Alpha/Beta T and CD19+ Depleted Peripheral Stem Cells for Patients With Primary Immunodeficiencies

Phase 2

Active, not recruiting

• Conditions: Immunodeficiencies; Immune Dysregulation Syndromes

• Registration Number: NCT02990819
• Lead Sponsor: Children's Hospital of Philadelphia

Brief Summary

This is a Phase II trial to determine the ability of a reduced intensity conditioning regimen to allow successful engraftment with alpha/beta T and CD19+ depleted peripheral stem cell grafts from unrelated or partially matched related donors. There are two conditioning regimens depending upon patient diagnosis and age.

Detailed Description

This is a Phase II trial to determine the ability of a reduced intensity conditioning regimen to allow successful engraftment with alpha/beta T and CD19+ depleted peripheral stem cell grafts from unrelated or partially matched related donors. There are two conditioning regimens depending upon patient diagnosis and age.

The study will include patients 0-25 years with PID, including immune dysregulation syndromes for which hematopoietic stem cell transplant is indicated.

Treatment: Either conditioning regimen (listed below) followed by alpha/beta T and CD19+ depleted donor peripheral stem cells

1. Reduced intensity conditioning with busulfan x 8 doses, fludarabine 40 mg/m2 x 4, thiotepa 5 mg/kg x 2, anti-thymocyte globulin (ATG) 3 mg/kg x 3.

OR

2. Myeloablative regimen with busulfan x 16 doses or Daily for four days, fludarabine 30 mg/m2 x 5, thiotepa 5 mg/kg x 2, ATG 3 mg/kg x 2.

OR

3. Immunotherapy regimen on days -9, 8, 7 with anti-thymocyte globulin 3 mg/kg/day (for severe combined immunodeficiency patients only).

4. Infusion of alpha/beta T and CD19+ depleted donor peripheral stem cells.

5. Follow up, including evaluation of chimerism and immune reconstitution.

Study Timeline

• Study Start: 2016-12
• Study First Submitted: 2016-12-05
• Study First Submitted QC: 2016-12-08
• Study First Posted: 2016-12-13
• Status Verified: 2024-12
• Last Update Submitted: 2024-12-31
• Last Update Posted: 2025-01-01
• Primary Completion: 2025-10
• Study Completion: 2026-12

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 60

Inclusion Criteria

1. Ages 0-25 years at time of enrollment

2. Diseases:

   • Immunodeficiencies for which allogeneic hematopoietic stem cell transplant is indicated, including severe combined immunodeficiencies, immunodeficiency polyendocrinopathy X-linked syndrome (IPEX), X-linked lymphoproliferative disease, chronic granulomatous disease, Wiskott-Aldrich syndrome (WAS), hyperIgM, and other life-threatening immunodeficiencies.
   • Immune dysregulation syndromes, including refractory or recurrent hemophagocytic lymphohistiocytosis, hemophagocytic lymphohistiocytosis (HLH) with genetic mutations, refractory multisystemic Langerhans cell histiocytosis, other macrophage activating syndrome (MAS) refractory to standard therapy.

3. Clinical status

   • Lansky or Karnofsky performance >=60

   • Organ Function:

     1. Serum creatinine <1.5 x upper limit of normal for age Hepatic: ALT <=250; AST <=350
     2. Cardiac shortening fraction >=27%
     3. Bilirubin <2.5x normal (unless elevation due to Gilberts disease).
     4. No active untreated infection

4. Signed informed consent

5. No HLA matched related donor available.

6. Females of childbearing potential must have negative pregnancy test.

Exclusion Criteria

• Uncontrolled bacterial, viral or fungal infections
• HLA matched related or unrelated donor able to donate mobilized peripheral stem cells.
• Pregnant Females
• Matched related donor available for bone marrow donation

Donors Selection Criteria:

• Donor selection will comply with 21 CFR 1271
• Unrelated donor matched or up to one antigen mismatch as per National Marrow Donor Program (NMDP).
• Haploidentical parent or sibling able to undergo mobilization for peripheral stem cell collection. Maternal donor preferred over paternal donor if both equally haploidentical.
• Children's Hospital of Philadelphia (CHOP) Blood and Marrow Transplant (BMT) procedures apply for determining donor eligibility, including donor screening and testing for relevant communicable disease agents and diseases.
• Unrelated donor identified through the National Marrow Donor Program (NMDP) and fulfills the NMDP criteria for donation. Unrelated donor willing and able to undergo mobilization of peripheral stem cells and apheresis

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Primary Outcome Measures

Name	Time	Method
Event free survival	One year	Event free survival in greater than 20 percent donor cells at one year for patients with primary immunodeficiencies (PID) who receive unrelated or partially matched related donor peripheral stem cell grafts which have been alpha/beta T depleted and CD19 depleted
Stable engraftment	One year	Stable engraftment in greater than 20 percent donor cells at one year for patients with primary immunodeficiencies (PID) who receive unrelated or partially matched related donor peripheral stem cell grafts which have been alpha/beta T depleted and CD19 depleted

Secondary Outcome Measures

Name	Time	Method
Severity of graft vs. host disease (GVHD)	One and two years	Severity of acute and chronic graft vs host disease (GVHD), incidence of mixed chimerism, primary and secondary graft rejection, and immune reconstitution at one and two years
Incidence of graft vs. host disease (GVHD)	One and two years	Evaluation of incidence of chronic graft vs host disease (GVHD), incidence of mixed chimerism, primary and secondary graft rejection, and immune reconstitution at one and two years

Trial Locations

Locations (1)

Children's Hospital of Philadelphia; 🇺🇸 Philadelphia, Pennsylvania, United States