<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/NCT03043729</url>
  </required_header>
  <id_info>
    <org_study_id>AIO-KRK-0214</org_study_id>
    <nct_id>NCT03043729</nct_id>
  </id_info>
  <brief_title>mFOLFOX6 vs. mFOLFOX6 + Aflibercept as Neoadjuvant Treatment in MRI-defined T3-rectal Cancer</brief_title>
  <official_title>mFOLFOX6 vs. mFOLFOX6 + Aflibercept as Neoadjuvant Treatment in MRI-defined T3-rectal Cancer: a Randomized Phase-II-trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>AIO-Studien-gGmbH</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Institut für Klinisch-Onkologische Forschung (IKF) Frankfurt</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Sanofi</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>AIO-Studien-gGmbH</source>
  <oversight_info>
    <has_dmc>No</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 locally advanced rectal or rectosigmoid cancer staged cT3 CRM-negative with MRI&#xD;
      will receive 6 cycles of neoadjuvant treatment with mFOLFOX6 (Arm A) vs. mFOLFOX6 +&#xD;
      aflibercept (Arm B) followed by surgery.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Patients with locally advanced rectal cancer are generally recommended to receive&#xD;
      preoperative radiotherapy or radiochemotherapy. The advantage of combined-modality therapy in&#xD;
      rectal cancer is that it has reduced local pelvic recurrence - a dreaded and morbid event -&#xD;
      to rates of about 10%. There is good quality evidence that preoperative radiotherapy reduces&#xD;
      local recurrence but there is little if any impact on overall survival. One strategy to&#xD;
      reduce the distant recurrence rate, and thereby increase the cure rate, would be to introduce&#xD;
      systemic treatment earlier to prevent dissemination of micrometastases. The present trial is&#xD;
      designed to compare two neoadjuvant chemotherapy regimens in patients with non-metastatic T3&#xD;
      CRM-negative rectal cancers using quality-controlled MRI of the pelvis as a main inclusion&#xD;
      criterion. This strategy is believed to reduce acute and long-term toxicity caused by&#xD;
      preoperative radiotherapy and to administer effective systemic chemotherapy early in the&#xD;
      course of disease as neoadjuvant chemotherapy.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">March 6, 2017</start_date>
  <completion_date type="Actual">June 1, 2022</completion_date>
  <primary_completion_date type="Actual">January 11, 2021</primary_completion_date>
  <phase>Phase 2</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>Pathologic complete response (pCR)</measure>
    <time_frame>20 weeks</time_frame>
    <description>number of patients with a pCR finding divided by the number of patients in the analysis set pCR will be assessed in a standardized manner independently by a central pathology</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Dose intensities of study medication</measure>
    <time_frame>12 weeks</time_frame>
    <description>The dose intensities of study medication will be calculated over the whole study duration and will be summarized descriptively by summary statistics.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Type, incidence and severity of AEs, SAEs</measure>
    <time_frame>20 weeks</time_frame>
    <description>AEs will be coded according to the NCI-CTC Criteria Version 4.03. For the analysis, all AEs will be classified as related and not related. AEs will be summarized by presenting the number and percentages of patients having any AE and having an AE in each NCI-CTC category. Summaries will also be presented for AEs by severity and relationship to study medication. Tables will be broken down by study arm. All deaths and serious adverse events will be listed and briefly described.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Dose reduction or discontinuation of study drug due to adverse events</measure>
    <time_frame>20 weeks</time_frame>
    <description>The dose intensities of study medication will be calculated over the whole study duration and will be summarized descriptively by summary statistics.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of treatment discontinuation due to toxicity</measure>
    <time_frame>20 weeks</time_frame>
    <description>Summaries will also be presented for AEs by severity and relationship to study medication. Tables will be broken down by study arm.&#xD;
