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Haploidentical Hematopoietic Stem Cell Transplantation

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ClinicalTrials.gov Identifier: NCT02165007
Recruitment Status : Recruiting
First Posted : June 17, 2014
Last Update Posted : July 14, 2020
Sponsor:
Collaborator:
Children's National Research Institute
Information provided by (Responsible Party):
Catherine Bollard, Children's National Research Institute

Tracking Information
First Submitted Date  ICMJE June 13, 2014
First Posted Date  ICMJE June 17, 2014
Last Update Posted Date July 14, 2020
Study Start Date  ICMJE January 2015
Estimated Primary Completion Date November 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 10, 2020)
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)
Original Primary Outcome Measures  ICMJE
 (submitted: June 16, 2014)
Safety [ 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)
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 16, 2014)
Overall survival [ Time Frame: 2 years ]
Overall survival upto 2 years
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: June 16, 2014)
  • Graft failure [ Time Frame: 2 years ]
    Graft failure upto 2 years
  • Grades II-IV and III-IV acute GVHD [ Time Frame: 180 days ]
    Grades II-IV and III-IV acute GVHD at day +180
  • Chronic GVHD [ Time Frame: 1 year ]
    Chronic GVHD by 1 yea
  • Transplant-related mortality [ Time Frame: 100 days ]
    Transplant-related mortality at Day+ 100
  • 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
  • Lymphocyte reconstitution [ Time Frame: 1 year ]
    Lymphocyte reconstitution upto 1 year post transplant
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Haploidentical Hematopoietic Stem Cell Transplantation
Official Title  ICMJE HAPLOIDENTICAL HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR CHILDREN WITH SICKLE CELL DISEASE AND THALASSEMIA USING CD34+ POSITIVE SELECTED GRAFTS
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Sickle Cell-thalassemia Disease
  • Thalassemia
Intervention  ICMJE 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
Study Arms  ICMJE 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).
Intervention: Drug: peripheral blood stem cell graft that are CD34+ selected
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: July 10, 2020)
27
Original Estimated Enrollment  ICMJE
 (submitted: June 16, 2014)
15
Estimated Study Completion Date  ICMJE April 2023
Estimated Primary Completion Date November 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 22 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Allistair Abraham, MD 2024765772 AAbraham@childrensnational.org
Contact: Fahmida Hoq, MBBS, MS 2024763634 fhoq@childrensnational.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02165007
Other Study ID Numbers  ICMJE HAPSICKLE
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Catherine Bollard, Children's National Research Institute
Study Sponsor  ICMJE Catherine Bollard
Collaborators  ICMJE Children's National Research Institute
Investigators  ICMJE Not Provided
PRS Account Children's National Research Institute
Verification Date July 2020

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