/ARO/AIO-18.2 randomized trial incorporates three novel aspects: (1)
      patient selection relies on strict and quality controlled MRI features and therefore
      identifies a cohort without imminent need for radiotherapy, (2) the sequence of chemotherapy
      and surgery is changed in a way that chemotherapy is administered preoperatively to increase
      the rate of patients treated with chemotherapy, and (3) three months of neoadjuvant FOLFOX or
      XELOX (instead of up to 6 months adjuvant chemotherapy) are used as a sole perioperative
      treatment in order to administer effective doses of the presumably most effective
      perioperative treatment at an early time point during the course of disease.

      Thus, patients with locally advanced rectal cancer but low risk for local failure (cT1/2N+ in
      all thirds of the rectum, cT3a/b N- in the middle third, and cT3-4 Nany in the upper third)
      will be included and randomized between three months of neoadjuvant FOLFOX/XELOX in Arm A and
      primary resection of the tumor followed by risk (i.e. stage) adapted chemotherapy in Arm B.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: multicenter, randomized, two-armed
primary purpose: Treatment
masking: None (Open Label)
masking description: open-label
measure: disease-free survival
time frame: up to 3 years
description: time from randomisation to one of the following events: no surgery or non-radical (R2) surgery of the primary tumour, locoregional recurrence after R0/1 resection of the primary tumour, second primary colorectal or other cancer, metastatic disease or progression, or death from any cause, whichever occurred first.
measure: Acute and late toxicity
time frame: From date of informed consent until the End of Treatment or 30 days after the last dose of study treatment
description: assessment of acute and late toxicity according to NCI CTCAE version 5.0
measure: Compliance (completion rate) of chemotherapy
time frame: From date of randomization until end of chemotherapy, approx. 12 (arm A) respectively up to 34 (arm B) weeks after randomization
description: Rate of completion of administered chemotherapy
measure: Surgical morbidity and complications
time frame: After surgery, approx. 2 (arm B) respectively 20 (arm A) weeks after randomization
description: Surgical morbidity and complications if surgery is performed and events occur
measure: Pathological UICC-staging, including pCR (ypT0N0) rate
time frame: After surgery, approx. 2 (arm B) respectively 20 (arm A) weeks after randomization
description: Pathological staging according UICC criteria, including detailed information about pathologically assessed complete response rate (ypT0N0)
measure: R0 resection rate, Negative circumferential resection rate (CRM > 1mm)
time frame: After surgery, approx. 2 (arm B) respectively 20 (arm A) weeks after randomization
description: defined as microscopically margin negative resection with no gross or microscopic tumor remains in the area of the primary tumor and/or samples regional lymph nodes based on evaluation by the local pathologist
measure: Tumor regression grading according to Dworak in the experimental arm
time frame: After surgery, approx. 2 (arm B) respectively 20 (arm A) weeks after randomization
description: Grading of tumor regression according to Dworak in the experimental arm
measure: Rate of sphincter-sparing surgery
time frame: After surgery, approx. 2 (arm B) respectively 20 (arm A) weeks after randomization
description: Rate of sphincter-sparing surgery if surgery is performed
measure: Rate of W&W with or without local regrowth
time frame: Up to 5 years after end of treatment
description: Number of performed watch&wait approaches with or without local regrowth compared to planned and performed surgery
measure: Cumulative incidence of local and distant recurrences
time frame: Up to 5 years after end of treatment
description: Total number of local and distant recurrences, if they occur
measure: Overall survival
time frame: Up to at least 3 years and until 5 years
description: Overall survival is defined as the time interval between the date of randomization and the date of death of any cause. Patients who are still alive when last traced will be censored at the date of last follow-up
measure: Patient reported outcome: Quality of life according to questionnaire EORTC-QLQ-C30
time frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever occured first, assessed up to approximately 68 months
description: Quality of life scores according to validated questionnaires EORTC-QLQ-C30, based on treatment arm, and surgical procedures. 30 questions; score values from 1 (not at all) to 4 (very much) respectively from 1 (very poor) to 7 (excellent). Score outcome depends on score type.
measure: Patient reported outcome: Quality of life according to questionnaire EORTC-QLQ-CR29
time frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever occured first, assessed up to approximately 68 months
description: Quality of life scores according to validated questionnaires EORTC-QLQ-CR29, based on treatment arm, and surgical procedures. 29 questions; score values from 1 (not at all) to 4 (very much). Score outcome depends on score type.
measure: Patient reported outcome: Functional outcome according to Wexner score
time frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever occured first, assessed up to approximately 68 months
description: Functional score according to validated Wexner score, based on treatment arm, and surgical procedures. 5 questions; five score values from "never" to "1 per day or more often". The more often the worse the outcome.
