<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/NCT01696669</url>
  </required_header>
  <id_info>
    <org_study_id>GEIS-21</org_study_id>
    <secondary_id>2009-016027-62</secondary_id>
    <nct_id>NCT01696669</nct_id>
  </id_info>
  <brief_title>Study of Intensive Chemotherapy, Surgery and Radiotherapy to Treat Ewing's Sarcoma in Children and Young Adults</brief_title>
  <official_title>Phase 2, Open-label, Uncontrolled, Multicenter and Prospective Study of Intensive Chemotherapy, Surgery and Radiotherapy to Treat Ewing's Sarcoma in Children and Young Adults</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Grupo Espanol de Investigacion en Sarcomas</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Grupo Espanol de Investigacion en Sarcomas</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Tumors of the Ewing sarcoma family (ES) affect children, adolescents and young adults. The&#xD;
      reported incidence is 0.6 cases per million inhabitants every year. The peak incidence occurs&#xD;
      between 10 and 20 years and it is rarely diagnosed beyond 30. The ES is a severe disease with&#xD;
      a progression-free survival after 5 years of 60% in cases without metastasis and deadly in&#xD;
      the majority of patients presenting metastasis. The ES is considered a systemic disease&#xD;
      because, despite receiving an adequate local treatment, over 90% of patients deaths occur due&#xD;
      to disseminated disease. Combined therapy of surgery, radiotherapy and chemotherapy has led&#xD;
      to an improvement in the prognosis, achieving a survival of about 60% in most series&#xD;
&#xD;
      The MSKCC P6 protocol was developed for the treatment of high risk ES. In 2003, Kolb et al.&#xD;
      reported the MSKCC experience after a 4-years follow-up of 68 patients who had been included&#xD;
      from 1990 to 2001. Following the MSKCC P6 protocol, a survival rate of 82% was achieved in&#xD;
      patients without metastasis, superior to the achieved with less intensive protocols.&#xD;
      Following the guidelines of the MSKCC P6 protocol, in 2002 we modified the treatment schedule&#xD;
      to create the modified P6 protocol (MP6). GEIS intends to develop MP6 as a clinical trial,&#xD;
      which could provide the following potential advantages about current treatments:&#xD;
&#xD;
        1. Lower total dose of alkylating agents.&#xD;
&#xD;
        2. Early cardioprotection with dexrazoxane.&#xD;
&#xD;
        3. Radiotherapy adjusted to the initial response.&#xD;
&#xD;
        4. Pilot trial with the combination of Gemcitabine + Docetaxel for high-risk patients.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">March 30, 2010</start_date>
  <completion_date type="Actual">January 18, 2018</completion_date>
  <primary_completion_date type="Actual">December 20, 2017</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group 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>Assessment of the progression free survival in all the patients enrolled in the study 3 years after the completion of the treatment under study.</time_frame>
    <description>Assessment of the progression free survival in all the patients enrolled in the study 3 years after the completion of the treatment under study.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Objective response rate (ORR)</measure>
    <time_frame>two months</time_frame>
    <description>To assess the objective response rate to treatment (ORR) defined following EMEA criteria (CPMP/EWP/205/95/Rev.3/Corr.2) in high risk patients with Ewing's sarcoma treated with an early window phase of Gemcitabine + docetaxel (G + D).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of disease progression</measure>
    <time_frame>to reach an index of disease progression &lt; 20% for high risk patients during the maintenance phase with Gemcitabine + Docetaxel.</time_frame>
    <description>To assess the disease progression, aiming to reach an index of disease progression &lt; 20% for high risk patients during the maintenance phase with Gemcitabine + Docetaxel.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>evaluate the toxicity and tolerance to the treatment Gemcitabine + Docetaxel in high risk patients, and toxicity and tolerance of mP6 treatment in all patients.</measure>
    <time_frame>12 months</time_frame>
    <description>To evaluate the toxicity and tolerance to the treatment Gemcitabine + Docetaxel in high risk patients, and toxicity and tolerance of mP6 treatment in all patients.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of bone marrow condition.</measure>
    <time_frame>24 months</time_frame>
    <description>Molecular diagnosis and extension study of bone marrow in all patients included in the trial. Assessment of prognostic significance of the type of translocation and the molecular effect in the bone marrow.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Study the impact of patients treated with Cardioxane in cardioprotection</measure>
    <time_frame>6 months</time_frame>
