TCR Alpha Beta T-cell Depleted Haploidentical HCT in the Treatment of Primary Immunodeficiency and Inherited Metabolic Disorders in Children

• ClinicalTrials.gov Identifier: NCT04414046
• Recruitment Status: Recruiting
• First Posted: June 4, 2020
• Last Update Posted: September 15, 2022
• Sponsor: Johns Hopkins All Children's Hospital
• Information provided by (Responsible Party): Johns Hopkins All Children's Hospital

Tracking Information

• First Submitted Date: May 24, 2020
• First Posted Date: June 4, 2020
• Last Update Posted Date: September 15, 2022
• Actual Study Start Date: July 22, 2020
• Estimated Primary Completion Date: June 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 29, 2020)

Incidence of successful donor engraftment [ Time Frame: Day 100 after transplantation ]

The incidence of engraftment at day 100 will be described based on donor chimerism in the whole blood and or fractions sorted for T-cell and myeloid subsets. The donor chimerism will be scored as autologous reconstitution (< 5% donor), mixed chimerism (5-49%=low mixed, 50-95%=high mixed), > 95%=full donor chimerism.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: May 29, 2020)

• Overall survival and Event-free survival [ Time Frame: Up to 2 years post transplant ]
  Overall survival is defined as the time of enrollment to death from any cause or last follow up. Event-free survival is defined as the time of enrollment to death, primary or secondary graft failure, graft failure necessitating a second HCT procedure, DLI or stem cell boost given for treatment of falling chimerism, or disease recurrence
• Kinetics of neutrophil engraftment [ Time Frame: Up to 42 days post transplant ]
  Neutrophil engraftment defined as absolute neutrophil count ≥500/μL for 3 consecutive measurements on different days
• Kinetics of platelet engraftment [ Time Frame: Up to 42 days post transplant ]
  Platelet engraftment defined as sustained platelet count >20,000/μL and >50,000//μL with no platelet transfusions in the preceding seven days.
• Transplant-related mortality [ Time Frame: Up to 100 days post transplant ]
  Rate of transplant-related mortality
• Acute grade II-IV GvHD [ Time Frame: Up to 2 years post transplant ]
  Incidence and severity of acute graft versus host disease
• Chronic GvHD [ Time Frame: Up to 2 years post transplant ]
  Incidence and severity of chronic graft versus host disease
• Primary graft failure [ Time Frame: Up to 2 years post transplant ]
  Rates of primary graft failure
• Secondary graft failure [ Time Frame: Up to 2 years post transplant ]
  Rates of secondary graft failure
• Transplant-related complications [ Time Frame: Up to 2 years post transplant ]
  Frequency of transplant-related complications following transplantation
• Transplant-related infections [ Time Frame: Up to 2 years post transplant ]
  Frequency of transplant-related infections following transplantation
• Cellular and Immunological reconstitution by laboratory evaluations [ Time Frame: Up to 2 years post transplant ]
  The recovery of different lymphocyte subpopulation (CD3+; CD4+; CD8+; CD3+CD45RA+and CD45RO; TCR alpha beta; TCR gamma delta; CD19+)

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: TCR Alpha Beta T-cell Depleted Haploidentical HCT in the Treatment of Primary Immunodeficiency and Inherited Metabolic Disorders in Children
• Official Title: Study of TCR Alpha Beta T-Cell and CD19 B-Cell Depletion for Hematopoietic Cell Transplantation From Haploidentical Donors in the Treatment of Primary Immunodeficiency and Inherited Metabolic Disorders in Children
• Brief Summary: This research is being done to learn if a new type of haploidentical transplantation using TCR alpha beta and CD19 depleted stem cell graft from the donor is safe and effective to treat the patient's underlying condition. This study will use stem cells obtained via peripheral blood or bone marrow from parent or other half-matched family member donor. These will be processed through a special device called CliniMACS, which is considered investigational.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Primary Immune Deficiency Disorders
• Metabolic Disease

