<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/NCT01710176</url>
  </required_header>
  <id_info>
    <org_study_id>ISG-STS 10-01</org_study_id>
    <nct_id>NCT01710176</nct_id>
  </id_info>
  <brief_title>Localized High-Risk Soft Tissue Sarcomas Of The Extremities And Trunk Wall In Adults: An Integrating Approach Comprising Standard Vs Histotype-Tailored Neoadjuvant Chemotherapy</brief_title>
  <official_title>Localized High-Risk Soft Tissue Sarcomas Of The Extremities And Trunk Wall In Adults: An Integrating Approach Comprising Standard Vs Histotype-Tailored Neoadjuvant Chemotherapy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Italian Sarcoma Group</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>French Sarcoma Group</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Grupo Espanol de Investigacion en Sarcomas</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Italian Sarcoma Group</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a randomized Phase III clinical trial in the setting of localized high-risk soft&#xD;
      tissue sarcomas (STS). This study will compare a standard neoadjuvant chemotherapy with&#xD;
      epirubicin plus ifosfamide versus a histology-driven chemotherapy, i.e. a chemotherapy&#xD;
      tailored to the specific histology within the family of adult STS. Chemotherapy will be&#xD;
      administered for 3 cycles. There will be five histological groups (representing 80% of STS),&#xD;
      as follows: leiomyosarcoma, myxoid liposarcoma with hypercellularity (round cell MLPS),&#xD;
      synovial sarcoma, malignant peripheral nerve sheath tumor (MPNST) and undifferentiated&#xD;
      pleomorphic sarcoma. The histology-driven chemotherapy for these groups will be,&#xD;
      respectively, gemcitabine plus dacarbazine, trabectedin, high-dose ifosfamide, ifosfamide&#xD;
      plus etoposide, gemcitabine plus docetaxel. Other histological groups will also be included&#xD;
      and registered, but treated only by standard chemotherapy. Patients who have already&#xD;
      undergone definitive surgery will receive treatment post-operatively and patients needing a&#xD;
      re-excision after inadequate surgery will be treated as patients in the two groups, but of&#xD;
      course will not be evaluable for response. A centralized pathological review will be&#xD;
      performed. Radiological response will be evaluated according to RECIST and to Choi criteria.&#xD;
      Pathological response will also be recorded.&#xD;
&#xD;
      The endpoint will be disease-free survival (DFS) and, secondarily, overall survival (OS) of&#xD;
      patients receiving standard chemotherapy versus those receiving histotype-tailored&#xD;
      chemotherapy. Additional aims will be to compare the probability of response of standard vs&#xD;
      histotype-tailored chemotherapy and to determine the radiological and pathological response&#xD;
      with standard chemotherapy vs tailored chemotherapy in each different histological group.&#xD;
      Another aim will be to validate the response (both radiological and pathological) to&#xD;
      preoperative chemotherapy as a surrogate endpoint for DFS and OS.&#xD;
&#xD;
      Three hundred patients will be randomized over a 3-years period, from a pool of 400-450&#xD;
      registered patients.&#xD;
&#xD;
      Translational research will be performed. Areas of research will include identification and&#xD;
      validation of the potential predictive markers for each histological subgroups.&#xD;
&#xD;
      The study is designed to verify the statistical hypothesis that histotype-tailored approach&#xD;
      is associated, overall, with a 30% reduction in the hazard of relapse. However, in each&#xD;
      different histological group, the effect of histotype-tailored chemotherapy, as compared to&#xD;
      standard chemotherapy, can be different. To address this weakness an orthogonal study of&#xD;
      response to chemotherapy as a surrogate of DFS and OS has been introduced into the trial.&#xD;
      This study intends to extensively investigate the response (radiological and pathological) to&#xD;
      preoperative chemotherapy and to validate it as a surrogate endpoint by showing that it&#xD;
      correlates with disease free survival and overall survival.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">June 1, 2011</start_date>
  <completion_date type="Anticipated">June 30, 2024</completion_date>
  <primary_completion_date type="Anticipated">June 30, 2024</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>To compare the effect on disease-free survival of full-dose standard chemotherapy with histotype-tailored chemotherapy within the context of an integrated strategy for high risk soft tissue sarcomas typical of the adult.</measure>
    <time_frame>5 years</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>1:overall survival 2:response in the whole population 3:response by RECIST and Choi in each different histotype 4:pathological response 5:feasibility of integration of preoperative chemotherapy with preoperative local-regional treatments 6:PET re</measure>
    <time_frame>5 years</time_frame>
  </secondary_outcome>
  <other_outcome>
