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Trial record 6 of 20 for:    diamond blackfan anemia | Recruiting, Not yet recruiting, Available Studies

T-Cell Depleted Alternative Donor Bone Marrow Transplant for Sickle Cell Disease (SCD) and Other Anemias

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ClinicalTrials.gov Identifier: NCT03653338
Recruitment Status : Recruiting
First Posted : August 31, 2018
Last Update Posted : May 5, 2021
Sponsor:
Information provided by (Responsible Party):
Paul Szabolcs, University of Pittsburgh

Tracking Information
First Submitted Date  ICMJE August 2, 2018
First Posted Date  ICMJE August 31, 2018
Last Update Posted Date May 5, 2021
Actual Study Start Date  ICMJE August 2, 2018
Estimated Primary Completion Date August 1, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 28, 2018)
  • Graft rejection [ Time Frame: Day -30 through study completion, an average of 2 years ]
    How frequent, if any, graft rejection occurs
  • Post Transplant treatment related mortality [ Time Frame: By day 100 ]
    Number of deaths that occurred from treatment
  • Acute Graft versus host disease [ Time Frame: Day 0 through study completion, an average of 2 years ]
    The number of patients who develop acute graft versus host disease (GVHD)post transplant
  • Chronic Graft versus host disease [ Time Frame: Day 0 through study completion, an average of 2 years ]
    The number of patients who develop chronic graft versus host disease (GVHD) post transplant
  • Post Transplant treatment related mortality [ Time Frame: Day 180 ]
    Number of deaths that occurred from treatment
  • Post Transplant treatment related mortality [ Time Frame: 1 year ]
    Number of deaths that occurred from treatment
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 28, 2018)
  • Neutrophil recovery [ Time Frame: Day 0 through study completion, an average of 2 years ]
    ≥ 0.5 x 103/μL neutrophils for three consecutive days tested on different days.
  • Donor Cell Engraftment [ Time Frame: From Day 0, Day 42, Day 100 and Day 180. Further testing can be done if clinically indicated up to 2 years post transplant ]
    ≥ 5% donor cells on day +42 and ≥ 10% donor cells on day +100. We will record if subjects have attained robust donor cell engraftment (> 50% donor chimerism at 180 days).
  • Neurological complications [ Time Frame: Day 0 through study completion, an average of 2 years ]
    To evaluate the incidence of neurological complications
  • Immune reconstitution [ Time Frame: Day 0 through study completion, an average of 2 years ]
    The pace of systemic immune reconstitution
  • Cytomegalovirus (CMV) infection [ Time Frame: Day 0 through study completion, an average of 2 years ]
    Incidence of CMV infection by Polymerase chain reaction (PCR) as clinically indicated
  • Donor Lymphocyte Infusions response [ Time Frame: Day 0 through study completion, an average of 2 years ]
    Evaluate for delayed immune reconstitution, mixed chimerism or viral reactivation
  • Response to donor-derived virus-specific cytotoxic T-cell therapy [ Time Frame: Day 0 through study completion, an average of 2 years ]
    Activation or reactivation of Cytomegalovirus (CMV), Epstein-Barr Virus (EBV) or adenovirus testing by PCR
  • Sickle Cell disease phenotype recurrence [ Time Frame: Day 0 through study completion, an average of 2 years ]
    The incidence of Sickle Cell recurrence as clinical evidence of vaso occlusive crisis, detection of HgbS>25% and acute chest syndrome.
  • Recurrence of transfusion-dependence [ Time Frame: Day 0 through study completion, an average of 2 years ]
    Chronic transfusion therapy defined as > 8 packed red blood cell transfusions per year in the year prior to enrollment and/or evidence of red blood cell alloimmunization.
  • Organ toxicity [ Time Frame: Day 0 through study completion, an average of 2 years ]
    Incidence of Grade 3-4
  • Long-term complications-Sterility, endocrinopathy, and secondary malignancy [ Time Frame: Day 0 through study completion, an average of 2 years ]
    Incidence of long term complications
  • Pediatric Quality of Life Inventory [ Time Frame: Baseline through study completion, an average of 2 years ]
    Measures Pain/Hurt ,Pain Impact,Pain Management/Control ,Worry ,Emotions ,Treatment , Communication
  • Platelet Recovery [ Time Frame: Day 0 through study completion, an average of 2 years ]
    Platelet count of ≥ 20,000/μL without platelet transfusion in the previous 7 days.
  • Adult Sickle Cell Quality of Life Measurement System (ASCQ) [ Time Frame: Baseline through study completion, an average of 2 years ]
    Patient reported outcome measurement system that assesses the physical, social and emotional impact of Sickle Cell Disease.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE T-Cell Depleted Alternative Donor Bone Marrow Transplant for Sickle Cell Disease (SCD) and Other Anemias
Official Title  ICMJE T-Cell Depleted, Alternative Donor Transplant in Pediatric and Adult Patients With Severe Sickle Cell Disease (SCD) and Other Transfusion-Dependent Anemias
Brief Summary The purpose of this study is to evaluate what effect, if any, mismatched unrelated volunteer donor and/or haploidentical related donor stem cell transplant may have on severe sickle cell disease and other transfusion dependent anemias. By using mismatched unrelated volunteer donor and/or haploidentical related donor stem cells, this study will increase the number of patients who can undergo a stem cell transplant for their specified disease. Additionally, using a T-cell depleted approach should reduce the incidence of graft-versus-host disease which would otherwise be increased in a mismatched transplant setting.
Detailed Description

