JSP191 Conditioning for Immunodeficiency

Overseen By Danielle E Pregent-Arnold, M.D.

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Investigational agents

Disqualifiers: Hematologic malignancy, Active malignancy, HIV, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 1

40 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: People with GATA2 deficiency have a mutation on the GATA2 gene. This gene affects immune function. People with this disease are prone to serious infections; in time, they may develop blood cancers. A hematopoietic stem cell (HSC) transplant can cure GATA2 deficiency, but using stem cells donated by other people can cause serious side effects. Objective: To test a new drug (Briquilimab) to see if it can make HSC transplants safer. Eligibility: People aged 6 to 70 years who have GATA2 deficiency. Design: Participants will be screened. They will have a physical exam, with blood and urine tests. They will have tests of their heart and lung function. They may have a bone marrow biopsy: Their hip will be numbed; a large needle will be inserted to draw out tissue from inside the pelvis. Participants will have a central venous catheter placed in a vein of the neck or chest. This will be used to draw blood and administer drugs. Briquilimab will be given through the catheter about 11 days before the transplant. This is part of conditioning: preparing the body to receive the new stem cells. Conditioning also includes other medications and total body irradiation. Donor stem cells will be administered through the catheter. Participants will receive other approved drugs to help prevent side effects. Participants will stay in the hospital from the beginning of the conditioning until several weeks after the transplant. They will remain in the local area for 100 days after discharge; they will come to the clinic at least once a week during this time. Follow-up visits will continue for 3 years.

Will I have to stop taking my current medications?

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

What data supports the effectiveness of the JSP191 Conditioning treatment for immunodeficiency?

Research shows that hematopoietic stem cell transplantation (HSCT) can be effective for treating severe combined immunodeficiency (SCID), with improved survival rates and immune recovery, especially when using reduced intensity conditioning (RIC) to enhance outcomes. Additionally, bone marrow transplantation has been effective in restoring T-cell immunity in patients with certain genetic immunodeficiencies. ^{1 2 3 4 5}

Research Team

Danielle E Pregent-Arnold, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

This trial is for people aged 6-70 with GATA2 deficiency, a condition affecting immune function and increasing cancer risk. Eligible participants must have certain blood cell counts, organ function within specific limits, and an available matched stem cell donor. They should be able to stay near the hospital for at least 100 days post-transplant with a caregiver.

Inclusion Criteria

I have a harmful GATA2 gene mutation.

I am between 6 and 70 years old.

Clinical manifestation(s) consistent with a diagnosis of GATA2 deficiency, including history of severe, disfiguring, and/or recurrent infections, low monocyte, B cell, and/or NK cell counts, myelodysplastic syndrome, early stage GATA2 deficiency, availability of specific HLA-matched donors, performance status criteria, left ventricular ejection fraction criteria, adequate organ function criteria, agreement to use contraception, discontinuation of breastfeeding, willingness to remain in or close to the NIH, approval for participants with HBV or HCV, ability to understand and sign informed consent document

Exclusion Criteria

Participants with a Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) score >8

Participants who have received investigational agents within 4 weeks before treatment initiation (except virus-specific T cells for viral infection/reactivation)

I do not have a history of blood cancer (except MDS), severe allergies, active cancer (except virus-driven or MDS), HIV, pregnancy, serious illness, or social issues affecting treatment compliance.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Conditioning

Participants receive JSP191 and other medications as part of the conditioning regimen, including total body irradiation

2 weeks

Inpatient stay

Transplantation

Donor stem cells are administered through the central venous catheter

1 day

Inpatient stay

Post-Transplant Monitoring

Participants remain in the hospital and local area for monitoring and receive immunosuppression for GVHD prophylaxis

100 days

Weekly clinic visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

Regular follow-up visits

Treatment Details

Interventions

• Cyclophosphamide
• Fludarabine
• JSP191
• Mycophenolate Mofetil
• Post-Transplant Cyclophosphamide
• Tacrolimus
• Total Body Irradiation

Trial Overview The study tests JSP191's ability to make hematopoietic stem cell transplants safer in GATA2 deficiency patients. It involves screening, conditioning (including JSP191 administration), transplanting donor stem cells, and taking other drugs to prevent side effects. Participants will be closely monitored for three years.

Participant Groups

Group I: Arm B Experimental Treatment 8 Interventions

Briquilimab, Fludarabine, Cyclophosphamide, Total Body Irradiation

Group II: Arm A Experimental Treatment 7 Interventions

Briquilimab, Fludarabine, Total Body Irradiation

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

Whole-exome sequencing has significantly improved the identification of genetic defects causing immunodeficiency syndromes, revealing new genes such as PGM3 and CTLA4, which expand our understanding of these conditions.

Newborn screening for T-cell deficiency is being implemented in more states, allowing for early detection and treatment of severe combined immunodeficiency, which is crucial for improving survival rates in affected infants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advances in basic and clinical immunology in 2014. Chinen, J., Notarangelo, LD., Shearer, WT.[2015]

Significant advancements in the treatment of severe combined immunodeficiencies (SCID) have led to successful cures in at least 75% of patients through bone marrow transplantation, whether from HLA identical or non-identical donors.

Emerging therapies, including enzyme substitution for adenosine deaminase (ADA) deficiency and the potential for gene therapy, offer promising alternatives for treating SCID and its various underlying causes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Severe combined immunodeficiencies. Fischer, A.[2008]

In a study of 28 ADA-deficient patients undergoing 31 HSCT procedures, the overall survival rate was 85.7%, indicating that unconditioned HSCT can be effective, especially with HLA-matched donors.

However, unconditioned procedures showed poorer myeloid engraftment and metabolic correction, leading to a higher need for additional treatments, suggesting that reduced intensity conditioning (RIC) may improve long-term outcomes and should be considered even when a matched donor is available.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Term Immune Recovery After Hematopoietic Stem Cell Transplantation for ADA Deficiency: a Single-Center Experience. Kreins, AY., Velasco, HF., Cheong, KN., et al.[2022]

In a study of 11,448 patients at risk for secondary immunodeficiency (SID), those receiving immunoglobulin replacement therapy (IgPro10) experienced significantly fewer infections compared to those who did not receive the treatment.

The IgPro10 group, which included patients with serious conditions like B-cell malignancies and solid organ transplants, showed better infection outcomes despite having more severe health issues at the start of the study, suggesting its effectiveness in preventing infections in SID.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced risk of infections with the intravenous immunoglobulin, IgPro10, in patients at risk of secondary immunodeficiency-related infections. Lahue, BJ., Mallick, R., Zhang, X., et al.[2022]

In a study of 10 SCID patients with various JAK3 mutations, bone marrow transplantation effectively restored T-cell immunity, with all but one patient showing normal T-cell function after the procedure.

However, the restoration of B-cell and NK cell functions was less successful, as only 3 patients regained antibody function and only 2 showed normal NK activity post-transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Janus kinase 3 (JAK3) deficiency: clinical, immunologic, and molecular analyses of 10 patients and outcomes of stem cell transplantation. Roberts, JL., Lengi, A., Brown, SM., et al.[2022]

References

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

Advances in basic and clinical immunology in 2014. [2015]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Severe combined immunodeficiencies. [2008]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Long-Term Immune Recovery After Hematopoietic Stem Cell Transplantation for ADA Deficiency: a Single-Center Experience. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Reduced risk of infections with the intravenous immunoglobulin, IgPro10, in patients at risk of secondary immunodeficiency-related infections. [2022]

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

Janus kinase 3 (JAK3) deficiency: clinical, immunologic, and molecular analyses of 10 patients and outcomes of stem cell transplantation. [2022]