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Haploidentical Hematopoietic Stem Cell Transplantation

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02165007
Recruitment Status : Active, not recruiting
First Posted : June 17, 2014
Last Update Posted : August 31, 2022
Sponsor:
Collaborator:
Children's National Research Institute
Information provided by (Responsible Party):
Catherine Bollard, Children's National Research Institute

Study Description
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Brief Summary:
The study is designed as a Pilot/Phase 1 trial of reduced intensity Haploidentical HSCT in patients with sickle cell disease and thalassemia. The purpose of the study is to assess the safety and toxicity of reduced intensity conditioning haploidentical hematopoietic stem cell transplantation.

Condition or disease Intervention/treatment Phase
Sickle Cell-thalassemia Disease Thalassemia Drug: peripheral blood stem cell graft that are CD34+ selected Phase 1

Detailed Description:

Research subjects will undergo reduced intensity conditioning (Hydroxyurea, ATG, Fludarabine, Thiotepa, Melphalan) followed by infusion of a peripheral blood stem cell graft collected from haploidentical family donors that are CD34+ positively selected using the CliniMACS device. Sirolimus will be used for GVHD prophylaxis and given for 9 months post-transplant and then tapered off by one year

The use of the CliniMACS device for CD34 selection will be performed at CNMC through cross-reference of the master file for CliniMACS CD34+ Reagent by Milteyni Biotech (BB-MF 8061).

CliniMACs is an electromechanical device intended to isolate certain cell subsets from mixed cell populations. When used in combination with the CliniMACs CD34 reagent, it is possible to prepare extremely pure populations of CD34+ cells with upwards of 5 logs depletion of contaminating T cells within a closed and sterile system.

We intend to use this system to select cells from HLA haploidentical related donors who have been mobilized with G-CSF prior to stem cell collection. Since previous investigations of this strategy in adult patients have not translated into enhanced long term survival, we intend to limit this protocol to patients under the age of 22 as they have more rapid immune reconstitution.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 27 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: HAPLOIDENTICAL HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR CHILDREN WITH SICKLE CELL DISEASE AND THALASSEMIA USING CD34+ POSITIVE SELECTED GRAFTS
Study Start Date : January 2015
Estimated Primary Completion Date : July 2023
Estimated Study Completion Date : November 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Thalassemia
Drug Information available for: Sirolimus

Arms and Interventions
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Arm Intervention/treatment
Experimental: peripheral blood stem cell graft that are CD34+ selected
peripheral blood stem cell graft that are CD34+ selected. All patients will undergo reduced intensity conditioning regimen which followed by infusion of a peripheral blood stem cell graft collected from haploidentical family donors that are CD34+ positively selected using the CliniMACS device and Sirolimus will be used for GVHD prophylaxis and given for 9 months post-transplant and then tapered off by one year (see intervention).
 Drug: peripheral blood stem cell graft that are CD34+ selected
The preparatory regimen will consist of Hydroxyurea from Days -50 to -22, Alemtuzumab from days -21 to -19 (test dose Alemtuzumab on day -22), Fludarabine days -8 to -4, Thiotepa Day -4, Melphalan day -3 to -2 (Table 4a). In patients with intolerance to or have received alemtuzumab in the prior 6 months, alemtuzumab will be replaced with rabbit ATG on days -10 through -7, followed by infusion of a peripheral blood stem cell graft collected from haploidentical family donors that are CD34+ positively selected using the CliniMACS device. Sirolimus will be used for GVHD prophylaxis and given for 9 months post-transplant and then tapered off by one year.
Other Names:
  • Reduced intensity conditioning
  • Sirolimus


Outcome Measures
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Primary Outcome Measures :
  1. Incidence of transplant related adverse outcomes [ Time Frame: 60 days ]

    The primary endpoint of this trial is safety. Transplant related adverse outcomes and non-hematological toxicity will be measured through Day +60 on this objective to include:

    • Non-hematological severe (Grade IV and V) organ specific toxicity according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0)
    • Rates of non-engraftment
    • Severe acute (Grade III-IV)
    • Veno-occlusive disease of the liver
    • Idiopathic pneumonia syndrome
    • Seizures/Posterior reversible encephalopathy syndrome (PRES)


Secondary Outcome Measures :
  1. Overall survival [ Time Frame: 2 years ]
    Overall survival upto 2 years


Other Outcome Measures:
  1. Graft failure [ Time Frame: 2 years ]
    Graft failure upto 2 years

  2. Grades II-IV and III-IV acute GVHD [ Time Frame: 180 days ]
    Grades II-IV and III-IV acute GVHD at day +180

  3. Chronic GVHD [ Time Frame: 1 year ]
    Chronic GVHD by 1 yea

  4. Transplant-related mortality [ Time Frame: 100 days ]
    Transplant-related mortality at Day+ 100

  5. Viral infection rates [ Time Frame: 6 months ]
    Viral infection rates at 6 months: Reactivation of CMV, Adenovirus and EBV detected on peripheral blood monitoring or any visceral disease with documented molecular studies for these viruses within the first six months post transplantation will be recorded

  6. Lymphocyte reconstitution [ Time Frame: 1 year ]
    Lymphocyte reconstitution upto 1 year post transplant


Eligibility Criteria
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Ages Eligible for Study:   up to 22 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • First allogeneic transplant
  • Age up to 22 years
  • Patients with severe sickle cell disease (stroke, elevated TCD velocities, >2 acute chest syndrome, ongoing chronic red cell transfusion > 6 months)
  • Patients with transfusion dependent thalassemia and evidence of iron overload
  • Patients must have a related donor that is HLA-matched at >/=4 of 8 but <8/8 HLA-A, -B, -C and -DRB1
  • Cardiac function: Shortening fraction >25%; ejection fraction >40%
  • Estimated creatinine clearance greater than 50 mL/minute
  • Pulmonary function: DLCO ≥40% (adjusted for hemoglobin) and FEV1≥50% in patients 7 years and older with normal cognitive function and able to perform the test adequately. If not able to complete the testing a CT chest will be required., oxygen saturation>91%
  • Liver function: direct (conjugated) bilirubin < 2x the upper limit of normal and ALT/AST < 2.5x the upper normal limit.
  • Signed informed consent.

Exclusion Criteria:

  • Life expectancy less than 6 months
  • Patients with uncontrolled bacterial, viral or fungal infections (undergoing appropriate treatment and with progression of clinical symptoms) within 1 month prior to conditioning. Patients with febrile illness or suspected minor infection should await clinical resolution prior to starting conditioning.
  • Pregnant or breastfeeding patients
  • Patients seropositive for the human immunodeficiency virus (HIV)
  • Patient with active Hepatitis B or C determined by serology and/or NAAT
  • Active hepatitis, bridging fibrosis or cirrhosis on liver biopsy (biopsy required for patients on chronic transfusion therapy for > 1 year and evidence of iron overload with ferritin >1000 ng/mL)
  • Patients with suitable 8/8 HLA matched related and unrelated donors
  • Patients who have an intolerance to or have received alemtuzumab in the prior 6 months will be excluded from enrollment unless alemtuzumab is replaced with rabbit ATG in the conditioning regimen
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02165007


Locations
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United States, District of Columbia
Childrens National Medical Center
Washington, District of Columbia, United States, 20010
Sponsors and Collaborators
Catherine Bollard
Children's National Research Institute
More Information
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Responsible Party: Catherine Bollard, Director- Center for Cancer and Immunology Research, Children's National Research Institute
ClinicalTrials.gov Identifier: NCT02165007    
Other Study ID Numbers: HAPSICKLE
First Posted: June 17, 2014    Key Record Dates
Last Update Posted: August 31, 2022
Last Verified: August 2022
Additional relevant MeSH terms:
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Thalassemia
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hematologic Diseases
Hemoglobinopathies
Genetic Diseases, Inborn
Sirolimus
 Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antineoplastic Agents
Antifungal Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs