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Haploidentical Hematopoietic Stem Cell Transplantation

Primary Purpose

Sickle Cell-thalassemia Disease, Thalassemia

Status
Active
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
peripheral blood stem cell graft that are CD34+ selected
Sponsored by
Catherine Bollard
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Sickle Cell-thalassemia Disease

Eligibility Criteria

undefined - 22 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Childrens National Medical Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

peripheral blood stem cell graft that are CD34+ selected

Arm Description

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).

Outcomes

Primary Outcome Measures

Incidence of transplant related adverse outcomes
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

Overall survival
Overall survival upto 2 years

Full Information

First Posted
June 13, 2014
Last Updated
September 19, 2023
Sponsor
Catherine Bollard
Collaborators
Children's National Research Institute
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1. Study Identification

Unique Protocol Identification Number
NCT02165007
Brief Title
Haploidentical Hematopoietic Stem Cell Transplantation
Official Title
HAPLOIDENTICAL HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR CHILDREN WITH SICKLE CELL DISEASE AND THALASSEMIA USING CD34+ POSITIVE SELECTED GRAFTS
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
January 2015 (undefined)
Primary Completion Date
July 2025 (Anticipated)
Study Completion Date
March 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Catherine Bollard
Collaborators
Children's National Research Institute

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Sickle Cell-thalassemia Disease, Thalassemia

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
27 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
peripheral blood stem cell graft that are CD34+ selected
Arm Type
Experimental
Arm Description
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).
Intervention Type
Drug
Intervention Name(s)
peripheral blood stem cell graft that are CD34+ selected
Other Intervention Name(s)
Reduced intensity conditioning, Sirolimus
Intervention Description
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.
Primary Outcome Measure Information:
Title
Incidence of transplant related adverse outcomes
Description
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)
Time Frame
60 days
Secondary Outcome Measure Information:
Title
Overall survival
Description
Overall survival upto 2 years
Time Frame
2 years
Other Pre-specified Outcome Measures:
Title
Graft failure
Description
Graft failure upto 2 years
Time Frame
2 years
Title
Grades II-IV and III-IV acute GVHD
Description
Grades II-IV and III-IV acute GVHD at day +180
Time Frame
180 days
Title
Chronic GVHD
Description
Chronic GVHD by 1 yea
Time Frame
1 year
Title
Transplant-related mortality
Description
Transplant-related mortality at Day+ 100
Time Frame
100 days
Title
Viral infection rates
Description
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
Time Frame
6 months
Title
Lymphocyte reconstitution
Description
Lymphocyte reconstitution upto 1 year post transplant
Time Frame
1 year

10. Eligibility

Sex
All
Maximum Age & Unit of Time
22 Years
Accepts Healthy Volunteers
No
Eligibility 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
Facility Information:
Facility Name
Childrens National Medical Center
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20010
Country
United States

12. IPD Sharing Statement

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Haploidentical Hematopoietic Stem Cell Transplantation

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