Haplocompatible Transplant for Severe Combined Immunodeficiency

Overseen By Ewelina Mamcarz, MD

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: St. Jude Children's Research Hospital

Disqualifiers: HIV, Active malignancy, Organ failure, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

4 Participants Needed

Trial Summary

What is the purpose of this trial?

Infants with severe combined immunodeficiency (SCID) have a profound decrease in number and function of immune cells, and therefore remain highly vulnerable to infection. If not corrected this often leads to death. Hematopoietic cell transplantation (HCT) from matched sibling donor is the standard treatment for these patients, unfortunately though; most SCID patients lack a sibling donor. Building upon experience and existing data, the investigators are proposing a trial the goals of which are: to provide a conditioning regimen that is well tolerated, and provision of immune cells that altogether should establish rapid immune recovery providing protection from life threatening infections without increasing the risk of dangerous Graft-Versus-Host-Disease. Primary Objectives 1. To evaluate the safety of a TCRα/β/CD19-depleted graft with CD45RA-depleted DLI in infants with SCID 2. To estimate overall survival at 1 year post transplantation Exploratory Objectives 1. To evaluate the significant donor T cell reconstitution of a TCRα/β/CD19 depleted graft with CD45RA-depleted DLI at 1 year (+/-2 weeks). 2. To evaluate engraftment at day 30, 100, month 6, and years 1 to 10 post HCT. 3. To evaluate B cell reconstitution at years 1 to 10 post HCT. 4. To evaluate biomarkers of immune reconstitution at day 30, 60 100, month 6 and years 1 to 10; e.g. immunophenotype (including epigenetic profiling) of T, B, and NK cells, and assays to determine their function. 5. To evaluate clinical outcomes, post HCT. 6. To define the incidence and severity of acute (at day 100, month 6), and chronic (month 6, 12, 24) GVHD following HCT.

Will I have to stop taking my current medications?

The trial information does not specify whether participants must stop taking their current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the treatment for Severe Combined Immunodeficiency?

Research shows that adding thiotepa to a regimen with busulfan and fludarabine improves disease-free survival and reduces relapse rates in patients with acute myeloid leukemia, without increasing toxicity. This suggests that the combination of these drugs may also be effective in other conditions requiring stem cell transplantation, like Severe Combined Immunodeficiency. ^{1 2 3 4 5}

How is the drug combination of Busulfan, Fludarabine, and Thiotepa unique for treating Severe Combined Immunodeficiency?

This drug combination is unique because it uses a mix of chemotherapy agents (Busulfan, Fludarabine, and Thiotepa) to prepare the body for a haplo-identical stem cell transplant, which is an option when a fully matched donor is not available. This approach is different from standard treatments as it allows for more donor flexibility and is tailored for patients with severe immune deficiencies. ^{2 6 7 8 9}

Research Team

Ewelina Mamcarz, MD

Principal Investigator

St. Jude Children's Research Hospital

Eligibility Criteria

This trial is for infants over 2 months old with severe combined immunodeficiency (SCID) who have a genetic mutation confirmed by DNA sequencing. They need to have a suitable sibling or unrelated donor, or a family member donor that's at least half-matched. Their heart and kidneys must function well, they should be able to breathe without assistance, and their liver enzymes should not be too high.

Inclusion Criteria

Inclusion Criteria - Transplant Recipient

My liver enzymes are within 5 times the normal limit.

My DNA test shows a specific genetic mutation.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning Regimen

Participants undergo a preparative regimen based on the type of SCID they have, including ATG, Fludarabine, Busulfan, and Thiotepa administration

9 days

Transplantation

Infusion of TCRα/β/CD19-depleted donor cells followed by CD45RA-depleted DLI

1 day

Follow-up

Participants are monitored for safety and effectiveness, including evaluation of engraftment and immune reconstitution

1 year

Treatment Details

Interventions

• Busulfan
• Donor Lymphocyte Infusion
• Fludarabine
• Thiotepa

Trial Overview The study tests a transplant method using TCRα/β depletion followed by CD45RA-depleted donor lymphocyte infusions in SCID patients lacking sibling donors. The goal is to establish rapid immune recovery with tolerable conditioning and reduce the risk of Graft-Versus-Host-Disease while monitoring survival rates after one year.

Participant Groups

Group I: Donor Lymphocyte Infusions Experimental Treatment 2 Interventions

Phase I: On the Phase I portion of the study, up to 4 different dose levels will be evaluated: Dose level -1, Dose ≥0.1 to ≤0.3; Dose level 1, Dose \>0.3 to ≤0.56; Dose level 2, Dose \>0.56 to ≤1.8; Dose level 3, Dose \>1.80 to ≤3.0 Dosing is determined based on the number of CD3+CD45RA-cells/kg and the patient weight in kilograms. Phase II: Participants will receive the Phase I determined maximum tolerated dose (MTD) of DLI. Cells for infusion are prepared using the CliniMACS System.

Group II: TCRα/β/CD19-depleted SCT Active Control 5 Interventions

A preparative regimen based on the type of SCID will be given followed by infusion of donor cells. Cells for infusion are prepared using the CliniMACS System Regimen 1 - IL2RG, JAK 3 (Haplocompatible) and all MSD ATG (rabbit) IV Days -9 -8 and -7, Rest Days -6 and -5, Busulfan IV Days -4, -3, and -2, Rest Day -1, TCRα/β/CD19-depleted SCT, Day 0 Regimen 2 - RAG1, RAG2 (Haplocompatible) ATG (rabbit) IV Days -9 -8 and -7, Fludarabine IV Days -7, -6, -5 and -4, Busulfan IV Days -5, -4 and -3, Thiotepa IV twice daily, Day -2, Rest Day -1, TCRα/β/CD19-depleted SCT, Day 0 Regimen 3 - ADA, IL7R, CD45 deficiency, CD3 subunits (Haplocompatible) ATG (rabbit) IV Days -9 -8 and -7, Fludarabine IV Days -7, -6, -5 and -4, Busulfan: IV Days -4, -3 and -2, Rest Day -1, TCRα/β/CD19-depleted SCT, Day 0

Busulfan is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Busulfex for:

• Chronic myeloid leukemia
• Acute myeloid leukemia
• Malignant lymphoma
• Bone marrow transplantation conditioning

Approved in European Union as Busulfan for:

• Chronic myeloid leukemia
• Acute myeloid leukemia
• Bone marrow transplantation conditioning

Approved in Canada as Busulfex for:

• Chronic myeloid leukemia
• Acute myeloid leukemia
• Bone marrow transplantation conditioning

Approved in Japan as Busulfan for:

• Chronic myeloid leukemia
• Acute myeloid leukemia
• Bone marrow transplantation conditioning

Who Is Running the Clinical Trial?

St. Jude Children's Research Hospital

Lead Sponsor

Trials

451

Recruited

5,326,000+

Findings from Research

In a study of 32 patients with acute myeloid leukemia in first complete remission, the busulfan/fludarabine (Bu/Flu) conditioning regimen resulted in significantly lower transplant-related toxicity compared to the busulfan/cyclophosphamide (Bu/Cy) regimen, with a lower incidence of severe side effects (68.8% vs. 25.0%).

Both regimens showed similar efficacy in terms of overall survival and event-free survival rates, indicating that Bu/Flu is a safer option without compromising treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[A comparison of toxicity and efficacy between busulfan plus fludarabine and busulfan plus cyclophosphamide for allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia]. Liu, H., Fan, ZP., Jiang, QL., et al.[2014]

In a study of 62 patients undergoing reduced-intensity conditioning for stem cell transplantation, therapeutic dose monitoring of oral busulfan did not significantly impact post-transplant outcomes compared to standard dosing.

The presence of chronic graft-versus-host disease was identified as a strong predictor of overall survival and leukemia-free survival, highlighting its importance in patient outcomes after transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced-intensity conditioning allogeneic blood stem cell transplantation with fludarabine and oral busulfan with or without pharmacokinetically targeted busulfan dosing in patients with myeloid leukemia ineligible for conventional conditioning. Martino, R., Pérez-Simón, JA., Moreno, E., et al.[2013]

The new conditioning regimen using thiotepa and fludarabine (TT-FLUDA) was well tolerated in six patients undergoing allogeneic bone marrow transplantation, with successful engraftment and stable donor chimerism in most cases.