arm group label: A (experimental arm)
arm group type: Experimental
description: The experimental arm A starts with 6 cycles of mFOLFOX or 4 cycles of XELOX. Surgery is scheduled four or six weeks after day 1 of the last mFOLFOX or XELOX cycle, respectively. No postoperative chemotherapy is planned
arm group label: B (control arm)
arm group type: Active Comparator
description: In the standard arm B, patients undergo surgical resection of the primary tumor followed by stage- (risk-)adapted adjuvant chemotherapy 4-8 weeks after surgery according to recommendations of the S3 guidelines in analogy to colon cancer. Details of the recommended protocols are provided in the protocol.
intervention type: Drug
intervention name: mFOLFOX (neoadjuvant)
description: neoadjuvant application Folinic acid: 400 mg/m2, 2h i.v., on day 1 Oxaliplatin: 85 mg/m2, 2-6h i.v., on day 1 5-FU: 2400 mg/m2, 46-48h i.v., on day 1. Cycles are repeated on day 15. A total of 6 cycles are administered.
arm group label: A (experimental arm)
other name: Folinic acid, Oxaliplatin, 5-FU
intervention type: Drug
intervention name: XELOX (neoadjuvant)
description: neoadjuvant application Capecitabine: 1,000 mg/m2 bid, po, on days 1-14 Oxaliplatin: 130 mg/m2, 2-6h i.v. day 1 Cycles are repeated on day 22. A total of 4 cycles are administered.
arm group label: A (experimental arm)
other name: Capecitabine, Oxaliplatin
intervention type: Drug
intervention name: mFOLFOX (adjuvant)
description: adjuvant application Folinic acid: 400 mg/m2, 2h i.v., on day 1 Oxaliplatin: 85 mg/m2, 2-6h i.v., on day 1 5-FU: 2400 mg/m2, 46-48h i.v., on day 1. Cycles are repeated on day 15. A total of 6 cycles are administered.
arm group label: B (control arm)
other name: Folinic acid, Oxaliplatin, 5-FU
intervention type: Drug
intervention name: XELOX (adjuvant)
description: adjuvant application Capecitabine: 1,000 mg/m2 bid, po, on days 1-14 Oxaliplatin: 130 mg/m2, 2-6h i.v. day 1 Cycles are repeated on day 22. A total of 4 cycles are administered.
arm group label: B (control arm)
other name: Capecitabine, Oxaliplatin
intervention type: Drug
intervention name: Capecitabine (adjuvant)
description: adjuvant application Capecitabine: 1,250 mg/m2 bid, po, on days 1-14 Cycles are repeated on day 22. A total of 8 cycles are administered.
arm group label: B (control arm)
other name: Capecitabine
intervention type: Drug
intervention name: infusional 5-FU/FA "AIO" regimen (adjuvant)
description: adjuvant application Folinic acid 2h i.v. 500 mg/m² 5-FU 2,600mg/m² (24h infusion) Days 1, 8, 15, 22, 29, 36; cycle is repeated day 57 (representing one cycle); a total of 3 cycles should be administered.
arm group label: B (control arm)
other name: 5-FU, Folinic acid
intervention type: Drug
intervention name: infusional 5-FU/FA "de Gramont" (adjuvant)
description: adjuvant application Folinic acid 2h i.v. 200 mg/m² days 1 and 2 5-FU 400mg/m² bolus followed by 600mg/m² 22h infusion days 1 and 2 The cycle is repeated day 15; a total of 12 cycles should be administered.
arm group label: B (control arm)
other name: 5-FU, Folinic acid
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Ralf-Dieter Hofheinz, Prof. Dr.
role: Principal Investigator
affiliation: Universitätsmedizin Mannheim
last name: Ralf-Dieter Hofheinz, Prof. Dr.
phone: +49 621 383
phone ext: 2855
email: ralf.hofheinz@umm.de
last name: Benedict Atzler
phone: +49 69 7601
phone ext: 7052
email: atzler.benedict@ikf-khnw.de
facility: 
status: Recruiting
contact: 
country: Germany
responsible party type: Sponsor-Investigator
investigator affiliation: Universitätsmedizin Mannheim
investigator full name: Ralf Hofheinz
investigator title: Prof. Dr.
mesh term: Rectal Neoplasms
mesh term: Leucovorin
mesh term: Folic Acid
mesh term: Capecitabine
mesh term: Fluorouracil
mesh term: Oxaliplatin
mesh term: Levoleucovorin
sharing ipd: No