<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/NCT02240017</url>
  </required_header>
  <id_info>
    <org_study_id>13 URO 02</org_study_id>
    <nct_id>NCT02240017</nct_id>
  </id_info>
  <brief_title>A Study Evaluating Chemotherapy With Fractionated Cisplatin/Gemcitabine Versus Carboplatin/Gemcitabine in the Treatment of Advanced or Metastatic Urothelial Cancer With Impaired Renal Function.</brief_title>
  <acronym>VEFORA</acronym>
  <official_title>Randomized, Multicenter, Phase II/III Study, Evaluating Fractionated Cisplatin Chemotherapy/Gemcitabine Versus Carboplatin/Gemcitabine in the Treatment of Advanced or Metastatic Urothelial Cancer With Impaired Renal Function.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Institut Claudius Regaud</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Institut Claudius Regaud</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a phase II/III, multicenter, randomized study which includes 420 patients on six&#xD;
      years + 3 years follow up. 92 patients will be included during the phase II ; additional 328&#xD;
      patients will be included.&#xD;
&#xD;
      Patients with an advanced or metastatic urothelial cancer with impaired renal function will&#xD;
      be randomized in one of the two following chemotherapy arm:&#xD;
&#xD;
        -  Fractionated Cisplatin + Gemcitabine.&#xD;
&#xD;
        -  Carboplatin + Gemcitabine.&#xD;
&#xD;
      The main objective of the part II study will be to evaluate the efficacy and the safety of a&#xD;
      chemotherapy with a doublet platinum salt compound/Gemcitabine with fractionated Cisplatin or&#xD;
      Carboplatin in this population.&#xD;
&#xD;
      The main objective of the part III study will be to compare the efficacy in terms of overall&#xD;
      survival of a chemotherapy with a doublet platinum salt/Gemcitabine with fractionated&#xD;
      Cisplatin or Carboplatin in this population.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 21, 2015</start_date>
  <completion_date type="Actual">July 15, 2019</completion_date>
  <primary_completion_date type="Actual">April 10, 2018</primary_completion_date>
  <phase>Phase 2/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>Phase II: Efficacy - Rate of non progression at the end of treatment (C6D21).</measure>
    <time_frame>5 years.</time_frame>
    <description>Progression is defined according to RECIST (Response Evaluation Criteria in Solid Tumors) criteria V1.1.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Phase III: Overall survival (in months).</measure>
    <time_frame>9 years.</time_frame>
    <description>Overall survival is defined as the time from randomization until death or last follow up news (censured data).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Phase II: Tolerance - Percentage of patients for whom at least one of the 3 defined tolerance criteria (see description) is observed.</measure>
    <time_frame>5 years.</time_frame>
    <description>Defined tolerance criteria :&#xD;
Postponement of chemotherapy &gt; or = 2 weeks.&#xD;
Alteration of renal function.&#xD;
Need to decrease twice Gemcitabine dose on day 1 for : NCI CTC (National Cancer Institut Common Toxicity Criteria) grade III or IV non-hematologic toxicity, hematologic toxicity.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Phase II and III: Objective response.</measure>
    <time_frame>Phase II: 5 years ; Phase III: 9 years.</time_frame>
    <description>Objective response (ie complete or partial response) will be evaluated according to RECIST v1.1 criteria.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Phase II and III: Tolerance according to NCI toxicity scale (version 4.0).</measure>
    <time_frame>Phase II: 5 years ; Phase III: 9 years.</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Phase II and III: Geriatric evaluation using questionnaires.</measure>
    <time_frame>Phase II: 5 years ; Phase III: 9 years.</time_frame>
    <description>The geriatric assessment will be evaluate using the following questionnaires: G8 (oncodage) , ADL (activity of daily living), CIRSG (cumulating illness rating scale geriatric) , MMS (mini-mental score), IADL (instrumental activities of daily living), GDS (geriatric depression scale), MNA (mini-nutritional assessment).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Phase II and III: Quality of life using the EORTC QLQ - C30 questionnaire (European Organization for research and treatment of Cancer - Quality of life questionnaire).</measure>
    <time_frame>Phase II: 5 years ; Phase III: 9 years.</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Phase II and III: Pharmacokinetics - Platin concentrations</measure>
    <time_frame>At cycles 1 and 2 day 1 - 5 mn before the end of infusion, one hour after the end of infusion, 3 hours (arm A) or 4 hours (arm B) after the end of infusion.</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Phase II and III: Pharmacogenetics, exploration of cytidine deaminase activity and study of its genetic polymorphisms.</measure>
    <time_frame>Prior to the initial dose on cycle 1 day 1.</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Phase II and III: Progression free survival.</measure>
    <time_frame>Phase II: 5 years ; phase III: 9 years.</time_frame>
    <description>Progression free survival will be evaluated according to RECIST v1.1 criteria.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Phase II and III: Overall survival.</measure>
    <time_frame>Phase II: 5 years ; Phase III: 9 years.</time_frame>
    <description>Overall survival is defined as the time from randomization until death from all causes combined.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Phase II and III: Time to treatment failure.</measure>
    <time_frame>Phase II: 5 years ; Phase III: 9 years.</time_frame>
    <description>Time to treatment failure is defined as the time from randomization to treatment discontinuation, whatever its cause.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">46</enrollment>
  <condition>Advanced Urothelial Cancer</condition>
  <condition>Metastatic Urothelial Cancer</condition>
  <arm_group>
    <arm_group_label>Carboplatin/Gemcitabine</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Fractionated Cisplatin/Gemcitabine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Carboplatin</intervention_name>
    <description>Carboplatin AUC (area under curve) 4,5 at day 1 of each cycle until 6 cycles.</description>
    <arm_group_label>Carboplatin/Gemcitabine</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Fractionated Cisplatin</intervention_name>
    <description>Cisplatin 35mg/m² at day 1 and day 8 of each cycle until 6 cycles.</description>
    <arm_group_label>Fractionated Cisplatin/Gemcitabine</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Gemcitabine</intervention_name>
    <description>Gemcitabine 1000mg/m² at day 1 and day 8 of each cycle until 6 cycles.</description>
    <arm_group_label>Carboplatin/Gemcitabine</arm_group_label>
    <arm_group_label>Fractionated Cisplatin/Gemcitabine</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. . Age &lt; or = 18 years, patients aged 75 years or more will benefit from a geriatric&#xD;
             assessment.&#xD;
&#xD;
          2. . Advanced or metastatic urothelial cancer confirmed histologically or cytologically.&#xD;
&#xD;
          3. . Patients liable to receive a first -line chemotherapy for advanced or metastatic&#xD;
             urothelial carcinoma.&#xD;
&#xD;
          4. . Measurable disease according to RECIST criteria V1.1.&#xD;
&#xD;
          5. . Patients who received neoadjuvant or adjuvant chemotherapy based on platinum salt&#xD;
             must have completed treatment at least 6 months before entering the study.&#xD;
&#xD;
          6. . Performance status &lt; or = 2.&#xD;
&#xD;
          7. . Life expectancy &gt; 3 months.&#xD;
&#xD;
          8. . Patients with creatinine clearance between 40 and 60 ml / min ( according to&#xD;
             Cockcroft and Gault ).&#xD;
&#xD;
          9. . Patients having no contra-indication to overhydration.&#xD;
&#xD;
         10. . Satisfactory hematological tests: Neutrophils &gt; 1.5 G / l Platelets &gt; 150 G / l ,&#xD;
             hemoglobin ≥ 10 g / dl.&#xD;
&#xD;
         11. . Satisfactory liver function tests: total bilirubin &lt; 1.5 x ULN (upper limit of&#xD;
             normal), AST (aspartate aminotransferase) and ALT (alanine aminotransferase)&lt;or = 2.5&#xD;
             x ULN (or 5 x ULN if liver metastases).&#xD;
&#xD;
         12. . In case of prior radiotherapy, a minimum of 14 days must relapse between the end of&#xD;
             radiotherapy and study entry.&#xD;
&#xD;
         13. . For women of childbearing age , use an effective contraceptive method to study entry&#xD;
             and for the duration of the study and 6 months after the last dose of study treatment&#xD;
             ; For sexually active fertile men having a partner of childbearing age using effective&#xD;
             contraception for the duration of the study and 6 months after the last dose of study&#xD;
             treatment.&#xD;
&#xD;
         14. . Patient affiliated to a social security system in France.&#xD;
&#xD;
         15. . Patient signed informed consent before inclusion in the study and before any&#xD;
             specific procedure for the study.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. . Any concomitant or previous malignancy within 5 years prior to the study ( with the&#xD;
             exception of basal cell or squamous cell carcinoma in situ).&#xD;
&#xD;
          2. . Pregnant or lactating women.&#xD;
&#xD;
          3. . Patients with brain metastases or meningeal or symptoms suggestive of such secondary&#xD;
             locations.&#xD;
&#xD;
          4. . Bisphosphonate or Denosumab treatment initiated within 28 days prior to&#xD;
             randomization into the study or patient who have started such treatment during the&#xD;
             study ( a bisphosphonate or denosumab treatment initiated within a period longer than&#xD;
             28 days before randomization may be continued without change during the study ).&#xD;
&#xD;
          5. . Other concomitant cancer (radiation therapy, radiopharmaceutical agent&#xD;
             chemotherapy).&#xD;
&#xD;
          6. . Patients with uncontrolled infection.&#xD;
&#xD;
          7. . Patients with peripheral neuropathy grade&gt; 1, whatever the origin or patients with&#xD;
             hearing loss.&#xD;
&#xD;
          8. . Patient with unstable disease (eg: unstable diabetes, poorly controlled hypertension&#xD;
             , congestive heart failure or myocardial infarction within 3 months prior to study&#xD;
             entry).&#xD;
&#xD;
          9. . Known hypersensitivity to study drugs.&#xD;
&#xD;
         10. . Treatment with any other investigational drug within 30 days before inclusion.&#xD;
&#xD;
         11. . Any psychological condition , familial, sociological or geographical not to comply&#xD;
             with medical monitoring and / or procedures in the study protocol.&#xD;
&#xD;
         12. . Patient protected by law.&#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>Loic MOUREY, MD</last_name>
    <role>Study Chair</role>
    <affiliation>Institut Claudius Regaud</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>INSTITUT DE CANCEROLOGIE DE L'OUEST - Site Paul Papin</name>
      <address>
        <city>Angers</city>
        <zip>49933</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Chru Besancon - Hopital Jean Minjoz</name>
      <address>
        <city>Besançon</city>
        <zip>25030</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institut Bergonie</name>
      <address>
        <city>Bordeaux</city>
        <zip>33076</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre Francois Baclesse</name>
      <address>
        <city>Caen</city>
        <zip>14076</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre Georges Francois Leclerc</name>
      <address>
        <city>Dijon</city>
        <zip>21079</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CH VERSAILLES - Hôpital André Mignot</name>
      <address>
        <city>Le Chesnay</city>
        <zip>78157</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU LIMOGES - Hôpital Dupuytren</name>
      <address>
        <city>Limoges</city>
        <zip>87042</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre Leon Berard</name>
      <address>
        <city>Lyon</city>
        <zip>69373</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institut Paoli Calmettes</name>
      <address>
        <city>Marseille</city>
        <zip>13273</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ch Mont de Marsan</name>
      <address>
        <city>Mont de Marsan</city>
        <zip>40024</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institut Regional Du Cancer Montpellier</name>
      <address>
        <city>Montpellier</city>
        <zip>34298</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ap-Hp-Hopital Saint-Louis</name>
      <address>
        <city>Paris</city>
        <zip>75010</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>INSTITUT DE CANCEROLOGIE DE L'OUEST - Site René Gauducheau</name>
      <address>
        <city>Saint-Herblain</city>
        <zip>44805</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institut de Cancerologie Lucien Neuwirth</name>
      <address>
        <city>Saint-Priest en Jarez</city>
        <zip>42271</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU de STRASBOURG</name>
      <address>
        <city>Strasbourg</city>
        <zip>67091</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institut Claudius Regaud</name>
      <address>
        <city>Toulouse</city>
        <zip>31052</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Chru Tours</name>
      <address>
        <city>Tours</city>
        <zip>37044</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institut Gustave Roussy</name>
      <address>
        <city>Villejuif</city>
        <zip>94805</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>August 2019</verification_date>
  <study_first_submitted>September 5, 2014</study_first_submitted>
  <study_first_submitted_qc>September 11, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 15, 2014</study_first_posted>
  <last_update_submitted>August 7, 2019</last_update_submitted>
  <last_update_submitted_qc>August 7, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">August 9, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Urothelial cancer, renal function impaired.</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Renal Insufficiency</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carboplatin</mesh_term>
    <mesh_term>Gemcitabine</mesh_term>
  </intervention_browse>
  <!-- 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/NCT02240017
org study id: 13 URO 02
nct id: NCT02240017
lead sponsor: 
has dmc: No
This is a phase II/III, multicenter, randomized study which includes 420 patients on six
      years + 3 years follow up. 92 patients will be included during the phase II ; additional 328
      patients will be included.

      Patients with an advanced or metastatic urothelial cancer with impaired renal function will
      be randomized in one of the two following chemotherapy arm:

        -  Fractionated Cisplatin + Gemcitabine.

        -  Carboplatin + Gemcitabine.

      The main objective of the part II study will be to evaluate the efficacy and the safety of a
      chemotherapy with a doublet platinum salt compound/Gemcitabine with fractionated Cisplatin or
      Carboplatin in this population.

      The main objective of the part III study will be to compare the efficacy in terms of overall
      survival of a chemotherapy with a doublet platinum salt/Gemcitabine with fractionated
      Cisplatin or Carboplatin in this population.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Phase II: Efficacy - Rate of non progression at the end of treatment (C6D21).
time frame: 5 years.
description: Progression is defined according to RECIST (Response Evaluation Criteria in Solid Tumors) criteria V1.1.
measure: Phase III: Overall survival (in months).
time frame: 9 years.
description: Overall survival is defined as the time from randomization until death or last follow up news (censured data).
measure: Phase II: Tolerance - Percentage of patients for whom at least one of the 3 defined tolerance criteria (see description) is observed.
time frame: 5 years.
description: Defined tolerance criteria :
Postponement of chemotherapy > or = 2 weeks.
Alteration of renal function.
Need to decrease twice Gemcitabine dose on day 1 for : NCI CTC (National Cancer Institut Common Toxicity Criteria) grade III or IV non-hematologic toxicity, hematologic toxicity.
measure: Phase II and III: Objective response.
time frame: Phase II: 5 years ; Phase III: 9 years.
description: Objective response (ie complete or partial response) will be evaluated according to RECIST v1.1 criteria.
measure: Phase II and III: Tolerance according to NCI toxicity scale (version 4.0).
time frame: Phase II: 5 years ; Phase III: 9 years.
measure: Phase II and III: Geriatric evaluation using questionnaires.
time frame: Phase II: 5 years ; Phase III: 9 years.
description: The geriatric assessment will be evaluate using the following questionnaires: G8 (oncodage) , ADL (activity of daily living), CIRSG (cumulating illness rating scale geriatric) , MMS (mini-mental score), IADL (instrumental activities of daily living), GDS (geriatric depression scale), MNA (mini-nutritional assessment).
measure: Phase II and III: Quality of life using the EORTC QLQ - C30 questionnaire (European Organization for research and treatment of Cancer - Quality of life questionnaire).
time frame: Phase II: 5 years ; Phase III: 9 years.
measure: Phase II and III: Pharmacokinetics - Platin concentrations
time frame: At cycles 1 and 2 day 1 - 5 mn before the end of infusion, one hour after the end of infusion, 3 hours (arm A) or 4 hours (arm B) after the end of infusion.
measure: Phase II and III: Pharmacogenetics, exploration of cytidine deaminase activity and study of its genetic polymorphisms.
time frame: Prior to the initial dose on cycle 1 day 1.
measure: Phase II and III: Progression free survival.
time frame: Phase II: 5 years ; phase III: 9 years.
description: Progression free survival will be evaluated according to RECIST v1.1 criteria.
measure: Phase II and III: Overall survival.
time frame: Phase II: 5 years ; Phase III: 9 years.
description: Overall survival is defined as the time from randomization until death from all causes combined.
measure: Phase II and III: Time to treatment failure.
time frame: Phase II: 5 years ; Phase III: 9 years.
description: Time to treatment failure is defined as the time from randomization to treatment discontinuation, whatever its cause.
arm group label: Carboplatin/Gemcitabine
arm group type: Active Comparator
arm group label: Fractionated Cisplatin/Gemcitabine
arm group type: Experimental
intervention type: Drug
intervention name: Carboplatin
description: Carboplatin AUC (area under curve) 4,5 at day 1 of each cycle until 6 cycles.
arm group label: Carboplatin/Gemcitabine
intervention type: Drug
intervention name: Fractionated Cisplatin
description: Cisplatin 35mg/m² at day 1 and day 8 of each cycle until 6 cycles.
arm group label: Fractionated Cisplatin/Gemcitabine
intervention type: Drug
intervention name: Gemcitabine
description: Gemcitabine 1000mg/m² at day 1 and day 8 of each cycle until 6 cycles.
arm group label: Carboplatin/Gemcitabine
arm group label: Fractionated Cisplatin/Gemcitabine
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Loic MOUREY, MD
role: Study Chair
affiliation: Institut Claudius Regaud
facility: 
facility: 
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country: France
responsible party type: Sponsor
mesh term: Renal Insufficiency
mesh term: Carboplatin
mesh term: Gemcitabine