<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/NCT02996773</url>
  </required_header>
  <id_info>
    <org_study_id>1609876907</org_study_id>
    <nct_id>NCT02996773</nct_id>
  </id_info>
  <brief_title>Haploidentical BMT With Post-Transplant Cyclophosphamide and Bendamustine</brief_title>
  <official_title>A Phase I/Ib Study of Haploidentical Bone Marrow Transplant With Post-Transplant Cyclophosphamide and/or Bendamustine</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Arizona</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Arizona</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to evaluate the safety of progressively substituting day +3 and&#xD;
      +4 post-transplant cyclophosphamide (PT-CY) with post-transplant bendamustine (PT-BEN) in&#xD;
      myeloablative (MAC) haploidentical hematopoietic cell transplantation (HHCT) for patients&#xD;
      with hematological malignancies.&#xD;
&#xD;
      The goal of the Phase 1 component of the study is to evaluate the safety of progressively&#xD;
      substituting post-transplant cyclophosphamide (PT-CY) given on Days +3 and +4 with&#xD;
      bendamustine (PT-BEN). The Phase I component of the study has been completed.&#xD;
&#xD;
      The Phase Ib component of the study will continue to evaluate the safety and efficacy of&#xD;
      subjects who receive PT-BEN on Days +3 and +4 at the maximum tolerated dose determined by&#xD;
      Phase I. The Phase Ib component of the study has been completed.&#xD;
&#xD;
      Approximately, 18-36 subjects will be treated as part of Phase I and 15 as part of Phase Ib.&#xD;
      Approximately 18 subjects will be used as controls, subjects that receive no PET-BEN, for&#xD;
      direct comparison. Total, approximately 38-56 treatment and control patients and 38-56 donor&#xD;
      subjects will be enrolled.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This study will follow the standard-of-care bone marrow transplant (BMT), with the only&#xD;
      exception being to progressively substitute post-transplant cyclophosphamide (on Days +3 and&#xD;
      +4 after BMT) with bendamustine. Six dose levels were planned for the Phase I component of&#xD;
      the study, consisting of a combination of sequentially reduced doses of cyclophosphamide&#xD;
      (PT-CY) and increased doses of bendamustine (PT-BEN) initially on Day +4 after BMT, followed&#xD;
      by the same sequential reduction and increase on Day +3. An interim analysis was performed&#xD;
      after cohort 3 was completed in Phase I and included a preliminary comparison between&#xD;
      treatment and control groups. Phase Ib will evaluate patients treated with PT-CY on day +3&#xD;
      and PT-BEN on day +4.&#xD;
&#xD;
      Control patients will be patients that have declined to participate in the main trial but&#xD;
      will receive haploidentical BMT with the current standard of two days of PT-CY (and no&#xD;
      PT-BEN) and will be consented for the immune monitoring studies only.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">November 29, 2016</start_date>
  <completion_date type="Anticipated">August 25, 2025</completion_date>
  <primary_completion_date type="Anticipated">August 25, 2025</primary_completion_date>
  <phase>Phase 1</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>Safety in regards to engraftment, incidence and grade of acute and chronic graft-versus-host-disease, graft failure, infections, relapse, and non-relapse mortality post-haploidentical bone marrow transplantation.</measure>
    <time_frame>Change from baseline to 3 years. Interim analysis will be performed after cohort 3 and cohort 6 in Phase 1, and include preliminary evaluation of treatment and control groups</time_frame>
    <description>Examine the effects of PT-BEN on immune reconstitution following human haploidentical BMT.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Incidence of regimen-related organ toxicities</measure>
    <time_frame>Change from baseline to 3 years. Interim analysis will be performed after cohort 3 and cohort 6 in Phase 1, and include preliminary evaluation of treatment and control groups]</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of acute GvHD</measure>
    <time_frame>Change from baseline to 3 years. Interim analysis will be performed after cohort 3 and cohort 6 in Phase 1, and include preliminary evaluation of treatment and control groups]</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Severity of acute GvHD</measure>
