xml: <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/NCT06034561</url>
    </required_header>
    <id_info>
      <org_study_id>4009/23</org_study_id>
      <nct_id>NCT06034561</nct_id>
    </id_info>
    <brief_title>Bortezomib-based Regimen for Refractory or Relapsed Acute Lymphoblastic Leukemia</brief_title>
    <official_title>Bortezomib-based Regimen for Refractory or Relapsed Acute Lymphoblastic Leukemia in Adults</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Instituto do Cancer do Estado de São Paulo</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>Libbs Farmacêutica LTDA</agency>
        <agency_class>Industry</agency_class>
      </collaborator>
    </sponsors>
    <source>Instituto do Cancer do Estado de São Paulo</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>
      <is_us_export>No</is_us_export>
    </oversight_info>
    <brief_summary>
      <textblock>
        This is a interventional phase II study aiming to examine the complete response rate of a&#xD;
        bortezomib-based salvage regimen in adults with refractory or relapsed acute lymphoblastic&#xD;
        leukemia (ALL), seeking to compare outcomes with the available literature and with our&#xD;
        historical data on relapsed/refractory ALL.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        Acute lymphoblastic leukemia (ALL) is a rare neoplasm in adults, with long-term survival&#xD;
        rates approaching 50% with current regimens. Although high rates of complete response are&#xD;
        achieved with the first-line therapy, many patients are primary refractory or may further&#xD;
        relapse. Arguably, these patients have a more resistant disease with higher risk genetic&#xD;
        alterations and a much less likely to be cured, which almost always only can be obtained by a&#xD;
        following allogeneic hematopoietic stem-cell transplantation (HSCT). Therefore, strategies to&#xD;
        salvage patients with detectable disease after induction blocks or with relapsed disease are&#xD;
        crucial to prolong survival and potentially cure those patients, working as a bridge therapy&#xD;
        to HSCT. Historically, patients with relapsed/refractory ALL have received multidrug regimens&#xD;
        based on high-dose cytarabine, such as fludarabine, cytarabine and idarubicin (FLAG-IDA).&#xD;
        Those regimens provide a 30-40% complete response rate with non-negligible toxicity.&#xD;
        Recently, new targeted agents such as blinatumomab, inotuzumab, and cellular therapies have&#xD;
        arisen for B-lineage disease, even though these agents are not available in the public health&#xD;
        setting. Previous studies have tested salvage regimens for ALL encompassing proteasome&#xD;
        inhibitors plus highly synergistic drugs (dexamethasone, vincristine, asparaginase,&#xD;
        doxorubicin), with exciting outcomes in limited case series. For adults, these regimens are&#xD;
        less studied. However, preliminary data suggest that they are less toxic and more potent&#xD;
        since patients can receive different drug combinations that they had not been exposed to&#xD;
        before. The primary objective of this study is to examine the complete response rate of this&#xD;
        regimen in our population, aiming to compare with the available literature and with our&#xD;
        historical data on relapsed/refractory ALL. Secondary objectives are:&#xD;
  &#xD;
          1. To determine the safety and feasibility of a bortezomib-based regimen for salvage&#xD;
             relapsed/refractory ALL in our setting.&#xD;
  &#xD;
          2. To determine the rate of patients who are able to proceed with HSCT after the treatment.&#xD;
  &#xD;
          3. To calculate event-free survival and overall survival after the salvage regimen for&#xD;
             relapsed/refractory ALL.&#xD;
  &#xD;
          4. To calculate the rate of measurable residual disease (MRD) negative status after the&#xD;
             treatment.&#xD;
  &#xD;
          5. To examine the rate of febrile neutropenia, liver toxicity, neurotoxicity, and&#xD;
             treatment-related mortality after this regimen in relapsed/refractory ALL.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">September 2023</start_date>
    <completion_date type="Anticipated">August 2029</completion_date>
    <primary_completion_date type="Anticipated">August 2028</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>Complete response</measure>
      <time_frame>30 days</time_frame>