CD3/CD19 depletion of mismatched donor grafts in the setting of reduced intensity, immune-ablative conditioning for patients with sickle cell disease and other transfusion-dependent anemias should sufficiently achieve engraftment while decreasing the incidence of treatment-related toxicities and achieving an acceptable incidence of graft versus host disease. Utilizing mismatched unrelated volunteer donors and haploidentical related donors will increase the number of patients able to undergo hematopoietic stem cell transplant (HSCT) for these diseases. Additionally, the institutional availability of virus-specific, donor-derived cytotoxic T lymphocytes should address complicated viral infections refractory to standard anti-viral therapy.

The purpose is to:

  • To provide alternate donor transplantation from cryopreserved stem cell grafts that are fully characterized for safety and potency to patients with severe sickle cell disease, beta-thalassemia major, or Diamond-Blackfan anemia who do not have matched sibling donor, matched unrelated donor or cord blood donor options.
  • To utilize a reduced-intensity conditioning regimen to achieve minimal treatment-related morbidity and mortality while attaining sustained donor engraftment and donor chimerism >20% in order to rescue disease phenotype, specifically in SCD patients.
  • To utilize ex-vivo T-cell depletion methods to prevent graft-versus-host disease in the setting of mismatched donor transplantation.
  • To utilize additional donor cell products to ensure sufficient immune reconstitution in the immediate post-transplant period, to improve mixed chimerism or provide non-specific anti-viral activity in patients with virus reactivation in the post-transplant period.
  • To utilize calcineurin inhibitor-free regimen in an effort to minimize/prevent central nervous system toxicity
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Sickle Cell Anemia
  • Beta-thalassemia Major
  • Diamond-blackfan Anemia
Intervention  ICMJE
  • Biological: CD3/CD19 depleted leukocytes
    Negative selection for CD3+/CD19+ cells will be performed on the CliniMACS® depletion device.
  • Biological: CD45RA depleted leukocytes
    Negative selection for CD45RA will be performed on the CliniMACS® depletion device.
  • Drug: Hydroxyurea
    Sickle Cell Disease Conditioning
    Other Name: HU, Hydrea
  • Drug: Rituximab
    Sickle Cell Disease Conditioning
    Other Name: Rituxan
  • Drug: Alemtuzumab
    Sickle Cell Disease Conditioning
    Other Name: Campath-1H
  • Drug: Fludarabine
    Sickle Cell Disease Conditioning
    Other Name: Fludara
  • Drug: Thiotepa
    Sickle Cell Disease Conditioning
Study Arms  ICMJE Experimental: Hematopoietic Stem Cell Transplantation

All patients will receive a CD3+/CD19+ depleted stem cell transplant. In this study, the investigators will use HLA mismatched unrelated or haploidentical related donor peripheral blood stem cells. Prior to transplantation, the marrow (90-95%) will be negatively selected for CD3/CD19 using the ClinicMACs® depletion device. The remaining (5-10%) will undergo CD45+RA+ depletion and be frozen for future use as an immune boost.

Subjects will undergo hematopoietic stem cell transplant utilizing CD3+/CD19+ depleted cells following conditioning therapy.

