<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/NCT03279289</url>
  </required_header>
  <id_info>
    <org_study_id>TTD-16-03</org_study_id>
    <nct_id>NCT03279289</nct_id>
  </id_info>
  <brief_title>Study to Assess the Efficacy and Safety of Treatment With FOLFIRI-aflibercept Compared to Initial Treatment With FOLFIRI-aflibercept (for 6 Cycles) Followed by Maintenance With 5FU-aflibercept, in an Elderly Population With mCRC After Failure of an Oxaliplatin-based Regimen</brief_title>
  <acronym>AFEMA</acronym>
  <official_title>Randomised, Multicentre, Phase II Pilot Study to Assess the Efficacy and Safety of Treatment With FOLFIRI-aflibercept Compared to Initial Treatment With FOLFIRI-aflibercept (for 6 Cycles) Followed by Maintenance With 5FU-aflibercept, in an Elderly Population With Metastatic Colorectal Cancer (mCRC) After Failure of an Oxaliplatin-based Regimen</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Spanish Cooperative Group for the Treatment of Digestive Tumours (TTD)</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Sanofi</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Spanish Cooperative Group for the Treatment of Digestive Tumours (TTD)</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>
      The purpose of this study is to assess the efficacy and safety of treatment with&#xD;
      FOLFIRI-aflibercept compared to initial treatment with FOLFIRI-aflibercept (for 6 cycles)&#xD;
      followed by maintenance with 5FU-aflibercept, in an elderly population with metastatic&#xD;
      colorectal cancer (mCRC) after failure of an oxaliplatin-based regimen&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 25, 2017</start_date>
  <completion_date type="Actual">February 9, 2023</completion_date>
  <primary_completion_date type="Actual">February 9, 2023</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>Progression-free survival</measure>
    <time_frame>48 months</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Objective response rate based on the RECIST criteria</measure>
    <time_frame>48 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disease control rate</measure>
    <time_frame>48 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Depth of response</measure>
    <time_frame>48 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to progression</measure>
    <time_frame>48 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to treatment failure</measure>
    <time_frame>48 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival</measure>
    <time_frame>48 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence and severity of AEs CTCAE v4.03 criteria</measure>
    <time_frame>48 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of dose adjustments and compliance</measure>
    <time_frame>48 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>VES-13 score (Vulnerable Elders Survey) as the utility measure for health deterioration</measure>
    <time_frame>48 months</time_frame>
  </secondary_outcome>
  <other_outcome>
    <measure>Biomarkers in serum and tumour tissue associated with cell and tumour growth and/or involved in the mechanism of action of FOLFIRI+aflibercept and their correlation with efficacy parameters</measure>
    <time_frame>48 months</time_frame>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">170</enrollment>
  <condition>Metastatic Colorectal Cancer</condition>
  <arm_group>
    <arm_group_label>Group A</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>INDUCTION PHASE: 6 cycles of FOLFIRI + aflibercept MAINTENANCE PHASE: 5FU/LV + aflibercept</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group B</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>FOLFIRI + aflibercept</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Aflibercept</intervention_name>
    <description>4 mg/kg administered intravenous infusion on day 1</description>
    <arm_group_label>Group A</arm_group_label>
    <arm_group_label>Group B</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Irinotecan</intervention_name>
    <description>180 mg/m2 intravenous infusion</description>
    <arm_group_label>Group A</arm_group_label>
    <arm_group_label>Group B</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>folinic acid (dl racemic)</intervention_name>
    <description>400 mg/m2 intravenous infusion</description>
    <arm_group_label>Group A</arm_group_label>
    <arm_group_label>Group B</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>5Fluorouracil</intervention_name>
    <description>400 mg/m2 intravenous bolus</description>
    <arm_group_label>Group A</arm_group_label>
    <arm_group_label>Group B</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>5-FU</intervention_name>
    <description>2400 mg/m2 continuous intravenous infusion over 46 hours</description>
    <arm_group_label>Group A</arm_group_label>
    <arm_group_label>Group B</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Signed and dated informed consent, and willing and able to comply with protocol&#xD;
             requirements,&#xD;
&#xD;
          2. Histologically proven adenocarcinoma of the colon and/or rectum,&#xD;
&#xD;
          3. Existence of at least one measurable unidimensional lesion using CT or MRI based on&#xD;
             the RECIST criteria, version 1.1&#xD;
&#xD;
          4. Patients with metastatic colorectal cancer (mCRC) that is resistant to or has&#xD;
             progressed after a first line oxaliplatin-containing regimen for metastatic disease.&#xD;
&#xD;
          5. Age ≥70 years&#xD;
&#xD;
          6. World Health Organization (WHO) Performance status (PS) 0-2,&#xD;
&#xD;
          7. Hematological status: neutrophils (ANC) ≥1.5x109 /L; platelets ≥100x109 /L;&#xD;
             haemoglobin ≥9 g/dL&#xD;
&#xD;
          8. Adequate renal function: Creatinine clearance ≥50 mL/min as calculated using the&#xD;
             Cockcroft-Gault equation.&#xD;
&#xD;
          9. Adequate liver function: serum bilirubin ≤1.5 x upper normal limit (ULN), alkaline&#xD;
             phosphatase (ALP) &lt;5xULN&#xD;
&#xD;
         10. Proteinuria &lt;2+ (dipstick urinalysis) or ≤1g/24hour.&#xD;
&#xD;
         11. Regular follow-up feasible.&#xD;
&#xD;
         12. Male patients with a partner of childbearing potential must agree to use contraception&#xD;
             in addition to having their partner use another contraceptive method during the trial.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Uncontrolled hypercalcemia,&#xD;
&#xD;
          2. Pre-existing permanent neuropathy (NCI grade &gt;2)&#xD;
&#xD;
          3. 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;
          4. Concomitant protocol unplanned antitumor therapy (e.g. chemotherapy, molecular&#xD;
             targeted therapy, immunotherapy),&#xD;
&#xD;
          5. Treatment with any other investigational medicinal product within 28 days prior to&#xD;
             study entry.&#xD;
&#xD;
          6. Other serious and uncontrolled non-malignant disease,&#xD;
&#xD;
          7. History or evidence upon physical examination of CNS metastasis unless adequately&#xD;
             treated (e.g. non irradiated CNS metastasis, seizure not controlled with standard&#xD;
             medical therapy),&#xD;
&#xD;
          8. Patients classified as fragile or delicate according to the following criteria:&#xD;
&#xD;
               1. Dependence in one or more activities of daily living according to the Katz Index&#xD;
                  of Independence in Activities of Daily Living (ADL) scale&#xD;
&#xD;
               2. Three or more comorbidities when assessing the presence of the following&#xD;
                  processes: congestive heart failure; heart valve disease; coronary artery&#xD;
                  disease; chronic (obstructive or restrictive) pulmonary disease; cerebrovascular&#xD;
                  disease; peripheral neuropathy, chronic kidney failure; hypertension; diabetes;&#xD;
                  concomitant cancers; collagen vascular disease; chronic liver disease; and&#xD;
                  disabling arthritis&#xD;
&#xD;
               3. Presence of geriatric syndromes: moderate-severe dementia; delirium in stressful&#xD;
                  situations (urinary or respiratory tract infection, angina or drugs);&#xD;
                  moderate-severe depression that interferes with the patient's usual activity;&#xD;
                  frequent falls (three or more per month); inattentiveness (who could help you in&#xD;
                  the event of an emergency?); urinary incontinence in the absence of stress,&#xD;
                  infection, diuretics or prostatic hyperplasia; faecal incontinence in the absence&#xD;
                  of diarrhoea or laxatives; osteoporotic fractures of large bones or vertebral&#xD;
                  compression fractures&#xD;
&#xD;
          9. Known Gilbert's syndrome&#xD;
&#xD;
         10. Intolerance to atropine sulfate or loperamide&#xD;
&#xD;
         11. Known dihydropyrimidine dehydrogenase deficiency&#xD;
&#xD;
         12. Treatment with CYP3A4 inducers unless discontinued &gt; 7 days prior to inclusion&#xD;
&#xD;
         13. Any of the following in 3 months prior to inclusion: grade 3-4 gastrointestinal&#xD;
             bleeding (unless due to resected tumor), treatment resistant peptic ulcer disease,&#xD;
             erosive esophagitis or gastritis, infectious or inflammatory bowel disease, or&#xD;
             diverticulitis.&#xD;
&#xD;
         14. Other concomitant or previous malignancy, except: i/ adequately treated insitu&#xD;
             carcinoma of the uterine cervix, ii/ basal or squamous cell carcinoma of the skin,&#xD;
             iii/ cancer in complete remission for &gt;5 years,&#xD;
&#xD;
         15. Any other serious and uncontrolled non-malignant disease, major surgery or traumatic&#xD;
             injury within the last 28 days&#xD;
&#xD;
         16. Patients with known allergy to any excipient to study drugs,&#xD;
&#xD;
         17. History of myocardial infarction and/or stroke within 6 months prior to inclusion,&#xD;
             NYHA class III and IV congestive heart failure&#xD;
&#xD;
         18. Bowel obstruction.&#xD;
&#xD;
         19. Less than 28 days elapsed from prior radiotherapy&#xD;
&#xD;
         20. Patients with pernicious anemia or other megaloblastic anemias due to vitamin B12&#xD;
             deficiency&#xD;
&#xD;
         21. Patients with severe infections&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>70 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Pilar García Alfonso</last_name>
    <role>Study Chair</role>
    <affiliation>Hospital Universitario Gregorio Marañón</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Javier Sastre Valera</last_name>
    <role>Study Chair</role>
    <affiliation>Hospital Universitario Clínico San Carlos</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Spanish Cooperative Group for Digestive Tumour Therapy (TTD)</name>
      <address>
        <city>Madrid</city>
        <zip>28046</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Spain</country>
  </location_countries>
  <verification_date>April 2023</verification_date>
  <study_first_submitted>August 3, 2017</study_first_submitted>
  <study_first_submitted_qc>September 8, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 12, 2017</study_first_posted>
  <last_update_submitted>April 12, 2023</last_update_submitted>
  <last_update_submitted_qc>April 12, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">April 13, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>FOLFIRI</keyword>
  <keyword>aflibercept</keyword>
  <keyword>5-FU</keyword>
  <keyword>oxaliplatin</keyword>
  <keyword>elderly</keyword>
  <keyword>metastatic colorectal cancer</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>Leucovorin</mesh_term>
    <mesh_term>Folic Acid</mesh_term>
    <mesh_term>Fluorouracil</mesh_term>
    <mesh_term>Irinotecan</mesh_term>
    <mesh_term>Aflibercept</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/NCT03279289
org study id: TTD-16-03
nct id: NCT03279289
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The purpose of this study is to assess the efficacy and safety of treatment with
      FOLFIRI-aflibercept compared to initial treatment with FOLFIRI-aflibercept (for 6 cycles)
      followed by maintenance with 5FU-aflibercept, in an elderly population with metastatic
      colorectal cancer (mCRC) after failure of an oxaliplatin-based regimen
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Progression-free survival
time frame: 48 months
measure: Objective response rate based on the RECIST criteria
time frame: 48 months
measure: Disease control rate
time frame: 48 months
measure: Depth of response
time frame: 48 months
measure: Time to progression
time frame: 48 months
measure: Time to treatment failure
time frame: 48 months
measure: Overall survival
time frame: 48 months
measure: Incidence and severity of AEs CTCAE v4.03 criteria
time frame: 48 months
measure: Incidence of dose adjustments and compliance
time frame: 48 months
measure: VES-13 score (Vulnerable Elders Survey) as the utility measure for health deterioration
time frame: 48 months
measure: Biomarkers in serum and tumour tissue associated with cell and tumour growth and/or involved in the mechanism of action of FOLFIRI+aflibercept and their correlation with efficacy parameters
time frame: 48 months
arm group label: Group A
arm group type: Experimental
description: INDUCTION PHASE: 6 cycles of FOLFIRI + aflibercept MAINTENANCE PHASE: 5FU/LV + aflibercept
arm group label: Group B
arm group type: Active Comparator
description: FOLFIRI + aflibercept
intervention type: Drug
intervention name: Aflibercept
description: 4 mg/kg administered intravenous infusion on day 1
arm group label: Group A
arm group label: Group B
intervention type: Drug
intervention name: Irinotecan
description: 180 mg/m2 intravenous infusion
arm group label: Group A
arm group label: Group B
intervention type: Drug
intervention name: folinic acid (dl racemic)
description: 400 mg/m2 intravenous infusion
arm group label: Group A
arm group label: Group B
intervention type: Drug
intervention name: 5Fluorouracil
description: 400 mg/m2 intravenous bolus
arm group label: Group A
arm group label: Group B
intervention type: Drug
intervention name: 5-FU
description: 2400 mg/m2 continuous intravenous infusion over 46 hours
arm group label: Group A
arm group label: Group B
criteria: 
gender: All
minimum age: 70 Years
maximum age: N/A
healthy volunteers: No
last name: Pilar García Alfonso
role: Study Chair
affiliation: Hospital Universitario Gregorio Marañón
last name: Javier Sastre Valera
role: Study Chair
affiliation: Hospital Universitario Clínico San Carlos
facility: 
country: Spain
responsible party type: Sponsor
mesh term: Colorectal Neoplasms
mesh term: Leucovorin
mesh term: Folic Acid
mesh term: Fluorouracil
mesh term: Irinotecan
mesh term: Aflibercept
mesh term: Levoleucovorin
sharing ipd: No