Intervention

Biological: Haploidentical Hematopoietic Cell Transplantation

TCR alpha beta T-cell and CD19 B-cell depleted haploidentical transplantation

Study Arms

Experimental: TCR alpha beta T cell depletion

The leukapheresis product will undergo TCR alpha beta negative selection following a standardized protocol

Intervention: Biological: Haploidentical Hematopoietic Cell Transplantation

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: May 29, 2020): 17
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: June 2024
• Estimated Primary Completion Date: June 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Patient with any form of primary immune deficiency/dysregulatory disorders characterized by aberrant immune function, abnormal hematopoiesis, systemic or organ specific autoimmunity and/or non-malignant lymphoproliferation. This includes, but not limited to:

   I. Disorders of phagocytes: Chronic granulomatous disease, Leukocyte adhesion deficiency, defects of IL-10 pathway, MonoMac syndrome

   II. Defects of cellular and humoral immunity: Severe Combined Immunodeficiency Disorder (infants with classic SCID up to 2 years of age will be excluded due to other open protocol), X-linked hyper-IgM syndrome, DOCK8 deficiency, ZAP70 deficiency, common variable immunodeficiency (CVID), Wiskott-Aldrich syndrome, NEMO deficiency.

   III. Disorder of immune dysregulation: Immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome, CTLA4 deficiency, LRBA deficiency, STAT1 GOF, STAT3 GOF, X-linked lymphoproliferative disease etc.

   IV. Other PIDs and immune dysregulatory disorders who can be benefitted by HCT as deemed appropriate by the PI and the treating immunologist.

2. Histiocytic disorders including hemophagocytic lymphohistiocytosis (familial HLH (types 1-5), secondary HLH (refractory to therapy or with recurrent episodes of hyper inflammation) and multisystem refractory Langerhans cell histiocytosis.
3. Metabolic disorders that could improve or stabilize after stem cell transplantation such as mucopolysaccharidoses, neurodegenerative disorders, osteopetrosis, etc.

Inclusion Criteria:

1. Patient has a suitable genotypic identical match of 5/10. The donor and recipient must be identical, as determined by high resolution typing, at least one allele of each of the following genetic loci: HLA-A, HLA-B, HLA-C, HLA-DRB1 and HLA-DQB1.

2. Patients must have adequate organ function measured by:

   1. Cardiac: asymptomatic or if symptomatic then LVEF at rest must be ≥ 40% or SF ≥ 26%
   2. Pulmonary: asymptomatic or if symptomatic DLCO ≥ 40% of predicted (corrected for hemoglobin) or pulse oximetry ≥ 92% on room air if the patient is unable to perform pulmonary function testing.
   3. Renal: Creatinine clearance (CrCl) or glomerular filtration rate (GFR) must be > 50 mL/min/1.73 m2.
   4. Hepatic: Serum conjugated (direct) bilirubin < 2.0 x ULN for age; AST and ALT < 5.0 x ULN for age.
   5. Karnofsky or Lansky (age-dependent) performance score ≥ 50
3. Signed written informed consent

Exclusion Criteria:

1. Participants who have an HLA-matched sibling who is able and willing to donate bone marrow. Patients with a HLA-matched unrelated donors are not excluded.
2. Pregnant or breastfeeding females.
3. Patient has HIV or uncontrolled fungal, bacterial or viral infections.
4. Patient has received prior solid organ transplant.
5. Patient has active GVHD (> grade II) or chronic extensive GVHD due to a previous allograft at the time of inclusion.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: up to 21 Years (Child, Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Jade Hanson, MSN; 7277676468; jade.hanson@jhmi.edu

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04414046
• Other Study ID Numbers: HAP-PID
• 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

• Plan to Share IPD: No

• Current Responsible Party: Johns Hopkins All Children's Hospital
• Original Responsible Party: Deepak Chellapandian, MD MBBS, Johns Hopkins All Children's Hospital, Sponsor-investigator
• Current Study Sponsor: Johns Hopkins All Children's Hospital
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Deepak Chellapandian, MD; Johns Hopkins All Children's Hospital

• PRS Account: Johns Hopkins All Children's Hospital
• Verification Date: September 2022