Interventions:
  • Biological: CD3/CD19 depleted leukocytes
  • Biological: CD45RA depleted leukocytes
  • Drug: Hydroxyurea
  • Drug: Rituximab
  • Drug: Alemtuzumab
  • Drug: Fludarabine
  • Drug: Thiotepa
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: August 28, 2018)
5
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE August 1, 2025
Estimated Primary Completion Date August 1, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria

  1. Patient, parent, or legal guardian must have given written informed consent and/or assent according to FDA guidelines.
  2. Ages 5 years to 40 years, at time of consent.
  3. Diagnosis of Sickle Cell Disease (Hemoglobin SS, Sβ0-thalassemia) complicated by any of the following:

    • Recurrent acute painful episodes (also known as vaso-occlusive crises; VOC) despite supportive care, minimum of 2 new pain events per year requiring hospitalization for parenteral pain management in the previous 2 years.
    • Recurrent acute chest syndrome (ACS) despite supportive care, minimum of 2 episodes in preceding 2-year period.
    • Stroke or neurologic event lasting > 24 hours with an accompanying infarct on MRI in any patient for all ages; Brain MRI with silent infarct without clinical event in patients ≤ 16 years.
    • Chronic transfusion therapy defined as > 8 packed red blood cell transfusions per year in the year prior to enrollment and/or evidence of red blood cell alloimmunization.
    • Elevated transcranial Doppler velocities - > 200 cm/s, via the non-imaging technique or > 185 cm/s by the imaging technique measured on 2 separate occasions ≥ 1-month apart
    • Elevated TRV > 2.6m/s in patients ≥ 16 years old.
    • Sickle-related renal insufficiency and/or sickle hepatopathy and/or any irreversible end-organ damage in patients ≥ 16 years old.

    OR Diagnosis of beta-thalassemia or Diamond-Blackfan anemia complicated by transfusion dependence with evidence of iron overload.

  4. A minimum donor match of 4/8 via high resolution HLA typing at HLA-A, -B, -C, -DRB1 loci in the related setting or minimum donor match of 6/8 via high resolution HLA typing at HLA-A, -B, -C, -DRB1 loci (with the DRB1 locus as a full match requirement). An unrelated donor and cord blood search must have been completed without an eligible 8/8 matched unrelated donor or 6/8 cord blood unit available. Patients who may have acceptable cord blood donor options (4/6 or better) but are limited by cell dose of a single cord will also be eligible for the proposed study.
  5. Adequate function of other organ systems as measured by:

    • Creatinine clearance or GFR ≥ 45 ml/min/1.73m.
    • Hepatic transaminases (ALT/AST) ≤ 3 x upper limit of normal.
    • Liver MR imaging for iron content should be performed in all patients with Ferritin > 500 ng/mL. If hepatic iron content > 10mg Fe/g liver should have hepatology consultation and liver biopsy to confirm absence of cirrhosis, fibrosis or hepatitis.
    • Adequate cardiac function as measure by echocardiogram (shortening fraction > 26% or ejection fraction > 40% or >80% of age-specific normal).
    • Pulmonary evaluation testing demonstrating FEV1/FVC ≥ 60% of predicted for age and/or resting pulse oximeter ≥ 92% on room air.
    • Cardiology clearance to proceed with conditioning regimen and HSCT.
    • Pulmonology clearance to proceed with conditioning regimen and HSCT.
  6. Subjects must be human immunodeficiency virus (HIV) negative by PCR.
  7. Negative pregnancy test for females ≥10 years old or who have reached menarche, unless surgically sterilized.
  8. All females of childbearing potential and sexually active males must agree to use an FDA approved method of birth control for up to 24 months after BMT or for as long as they are taking any medication that may harm a pregnancy, an unborn child or may cause a birth defect.
  9. Subject and/or parent guardian will also be counseled regarding the potential risks of infertility following BMT and advised to discuss sperm banking or oocyte harvesting (Refer to section,
  10. Hydroxyurea must have been trialed and failed in patients with sickle cell disease.

Patient Exclusion Criteria

  1. Patients with alternate, superior donor options (matched sibling donor or matched unrelated donor).
  2. Patients who have undergone stem cell transplantation in the 6 months prior to anticipated conditioning.
  3. Patients with history of a central nervous system (CNS) event within six months prior to start of conditioning (patient will be delayed until eligible).
  4. Patients who are pregnant or lactating
  5. Patients with uncontrolled bacterial, viral or fungal infection
  6. Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements or that may impact the quality or interpretation of the data obtained from the study.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 5 Years to 40 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Paul Szabolcs, MD 412-692-6225 paul.szabolcs@chp.edu
Contact: Shawna McIntyre, RN 412-692-5552 mcintyresm@upmc.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03653338
Other Study ID Numbers  ICMJE STUDY19050050
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Paul Szabolcs, University of Pittsburgh
Study Sponsor  ICMJE Paul Szabolcs
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Paul Szabolcs, MD University of Pittsburgh
PRS Account University of Pittsburgh
Verification Date May 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP