<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/NCT01684449</url>
  </required_header>
  <id_info>
    <org_study_id>GEIS-24</org_study_id>
    <secondary_id>2009-017232-41</secondary_id>
    <nct_id>NCT01684449</nct_id>
  </id_info>
  <brief_title>Gemcitabine Plus Rapamycin Versus Gemcitabine to Treat Advanced Soft Tissue Sarcoma</brief_title>
  <official_title>Phase 1/2, Randomized, Multicenter, Prospective Study of Gemcitabine and Rapamycin (Sirolimus) Combination Versus Gemcitabine Only to Treat Advanced Soft Tissue Sarcoma</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>
      The soft tissue sarcomas (STS) constitute an infrequent group of malignant neoplasms of&#xD;
      mesenchymal origin. In Spain, the approximate incidence is of 2 new cases per 100.000&#xD;
      inhabitants every year. In patients with metastatic STS, the average survival is very short,&#xD;
      approximately 12 months. The systemic treatment of the metastatic disease has had a very&#xD;
      limited development, with few satisfactory results. This facts reflect the urgent need to&#xD;
      identify new active agents for treatment of these patients.&#xD;
&#xD;
      The molecular pathway of the serine/threonine kinase mammalian target of rapamycin (mTOR)&#xD;
      plays a central role in the regulation of the proteins translation, cellular growth and&#xD;
      metabolism (Meric-Bernstam F et al. 2009). Currently, the mTOR pathway is considered a&#xD;
      relevant target for the development of anti-cancer drugs, as rapamycin. Preliminary results&#xD;
      of some clinical trials suggest that mTOR inhibitors could have some clinical activity for&#xD;
      different types of sarcoma, including STS (Chawla et al Proc.ASCO 2006; Schuetze et al.&#xD;
      Proc.ASCO 2006).&#xD;
&#xD;
      Gemcitabine is a chemotherapy antimetabolite agent with a broad antitumoral spectrum. The&#xD;
      activity of this drug to treat resistant sarcomas and its reduced toxicity make from&#xD;
      gemcitabine an adequate candidate for its study in combination with new drugs addressed to&#xD;
      molecular targets in the STS treatment.&#xD;
&#xD;
      Pre-clinical studies suggest that mTOR inhibitors could have a potential synergistic or&#xD;
      additive effect with some chemotherapy agents. The combination of rapamycin and gemcitabine&#xD;
      seems to be a reasonable strategy to explore for the STS treatment.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>January 2010</start_date>
  <completion_date type="Actual">December 2013</completion_date>
  <primary_completion_date type="Actual">May 2013</primary_completion_date>
  <phase>Phase 1/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>Phase 1: Determination of dosage: Security and toxicity of the combination gemcitabine and rapamycin.</measure>
    <time_frame>15 months</time_frame>
    <description>Type, frequency, seriousness and relation with the treatment of the adverse events in patients treated with the investigational medicinal products.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Phase 2: Progression Free Survival</measure>
    <time_frame>12 months</time_frame>
    <description>Progression free survival rate at 3 months to compare the effectiveness of the the treatment.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Phase 2: Overall Survival</measure>
    <time_frame>12 months</time_frame>
    <description>Overall survival rate of the patients included in the experimental arm.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Phase 2: Toxicity</measure>
    <time_frame>12 months</time_frame>
    <description>Tolerance to the drugs combination of the patients treated with gemcitabine + sirolimus</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Phase 1 and 2: Assessment of molecular biomarkers</measure>
    <time_frame>36 months</time_frame>
    <description>Assess, both in models of sarcomas induced in immunodeficient mice and tumor samples from patients enrolled in the trial, the predictive value of the response to combination therapy of certain molecular markers for survival and mTOR pathway.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">28</enrollment>
  <condition>Advanced Soft Tissue Sarcoma</condition>
  <arm_group>
    <arm_group_label>Phase 2: Experimental Arm</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Gemcitabine + rapamycin at recommended dose of Phase 1. Recommended dose is defined as, the dose one level below of the (MTD). Being MTD, the dose of the cohort in which a maximum of one patient of 6 has presented dose-limiting toxicity (DLT).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Gemcitabine + Rapamycin</intervention_name>
    <description>Gemcitabine + rapamycin at recommended dose of Phase 1. Recommended dose is defined as, the dose one level below of the (MTD). Being MTD, the dose of the cohort in which a maximum of one patient of 6 has presented dose-limiting toxicity (DLT).&#xD;
Every three weeks until disease progression or unacceptable toxicity. The treatment will last for 6 cycles if there is not progression or intolerable toxicity.&#xD;
Additionally, there will be a pharmacokinetic study in a minimum of 9 patients treated with the drug combination.</description>
    <arm_group_label>Phase 2: Experimental Arm</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Patients with anatomopathological diagnosis of metastatic or locally advanced&#xD;
             unresectable soft tissue sarcoma (STS). Patients with the following STS types will be&#xD;
             excluded: chondrosarcoma, Ewing's sarcoma and embryonal or alveolar rhabdomyosarcoma.&#xD;
             In phase 1 it will be allowed to include patients having other types of advanced&#xD;
             cancer which are resistant to the standard treatment and can benefit from any of the&#xD;
             study drugs.&#xD;
&#xD;
          2. Prior treatment with chemotherapy including doxorubicin and ifosfamide, or&#xD;
             contraindication for its administration. The previous treatment with gemcitabine or&#xD;
             inhibitors of mTOR is not allowed.&#xD;
&#xD;
          3. Age ≥ 18 y ≤ 70 years.&#xD;
&#xD;
          4. ECOG performance status: 0 - 1. In Phase 1 only patients with ECOG 0-1 will be&#xD;
             enrolled.&#xD;
&#xD;
          5. Disease measurable according to RECIST criteria. Proven relapsed disease.&#xD;
&#xD;
          6. Adequate bone marrow function, defined as neutrophil count ≥ 1.500/mm^3 and platelets&#xD;
             ≥ 100.000/mm^3.&#xD;
&#xD;
          7. Adequate renal and hepatic function , defined as calculated creatinine clearance ≥ 60&#xD;
             ml/min, creatinine, total bilirubin, AST and/or ALT ≤ 1,5 times the upper limit of&#xD;
             normal (ULN).&#xD;
&#xD;
          8. Informed consent form signed by the patient prior to the beginning of the treatment.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. 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;
&#xD;
          2. Presence of brain metastases.&#xD;
&#xD;
          3. Active infection or other severe concomitant diseases.&#xD;
&#xD;
          4. Concurrent treatment with other experimental drugs within 30 days prior to study&#xD;
             entry.&#xD;
&#xD;
          5. Pregnancy or breastfeeding.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Xavier García del Muro Solans, MD</last_name>
    <role>Study Chair</role>
    <affiliation>GEIS</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>H. Universitario de Canarias</name>
      <address>
        <city>Tenerife</city>
        <state>Santa Cruz de Tenerife</state>
        <zip>38320</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>H. Sant Pau</name>
      <address>
        <city>Barcelona</city>
        <zip>08024</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institut Català d'Oncologia - Hospital Duran i Reynals</name>
      <address>
        <city>L'Hospitalet de Llobregat</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>H. La Paz</name>
      <address>
        <city>Madrid</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario 12 de Octubre</name>
      <address>
        <city>Madrid</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario Puerta de Hierro</name>
      <address>
        <city>Majadahonda</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>H. Son Espases</name>
      <address>
        <city>Mallorca</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Instituto Valenciano de Oncología</name>
      <address>
        <city>Valencia</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>H. Universitario Miguel Servet</name>
      <address>
        <city>Zaragoza</city>
        <zip>50009</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Spain</country>
  </location_countries>
  <verification_date>October 2015</verification_date>
  <study_first_submitted>June 30, 2011</study_first_submitted>
  <study_first_submitted_qc>September 10, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 13, 2012</study_first_posted>
  <last_update_submitted>October 26, 2015</last_update_submitted>
  <last_update_submitted_qc>October 26, 2015</last_update_submitted_qc>
  <last_update_posted type="Estimate">October 27, 2015</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Soft tissue sarcoma</keyword>
  <keyword>Gemcitabine</keyword>
  <keyword>Rapamycin</keyword>
  <keyword>Sirolimus</keyword>
  <keyword>mTOR inhibitor</keyword>
  <keyword>Molecular biomarkers</keyword>
  <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>Sirolimus</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/NCT01684449
org study id: GEIS-24
secondary id: 2009-017232-41
nct id: NCT01684449
lead sponsor: 
has dmc: Yes
The soft tissue sarcomas (STS) constitute an infrequent group of malignant neoplasms of
      mesenchymal origin. In Spain, the approximate incidence is of 2 new cases per 100.000
      inhabitants every year. In patients with metastatic STS, the average survival is very short,
      approximately 12 months. The systemic treatment of the metastatic disease has had a very
      limited development, with few satisfactory results. This facts reflect the urgent need to
      identify new active agents for treatment of these patients.

      The molecular pathway of the serine/threonine kinase mammalian target of rapamycin (mTOR)
      plays a central role in the regulation of the proteins translation, cellular growth and
      metabolism (Meric-Bernstam F et al. 2009). Currently, the mTOR pathway is considered a
      relevant target for the development of anti-cancer drugs, as rapamycin. Preliminary results
      of some clinical trials suggest that mTOR inhibitors could have some clinical activity for
      different types of sarcoma, including STS (Chawla et al Proc.ASCO 2006; Schuetze et al.
      Proc.ASCO 2006).

      Gemcitabine is a chemotherapy antimetabolite agent with a broad antitumoral spectrum. The
      activity of this drug to treat resistant sarcomas and its reduced toxicity make from
      gemcitabine an adequate candidate for its study in combination with new drugs addressed to
      molecular targets in the STS treatment.

      Pre-clinical studies suggest that mTOR inhibitors could have a potential synergistic or
      additive effect with some chemotherapy agents. The combination of rapamycin and gemcitabine
      seems to be a reasonable strategy to explore for the STS treatment.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Phase 1: Determination of dosage: Security and toxicity of the combination gemcitabine and rapamycin.
time frame: 15 months
description: Type, frequency, seriousness and relation with the treatment of the adverse events in patients treated with the investigational medicinal products.
measure: Phase 2: Progression Free Survival
time frame: 12 months
description: Progression free survival rate at 3 months to compare the effectiveness of the the treatment.
measure: Phase 2: Overall Survival
time frame: 12 months
description: Overall survival rate of the patients included in the experimental arm.
measure: Phase 2: Toxicity
time frame: 12 months
description: Tolerance to the drugs combination of the patients treated with gemcitabine + sirolimus
measure: Phase 1 and 2: Assessment of molecular biomarkers
time frame: 36 months
description: Assess, both in models of sarcomas induced in immunodeficient mice and tumor samples from patients enrolled in the trial, the predictive value of the response to combination therapy of certain molecular markers for survival and mTOR pathway.
arm group label: Phase 2: Experimental Arm
arm group type: Experimental
description: Gemcitabine + rapamycin at recommended dose of Phase 1. Recommended dose is defined as, the dose one level below of the (MTD). Being MTD, the dose of the cohort in which a maximum of one patient of 6 has presented dose-limiting toxicity (DLT).
intervention type: Drug
intervention name: Gemcitabine + Rapamycin
description: Gemcitabine + rapamycin at recommended dose of Phase 1. Recommended dose is defined as, the dose one level below of the (MTD). Being MTD, the dose of the cohort in which a maximum of one patient of 6 has presented dose-limiting toxicity (DLT).
Every three weeks until disease progression or unacceptable toxicity. The treatment will last for 6 cycles if there is not progression or intolerable toxicity.
Additionally, there will be a pharmacokinetic study in a minimum of 9 patients treated with the drug combination.
arm group label: Phase 2: Experimental Arm
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
last name: Xavier García del Muro Solans, MD
role: Study Chair
affiliation: GEIS
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Spain
responsible party type: Sponsor
mesh term: Sarcoma
mesh term: Sirolimus
mesh term: Gemcitabine