Despite the patients being poor candidates for standard treatments, the TT-FLUDA regimen showed no major toxicity, although one patient died from acute graft-versus-host disease (GVHD), indicating a need for careful monitoring of GVHD prophylaxis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Thiotepa and fludarabine (TT-FLUDA) as conditioning regimen in poor candidates for conventional allogeneic hemopoietic stem cell transplant. Alessandrino, EP., Bernasconi, P., Colombo, AA., et al.[2019]

In a study involving three children with refractory severe aplastic anemia (SAA), a radiotherapy-free conditioning regimen using fludarabine and other agents was effective in preparing them for hemopoietic cell transplantation (HCT) without the development of graft-versus-host disease (GVHD).

All patients achieved normal blood counts and complete donor chimerism after the transplant, demonstrating that fludarabine-based conditioning can be a safe and effective option for children undergoing HCT from alternative donors, even after previous transplant failures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Non-radiotherapy conditioning with stem cell transplantation from alternative donors in children with refractory severe aplastic anemia. Urban, C., Benesch, M., Sykora, KW., et al.[2013]

In a study of 30 patients undergoing matched sibling or alternative donor transplantation with a conditioning regimen of fludarabine, thiotepa, and total body irradiation, most patients achieved prompt engraftment, but there were significant complications, including regimen-related toxicity leading to 18 deaths.

The 12-month progression-free survival rates were 47% for HLA-identical sibling transplants and 30% for all patients, but due to high rates of complications and relapses, the researchers decided to discontinue this conditioning regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and outcome after fludarabine-thiotepa-TBI conditioning for allogeneic transplantation: a prospective study of 30 patients with hematologic malignancies. van Besien, K., Devine, S., Wickrema, A., et al.[2013]

In a study of 95 patients undergoing allogeneic stem cell transplantation, replacing cyclophosphamide with fludarabine in the conditioning regimen (busulfan+fludarabine) led to faster engraftment and significantly lower rates of acute and chronic graft-versus-host disease (GVHD).

The fludarabine regimen also resulted in better event-free survival and overall survival rates compared to the standard busulfan and cyclophosphamide regimen, indicating it may be a more effective option for myeloablative conditioning in allogeneic SCT.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New myeloablative conditioning regimen with fludarabine and busulfan for allogeneic stem cell transplantation: comparison with BuCy2. Chae, YS., Sohn, SK., Kim, JG., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Augmented myeloablative conditioning with thiotepa in acute myeloid leukemia - improved outcomes with similar toxicity. [2020]

2. China pubmed.ncbi.nlm.nih.gov

[A comparison of toxicity and efficacy between busulfan plus fludarabine and busulfan plus cyclophosphamide for allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia]. [2014]

3. United States pubmed.ncbi.nlm.nih.gov

Reduced-intensity conditioning allogeneic blood stem cell transplantation with fludarabine and oral busulfan with or without pharmacokinetically targeted busulfan dosing in patients with myeloid leukemia ineligible for conventional conditioning. [2013]

4. Germany pubmed.ncbi.nlm.nih.gov

Thiotepa and fludarabine (TT-FLUDA) as conditioning regimen in poor candidates for conventional allogeneic hemopoietic stem cell transplant. [2019]

5. England pubmed.ncbi.nlm.nih.gov

Non-radiotherapy conditioning with stem cell transplantation from alternative donors in children with refractory severe aplastic anemia. [2013]

6. England pubmed.ncbi.nlm.nih.gov

Safety and outcome after fludarabine-thiotepa-TBI conditioning for allogeneic transplantation: a prospective study of 30 patients with hematologic malignancies. [2013]

7. England pubmed.ncbi.nlm.nih.gov

New myeloablative conditioning regimen with fludarabine and busulfan for allogeneic stem cell transplantation: comparison with BuCy2. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Busulfan Plus Fludarabine Compared With Busulfan Plus Cyclophosphamide for AML Undergoing HLA-Haploidentical Hematopoietic Cell Transplantation: A Multicenter Randomized Phase III Trial. [2023]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Case Series Using Salvage Haplo-Identical Stem Cells for Secondary Transplantation. [2023]