      <description>Disappearance of lymphoid blasts in peripheral blood, with fewer than 5% of lymphoid blasts quantified in the bone marrow aspirate through immunophenotyping.</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Event-free survival</measure>
      <time_frame>1 year</time_frame>
      <description>Time interval between study enrollment and the occurrence of an event (non-response, relapse, or death) or last follow-up (censorship).</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Overall survival</measure>
      <time_frame>1 year</time_frame>
      <description>Time interval between study enrollment and the occurrence of death or last follow-up (censorship).</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Rate of MRD-negativity</measure>
      <time_frame>60 days</time_frame>
      <description>Absence of pathological lymphoid blasts in a bone marrow sample detected through immunophenotyping with a minimum sensitivity of 10-4.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Rate of allogeneic hematopoietic stem-cell transplantation</measure>
      <time_frame>1 year</time_frame>
      <description>Proportion of patients who successfully underwent allogeneic hematopoietic stem-cell transplantation after the study therapy</description>
    </secondary_outcome>
    <number_of_arms>1</number_of_arms>
    <enrollment type="Anticipated">50</enrollment>
    <condition>Acute Lymphoblastic Leukemia, in Relapse</condition>
    <condition>Acute Lymphoblastic Leukemia With Failed Remission</condition>
    <arm_group>
      <arm_group_label>Bortezomib</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Patients with refractory or relapsed acute lymphoblastic leukemia will receive one-two courses of salvage regimen composed by:&#xD;
  Bortezomib 1.3 mg/m2 I.V. D1,D4,D8,D11;&#xD;
  Vincristine 1.5 mg/m2 I.V. (maximum at 2 mg) - D1, D8,D15,D22;&#xD;
  Doxorubicin 60 mg/m2 I.V. - D1;&#xD;
  Peg-asparaginase 2000 IU/m2 I.V. - D4 and D18;&#xD;
  Dexamethasone 20 mg/m2 P.O. or I.V. (divided BID) - D1-D5 and D15-D19&#xD;
  Intrathecal chemotherapy: methotrexate 12 mg + dexamethasone 2 mg.</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Bortezomib</intervention_name>
      <description>Patients should receive one or two courses of this regimen, aiming to achieve complete remission as a bridge to proceed with allogeneic HSCT.</description>
      <arm_group_label>Bortezomib</arm_group_label>
      <other_name>Vincristine</other_name>
      <other_name>Doxorubicin</other_name>
      <other_name>Peg-asparaginase</other_name>
      <other_name>Dexamethasone</other_name>
      <other_name>Methotrexate</other_name>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  Patients between 16 and 60 years-old with refractory or relapsed ALL (≥1% of anomalous&#xD;
               blasts by flow cytometry in bone marrow or peripheral blood) after one or two lines of&#xD;
               therapy, regardless of their phenotype or baseline genetic alteration;&#xD;
  &#xD;
            -  Patients are eligible after allogeneic HSCT as long as patients are not actively being&#xD;
               treated for graft-versus-host-disease (GvHD).&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  Burkitt leukemia;&#xD;
  &#xD;
            -  Prior myeloproliferative disease;&#xD;
  &#xD;
            -  Drug allergies;&#xD;
  &#xD;
            -  Eastern Cooperative Oncology Group (ECOG) scale &gt;2;&#xD;
  &#xD;
            -  Total bilirubin&gt;2x upper limit of normal (ULN);&#xD;
  &#xD;
            -  Transaminases&gt;5x ULN;&#xD;
  &#xD;
            -  Creatinine&gt;2,5 mg/dl;&#xD;
  &#xD;
            -  Active uncontrolled infection;&#xD;
  &#xD;
            -  History of asparaginase-induced pancreatitis;&#xD;
  &#xD;
            -  Prior exposure to bortezomib;&#xD;
  &#xD;
            -  Heart failure New York Heart Association (NYHA) Class III or IV;&#xD;
  &#xD;
            -  Patients with more than 400mg/m2 lifetime exposure of anthracycline;&#xD;
  &#xD;
            -  Severe psychiatric disorder which prevents adequate compliance;&#xD;
  &#xD;
            -  Refusal to participate in the study.&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>16 Years</minimum_age>
      <maximum_age>60 Years</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_official>
      <last_name>Wellington Silva, MD PhD</last_name>
      <role>Principal Investigator</role>
      <affiliation>Instituto do Cancer do Estado de Sao Paulo</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Graziela S Silva</last_name>
      <phone>551138934677</phone>
      <email>graziela.sasilva@hc.fm.usp.br</email>
    </overall_contact>
    <overall_contact_backup>
      <last_name>Bruna Moraes, MSc</last_name>
      <phone>551126628112</phone>
      <email>pesquisa.hematologia@hc.fm.usp.br</email>
    </overall_contact_backup>
    <location>
      <facility>
        <name>Instituto do Cancer do Estado de Sao Paulo</name>
        <address>
          <city>São Paulo</city>
          <state>SP</state>
          <zip>01246000</zip>
          <country>Brazil</country>
        </address>
      </facility>
    </location>
    <location_countries>
      <country>Brazil</country>
    </location_countries>
    <verification_date>August 2023</verification_date>
    <study_first_submitted>September 6, 2023</study_first_submitted>
    <study_first_submitted_qc>September 12, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">September 13, 2023</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>
    <keyword>Acute lymphoblastic leukemia</keyword>
    <keyword>Bortezomib</keyword>
    <keyword>Salvage therapy</keyword>
    <keyword>Bridge therapy</keyword>
    <keyword>Response rate</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Leukemia</mesh_term>
      <mesh_term>Precursor Cell Lymphoblastic Leukemia-Lymphoma</mesh_term>
      <mesh_term>Leukemia, Lymphoid</mesh_term>
    </condition_browse>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Dexamethasone</mesh_term>
      <mesh_term>Doxorubicin</mesh_term>
      <mesh_term>Methotrexate</mesh_term>
      <mesh_term>Vincristine</mesh_term>
      <mesh_term>Bortezomib</mesh_term>
      <mesh_term>Asparaginase</mesh_term>
      <mesh_term>Pegaspargase</mesh_term>
    </intervention_browse>
    <patient_data>
      <sharing_ipd>No</sharing_ipd>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT06034561
  org study id: 4009/23
  nct id: NCT06034561
  lead sponsor: 
  collaborator: 
  has dmc: No
  is fda regulated drug: No
  is fda regulated device: No
  is us export: No
  This is a interventional phase II study aiming to examine the complete response rate of a
        bortezomib-based salvage regimen in adults with refractory or relapsed acute lymphoblastic
        leukemia (ALL), seeking to compare outcomes with the available literature and with our
        historical data on relapsed/refractory ALL.
  Acute lymphoblastic leukemia (ALL) is a rare neoplasm in adults, with long-term survival
        rates approaching 50% with current regimens. Although high rates of complete response are
        achieved with the first-line therapy, many patients are primary refractory or may further
        relapse. Arguably, these patients have a more resistant disease with higher risk genetic
        alterations and a much less likely to be cured, which almost always only can be obtained by a
        following allogeneic hematopoietic stem-cell transplantation (HSCT). Therefore, strategies to
        salvage patients with detectable disease after induction blocks or with relapsed disease are
        crucial to prolong survival and potentially cure those patients, working as a bridge therapy
        to HSCT. Historically, patients with relapsed/refractory ALL have received multidrug regimens
        based on high-dose cytarabine, such as fludarabine, cytarabine and idarubicin (FLAG-IDA).
        Those regimens provide a 30-40% complete response rate with non-negligible toxicity.
        Recently, new targeted agents such as blinatumomab, inotuzumab, and cellular therapies have
        arisen for B-lineage disease, even though these agents are not available in the public health
        setting. Previous studies have tested salvage regimens for ALL encompassing proteasome
        inhibitors plus highly synergistic drugs (dexamethasone, vincristine, asparaginase,
        doxorubicin), with exciting outcomes in limited case series. For adults, these regimens are
        less studied. However, preliminary data suggest that they are less toxic and more potent
        since patients can receive different drug combinations that they had not been exposed to
        before. The primary objective of this study is to examine the complete response rate of this
        regimen in our population, aiming to compare with the available literature and with our
        historical data on relapsed/refractory ALL. Secondary objectives are:
  
          1. To determine the safety and feasibility of a bortezomib-based regimen for salvage
             relapsed/refractory ALL in our setting.
