<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/NCT03805178</url>
  </required_header>
  <id_info>
    <org_study_id>Pro00101289</org_study_id>
    <secondary_id>IM103-407</secondary_id>
    <nct_id>NCT03805178</nct_id>
  </id_info>
  <brief_title>Lung Transplant Plasmapheresis/Belatacept/Carfilzomib for Antibody Mediated Rejection and Desensitization</brief_title>
  <official_title>Lung Transplant Plasmapheresis (PLEX)/Belatacept/Carfilzomib Protocol for Treatment of Antibody Mediated Rejection (AMR) and Desensitization</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Duke University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Bristol-Myers Squibb</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Duke University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</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>
      Antibody mediated rejection (AMR) post transplant contributes to poor long term outcomes&#xD;
      after lung transplantation. Additionally, high antibodies detected pre transplant in&#xD;
      candidates limit donor availability for lung transplant. This proposal would include&#xD;
      belatacept in a multi-therapy regimen. Open label study with two patient cohorts for safety&#xD;
      and efficacy of belatacept in a multi-modal protocol. The two patient cohorts are an AMR&#xD;
      post-transplant cohort and pre-transplant desensitization cohort. A total of 10 patients will&#xD;
      be enrolled.The primary objection is drug tolerability and secondary objectives are antibody&#xD;
      measurements and allograft function.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Antibody mediated rejection (AMR) post transplant contributes to poor long term outcomes&#xD;
      after lung transplantation. Additionally, high antibodies detected pre transplant in&#xD;
      candidates limit donor availability for lung transplant. Multimodal therapies with rituximab,&#xD;
      intravenous immunoglobulin, plasmapheresis and proteasome inhibitors have not significantly&#xD;
      altered the antibodies in these patients. Belatacept targets the T and B cell interaction&#xD;
      such that it represents a novel therapeutic strategy. This proposal would include belatacept&#xD;
      in a multi-therapy regimen.&#xD;
&#xD;
      This is an open label study with two patient cohorts for safety and efficacy of belatacept in&#xD;
      a multi-modal protocol. The two patient cohorts are an AMR post-transplant cohort and&#xD;
      pre-transplant desensitization cohort. A total of 10 patients will be enrolled.The primary&#xD;
      objection is drug tolerability and secondary objectives are antibody measurements and&#xD;
      allograft function.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    Not activated at Duke&#xD;
  </why_stopped>
  <start_date type="Anticipated">May 1, 2019</start_date>
  <completion_date type="Anticipated">October 30, 2020</completion_date>
  <primary_completion_date type="Anticipated">August 1, 2020</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Occurrence of drug side effects</measure>
    <time_frame>Within 28 days of last administration of study drugs</time_frame>
    <description>Drug tolerability with respect to freedom from drug side effects measured using descriptive statistics</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Occurrence of infection</measure>
    <time_frame>Within 28 days of last administration of study drugs</time_frame>
    <description>Drug tolerability with respect to freedom from infection measured using descriptive statistics</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Occurrence of malignancy</measure>
    <time_frame>Within 28 days of last administration of study drugs</time_frame>
    <description>Drug tolerability with respect to freedom from malignancy measured using descriptive statistics</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of subjects in the AMR cohort with resolution of at least one donor specific human leukocyte antigen (HLA) antibody (DSA)</measure>
    <time_frame>Within 4 weeks of completion of treatment</time_frame>
    <description>Descriptive statistical report of number of subjects who had resolution of at least one DSA measured by absolute Mean Fluorescent Intensity (MFI) change and log change using pre and post treatment values for each antibody.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of subjects in the AMR cohort with improvement or stabilization of lung function as measured by spirometry data</measure>
    <time_frame>Within 4 weeks of completion of treatment</time_frame>
    <description>Pulmonary function (spirometry) data will track forced vital capacity (FVC), forced expiratory volume (FEV1) and forced expiratory flow (FEF) 25-75%. Changes in spirometry will be reported as stabilized, improved or worsened based on comparison of baseline spirometry values obtained prior to treatment plan with serial spirometric testing performed at specified intervals in treatment plan.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of subjects in the AMR cohort with improvement in oxygenation as measured by Liters/min oxygen at rest</measure>
    <time_frame>Within 4 weeks of completion of treatment</time_frame>
    <description>Gas exchange will be reported as no change, worsening exchange or improving exchange based on comparison of resting oxygen requirements before and following treatment plan.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of subjects in the AMR cohort with decrease in DSA by one log</measure>
    <time_frame>Within 4 weeks of completion of treatment</time_frame>
    <description>Descriptive statistical report of number of subjects who had a decrease in DSA measured by absolute Mean Fluorescent Intensity (MFI) change and log change using pre and post treatment values for each antibody.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of subjects in the AMR cohort with elimination of DSA at 1:16 dilution</measure>
    <time_frame>Within 4 weeks of completion of treatment</time_frame>
    <description>Descriptive statistical report of number of subjects who had elimination of DSA at 1:16 dilution measured by absolute Mean Fluorescent Intensity (MFI) change and log change using pre and post treatment values for each antibody.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of subjects in the transplant desensitization cohort with decrease in non-DSA HLA antibodies by one log</measure>
    <time_frame>Within 4 weeks of completion of treatment</time_frame>
    <description>Descriptive statistical report of number of subjects who had a decrease in non-DSA HLA antibodies measured by absolute Mean Fluorescent Intensity (MFI) change and log change using pre and post treatment values for each antibody.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of subjects in the transplant desensitization cohort with elimination of non-DSA HLA antibodies at 1:16 dilution</measure>
    <time_frame>Within 4 weeks of completion of treatment</time_frame>
    <description>Descriptive statistical report of number of subjects who had elimination of non-DSA HLA antibodies at 1:16 dilution measured by absolute Mean Fluorescent Intensity (MFI) change and log change using pre and post treatment values for each antibody.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Lung Transplant Rejection</condition>
  <condition>Antibody-mediated Rejection</condition>
  <arm_group>
    <arm_group_label>Rejection post-transplant</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Treatment with Belatacept and Carfilzomib for subjects who show evidence of antibody-mediated rejection (AMR) following lung transplantation.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Pre-transplant desensitization</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Treatment with Belatacept and Carfilzomib for subjects with elevated human leukocyte antigen (HLA) antibodies prior to lung transplantation.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Belatacept</intervention_name>
    <description>Initial phase: 10 mg/kg on days 0 and 4, and again at weeks 2 and 4. Maintenance phase: 10 mg/kg every month beginning 4 weeks after completion of the initial phase.&#xD;
No dosage adjustments required for renal or hepatic impairment. No known drug interactions for usual post-transplant medication regimen.</description>
    <arm_group_label>Pre-transplant desensitization</arm_group_label>
    <arm_group_label>Rejection post-transplant</arm_group_label>
    <other_name>Nulojix</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Carfilzomib</intervention_name>
    <description>20mg/m2 Plasmapheresis</description>
    <arm_group_label>Pre-transplant desensitization</arm_group_label>
    <arm_group_label>Rejection post-transplant</arm_group_label>
    <other_name>Kyprolis</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Inclusion criteria for the AMR post-transplant cohort&#xD;
&#xD;
          -  Positive DSAs and allograft dysfunction defined by changes in pulmonary physiology,&#xD;
             gas exchange, radiological features or deteriorating functional performance that is&#xD;
             highly suspicious for AMR&#xD;
&#xD;
          -  Recipient is Epstein-Barr virus positive (EBV+) by serology&#xD;
&#xD;
          -  Ability to provide signed and dated IRB approved written consent in accordance with&#xD;
             regulatory and institutional guidelines prior to any protocol-related procedure&#xD;
&#xD;
        Inclusion criteria for the pre-transplant desensitization cohort&#xD;
&#xD;
          -  Elevated HLA antibodies (defined as MFI &gt;1000) such that the calculated panel reactive&#xD;
             antibodies are &gt;60%&#xD;
&#xD;
          -  At least 2 HLA antibodies with Mean Fluorescent Intensity (MFI) &lt;10,000 and at least 2&#xD;
             HLA antibodies with MFI &lt;5,000 on undiluted serum that do not demonstrate an increase&#xD;
             in MFI with dilution at 1:16 (no evidence of a prozone effect).&#xD;
&#xD;
          -  EBV+ by serology&#xD;
&#xD;
          -  Clinically stable defined by not on invasive mechanical ventilation, extracorporeal&#xD;
             membrane oxygenation support or other invasive life support requiring ICU level of&#xD;
             care&#xD;
&#xD;
          -  Ability to provide signed and dated IRB approved written consent in accordance with&#xD;
             regulatory and institutional guidelines prior to any protocol-related procedure&#xD;
&#xD;
        Exclusion criteria for both AMR post-transplant cohort and pre-transplant cohort&#xD;
&#xD;
          -  Active systemic infection&#xD;
&#xD;
          -  Allergy to carfilzomib or belatacept&#xD;
&#xD;
          -  Known malignancy in the previous 2 years except for non-melanomatous skin cancer&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  Inability to commit to complete treatment protocol at Duke as all procedures must be&#xD;
             completed at Duke&#xD;
&#xD;
          -  Prisoners or those who are compulsory detained&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Laurie Snyder</last_name>
    <role>Principal Investigator</role>
    <affiliation>Duke University</affiliation>
  </overall_official>
  <removed_countries>
    <country>United States</country>
  </removed_countries>
  <verification_date>April 2019</verification_date>
  <study_first_submitted>January 14, 2019</study_first_submitted>
  <study_first_submitted_qc>January 14, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 15, 2019</study_first_posted>
  <last_update_submitted>April 30, 2019</last_update_submitted>
  <last_update_submitted_qc>April 30, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">May 2, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Abatacept</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- 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/NCT03805178
org study id: Pro00101289
secondary id: IM103-407
nct id: NCT03805178
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
Antibody mediated rejection (AMR) post transplant contributes to poor long term outcomes
      after lung transplantation. Additionally, high antibodies detected pre transplant in
      candidates limit donor availability for lung transplant. This proposal would include
      belatacept in a multi-therapy regimen. Open label study with two patient cohorts for safety
      and efficacy of belatacept in a multi-modal protocol. The two patient cohorts are an AMR
      post-transplant cohort and pre-transplant desensitization cohort. A total of 10 patients will
      be enrolled.The primary objection is drug tolerability and secondary objectives are antibody
      measurements and allograft function.
Antibody mediated rejection (AMR) post transplant contributes to poor long term outcomes
      after lung transplantation. Additionally, high antibodies detected pre transplant in
      candidates limit donor availability for lung transplant. Multimodal therapies with rituximab,
      intravenous immunoglobulin, plasmapheresis and proteasome inhibitors have not significantly
      altered the antibodies in these patients. Belatacept targets the T and B cell interaction
      such that it represents a novel therapeutic strategy. This proposal would include belatacept
      in a multi-therapy regimen.

      This is an open label study with two patient cohorts for safety and efficacy of belatacept in
      a multi-modal protocol. The two patient cohorts are an AMR post-transplant cohort and
      pre-transplant desensitization cohort. A total of 10 patients will be enrolled.The primary
      objection is drug tolerability and secondary objectives are antibody measurements and
      allograft function.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Occurrence of drug side effects
time frame: Within 28 days of last administration of study drugs
description: Drug tolerability with respect to freedom from drug side effects measured using descriptive statistics
measure: Occurrence of infection
time frame: Within 28 days of last administration of study drugs
description: Drug tolerability with respect to freedom from infection measured using descriptive statistics
measure: Occurrence of malignancy
time frame: Within 28 days of last administration of study drugs
description: Drug tolerability with respect to freedom from malignancy measured using descriptive statistics
measure: Number of subjects in the AMR cohort with resolution of at least one donor specific human leukocyte antigen (HLA) antibody (DSA)
time frame: Within 4 weeks of completion of treatment
description: Descriptive statistical report of number of subjects who had resolution of at least one DSA measured by absolute Mean Fluorescent Intensity (MFI) change and log change using pre and post treatment values for each antibody.
measure: Number of subjects in the AMR cohort with improvement or stabilization of lung function as measured by spirometry data
time frame: Within 4 weeks of completion of treatment
description: Pulmonary function (spirometry) data will track forced vital capacity (FVC), forced expiratory volume (FEV1) and forced expiratory flow (FEF) 25-75%. Changes in spirometry will be reported as stabilized, improved or worsened based on comparison of baseline spirometry values obtained prior to treatment plan with serial spirometric testing performed at specified intervals in treatment plan.
measure: Number of subjects in the AMR cohort with improvement in oxygenation as measured by Liters/min oxygen at rest
time frame: Within 4 weeks of completion of treatment
description: Gas exchange will be reported as no change, worsening exchange or improving exchange based on comparison of resting oxygen requirements before and following treatment plan.
measure: Number of subjects in the AMR cohort with decrease in DSA by one log
time frame: Within 4 weeks of completion of treatment
description: Descriptive statistical report of number of subjects who had a decrease in DSA measured by absolute Mean Fluorescent Intensity (MFI) change and log change using pre and post treatment values for each antibody.
measure: Number of subjects in the AMR cohort with elimination of DSA at 1:16 dilution
time frame: Within 4 weeks of completion of treatment
description: Descriptive statistical report of number of subjects who had elimination of DSA at 1:16 dilution measured by absolute Mean Fluorescent Intensity (MFI) change and log change using pre and post treatment values for each antibody.
measure: Number of subjects in the transplant desensitization cohort with decrease in non-DSA HLA antibodies by one log
time frame: Within 4 weeks of completion of treatment
description: Descriptive statistical report of number of subjects who had a decrease in non-DSA HLA antibodies measured by absolute Mean Fluorescent Intensity (MFI) change and log change using pre and post treatment values for each antibody.
measure: Number of subjects in the transplant desensitization cohort with elimination of non-DSA HLA antibodies at 1:16 dilution
time frame: Within 4 weeks of completion of treatment
description: Descriptive statistical report of number of subjects who had elimination of non-DSA HLA antibodies at 1:16 dilution measured by absolute Mean Fluorescent Intensity (MFI) change and log change using pre and post treatment values for each antibody.
arm group label: Rejection post-transplant
arm group type: Experimental
description: Treatment with Belatacept and Carfilzomib for subjects who show evidence of antibody-mediated rejection (AMR) following lung transplantation.
arm group label: Pre-transplant desensitization
arm group type: Experimental
description: Treatment with Belatacept and Carfilzomib for subjects with elevated human leukocyte antigen (HLA) antibodies prior to lung transplantation.
intervention type: Drug
intervention name: Belatacept
description: Initial phase: 10 mg/kg on days 0 and 4, and again at weeks 2 and 4. Maintenance phase: 10 mg/kg every month beginning 4 weeks after completion of the initial phase.
No dosage adjustments required for renal or hepatic impairment. No known drug interactions for usual post-transplant medication regimen.
arm group label: Pre-transplant desensitization
arm group label: Rejection post-transplant
other name: Nulojix
intervention type: Drug
intervention name: Carfilzomib
description: 20mg/m2 Plasmapheresis
arm group label: Pre-transplant desensitization
arm group label: Rejection post-transplant
other name: Kyprolis
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Laurie Snyder
role: Principal Investigator
affiliation: Duke University
country: United States
responsible party type: Sponsor
mesh term: Abatacept
sharing ipd: No