    <time_frame>Change from baseline to 3 years. Interim analysis will be performed after cohort 3 and cohort 6 in Phase 1, and include preliminary evaluation of treatment and control groups]</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of chronic GvHD</measure>
    <time_frame>Change from baseline to 3 years. Interim analysis will be performed after cohort 3 and cohort 6 in Phase 1, and include preliminary evaluation of treatment and control groups]</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Extent of chronic GvHD</measure>
    <time_frame>Change from baseline to 3 years. Interim analysis will be performed after cohort 3 and cohort 6 in Phase 1, and include preliminary evaluation of treatment and control groups]</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of graft failure</measure>
    <time_frame>Change from baseline to 3 years. Interim analysis will be performed after cohort 3 and cohort 6 in Phase 1, and include preliminary evaluation of treatment and control groups]</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Infection risk</measure>
    <time_frame>Change from baseline to 3 years. Interim analysis will be performed after cohort 3 and cohort 6 in Phase 1, and include preliminary evaluation of treatment and control groups]</time_frame>
    <description>Immune reconstitution will be studied prospectively. Viral and fungal prophylaxis and treatment will be done according to our BMT programs guidelines</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Infection severity</measure>
    <time_frame>Change from baseline to 3 years. Interim analysis will be performed after cohort 3 and cohort 6 in Phase 1, and include preliminary evaluation of treatment and control groups]</time_frame>
    <description>Immune reconstitution will be studied prospectively. Viral and fungal prophylaxis and treatment will be done according to our BMT programs guidelines</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall patient survival</measure>
    <time_frame>Change from baseline to 3 years. Interim analysis will be performed after cohort 3 and cohort 6 in Phase 1, and include preliminary evaluation of treatment and control groups]</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Immune reconstitution following haploidentical BMT</measure>
    <time_frame>Change from baseline to 3 years. Interim analysis will be performed after cohort 3 and cohort 6 in Phase 1, and include preliminary evaluation of treatment and control groups]</time_frame>
    <description>T cell immune reconstitution (CD4, cluster of differentiation 8 (CD8), Treg, NK), B cell and myeloid cell reconstitution will be evaluated serially until 6 months post-BMT</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of bacterial, fungal and viral infections/reactivations</measure>
    <time_frame>Change from baseline to 3 years. Interim analysis will be performed after cohort 3 and cohort 6 in Phase 1, and include preliminary evaluation of treatment and control groups]</time_frame>
    <description>Gather data on Incidence of bacterial, fungal and viral infections/reactivations</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">50</enrollment>
  <condition>Acute Lymphoblastic Leukemia</condition>
  <condition>Acute Myelogenous Leukemia</condition>
  <condition>Myelodysplastic Syndromes</condition>
  <condition>Chronic Myelogenous Leukemia</condition>
  <condition>Lymphoma,Non-Hodgkin</condition>
  <condition>Lymphoma, Hodgkin</condition>
  <condition>Lymphoma, Follicular</condition>
  <condition>Marginal Zone Lymphoma</condition>
  <condition>Large Cell Lymphoma</condition>
  <condition>Mantle-Cell Lymphoma</condition>
  <condition>Gray Zone Lymphoma</condition>
  <condition>Burkitt Lymphoma</condition>
  <condition>High Risk Undifferentiated Acute Leukemia</condition>
  <arm_group>
    <arm_group_label>Cyclophosphamide and Bendamustine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Experimental: Cyclophosphamide and Bendamustine Control: Cyclophosphamide&#xD;
Interventions:&#xD;
Drug: Bendamustine&#xD;
Drug: Cyclophosphamide</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Bendamustine</intervention_name>
    <description>After transplant, given intravenously on day +4 as part of Phase Ib.</description>
    <arm_group_label>Cyclophosphamide and Bendamustine</arm_group_label>
    <other_name>BEN</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cyclophosphamide</intervention_name>
    <description>After transplant, given intravenously on day +3 as part of Phase 1b.</description>
    <arm_group_label>Cyclophosphamide and Bendamustine</arm_group_label>
    <other_name>CY</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Be willing and able to provide written consent/assent for the trial.&#xD;
&#xD;
          -  Diagnosed with one of the following high-risk malignancies, which require&#xD;
             hematopoietic cell transplantation (HCT) but do not have an available Human Leukocyte&#xD;
             Antigen (HLA)-matched related or unrelated donor or acceptable cord blood&#xD;
&#xD;
          -  High risk acute lymphoblastic leukemia (ALL) in 1st complete remission (CR1) or&#xD;
             greater&#xD;
&#xD;
          -  High risk acute myelogenous leukemia (AML) in CR1 or greater&#xD;
&#xD;
          -  High risk undifferentiated acute leukemia&#xD;
&#xD;
          -  High risk myelodysplastic syndrome (MDS)&#xD;
&#xD;
          -  Chronic Myelogenous Leukemia (CML) failing or intolerant to Tyrosine Kinase Inhibitors&#xD;
             (TKIs) or in accelerated, blastic phase, or in second or subsequent chronic phase&#xD;
&#xD;
          -  Lymphoma, (Hodgkin and Non-Hodgkins Lymphoma including marginal zone, follicular&#xD;
             lymphoma, chemotherapy-sensitive large-cell, mantle cell lymphoma, gray zone, and&#xD;
             Burkitt's lymphoma in remission).&#xD;
&#xD;
          -  At least one haploidentical related donor is available for bone marrow harvest.&#xD;
&#xD;
          -  Molecular based HLA typing for the HLA-A, -B, -Cw, beta chain (-DRB1) and - DQ Beta 1&#xD;
             Locus (DQB1loci) to the resolution is needed to establish haploidentity.&#xD;
&#xD;
          -  A minimum match of 5/10 is required.&#xD;
&#xD;
          -  No availability of an 8/8 HLA-matched related or unrelated donor or clinical urgency&#xD;
             for transplant (e.g., needed within 4-8 weeks) at which time an acceptable unrelated&#xD;
             donor will not be available.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Refractory acute leukemia (&gt;5% blasts) or progressive disease&#xD;
&#xD;
          -  Untreated or progressive central nervous system leukemia&#xD;
&#xD;
          -  Refractory to chemotherapy lymphoma&#xD;
&#xD;
          -  Co-morbidities precluding patient's ability to tolerate BMT&#xD;
&#xD;
          -  Aspartate Aminotransferase (AST)/ Alanine Aminotransferase (ALT) &gt; 5 x upper limit of&#xD;
             normal (ULN)&#xD;
&#xD;
          -  Bilirubin &gt; 2 x ULN&#xD;
&#xD;
          -  Creatinine greater than &gt;2 x ULN for age or creatinine clearance/glomerular filtration&#xD;
             rate (GFR) &lt;40 ml/min/1.73m2&#xD;
&#xD;
          -  Pulmonary function: Diffusing capacity of the lung for carbon monoxide (DLCO) &lt; 40% of&#xD;
             normal or O2 Sat &lt;92%&#xD;
&#xD;
          -  Cardiac: left ventricular ejection fraction &lt;35%&#xD;
&#xD;
          -  Active infection at time of hospital admission of Haplo BMT&#xD;
&#xD;
          -  Documented fungal infection or highly suspected and receiving treatment for presumed&#xD;
             fungal infection within 3 months of BMT&#xD;
&#xD;
          -  HIV positive&#xD;
&#xD;
          -  Karnofsky score (adults) &lt; 60% or Lansky score &lt; 50% (pediatrics).&#xD;
&#xD;
          -  Positive pregnancy test for girls post menarche or women of childbearing age.&#xD;
&#xD;
          -  Severe psychiatric illness or mental deficiency making compliance to treatment&#xD;
             unlikely and/or informed consent impossible.&#xD;
&#xD;
          -  Any reason, at the investigator's discretion, that the participation of the patient in&#xD;
             this protocol would not be in patient's best interest, or where the patient would be&#xD;
             unable to adhere to the study requirements.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>4 Years</minimum_age>
    <maximum_age>30 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Emmanuel Katsanis, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>The University of Arizona Cancer Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>The University of Arizona Cancer Center</name>
      <address>
        <city>Tucson</city>
        <state>Arizona</state>
        <zip>85724</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>July 2023</verification_date>
  <study_first_submitted>December 1, 2016</study_first_submitted>
  <study_first_submitted_qc>December 14, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 19, 2016</study_first_posted>
  <last_update_submitted>July 13, 2023</last_update_submitted>
  <last_update_submitted_qc>July 13, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">July 17, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>high-risk malignancies</keyword>
  <keyword>Lymphoma</keyword>
  <keyword>Haploidentical</keyword>
  <keyword>Bone Marrow Transplant (BMT)</keyword>
  <keyword>Post-transplant</keyword>
  <keyword>myeloablative (MAC)</keyword>
  <keyword>reduced intensity conditioning (RIC)</keyword>
  <keyword>haploidentical hematopoietic cell transplantation (HHCT)</keyword>
  <keyword>Leukemia</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Burkitt Lymphoma</mesh_term>
    <mesh_term>Lymphoma</mesh_term>
    <mesh_term>Leukemia</mesh_term>
    <mesh_term>Precursor Cell Lymphoblastic Leukemia-Lymphoma</mesh_term>
    <mesh_term>Leukemia, Myeloid</mesh_term>
    <mesh_term>Lymphoma, Mantle-Cell</mesh_term>
    <mesh_term>Leukemia, Myelogenous, Chronic, BCR-ABL Positive</mesh_term>
    <mesh_term>Leukemia, Myeloid, Acute</mesh_term>
    <mesh_term>Lymphoma, Non-Hodgkin</mesh_term>
    <mesh_term>Lymphoma, Follicular</mesh_term>
    <mesh_term>Hodgkin Disease</mesh_term>
    <mesh_term>Myelodysplastic Syndromes</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cyclophosphamide</mesh_term>
    <mesh_term>Bendamustine Hydrochloride</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/NCT02996773
org study id: 1609876907
nct id: NCT02996773
lead sponsor: 
has dmc: Yes
The purpose of this study is to evaluate the safety of progressively substituting day +3 and
      +4 post-transplant cyclophosphamide (PT-CY) with post-transplant bendamustine (PT-BEN) in
      myeloablative (MAC) haploidentical hematopoietic cell transplantation (HHCT) for patients
      with hematological malignancies.

      The goal of the Phase 1 component of the study is to evaluate the safety of progressively
      substituting post-transplant cyclophosphamide (PT-CY) given on Days +3 and +4 with
      bendamustine (PT-BEN). The Phase I component of the study has been completed.

      The Phase Ib component of the study will continue to evaluate the safety and efficacy of
      subjects who receive PT-BEN on Days +3 and +4 at the maximum tolerated dose determined by
      Phase I. The Phase Ib component of the study has been completed.

      Approximately, 18-36 subjects will be treated as part of Phase I and 15 as part of Phase Ib.
      Approximately 18 subjects will be used as controls, subjects that receive no PET-BEN, for
      direct comparison. Total, approximately 38-56 treatment and control patients and 38-56 donor
      subjects will be enrolled.
This study will follow the standard-of-care bone marrow transplant (BMT), with the only
      exception being to progressively substitute post-transplant cyclophosphamide (on Days +3 and
      +4 after BMT) with bendamustine. Six dose levels were planned for the Phase I component of
      the study, consisting of a combination of sequentially reduced doses of cyclophosphamide
      (PT-CY) and increased doses of bendamustine (PT-BEN) initially on Day +4 after BMT, followed
      by the same sequential reduction and increase on Day +3. An interim analysis was performed
      after cohort 3 was completed in Phase I and included a preliminary comparison between
      treatment and control groups. Phase Ib will evaluate patients treated with PT-CY on day +3
      and PT-BEN on day +4.

      Control patients will be patients that have declined to participate in the main trial but
      will receive haploidentical BMT with the current standard of two days of PT-CY (and no
      PT-BEN) and will be consented for the immune monitoring studies only.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Safety in regards to engraftment, incidence and grade of acute and chronic graft-versus-host-disease, graft failure, infections, relapse, and non-relapse mortality post-haploidentical bone marrow transplantation.
time frame: Change from baseline to 3 years. Interim analysis will be performed after cohort 3 and cohort 6 in Phase 1, and include preliminary evaluation of treatment and control groups
description: Examine the effects of PT-BEN on immune reconstitution following human haploidentical BMT.
measure: Incidence of regimen-related organ toxicities
time frame: Change from baseline to 3 years. Interim analysis will be performed after cohort 3 and cohort 6 in Phase 1, and include preliminary evaluation of treatment and control groups]
measure: Incidence of acute GvHD
time frame: Change from baseline to 3 years. Interim analysis will be performed after cohort 3 and cohort 6 in Phase 1, and include preliminary evaluation of treatment and control groups]
measure: Severity of acute GvHD
time frame: Change from baseline to 3 years. Interim analysis will be performed after cohort 3 and cohort 6 in Phase 1, and include preliminary evaluation of treatment and control groups]
measure: Incidence of chronic GvHD
time frame: Change from baseline to 3 years. Interim analysis will be performed after cohort 3 and cohort 6 in Phase 1, and include preliminary evaluation of treatment and control groups]
measure: Extent of chronic GvHD
time frame: Change from baseline to 3 years. Interim analysis will be performed after cohort 3 and cohort 6 in Phase 1, and include preliminary evaluation of treatment and control groups]
measure: Incidence of graft failure
time frame: Change from baseline to 3 years. Interim analysis will be performed after cohort 3 and cohort 6 in Phase 1, and include preliminary evaluation of treatment and control groups]
measure: Infection risk
time frame: Change from baseline to 3 years. Interim analysis will be performed after cohort 3 and cohort 6 in Phase 1, and include preliminary evaluation of treatment and control groups]
description: Immune reconstitution will be studied prospectively. Viral and fungal prophylaxis and treatment will be done according to our BMT programs guidelines
measure: Infection severity
time frame: Change from baseline to 3 years. Interim analysis will be performed after cohort 3 and cohort 6 in Phase 1, and include preliminary evaluation of treatment and control groups]
description: Immune reconstitution will be studied prospectively. Viral and fungal prophylaxis and treatment will be done according to our BMT programs guidelines
measure: Overall patient survival
time frame: Change from baseline to 3 years. Interim analysis will be performed after cohort 3 and cohort 6 in Phase 1, and include preliminary evaluation of treatment and control groups]
measure: Immune reconstitution following haploidentical BMT
time frame: Change from baseline to 3 years. Interim analysis will be performed after cohort 3 and cohort 6 in Phase 1, and include preliminary evaluation of treatment and control groups]
description: T cell immune reconstitution (CD4, cluster of differentiation 8 (CD8), Treg, NK), B cell and myeloid cell reconstitution will be evaluated serially until 6 months post-BMT
measure: Incidence of bacterial, fungal and viral infections/reactivations
time frame: Change from baseline to 3 years. Interim analysis will be performed after cohort 3 and cohort 6 in Phase 1, and include preliminary evaluation of treatment and control groups]
description: Gather data on Incidence of bacterial, fungal and viral infections/reactivations
arm group label: Cyclophosphamide and Bendamustine
arm group type: Experimental
description: Experimental: Cyclophosphamide and Bendamustine Control: Cyclophosphamide
Interventions:
Drug: Bendamustine
Drug: Cyclophosphamide
intervention type: Drug
intervention name: Bendamustine
description: After transplant, given intravenously on day +4 as part of Phase Ib.
arm group label: Cyclophosphamide and Bendamustine
other name: BEN
intervention type: Drug
intervention name: Cyclophosphamide
description: After transplant, given intravenously on day +3 as part of Phase 1b.
arm group label: Cyclophosphamide and Bendamustine
other name: CY
criteria: 
gender: All
minimum age: 4 Years
maximum age: 30 Years
healthy volunteers: No
last name: Emmanuel Katsanis, MD
role: Principal Investigator
affiliation: The University of Arizona Cancer Center
facility: 
country: United States
responsible party type: Sponsor
mesh term: Burkitt Lymphoma
mesh term: Lymphoma
mesh term: Leukemia
mesh term: Precursor Cell Lymphoblastic Leukemia-Lymphoma
mesh term: Leukemia, Myeloid
mesh term: Lymphoma, Mantle-Cell
mesh term: Leukemia, Myelogenous, Chronic, BCR-ABL Positive
mesh term: Leukemia, Myeloid, Acute
mesh term: Lymphoma, Non-Hodgkin
mesh term: Lymphoma, Follicular
mesh term: Hodgkin Disease
mesh term: Myelodysplastic Syndromes
mesh term: Cyclophosphamide
mesh term: Bendamustine Hydrochloride