<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/NCT03279094</url>
  </required_header>
  <id_info>
    <org_study_id>17136</org_study_id>
    <nct_id>NCT03279094</nct_id>
  </id_info>
  <brief_title>Haploidentical Transplantation With Pre-Transplant Immunosuppressive Therapy for Patients With Sickle Cell Disease</brief_title>
  <official_title>A Pilot Study of Pre-transplant Immunosuppressive Therapy for Haploidentical Transplants in Patients With Sickle Cell Disease</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>City of Hope Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>City of Hope Medical Center</source>
  <oversight_info>
    <has_dmc>Yes</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>
      This is a study to evaluate the safety and toxicity of a treatment regimen consisting of 2&#xD;
      cycles of pre-transplant immunosuppressive therapy followed by myeloablative preparative&#xD;
      regimen and allogeneic hematopoietic stem cell transplantation from a haploidentical donor in&#xD;
      patients with sickle cell disease.&#xD;
&#xD;
      The overall goal of this study is to expand the donor pool for hematopoietic stem cell&#xD;
      transplantation in sickle cell disease using haploidentical donors, and to develop a&#xD;
      non-toxic, myeloablative regimen, with the goal of achieving a consistent donor chimerism&#xD;
      utilizing pre-transplant immunosuppressive therapy.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      All patients will receive an haploidentical hematopoietic stem cell transplant with the&#xD;
      following conditioning and GvHD prevention:&#xD;
&#xD;
      Pre-transplant immunosuppressive therapy:&#xD;
&#xD;
      2 cycles of Fludarabine and Dexamethasone x 5 days each cycle&#xD;
&#xD;
      Conditioning regimen:&#xD;
&#xD;
      rATG daily x 3 days, Fludarabine daily x 6 days and Busulfan daily x 4 days&#xD;
&#xD;
      GVHD prophylaxis:&#xD;
&#xD;
      Cyclophosphamide day +3 and +4, Tacrolimus and Mycophenolate mofetil&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">February 2, 2018</start_date>
  <completion_date type="Anticipated">December 20, 2023</completion_date>
  <primary_completion_date type="Anticipated">December 20, 2023</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>Rate of unacceptable adverse events that are defined as any of the following events that occur from start of pre-transplant immunosuppressive therapy to the first 100 days post HCT:</measure>
    <time_frame>190 days</time_frame>
    <description>Rate of death of any causes&#xD;
Rate of study discontinuation or early withdrawal&#xD;
Rate of graft failure&#xD;
• Primary graft failure is defined as failure to achieve a neutrophil count of 0.5 x 109/L before day +42 or mixed chimerism with failure to achieve &lt;30% Hgb S on electrophoresis after day +180. Secondary graft failure is defined as recovery followed by a sustained loss of initial graft.&#xD;
Rate of grade 4 non-hematological toxicities per NCI CTCAE v4.03 that last more than 21 days</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Time to donor neutrophil engraftment</measure>
    <time_frame>24 months</time_frame>
    <description>Day of Neutrophil Engraftment: The first of three consecutive days on which the ANC is ≥0.5x109/L</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to donor platelets engraftment</measure>
    <time_frame>24 months</time_frame>
    <description>Day of Platelet engraftment: The first documented day on which the platelet count is &gt;20x109/L unsupported by platelet transfusions for 7 days</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of graft failure</measure>
    <time_frame>24 months</time_frame>
    <description>Primary graft failure is defined as failure to achieve a neutrophil count of 0.5 x 109/L before day +42 or mixed chimerism with failure to achieve &lt;30% Hgb S on electrophoresis after day +180. Secondary graft failure is defined as recovery followed by a sustained loss of initial graft.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of acute GvHD (grade II - IV) during the first 100 days after transplantation</measure>
    <time_frame>100 days after transplantation</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of chronic GvHD</measure>
    <time_frame>24 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival rate</measure>
    <time_frame>24 months</time_frame>
    <description>• Overall survival: the time from start of PTIS to death, or last follow-up, whichever comes first.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Event-free survival rate</measure>
    <time_frame>24 months</time_frame>
    <description>• Event-free survival: the time from start of PTIS to death, the unacceptable events, or last follow-up, whichever comes first.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disease free survival rate</measure>
    <time_frame>24 months</time_frame>
    <description>• Disease free survival: the time from HCT to death, secondary graft failure, or last follow-up, whichever comes first.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Immune reconstitution at day 100, 180 and 365</measure>
    <time_frame>24 months</time_frame>
    <description>• Immune reconstitution: measurement of CD3, CD4, CD8, CD11b, CD14, CD56, CD20/19, FoxP3+ Treg, and memory subsets.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE v4.0 from start of pre-transplant immunosuppressive therapy to 24 months post transplant</measure>
    <time_frame>24 months post-transplant</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percent of donor chimerism at 12 and 24 months after HCT</measure>
    <time_frame>12 and 24 months after HCT</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Pain Scores using Numerical Rating Scale or Faces Pain Rating Scale at 100 days, 6 months and 12 months post-transplant</measure>
    <time_frame>100 days, 6 months and 12 months post-transplant</time_frame>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">15</enrollment>
  <condition>Sickle Cell Disease</condition>
  <arm_group>
    <arm_group_label>Haploidentical stem cell transplantation</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Hematopoietic stem cell transplantation</intervention_name>
    <description>Haploidentical stem cell transplantation with pre-transplant immunosuppressive therapy</description>
    <arm_group_label>Haploidentical stem cell transplantation</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion criteria&#xD;
&#xD;
          -  Diagnosis: Patients with sickle cell anemia (Hgb SS or SB° Thalassemia) with baseline&#xD;
             Hgb S more than 60%.&#xD;
&#xD;
          -  Disease status:&#xD;
&#xD;
          -  Significant neurologic event (stroke) or any neurological deficit lasting &gt; 24 hours;&#xD;
             or increased transcranial Doppler velocity (&gt;200 m/s).&#xD;
&#xD;
          -  History of one or more episodes of acute chest syndrome (ACS) in the 2-year period&#xD;
             preceding enrollment despite the institution of supportive care measures (i.e. asthma&#xD;
             therapy and/or hydroxyurea).&#xD;
&#xD;
          -  History of one or more severe vaso-occlusive pain crises per year in the 2-year period&#xD;
             preceding enrollment despite the institution of supportive care measures (i.e. a pain&#xD;
             management plan and/or treatment with hydroxyurea).&#xD;
&#xD;
          -  Recurrent priapism requiring medical therapy.&#xD;
&#xD;
          -  Osteonecrosis of two or more joints despite the institution of supportive care&#xD;
             measures.&#xD;
&#xD;
          -  Prior treatment with regular RBC transfusion therapy, defined as receiving 8 or more&#xD;
             transfusions per year for &gt; 1 year to prevent vaso-occlusive clinical complications&#xD;
             (i.e. pain, stroke, and acute chest syndrome)&#xD;
&#xD;
          -  Echocardiograph finding of tricuspid valve regurgitation jet (TRJ) velocity ≥ 2.5&#xD;
             m/sec.&#xD;
&#xD;
          -  Ages 1 to 30.&#xD;
&#xD;
          -  Child Bearing Potential- Transplantation could be teratogenic and/or lethal to the&#xD;
             developing fetus. For this reason, women of child-bearing potential and men must agree&#xD;
             to use adequate contraception (hormonal or barrier method of birth control or&#xD;
             abstinence) prior to study entry and for six months following duration of study&#xD;
             participation. Should a woman become pregnant or suspect that she is pregnant while&#xD;
             participating on the trial, she should inform her treating physician immediately.&#xD;
&#xD;
          -  Informed Consent/Assent: All subjects must have the ability to understand and the&#xD;
             willingness to sign a written informed consent.&#xD;
&#xD;
          -  The recipient must have a related donor who is genotypically haploidentical on HLA-A,&#xD;
             B, C and DRB1 loci.&#xD;
&#xD;
          -  No HLA matched sibling or 10/10 matched unrelated donor is available.&#xD;
&#xD;
        Exclusion criteria:&#xD;
&#xD;
          -  Any uncontrolled illness including ongoing or active bacterial, viral or fungal&#xD;
             infection.&#xD;
&#xD;
          -  Patients may not be receiving any other investigational agents, or concurrent&#xD;
             biological, chemotherapy, or radiation therapy.&#xD;
&#xD;
          -  History of allergic reactions attributed to compounds of similar chemical or biologic&#xD;
             composition to any in the pre- or post-transplant regimen.&#xD;
&#xD;
          -  Pregnant women are excluded from this study.&#xD;
&#xD;
          -  Patients with any active malignancy are ineligible for this study, other than&#xD;
             non-melanoma skin cancers.&#xD;
&#xD;
          -  Medical problem or neurologic/psychiatric dysfunction which would impair patient&#xD;
             ability to be compliant with the medical regimen and to tolerate transplantation or&#xD;
             would prolong hematologic recovery which in the opinion of the principal investigator&#xD;
             would place the recipient at unacceptable risk.&#xD;
&#xD;
          -  Prior autologous or allogeneic transplant.&#xD;
&#xD;
          -  Fully HLA-matched related or unrelated donor is available to donate.&#xD;
&#xD;
          -  Non-Compliance: Subjects, who in the opinion of the investigator, may not be able to&#xD;
             comply with the safety monitoring requirements of the study.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>1 Year</minimum_age>
    <maximum_age>30 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Anna B. Pawlowska, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>City of Hope Medical Center</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Anna B. Pawlowska, MD</last_name>
    <phone>626-218-8442</phone>
    <email>apawlowska@coh.org</email>
  </overall_contact>
  <location>
    <facility>
      <name>City of Hope Medical Center</name>
      <address>
        <city>Duarte</city>
        <state>California</state>
        <zip>91010</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Mary Suarez, CRC</last_name>
      <phone>626-218-5795</phone>
      <email>masuarez@coh.org</email>
    </contact>
    <investigator>
      <last_name>Anna B. Pawlowska, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>September 6, 2017</study_first_submitted>
  <study_first_submitted_qc>September 8, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 12, 2017</study_first_posted>
  <last_update_submitted>May 26, 2023</last_update_submitted>
  <last_update_submitted_qc>May 26, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 31, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Sickle Cell Disease</keyword>
  <keyword>Hematopoietic stem cell transplantation</keyword>
  <keyword>Haploidentical stem cell transplantation</keyword>
  <keyword>Post-transplant Cytoxan</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Anemia, Sickle Cell</mesh_term>
  </condition_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/NCT03279094
org study id: 17136
nct id: NCT03279094
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
This is a study to evaluate the safety and toxicity of a treatment regimen consisting of 2
      cycles of pre-transplant immunosuppressive therapy followed by myeloablative preparative
      regimen and allogeneic hematopoietic stem cell transplantation from a haploidentical donor in
      patients with sickle cell disease.

      The overall goal of this study is to expand the donor pool for hematopoietic stem cell
      transplantation in sickle cell disease using haploidentical donors, and to develop a
      non-toxic, myeloablative regimen, with the goal of achieving a consistent donor chimerism
      utilizing pre-transplant immunosuppressive therapy.
All patients will receive an haploidentical hematopoietic stem cell transplant with the
      following conditioning and GvHD prevention:

      Pre-transplant immunosuppressive therapy:

      2 cycles of Fludarabine and Dexamethasone x 5 days each cycle

      Conditioning regimen:

      rATG daily x 3 days, Fludarabine daily x 6 days and Busulfan daily x 4 days

      GVHD prophylaxis:

      Cyclophosphamide day +3 and +4, Tacrolimus and Mycophenolate mofetil
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Rate of unacceptable adverse events that are defined as any of the following events that occur from start of pre-transplant immunosuppressive therapy to the first 100 days post HCT:
time frame: 190 days
description: Rate of death of any causes
Rate of study discontinuation or early withdrawal
Rate of graft failure
• Primary graft failure is defined as failure to achieve a neutrophil count of 0.5 x 109/L before day +42 or mixed chimerism with failure to achieve <30% Hgb S on electrophoresis after day +180. Secondary graft failure is defined as recovery followed by a sustained loss of initial graft.
Rate of grade 4 non-hematological toxicities per NCI CTCAE v4.03 that last more than 21 days
measure: Time to donor neutrophil engraftment
time frame: 24 months
description: Day of Neutrophil Engraftment: The first of three consecutive days on which the ANC is ≥0.5x109/L
measure: Time to donor platelets engraftment
time frame: 24 months
description: Day of Platelet engraftment: The first documented day on which the platelet count is >20x109/L unsupported by platelet transfusions for 7 days
measure: Rate of graft failure
time frame: 24 months
description: Primary graft failure is defined as failure to achieve a neutrophil count of 0.5 x 109/L before day +42 or mixed chimerism with failure to achieve <30% Hgb S on electrophoresis after day +180. Secondary graft failure is defined as recovery followed by a sustained loss of initial graft.
measure: Incidence of acute GvHD (grade II - IV) during the first 100 days after transplantation
time frame: 100 days after transplantation
measure: Incidence of chronic GvHD
time frame: 24 months
measure: Overall survival rate
time frame: 24 months
description: • Overall survival: the time from start of PTIS to death, or last follow-up, whichever comes first.
measure: Event-free survival rate
time frame: 24 months
description: • Event-free survival: the time from start of PTIS to death, the unacceptable events, or last follow-up, whichever comes first.
measure: Disease free survival rate
time frame: 24 months
description: • Disease free survival: the time from HCT to death, secondary graft failure, or last follow-up, whichever comes first.
measure: Immune reconstitution at day 100, 180 and 365
time frame: 24 months
description: • Immune reconstitution: measurement of CD3, CD4, CD8, CD11b, CD14, CD56, CD20/19, FoxP3+ Treg, and memory subsets.
measure: Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE v4.0 from start of pre-transplant immunosuppressive therapy to 24 months post transplant
time frame: 24 months post-transplant
measure: Percent of donor chimerism at 12 and 24 months after HCT
time frame: 12 and 24 months after HCT
measure: Change From Baseline in Pain Scores using Numerical Rating Scale or Faces Pain Rating Scale at 100 days, 6 months and 12 months post-transplant
time frame: 100 days, 6 months and 12 months post-transplant
arm group label: Haploidentical stem cell transplantation
arm group type: Experimental
intervention type: Biological
intervention name: Hematopoietic stem cell transplantation
description: Haploidentical stem cell transplantation with pre-transplant immunosuppressive therapy
arm group label: Haploidentical stem cell transplantation
criteria: 
gender: All
minimum age: 1 Year
maximum age: 30 Years
healthy volunteers: No
last name: Anna B. Pawlowska, MD
role: Principal Investigator
affiliation: City of Hope Medical Center
last name: Anna B. Pawlowska, MD
phone: 626-218-8442
email: apawlowska@coh.org
facility: 
status: Recruiting
contact: 
investigator: 
country: United States
responsible party type: Sponsor
mesh term: Anemia, Sickle Cell