  
          2. To determine the rate of patients who are able to proceed with HSCT after the treatment.
  
          3. To calculate event-free survival and overall survival after the salvage regimen for
             relapsed/refractory ALL.
  
          4. To calculate the rate of measurable residual disease (MRD) negative status after the
             treatment.
  
          5. To examine the rate of febrile neutropenia, liver toxicity, neurotoxicity, and
             treatment-related mortality after this regimen in relapsed/refractory ALL.
  allocation: N/A
  intervention model: Single Group Assignment
  primary purpose: Treatment
  masking: None (Open Label)
  measure: Complete response
  time frame: 30 days
  description: Disappearance of lymphoid blasts in peripheral blood, with fewer than 5% of lymphoid blasts quantified in the bone marrow aspirate through immunophenotyping.
  measure: Event-free survival
  time frame: 1 year
  description: Time interval between study enrollment and the occurrence of an event (non-response, relapse, or death) or last follow-up (censorship).
  measure: Overall survival
  time frame: 1 year
  description: Time interval between study enrollment and the occurrence of death or last follow-up (censorship).
  measure: Rate of MRD-negativity
  time frame: 60 days
  description: Absence of pathological lymphoid blasts in a bone marrow sample detected through immunophenotyping with a minimum sensitivity of 10-4.
  measure: Rate of allogeneic hematopoietic stem-cell transplantation
  time frame: 1 year
  description: Proportion of patients who successfully underwent allogeneic hematopoietic stem-cell transplantation after the study therapy
  arm group label: Bortezomib
  arm group type: Experimental
  description: Patients with refractory or relapsed acute lymphoblastic leukemia will receive one-two courses of salvage regimen composed by:
  Bortezomib 1.3 mg/m2 I.V. D1,D4,D8,D11;
  Vincristine 1.5 mg/m2 I.V. (maximum at 2 mg) - D1, D8,D15,D22;
  Doxorubicin 60 mg/m2 I.V. - D1;
  Peg-asparaginase 2000 IU/m2 I.V. - D4 and D18;
  Dexamethasone 20 mg/m2 P.O. or I.V. (divided BID) - D1-D5 and D15-D19
  Intrathecal chemotherapy: methotrexate 12 mg + dexamethasone 2 mg.
  intervention type: Drug
  intervention name: Bortezomib
  description: Patients should receive one or two courses of this regimen, aiming to achieve complete remission as a bridge to proceed with allogeneic HSCT.
  arm group label: Bortezomib
  other name: Vincristine
  other name: Doxorubicin
  other name: Peg-asparaginase
  other name: Dexamethasone
  other name: Methotrexate
  criteria: 
  gender: All
  minimum age: 16 Years
  maximum age: 60 Years
  healthy volunteers: No
  last name: Wellington Silva, MD PhD
  role: Principal Investigator
  affiliation: Instituto do Cancer do Estado de Sao Paulo
  last name: Graziela S Silva
  phone: 551138934677
  email: graziela.sasilva@hc.fm.usp.br
  last name: Bruna Moraes, MSc
  phone: 551126628112
  email: pesquisa.hematologia@hc.fm.usp.br
  facility: 
  country: Brazil
  responsible party type: Sponsor
  mesh term: Leukemia
  mesh term: Precursor Cell Lymphoblastic Leukemia-Lymphoma
  mesh term: Leukemia, Lymphoid
  mesh term: Dexamethasone
  mesh term: Doxorubicin
  mesh term: Methotrexate
  mesh term: Vincristine
  mesh term: Bortezomib
  mesh term: Asparaginase
  mesh term: Pegaspargase
  sharing ipd: No