    <measure>To validate the response to preoperative chemotherapy (both radiological and pathological) as a surrogate endpoint by showing that disease free survival and overall survival depend on response status and are independent of the treatment arm.</measure>
    <time_frame>5 years</time_frame>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">550</enrollment>
  <condition>Localized High-risk Soft Tissue Sarcomas of the Extremities and Trunk Wall in Adults</condition>
  <arm_group>
    <arm_group_label>standard chemotherapy with full-dose epirubicin + ifosfamide</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Standard arm foresees 3 cycles of preoperative chemotherapy, each cycle will be repeated every 21 days and includes: epirubicin 60 mg/m2/day, short infusion, days 1 and 2; ifosfamide 3 g/m2/day, days 1, 2, 3</description>
  </arm_group>
  <arm_group>
    <arm_group_label>histotype-tailored chemotherapy according to the histotype</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>gemcitabine+docetaxel for undifferentiated pleomorphic sarcoma, trabectedin for myxoid liposarcoma with hypercellularity, ifosfamide for synovial sarcoma, ifosfamide+etoposide for malignant peripheral nerve sheath tumor, gemcitabine+dacarbazine for leiomyosarcoma</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>epirubicin 60 mg/m2/day (days 1, 2) and ifosfamide 3 g/m2/day (days 1, 2, 3)</intervention_name>
    <arm_group_label>standard chemotherapy with full-dose epirubicin + ifosfamide</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>gemcitabine 900 mg/m2 (days 1 and 8) and docetaxel 75 mg/m2 (day 8)</intervention_name>
    <arm_group_label>histotype-tailored chemotherapy according to the histotype</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>trabectedin 1.3 mg/m2</intervention_name>
    <arm_group_label>histotype-tailored chemotherapy according to the histotype</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>high-dose ifosfamide 14 g/m2, given in in 14 days</intervention_name>
    <arm_group_label>histotype-tailored chemotherapy according to the histotype</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>etoposide 150 mg/m2/day (days 1, 2, 3) and ifosfamide 3g/m2/day (days 1, 2, 3)</intervention_name>
    <arm_group_label>histotype-tailored chemotherapy according to the histotype</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>gemcitabine 1800 mg/m2 (day 1) and dacarbazine 500 mg/m2 (day 1)</intervention_name>
    <arm_group_label>histotype-tailored chemotherapy according to the histotype</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Soft tissue sarcoma of adults, primary or locally recurrent, with spindle-cell or&#xD;
             pleomorphic histology, belonging to one of the following for the randomization&#xD;
             (Group1):&#xD;
&#xD;
             myxoid-Round Cell liposarcoma (cellular component &gt;5 %), leiomyosarcoma, synovial&#xD;
             sarcoma, malignant peripheral nerve sheat tumor, undifferentiated pleomorphic sarcoma&#xD;
             (ex Malignant fibrous histiocytoma)&#xD;
&#xD;
             Or belonging to one of the following for the registration (Group 2):&#xD;
&#xD;
             myxofibrosarcoma, unclassified Spindle Cell, pleomorphic liposarcoma, pleomorphic&#xD;
             rabdomiosarcoma Or belonging to either group but not being evaluable for response&#xD;
             (re-excision after previous inadequate resection or primary definitive surgery)&#xD;
             (Group3).&#xD;
&#xD;
             The histological diagnosis must be made according to the WHO criteria and will have to&#xD;
             be centrally reviewed before randomization.&#xD;
&#xD;
          2. High malignancy grade: grade 3 of 3, according to Coindre, or grade 2 at biopsy with a&#xD;
             radiological evidence of more than 50% of necrosis in the tumor mass.&#xD;
&#xD;
          3. Deep seated extremities, girdles and/or superficial trunk (thoracic or abdominal&#xD;
             wall)lesion.&#xD;
&#xD;
          4. Size of primary tumor (visible or previously inadequately resected) &gt;5 cm at&#xD;
             instrumental staging (CT, MRI), or locally recurrent of any size.&#xD;
&#xD;
          5. Age &gt; 18 years.&#xD;
&#xD;
          6. ECOG performance status &lt;1.&#xD;
&#xD;
          7. Adequate bone marrow function:&#xD;
&#xD;
             WBC &gt;3.500/mm3 neutrophil &gt;1.500/mm3 platelets &gt;150.000/mm3 hemoglobin &gt;11 g%.&#xD;
&#xD;
          8. Adequate renal (creatinine &lt;1.3 mg%), and hepatic function (bilirubin &lt;1.5 mg% and&#xD;
             transaminases &lt;2 x n.v. If ALP &gt; 2.5 x ULN, ALP LF and/or GGT &lt; ULN).&#xD;
&#xD;
          9. Adequate cardiac function (FE &gt;50%).&#xD;
&#xD;
         10. Signed informed consent.&#xD;
&#xD;
         11. Complete compliance of the participating center with the protocol requirements.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Pregnancy or lactation.&#xD;
&#xD;
          2. Distant metastasis.&#xD;
&#xD;
          3. Other malignancies within past 5 years, with the exception of carcinoma in situ of&#xD;
             cervix and basocellular skin cancers treated with eradicating intent.&#xD;
&#xD;
          4. Sarcoma histotypes other than those mentioned in the inclusion criteria.&#xD;
&#xD;
          5. Prior CT and/or RT.&#xD;
&#xD;
          6. Serious psychiatric disease that precludes informed consent or limits compliance.&#xD;
&#xD;
          7. Medical disease limiting survival to less than two years, limiting compliance or which&#xD;
             in the physician's opinion might interfere significantly with the toxicity of the&#xD;
             treatments.&#xD;
&#xD;
          8. Cardiovascular diseases resulting in a New York Heart Association Functional Status &gt;&#xD;
             2.&#xD;
&#xD;
          9. Uncontrolled bacterial, viral or fungal infection.&#xD;
&#xD;
         10. Impossibility of ensuring adequate follow-up.&#xD;
&#xD;
         11. Failure to comply with the requirements of the present protocol leading to exclusion&#xD;
             of the participating center.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Fondazione Del Piemonte Per L'Oncologia Ircc Di Candiolo -</name>
      <address>
        <city>Candiolo</city>
        <state>TO</state>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Irccs Centro Di Riferimento Oncologico (Cro) -</name>
      <address>
        <city>Aviano (pn)</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Irccs Istituto Ortopedico Rizzoli (Ior) -</name>
      <address>
        <city>Bologna</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Pres.Ospedal.Spedali Civili Brescia -</name>
      <address>
        <city>Brescia</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Irst - Istituto Scientifico Romagnolo Per Lo Studio E La Cura Dei Tumori -</name>
      <address>
        <city>Meldola (fc)</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Irccs Istituto Europeo Di Oncologia (Ieo) -</name>
      <address>
        <city>Milano</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Irccs Istituto Nazionale Dei Tumori (Int)</name>
      <address>
        <city>Milano</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Irccs Istituto Nazionale Tumori Fondazione Pascale -</name>
      <address>
        <city>Napoli</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Irccs Istituto Oncologico Veneto (Iov)</name>
      <address>
        <city>Padova</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Irccs Istituto Regina Elena (Ifo)</name>
      <address>
        <city>Roma</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Irccs Istituto Clinico Humanitas -</name>
      <address>
        <city>Rozzano (mi)</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Presidio Sanitario Gradenigo Di Torino</name>
      <address>
        <city>Torino</city>
        <country>Italy</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 Clínico de Malaga</name>
      <address>
        <city>Malaga</city>
        <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_countries>
    <country>Italy</country>
    <country>Spain</country>
  </location_countries>
  <verification_date>September 2023</verification_date>
  <study_first_submitted>October 17, 2012</study_first_submitted>
  <study_first_submitted_qc>October 18, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 19, 2012</study_first_posted>
  <last_update_submitted>September 12, 2023</last_update_submitted>
  <last_update_submitted_qc>September 12, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 13, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Sarcoma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Gemcitabine</mesh_term>
    <mesh_term>Docetaxel</mesh_term>
    <mesh_term>Etoposide</mesh_term>
    <mesh_term>Epirubicin</mesh_term>
    <mesh_term>Ifosfamide</mesh_term>
    <mesh_term>Isophosphamide mustard</mesh_term>
    <mesh_term>Dacarbazine</mesh_term>
    <mesh_term>Trabectedin</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/NCT01710176
org study id: ISG-STS 10-01
nct id: NCT01710176
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
This is a randomized Phase III clinical trial in the setting of localized high-risk soft
      tissue sarcomas (STS). This study will compare a standard neoadjuvant chemotherapy with
      epirubicin plus ifosfamide versus a histology-driven chemotherapy, i.e. a chemotherapy
      tailored to the specific histology within the family of adult STS. Chemotherapy will be
      administered for 3 cycles. There will be five histological groups (representing 80% of STS),
      as follows: leiomyosarcoma, myxoid liposarcoma with hypercellularity (round cell MLPS),
      synovial sarcoma, malignant peripheral nerve sheath tumor (MPNST) and undifferentiated
      pleomorphic sarcoma. The histology-driven chemotherapy for these groups will be,
      respectively, gemcitabine plus dacarbazine, trabectedin, high-dose ifosfamide, ifosfamide
      plus etoposide, gemcitabine plus docetaxel. Other histological groups will also be included
      and registered, but treated only by standard chemotherapy. Patients who have already
      undergone definitive surgery will receive treatment post-operatively and patients needing a
      re-excision after inadequate surgery will be treated as patients in the two groups, but of
      course will not be evaluable for response. A centralized pathological review will be
      performed. Radiological response will be evaluated according to RECIST and to Choi criteria.
      Pathological response will also be recorded.

      The endpoint will be disease-free survival (DFS) and, secondarily, overall survival (OS) of
      patients receiving standard chemotherapy versus those receiving histotype-tailored
      chemotherapy. Additional aims will be to compare the probability of response of standard vs
      histotype-tailored chemotherapy and to determine the radiological and pathological response
      with standard chemotherapy vs tailored chemotherapy in each different histological group.
      Another aim will be to validate the response (both radiological and pathological) to
      preoperative chemotherapy as a surrogate endpoint for DFS and OS.

      Three hundred patients will be randomized over a 3-years period, from a pool of 400-450
      registered patients.

      Translational research will be performed. Areas of research will include identification and
      validation of the potential predictive markers for each histological subgroups.

      The study is designed to verify the statistical hypothesis that histotype-tailored approach
      is associated, overall, with a 30% reduction in the hazard of relapse. However, in each
      different histological group, the effect of histotype-tailored chemotherapy, as compared to
      standard chemotherapy, can be different. To address this weakness an orthogonal study of
      response to chemotherapy as a surrogate of DFS and OS has been introduced into the trial.
      This study intends to extensively investigate the response (radiological and pathological) to
      preoperative chemotherapy and to validate it as a surrogate endpoint by showing that it
      correlates with disease free survival and overall survival.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: To compare the effect on disease-free survival of full-dose standard chemotherapy with histotype-tailored chemotherapy within the context of an integrated strategy for high risk soft tissue sarcomas typical of the adult.
time frame: 5 years
measure: 1:overall survival 2:response in the whole population 3:response by RECIST and Choi in each different histotype 4:pathological response 5:feasibility of integration of preoperative chemotherapy with preoperative local-regional treatments 6:PET re
time frame: 5 years
measure: To validate the response to preoperative chemotherapy (both radiological and pathological) as a surrogate endpoint by showing that disease free survival and overall survival depend on response status and are independent of the treatment arm.
time frame: 5 years
arm group label: standard chemotherapy with full-dose epirubicin + ifosfamide
arm group type: Active Comparator
description: Standard arm foresees 3 cycles of preoperative chemotherapy, each cycle will be repeated every 21 days and includes: epirubicin 60 mg/m2/day, short infusion, days 1 and 2; ifosfamide 3 g/m2/day, days 1, 2, 3
arm group label: histotype-tailored chemotherapy according to the histotype
arm group type: Experimental
description: gemcitabine+docetaxel for undifferentiated pleomorphic sarcoma, trabectedin for myxoid liposarcoma with hypercellularity, ifosfamide for synovial sarcoma, ifosfamide+etoposide for malignant peripheral nerve sheath tumor, gemcitabine+dacarbazine for leiomyosarcoma
intervention type: Drug
intervention name: epirubicin 60 mg/m2/day (days 1, 2) and ifosfamide 3 g/m2/day (days 1, 2, 3)
arm group label: standard chemotherapy with full-dose epirubicin + ifosfamide
intervention type: Drug
intervention name: gemcitabine 900 mg/m2 (days 1 and 8) and docetaxel 75 mg/m2 (day 8)
arm group label: histotype-tailored chemotherapy according to the histotype
intervention type: Drug
intervention name: trabectedin 1.3 mg/m2
arm group label: histotype-tailored chemotherapy according to the histotype
intervention type: Drug
intervention name: high-dose ifosfamide 14 g/m2, given in in 14 days
arm group label: histotype-tailored chemotherapy according to the histotype
intervention type: Drug
intervention name: etoposide 150 mg/m2/day (days 1, 2, 3) and ifosfamide 3g/m2/day (days 1, 2, 3)
arm group label: histotype-tailored chemotherapy according to the histotype
intervention type: Drug
intervention name: gemcitabine 1800 mg/m2 (day 1) and dacarbazine 500 mg/m2 (day 1)
arm group label: histotype-tailored chemotherapy according to the histotype
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Italy
country: Spain
responsible party type: Sponsor
mesh term: Sarcoma
mesh term: Gemcitabine
mesh term: Docetaxel
mesh term: Etoposide
mesh term: Epirubicin
mesh term: Ifosfamide
mesh term: Isophosphamide mustard
mesh term: Dacarbazine
mesh term: Trabectedin