Haploidentical Hematopoietic Stem Cell Transplantation

• ClinicalTrials.gov Identifier: NCT02165007
• Recruitment Status: Active, not recruiting
• First Posted: June 17, 2014
• Last Update Posted: August 31, 2022
• Sponsor: Catherine Bollard
• Collaborator: Children's National Research Institute
• Information provided by (Responsible Party): Catherine Bollard, Children's National Research Institute

Tracking Information

• First Submitted Date: June 13, 2014
• First Posted Date: June 17, 2014
• Last Update Posted Date: August 31, 2022
• Study Start Date: January 2015
• Estimated Primary Completion Date: July 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (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 (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)

Current Secondary Outcome Measures (submitted: June 16, 2014)

Overall survival [ Time Frame: 2 years ]

Overall survival upto 2 years

• Original Secondary Outcome Measures: 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: 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
• 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: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Sickle Cell-thalassemia Disease
• Thalassemia

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

Study Arms

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

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: July 10, 2020): 27
• Original Estimated Enrollment (submitted: June 16, 2014): 15
• Estimated Study Completion Date: November 2023
• Estimated Primary Completion Date: July 2023 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: up to 22 Years (Child, Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02165007
• Other Study ID Numbers: HAPSICKLE
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Catherine Bollard, Children's National Research Institute
• Original Responsible Party: Catherine Bollard, Children's National Research Institute, Director- CETI Lab
• Current Study Sponsor: Catherine Bollard
• Original Study Sponsor: Same as current
• Collaborators: Children's National Research Institute
• Investigators: Not Provided
• PRS Account: Children's National Research Institute
• Verification Date: August 2022