All deaths and serious adverse events will be listed and briefly described.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Type, incidence and severity of laboratory abnormalities</measure>
    <time_frame>20 weeks</time_frame>
    <description>For relevant laboratory parameters, the distribution over time as well as changes from randomization will be calculated and analyzed descriptively.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of patients with R0-wide resection (according to CRM definitions in S3 guideline-Version 1.1 August 2014)</measure>
    <time_frame>20 weeks</time_frame>
    <description>The R0- and R1 resection as well as downstaging and downsizing using a standardized regression grading (Dworak regression grading) will be analyzed descriptively by means of frequencies and percentages.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of patients with R0-narrow resection (according to CRM definitions in S3 guideline-Version 1.1 August 2014)</measure>
    <time_frame>20 weeks</time_frame>
    <description>The R0- and R1 resection as well as downstaging and downsizing using a standardized regression grading (Dworak regression grading) will be analyzed descriptively by means of frequencies and percentages.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of patients with R1 resection (according to CRM definitions in S3 guideline-Version 1.1 August 2014)</measure>
    <time_frame>20 weeks</time_frame>
    <description>The R0- and R1 resection as well as downstaging and downsizing using a standardized regression grading (Dworak regression grading) will be analyzed descriptively by means of frequencies and percentages.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of patients with locoregional R2 resection (according to CRM definitions in S3 guideline-Version 1.1 August 2014)</measure>
    <time_frame>20 weeks</time_frame>
    <description>The R0- and R1 resection as well as downstaging and downsizing using a standardized regression grading (Dworak regression grading) will be analyzed descriptively by means of frequencies and percentages.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of number of patients with R0-wide, R0-narrow (according to CRM definitions in S3 guideline-Version 1.1 August 2014), R1 and locoregional R2 resection</measure>
    <time_frame>20 weeks</time_frame>
    <description>The R0- and R1 resection as well as downstaging and downsizing using a standardized regression grading (Dworak regression grading) will be analyzed descriptively by means of frequencies and percentages.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disease-free survival (DFS)</measure>
    <time_frame>44 weeks</time_frame>
    <description>Disease-free survival rate will be analyzed using a two-sided Fisher's exact test at a 5% significance level. In addition, two-sided 95% confidence intervals for DFS rates and difference in rates between both treatment arms will be calculated.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Relapse-free survival (RFS) in resected patients</measure>
    <time_frame>44 weeks</time_frame>
    <description>Relapse-free survival: The length of time after completion of primary treatment (neoadjuvant chemotherapy + surgery) until documented relapse (i.e. local relapse, liver metastasis, systemic metastases).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival (OS) rate</measure>
    <time_frame>44 weeks</time_frame>
    <description>Overall survival: Survival will be calculated from the date of subject enrollment until the date of death from any cause. If no event is observed (e.g. lost to follow-up) OS is censored at the day of last subject contact.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Downstaging ability in resected patients using a standardized regression grading (Dworak regression grading)</measure>
    <time_frame>20 weeks</time_frame>
    <description>The R0- and R1 resection as well as downstaging and downsizing using a standardized regression grading (Dworak regression grading) will be analyzed descriptively by means of frequencies and percentages.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Downsizing ability in resected patients using a standardized regression grading (Dworak regression grading)</measure>
    <time_frame>20 weeks</time_frame>
    <description>The R0- and R1 resection as well as downstaging and downsizing using a standardized regression grading (Dworak regression grading) will be analyzed descriptively by means of frequencies and percentages.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Type, incidence and severity of perioperative medical events within 28 days after surgery are assessed. Perioperative morbidity is categorized according to the Clavien-Dindo-Classification</measure>
    <time_frame>20 weeks</time_frame>
    <description>Perioperative medical events as well as mortality within 28 days after surgery will be summarized by frequencies and percentages broken down per treatment arm.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mortality after surgery</measure>
    <time_frame>20 weeks</time_frame>
    <description>Perioperative medical events as well as mortality within 28 days after surgery will be summarized by frequencies and percentages broken down per treatment arm.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Vital signs</measure>
    <time_frame>20 weeks</time_frame>
    <description>Vital signs will be analyzed using summary statistics broken down per treatment group and visit.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Physical examination</measure>
    <time_frame>20 weeks</time_frame>
    <description>Physical examination as well as WHO/ECOG will be analyzed by calculating frequencies and percentages broken down per treatment group and visit.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>ECOG</measure>
    <time_frame>20 weeks</time_frame>
    <description>Physical examination as well as WHO/ECOG will be analyzed by calculating frequencies and percentages broken down per treatment group and visit.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">119</enrollment>
  <condition>Rectal Cancer</condition>
  <condition>Rectosigmoid Cancer</condition>
  <arm_group>
    <arm_group_label>Arm A</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>6 cycles chemotherapy with Oxaliplatin 85 mg/m^2 and Leucovorin 350 mg/m^2 i.v. as 2h infusion on Day 1 and 5-FU 400 mg/m^2 i.v. as bolus on Day 1 and 2400 mg/m^2 as 46 h infusion q2w followed by surgery 4 weeks after last neoadjuvant chemotherapy treatment</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm B</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>6 cycles chemotherapy with Oxaliplatin 85 mg/m^2 and Leucovorin 350 mg/m^2 i.v. as 2h infusion on Day 1 and 5-FU 400 mg/m^2 i.v. as bolus on Day 1 and 2400 mg/m^2 as 46 h infusionq2w + Aflibercept 4 mg/kg BW i.v. on Day 1 q2w (6th cycle without Aflibercept) followed by surgery 4 weeks after last neoadjuvant chemotherapy treatment</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Oxaliplatin</intervention_name>
    <description>Oxaliplatin 85 mg/m^2, as 2h infusion on Day 1 (Arm A + Arm B)</description>
    <arm_group_label>Arm A</arm_group_label>
    <arm_group_label>Arm B</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>5-FU</intervention_name>
    <description>5-FU 400 mg/m^2 i.v. as bolus on Day 1 and 2400 mg/m^2 as 46 h infusion q2w (Arm A + Arm B)</description>
    <arm_group_label>Arm A</arm_group_label>
    <arm_group_label>Arm B</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Leucovorin</intervention_name>
    <description>Leucovorin 350 mg/m^2 i.v. as 2h infusion on Day 1 (Arm A + Arm B)</description>
    <arm_group_label>Arm A</arm_group_label>
    <arm_group_label>Arm B</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Aflibercept</intervention_name>
    <description>Aflibercept 4 mg/kg BW i.v. on Day 1 q2w (Arm B, Cycles 1 to 5)</description>
    <arm_group_label>Arm B</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age ≥ 18 years on day of signing informed consent&#xD;
&#xD;
          2. Signed and dated informed consent, and willing and able to comply with protocol&#xD;
             requirements&#xD;
&#xD;
          3. WHO/ECOG Performance Status (PS) 0-1&#xD;
&#xD;
          4. Diagnosis of rectal adenocarcinoma&#xD;
&#xD;
          5. Candidate for sphincter-sparing surgical resection prior to neoadjuvant therapy&#xD;
             according to the primary surgeon, i.e. no patient will be included for whom surgeon&#xD;
             indicates need for abdomino-perineal resection (APR) at baseline.&#xD;
&#xD;
          6. Clinical staging is based on the combination of the following assessments:&#xD;
&#xD;
               -  Physical examination by the primary surgeon&#xD;
&#xD;
               -  CT scan of the chest/abdomen&#xD;