    <description>Creation of a cohort of patients treated with anthracyclines at high doses and early cardioprotection with dexrazoxane (Cardioxane). Long-term study of cardioprotection in these patients compared with historical series from the P6 protocol that did not received cardioprotection.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">43</enrollment>
  <condition>Ewing's Sarcoma</condition>
  <arm_group>
    <arm_group_label>Chemotherapy + Surgery + Radiotherapy</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Standard risk patients: MP6 Treatment:&#xD;
CHEMOTHERAPY: 2 cycles of vincristine-doxorubicin + dexrazoxane-cyclophosphamide, 1 cycle of ifosfamide-etoposide. SURGERY: Ideally within 21 days after chemotherapy.&#xD;
CHEMOTHERAPY: 1 cycle of vincristine-doxorubicin + dexrazoxane-cyclophosphamide, 1 cycle of ifosfamide-etoposide.&#xD;
RADIOTHERAPY: On the primary tumor bed in case of unresectable tumors, resected tumors with inadequate margins, or those with histologic response &lt;90%.&#xD;
High risk patients:&#xD;
CHEMOTHERAPY: Window phase with 2 cycles of gemcitabine + docetaxel. MP6 TREATMENT. CHEMOTHERAPY: Maintenance therapy for 1 year with gemcitabine + docetaxel.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Chemotherapy</intervention_name>
    <description>Vincristine, 2 mg/m^2 IV bolus, day 1.&#xD;
Doxorubicin: 75 mg/m^2 per cycle, or 25 mg/m^2/day x 3 days, IV infusion, 1 hour (after dexrazoxane administration at the dose of 10:1).&#xD;
Dexrazoxane: administered at a dose of 10:1, before doxorubicin only in adults.&#xD;
Cyclophosphamide: 2100 mg/m^2 IV infusion, 6 hours, with MESNA protection, days 1 and 2.&#xD;
MESNA: used with cyclophosphamide and ifosfamide. The total daily dose of MESNA is equivalent to at least 60% of the daily dose of cyclophosphamide or ifosfamide.&#xD;
G-CSF: 5 micrograms/kg/day SC. It starts 24 hours after the last dose of chemotherapy and continues until the absolute neutrophil count is ≥ 750 mm^3/L.&#xD;
Ifosfamide: 1800 mg/m^2/day IV infusion, 1 hour, days 1-5 of each cycle (9,000 mg/m^2 total maximum dose).&#xD;
Window phase in high-risk patients (21-days cycle):&#xD;
Gemcitabine: 1000 mg/m^2 IV, 90 minutes on day 1 and 8.&#xD;
Docetaxel 100 mg/m^2, 2-3 hour infusion on day 8.</description>
    <arm_group_label>Chemotherapy + Surgery + Radiotherapy</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Surgery</intervention_name>
    <description>Surgical intervention aiming to completely resect the tumor with negative margins.</description>
    <arm_group_label>Chemotherapy + Surgery + Radiotherapy</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>Radiotherapy</intervention_name>
    <description>On the primary tumor bed in case of unresectable tumors, resected tumors with inadequate margins, or those with histologic response &lt;90%. Patients will receive radiotherapy 21 days after the completion of chemotherapy.</description>
    <arm_group_label>Chemotherapy + Surgery + Radiotherapy</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients with Ewing's Sarcoma in which the molecular analysis has been performed in&#xD;
             one of the 2 reference laboratories of the study and the EWS gene rearrangement has&#xD;
             been confirmed by RT-PCR in the Hospital Sant Joan de Déu de Barcelona, or by&#xD;
             fluorescence in situ hybridization (FISH) in the Cancer Research Center of Salamanca.&#xD;
&#xD;
          -  High-risk patients will be those patients with metastases, patients with primary tumor&#xD;
             in pelvis or axial bones and patients with (micro) metastases in bone marrow detected&#xD;
             by the molecular study. The remaining patients will be considered as standard risk.&#xD;
             Lung nodules identified by CT-scan with diameter &gt; 5 mm will be considered metastatic.&#xD;
             Nodules ≤ 5 mm will be biopsied.&#xD;
&#xD;
          -  Age ≤ 40 years.&#xD;
&#xD;
          -  Adequate renal and hepatic function , defined as calculated creatinine clearance &gt; 60&#xD;
             ml/min, creatinine, total bilirubin, AST and/or ALT &lt; 1,5 times the upper limit of&#xD;
             normal (ULN).&#xD;
&#xD;
          -  Normal cardiac function defined by echocardiography, or ejection fraction ≥ 55%.&#xD;
&#xD;
          -  ECOG performance status 0 - 1 (Appendix VIII).&#xD;
&#xD;
          -  Informed consent form signed by parents, guardians or the patient (if over 18 years),&#xD;
             prior to the start of treatment.&#xD;
&#xD;
          -  Patients of childbearing age (both men and women) must use effective contraceptive&#xD;
             methods before study entry and during the realization of it. Effective contraceptive&#xD;
             methods for both women and men should be extended to 6 months after stopping the&#xD;
             treatment under study. Pregnancy must be excluded by urine test (negative pregnancy&#xD;
             test) prior to the inclusion in the study.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Pregnancy or breastfeeding.&#xD;
&#xD;
          -  Active infection or other severe concomitant diseases.&#xD;
&#xD;
          -  Severe psychiatric conditions that make impossible to obtain the signed informed&#xD;
             consent form or limit the treatment compliance.&#xD;
&#xD;
          -  Concurrent treatment with other experimental drugs within 30 days prior to study&#xD;
             entry.&#xD;
&#xD;
          -  History of previous cancer diagnosed or treated in the past 5 years except basal cell&#xD;
             carcinoma, cervical carcinoma in situ or superficial bladder cancer.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>40 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jaume Mora Graupera, MD</last_name>
    <role>Study Chair</role>
    <affiliation>GEIS</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Hospital Clínic de Barcelona</name>
      <address>
        <city>Barcelona</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital de la Santa Creu i Sant Pau</name>
      <address>
        <city>Barcelona</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Vall d'Hebron</name>
      <address>
        <city>Barcelona</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Sant Joan de Déu</name>
      <address>
        <city>Esplugues de Llobregat</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institut Català d'Oncologia l'Hospitalet</name>
      <address>
        <city>Hospitalet de Llobregat</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario de Canarias</name>
      <address>
        <city>La Laguna</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Ramón y Cajal</name>
      <address>
        <city>Madrid</city>
        <zip>28034</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Son Espases</name>
      <address>
        <city>Palma de Mallorca</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario Miguel Servet</name>
      <address>
        <city>Zaragoza</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Spain</country>
  </location_countries>
  <verification_date>July 2018</verification_date>
  <study_first_submitted>June 30, 2011</study_first_submitted>
  <study_first_submitted_qc>September 26, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 1, 2012</study_first_posted>
  <last_update_submitted>July 31, 2018</last_update_submitted>
  <last_update_submitted_qc>July 31, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">August 1, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Grupo Espanol de Investigacion en Sarcomas</investigator_affiliation>
    <investigator_full_name>Mariló de Carrillo</investigator_full_name>
    <investigator_title>Jaume Mora</investigator_title>
  </responsible_party>
  <keyword>Ewing's Sarcoma</keyword>
  <keyword>P6 protocol MSKCC</keyword>
  <keyword>Gemcitabine</keyword>
  <keyword>Docetaxel</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Sarcoma</mesh_term>
    <mesh_term>Sarcoma, Ewing</mesh_term>
  </condition_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/NCT01696669
org study id: GEIS-21
secondary id: 2009-016027-62
nct id: NCT01696669
lead sponsor: 
has dmc: Yes
Tumors of the Ewing sarcoma family (ES) affect children, adolescents and young adults. The
      reported incidence is 0.6 cases per million inhabitants every year. The peak incidence occurs
      between 10 and 20 years and it is rarely diagnosed beyond 30. The ES is a severe disease with
      a progression-free survival after 5 years of 60% in cases without metastasis and deadly in
      the majority of patients presenting metastasis. The ES is considered a systemic disease
      because, despite receiving an adequate local treatment, over 90% of patients deaths occur due
      to disseminated disease. Combined therapy of surgery, radiotherapy and chemotherapy has led
      to an improvement in the prognosis, achieving a survival of about 60% in most series

      The MSKCC P6 protocol was developed for the treatment of high risk ES. In 2003, Kolb et al.
      reported the MSKCC experience after a 4-years follow-up of 68 patients who had been included
      from 1990 to 2001. Following the MSKCC P6 protocol, a survival rate of 82% was achieved in
      patients without metastasis, superior to the achieved with less intensive protocols.
      Following the guidelines of the MSKCC P6 protocol, in 2002 we modified the treatment schedule
      to create the modified P6 protocol (MP6). GEIS intends to develop MP6 as a clinical trial,
      which could provide the following potential advantages about current treatments:

        1. Lower total dose of alkylating agents.

        2. Early cardioprotection with dexrazoxane.

        3. Radiotherapy adjusted to the initial response.

        4. Pilot trial with the combination of Gemcitabine + Docetaxel for high-risk patients.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Progression Free Survival
time frame: Assessment of the progression free survival in all the patients enrolled in the study 3 years after the completion of the treatment under study.
description: Assessment of the progression free survival in all the patients enrolled in the study 3 years after the completion of the treatment under study.
measure: Objective response rate (ORR)
time frame: two months
description: To assess the objective response rate to treatment (ORR) defined following EMEA criteria (CPMP/EWP/205/95/Rev.3/Corr.2) in high risk patients with Ewing's sarcoma treated with an early window phase of Gemcitabine + docetaxel (G + D).
measure: Assessment of disease progression
time frame: to reach an index of disease progression < 20% for high risk patients during the maintenance phase with Gemcitabine + Docetaxel.
description: To assess the disease progression, aiming to reach an index of disease progression < 20% for high risk patients during the maintenance phase with Gemcitabine + Docetaxel.
measure: evaluate the toxicity and tolerance to the treatment Gemcitabine + Docetaxel in high risk patients, and toxicity and tolerance of mP6 treatment in all patients.
time frame: 12 months
description: To evaluate the toxicity and tolerance to the treatment Gemcitabine + Docetaxel in high risk patients, and toxicity and tolerance of mP6 treatment in all patients.
measure: Assessment of bone marrow condition.
time frame: 24 months
description: Molecular diagnosis and extension study of bone marrow in all patients included in the trial. Assessment of prognostic significance of the type of translocation and the molecular effect in the bone marrow.
measure: Study the impact of patients treated with Cardioxane in cardioprotection
time frame: 6 months
description: Creation of a cohort of patients treated with anthracyclines at high doses and early cardioprotection with dexrazoxane (Cardioxane). Long-term study of cardioprotection in these patients compared with historical series from the P6 protocol that did not received cardioprotection.
arm group label: Chemotherapy + Surgery + Radiotherapy
arm group type: Experimental
description: Standard risk patients: MP6 Treatment:
CHEMOTHERAPY: 2 cycles of vincristine-doxorubicin + dexrazoxane-cyclophosphamide, 1 cycle of ifosfamide-etoposide. SURGERY: Ideally within 21 days after chemotherapy.
CHEMOTHERAPY: 1 cycle of vincristine-doxorubicin + dexrazoxane-cyclophosphamide, 1 cycle of ifosfamide-etoposide.
RADIOTHERAPY: On the primary tumor bed in case of unresectable tumors, resected tumors with inadequate margins, or those with histologic response <90%.
High risk patients:
CHEMOTHERAPY: Window phase with 2 cycles of gemcitabine + docetaxel. MP6 TREATMENT. CHEMOTHERAPY: Maintenance therapy for 1 year with gemcitabine + docetaxel.
intervention type: Drug
intervention name: Chemotherapy
description: Vincristine, 2 mg/m^2 IV bolus, day 1.
Doxorubicin: 75 mg/m^2 per cycle, or 25 mg/m^2/day x 3 days, IV infusion, 1 hour (after dexrazoxane administration at the dose of 10:1).
Dexrazoxane: administered at a dose of 10:1, before doxorubicin only in adults.
Cyclophosphamide: 2100 mg/m^2 IV infusion, 6 hours, with MESNA protection, days 1 and 2.
MESNA: used with cyclophosphamide and ifosfamide. The total daily dose of MESNA is equivalent to at least 60% of the daily dose of cyclophosphamide or ifosfamide.
G-CSF: 5 micrograms/kg/day SC. It starts 24 hours after the last dose of chemotherapy and continues until the absolute neutrophil count is ≥ 750 mm^3/L.
Ifosfamide: 1800 mg/m^2/day IV infusion, 1 hour, days 1-5 of each cycle (9,000 mg/m^2 total maximum dose).
Window phase in high-risk patients (21-days cycle):
Gemcitabine: 1000 mg/m^2 IV, 90 minutes on day 1 and 8.
Docetaxel 100 mg/m^2, 2-3 hour infusion on day 8.
arm group label: Chemotherapy + Surgery + Radiotherapy
intervention type: Procedure
intervention name: Surgery
description: Surgical intervention aiming to completely resect the tumor with negative margins.
arm group label: Chemotherapy + Surgery + Radiotherapy
intervention type: Radiation
intervention name: Radiotherapy
description: On the primary tumor bed in case of unresectable tumors, resected tumors with inadequate margins, or those with histologic response <90%. Patients will receive radiotherapy 21 days after the completion of chemotherapy.
arm group label: Chemotherapy + Surgery + Radiotherapy
criteria: 
gender: All
minimum age: N/A
maximum age: 40 Years
healthy volunteers: No
last name: Jaume Mora Graupera, MD
role: Study Chair
affiliation: GEIS
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Spain
responsible party type: Principal Investigator
investigator affiliation: Grupo Espanol de Investigacion en Sarcomas
investigator full name: Mariló de Carrillo
investigator title: Jaume Mora
mesh term: Sarcoma
mesh term: Sarcoma, Ewing