&#xD;
               -  Pelvic MRI&#xD;
&#xD;
               -  Rigid rectoscopy / endoscopic ultrasound (ERUS).&#xD;
&#xD;
               -  Both examinations (i.e. MRI and ERUS) are mandatory.&#xD;
&#xD;
          7. The tumor has to fulfill the following criteria:&#xD;
&#xD;
               -  No symptomatic bowel obstruction&#xD;
&#xD;
               -  Locally advanced rectal and rectosigmoid cancer, i.e. lower border of tumor &gt; 5&#xD;
                  cm and &lt; 16 cm from anal verge as determined by rigid rectoscopy&#xD;
&#xD;
               -  MRI criteria:&#xD;
&#xD;
                    1. Lower border of tumor below a line defined by promontorium and symphysis,&#xD;
                       regardless of the criterion &quot;&lt; 16 cm from anal verge as determined by rigid&#xD;
                       rectoscopy&quot;.&#xD;
&#xD;
                    2. No evidence that tumor is adjacent to (defined as within 2 mm of) the&#xD;
                       mesorectal fascia on MRI (i.e. CRM &gt; 2 mm)&#xD;
&#xD;
                    3. Only T3-tumors are included, i.e infiltration into perirectal fat &lt; 10 mm&#xD;
                       provided CRM &gt; 2 mm&#xD;
&#xD;
                    4. Note: MRI criteria are used for the definition of T3 tumor (i.e. exclusion&#xD;
                       of T2 and T4 situation).&#xD;
&#xD;
          8. Hematological status:&#xD;
&#xD;
               -  Neutrophils (ANC) ≥ 2 x 10^9/L&#xD;
&#xD;
               -  Platelets ≥ 100 x 10^9/L&#xD;
&#xD;
               -  Hemoglobin ≥ 9 g/dL (previous transfusion of packed blood cells allowed)&#xD;
&#xD;
          9. Adequate renal function:&#xD;
&#xD;
               -  Serum creatinine level ≤ 1.5 x upper limit normal (ULN) or ≤ 1.5 mg/dl&#xD;
&#xD;
               -  Creatinine clearance ≥ 30 ml/min&#xD;
&#xD;
         10. Adequate liver function:&#xD;
&#xD;
               -  Serum bilirubin ≤ 1.5 x upper limit normal (ULN)&#xD;
&#xD;
               -  Alkaline phosphatase &lt; 3 x ULN&#xD;
&#xD;
               -  AST and ALT &lt; 3 x ULN&#xD;
&#xD;
         11. Proteinuria &lt; 2+ (dipstick urinalysis) or ≤ 1 g/24hour or ≤ 500mg/dl&#xD;
&#xD;
         12. Regular follow-up feasible&#xD;
&#xD;
         13. For female patients of childbearing potential, negative pregnancy test within 1 week&#xD;
             (7 Days) prior of starting study treatment&#xD;
&#xD;
         14. Female patients of childbearing potential (i.e. did not undergo surgical sterilization&#xD;
             - hysterectomy, bilateral tubal ligation, or bilateral oophorectomy - and is not&#xD;
             post-menopausal for at least 24 consecutive months) must commit to using high&#xD;
             effective and appropriate methods of contraception until at least 6 months after the&#xD;
             end of study treatment such as combined (estrogen and progestogen containing) hormonal&#xD;
             contraception associated with inhibition of ovulation, progestogen-only hormonal&#xD;
             contraception associated with inhibition of ovulation, intrauterine device (IUD),&#xD;
             intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized&#xD;
             partner, sexual abstinence. If an oral contraception is used, a barrier method of&#xD;
             contraception (e.g. male condom, female condom, cervical cap, diaphragm, contraceptive&#xD;
             sponge) has to be applied additionally&#xD;
&#xD;
         15. Fertile male patients with a partner of childbearing potential must commit to using&#xD;
             high effective and appropriate methods of contraception (details see above) until at&#xD;
             least 9 months after the end of study treatment.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Distant metastases (CT scans of thorax and abdomen are mandatory)&#xD;
&#xD;
          2. cT2 and cT4 tumors (defined by MRI criteria)&#xD;
&#xD;
          3. Exclusion of potentially compromised CRM as defined by MRI criteria (i.e. &gt; 2 mm&#xD;
             distance from CRM)&#xD;
&#xD;
          4. Prior antineoplastic therapy for rectal cancer&#xD;
&#xD;
          5. History or evidence upon physical examination of CNS metastasis&#xD;
&#xD;
          6. Uncontrolled hypercalcemia&#xD;
&#xD;
          7. Pre-existing permanent neuropathy (NCI-CTCAE grade ≥ 2)&#xD;
&#xD;
          8. Uncontrolled hypertension (defined as systolic blood pressure &gt; 150 mmHg and/or&#xD;
             diastolic blood pressure &gt; 100 mmHg), or history of hypertensive crisis, or&#xD;
             hypertensive encephalopathy&#xD;
&#xD;
          9. Concomitant protocol unplanned antitumor therapy (e.g. chemotherapy, molecular&#xD;
             targeted therapy, immunotherapy, radiotherapy)&#xD;
&#xD;
         10. Treatment with any other investigational medicinal product within 28 days prior to&#xD;
             study entry&#xD;
&#xD;
         11. Known dihydropyrimidine dehydrogenase (DPD) deficiency&#xD;
&#xD;
         12. Treatment with CYP3A4 inducers unless discontinued &gt; 7 Days prior to randomization&#xD;
&#xD;
         13. Any of the following in 3 months prior to inclusion:&#xD;
&#xD;
               -  Grade 3-4 gastrointestinal bleeding&#xD;
&#xD;
               -  Treatment resistant peptic ulcer disease&#xD;
&#xD;
               -  Erosive esophagitis or gastritis&#xD;
&#xD;
               -  Infectious or inflammatory bowel disease&#xD;
&#xD;
               -  Diverticulitis&#xD;
&#xD;
         14. Any active infection within 2 weeks prior to study inclusion&#xD;
&#xD;
         15. Vaccination with a live, attenuated vaccine within 4 weeks prior to the first&#xD;
             administration of the study medication&#xD;
&#xD;
         16. Other concomitant or previous malignancy, except:&#xD;
&#xD;
               -  Adequately treated in-situ carcinoma of the uterine cervix&#xD;
&#xD;
               -  Basal or squamous cell carcinoma of the skin&#xD;
&#xD;
               -  Cancer in complete remission for &gt; 5 years&#xD;
&#xD;
         17. Any other serious and uncontrolled non-malignant disease, major surgery or traumatic&#xD;
             injury within the last 28 days prior to study entry&#xD;
&#xD;
         18. Pregnant or breastfeeding women&#xD;
&#xD;
         19. Patients with known allergy to any constituent to study drugs&#xD;
&#xD;
         20. History of myocardial infarction and/or stroke within 6 months prior to randomization,&#xD;
             NYHA class III and IV congestive heart failure&#xD;
&#xD;
         21. Severe renal insufficiency (creatinin clearance &lt; 30 ml/min)&#xD;
&#xD;
         22. Bowel obstruction&#xD;
&#xD;
         23. Contra-indication to the assessment by MRI&#xD;
&#xD;
         24. Involvement in the planning and/or conduct of the study (applies to both Sanofi staff&#xD;
             and/or staff of Sponsor and study site)&#xD;
&#xD;
         25. Patient who might be dependent on the sponsor, site or the investigator&#xD;
&#xD;
         26. Patient who has been incarcerated or involuntarily institutionalized by court order or&#xD;
             by the authorities § 40 Abs. 1 S. 3 Nr. 4 AMG&#xD;
&#xD;
         27. Patients who are unable to consent because they do not understand the nature,&#xD;
             significance and implications of the clinical trial and therefore cannot form a&#xD;
             rational intention in the light of the facts [§ 40 Abs. 1 S. 3 Nr. 3a AMG].&#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>Tagestherapiezentrum am ITM &amp; III. Med. Klinik, Universitätsmedizin Mannheim</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Tagestherapiezentrum am ITM &amp; III. Med. Klinik</name>
      <address>
        <city>Mannheim</city>
        <zip>68167</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Germany</country>
  </location_countries>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>January 31, 2017</study_first_submitted>
  <study_first_submitted_qc>February 2, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">February 6, 2017</study_first_posted>
  <last_update_submitted>February 3, 2023</last_update_submitted>
  <last_update_submitted_qc>February 3, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 6, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>neoadjuvant</keyword>
  <keyword>MRI-defined T3</keyword>
  <keyword>mFOLFOX6</keyword>
  <keyword>Aflibercept</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>Oxaliplatin</mesh_term>
    <mesh_term>Aflibercept</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/NCT03043729
org study id: AIO-KRK-0214
nct id: NCT03043729
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Patients with locally advanced rectal or rectosigmoid cancer staged cT3 CRM-negative with MRI
      will receive 6 cycles of neoadjuvant treatment with mFOLFOX6 (Arm A) vs. mFOLFOX6 +
      aflibercept (Arm B) followed by surgery.
Patients with locally advanced rectal cancer are generally recommended to receive
      preoperative radiotherapy or radiochemotherapy. The advantage of combined-modality therapy in
      rectal cancer is that it has reduced local pelvic recurrence - a dreaded and morbid event -
      to rates of about 10%. There is good quality evidence that preoperative radiotherapy reduces
      local recurrence but there is little if any impact on overall survival. One strategy to
      reduce the distant recurrence rate, and thereby increase the cure rate, would be to introduce
      systemic treatment earlier to prevent dissemination of micrometastases. The present trial is
      designed to compare two neoadjuvant chemotherapy regimens in patients with non-metastatic T3
      CRM-negative rectal cancers using quality-controlled MRI of the pelvis as a main inclusion
      criterion. This strategy is believed to reduce acute and long-term toxicity caused by
      preoperative radiotherapy and to administer effective systemic chemotherapy early in the
      course of disease as neoadjuvant chemotherapy.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Pathologic complete response (pCR)
time frame: 20 weeks
description: number of patients with a pCR finding divided by the number of patients in the analysis set pCR will be assessed in a standardized manner independently by a central pathology
measure: Dose intensities of study medication
time frame: 12 weeks
description: The dose intensities of study medication will be calculated over the whole study duration and will be summarized descriptively by summary statistics.
measure: Type, incidence and severity of AEs, SAEs
time frame: 20 weeks
description: AEs will be coded according to the NCI-CTC Criteria Version 4.03. For the analysis, all AEs will be classified as related and not related. AEs will be summarized by presenting the number and percentages of patients having any AE and having an AE in each NCI-CTC category. Summaries will also be presented for AEs by severity and relationship to study medication. Tables will be broken down by study arm. All deaths and serious adverse events will be listed and briefly described.
measure: Dose reduction or discontinuation of study drug due to adverse events
time frame: 20 weeks
description: The dose intensities of study medication will be calculated over the whole study duration and will be summarized descriptively by summary statistics.
measure: Rate of treatment discontinuation due to toxicity
time frame: 20 weeks
description: Summaries will also be presented for AEs by severity and relationship to study medication. Tables will be broken down by study arm.
All deaths and serious adverse events will be listed and briefly described.
measure: Type, incidence and severity of laboratory abnormalities
time frame: 20 weeks
description: For relevant laboratory parameters, the distribution over time as well as changes from randomization will be calculated and analyzed descriptively.
measure: Rate of patients with R0-wide resection (according to CRM definitions in S3 guideline-Version 1.1 August 2014)
time frame: 20 weeks
description: The R0- and R1 resection as well as downstaging and downsizing using a standardized regression grading (Dworak regression grading) will be analyzed descriptively by means of frequencies and percentages.
measure: Rate of patients with R0-narrow resection (according to CRM definitions in S3 guideline-Version 1.1 August 2014)
time frame: 20 weeks
description: The R0- and R1 resection as well as downstaging and downsizing using a standardized regression grading (Dworak regression grading) will be analyzed descriptively by means of frequencies and percentages.
measure: Rate of patients with R1 resection (according to CRM definitions in S3 guideline-Version 1.1 August 2014)
time frame: 20 weeks
description: The R0- and R1 resection as well as downstaging and downsizing using a standardized regression grading (Dworak regression grading) will be analyzed descriptively by means of frequencies and percentages.
measure: Rate of patients with locoregional R2 resection (according to CRM definitions in S3 guideline-Version 1.1 August 2014)
time frame: 20 weeks
description: The R0- and R1 resection as well as downstaging and downsizing using a standardized regression grading (Dworak regression grading) will be analyzed descriptively by means of frequencies and percentages.
measure: Rate of number of patients with R0-wide, R0-narrow (according to CRM definitions in S3 guideline-Version 1.1 August 2014), R1 and locoregional R2 resection
time frame: 20 weeks
description: The R0- and R1 resection as well as downstaging and downsizing using a standardized regression grading (Dworak regression grading) will be analyzed descriptively by means of frequencies and percentages.
measure: Disease-free survival (DFS)
time frame: 44 weeks
description: Disease-free survival rate will be analyzed using a two-sided Fisher's exact test at a 5% significance level. In addition, two-sided 95% confidence intervals for DFS rates and difference in rates between both treatment arms will be calculated.
measure: Relapse-free survival (RFS) in resected patients
time frame: 44 weeks
description: Relapse-free survival: The length of time after completion of primary treatment (neoadjuvant chemotherapy + surgery) until documented relapse (i.e. local relapse, liver metastasis, systemic metastases).
measure: Overall survival (OS) rate
time frame: 44 weeks
description: Overall survival: Survival will be calculated from the date of subject enrollment until the date of death from any cause. If no event is observed (e.g. lost to follow-up) OS is censored at the day of last subject contact.
measure: Downstaging ability in resected patients using a standardized regression grading (Dworak regression grading)
time frame: 20 weeks
description: The R0- and R1 resection as well as downstaging and downsizing using a standardized regression grading (Dworak regression grading) will be analyzed descriptively by means of frequencies and percentages.
measure: Downsizing ability in resected patients using a standardized regression grading (Dworak regression grading)
time frame: 20 weeks
description: The R0- and R1 resection as well as downstaging and downsizing using a standardized regression grading (Dworak regression grading) will be analyzed descriptively by means of frequencies and percentages.
measure: Type, incidence and severity of perioperative medical events within 28 days after surgery are assessed. Perioperative morbidity is categorized according to the Clavien-Dindo-Classification
time frame: 20 weeks
description: Perioperative medical events as well as mortality within 28 days after surgery will be summarized by frequencies and percentages broken down per treatment arm.
measure: Mortality after surgery
time frame: 20 weeks
description: Perioperative medical events as well as mortality within 28 days after surgery will be summarized by frequencies and percentages broken down per treatment arm.
measure: Vital signs
time frame: 20 weeks
description: Vital signs will be analyzed using summary statistics broken down per treatment group and visit.
measure: Physical examination
time frame: 20 weeks
description: Physical examination as well as WHO/ECOG will be analyzed by calculating frequencies and percentages broken down per treatment group and visit.
measure: ECOG
time frame: 20 weeks
description: Physical examination as well as WHO/ECOG will be analyzed by calculating frequencies and percentages broken down per treatment group and visit.
arm group label: Arm A
arm group type: Active Comparator
description: 6 cycles chemotherapy with Oxaliplatin 85 mg/m^2 and Leucovorin 350 mg/m^2 i.v. as 2h infusion on Day 1 and 5-FU 400 mg/m^2 i.v. as bolus on Day 1 and 2400 mg/m^2 as 46 h infusion q2w followed by surgery 4 weeks after last neoadjuvant chemotherapy treatment
arm group label: Arm B
arm group type: Experimental
description: 6 cycles chemotherapy with Oxaliplatin 85 mg/m^2 and Leucovorin 350 mg/m^2 i.v. as 2h infusion on Day 1 and 5-FU 400 mg/m^2 i.v. as bolus on Day 1 and 2400 mg/m^2 as 46 h infusionq2w + Aflibercept 4 mg/kg BW i.v. on Day 1 q2w (6th cycle without Aflibercept) followed by surgery 4 weeks after last neoadjuvant chemotherapy treatment
intervention type: Drug
intervention name: Oxaliplatin
description: Oxaliplatin 85 mg/m^2, as 2h infusion on Day 1 (Arm A + Arm B)
arm group label: Arm A
arm group label: Arm B
intervention type: Drug
intervention name: 5-FU
description: 5-FU 400 mg/m^2 i.v. as bolus on Day 1 and 2400 mg/m^2 as 46 h infusion q2w (Arm A + Arm B)
arm group label: Arm A
arm group label: Arm B
intervention type: Drug
intervention name: Leucovorin
description: Leucovorin 350 mg/m^2 i.v. as 2h infusion on Day 1 (Arm A + Arm B)
arm group label: Arm A
arm group label: Arm B
intervention type: Biological
intervention name: Aflibercept
description: Aflibercept 4 mg/kg BW i.v. on Day 1 q2w (Arm B, Cycles 1 to 5)
arm group label: Arm B
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: Tagestherapiezentrum am ITM & III. Med. Klinik, Universitätsmedizin Mannheim
facility: 
country: Germany
responsible party type: Sponsor
mesh term: Rectal Neoplasms
mesh term: Leucovorin
mesh term: Oxaliplatin
mesh term: Aflibercept
sharing ipd: No