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NCT Number: NCT05907746

Allogeneic Hematopoietic Stem Cell Transplantation With Briquilimab-Based Conditioning in Participants With GATA2 Deficiency

Background:

People with GATA-binding factor 2 (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....

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Key information

Conditions

GATA2 Immune System Diseases Immunodeficiency Immunologic Deficiency Syndromes

Age range

6 year–70 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

About this study

Background:

  • GATA-binding factor 2 (GATA2) deficiency, an immunodeficiency and bone marrow failure disorder due to inherited or sporadic mutations in or loss of one allele of the GATA2 gene, is characterized by: 1) nontuberculous mycobacteria (NTM) and other opportunistic infections, 2) deficiency of monocytes, B lymphocytes, and Natural Killer (NK) cells in the peripheral blood, and 3) progression to myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML), and acute myelogenous leukemia (AML).
  • Allogeneic hematopoietic cell transplantation (HCT) appears to be curative, and interim results from protocol #13-C-0132, NCT01861106, demonstrated a 2-year event-free survival rate of 83% for 59 participants with GATA2 deficiency who underwent HCT with a busulfan-based conditioning regimen.
  • However, traditional HCT approaches using alkylating agents such as busulfan continue to place recipients at risk for potentially life-threatening, transplant-related toxicities as well as late effects such as infertility and secondary malignancy.
  • Briquilimab is a humanized, glycosylated immunoglobulin G1 (IgG1) monoclonal antibody that targets CD117 (human c-Kit) present on endogenous hematopoietic stem cells (HSC). Briquilimab has been shown in pre-clinical and early clinical studies to safely deplete human and non-human primate HSC with minimal toxicity.

Primary Objective:

-To determine whether allogeneic hematopoietic cell transplantation with Briquilimab-based conditioning results in sustained donor engraftment by 100 days post-transplant in participants with GATA2 deficiency

Eligibility:

  • Recipients aged 6-70 years old with pathogenic germline mutations in GATA2 and clinical manifestations consistent with a diagnosis of GATA2 deficiency
  • Have an 8/8 Human leukocyte antigen (HLA)-matched related or unrelated donor or a 7/8 HLA-matched unrelated donor or haploidentical related donor
  • Have "early stage" GATA2 deficiency defined as a hypocellular for age bone marrow with less than 5% blasts and normal or favorable cytogenetics (defined as "good" or "very good" cytogenetics risk groups plus trisomy 8)

Design:

  • All participants with GATA2 deficiency will receive a pre-transplant conditioning regimen consisting of Briquilimab administered as a single intravenous (IV) infusion on day -11 (range day -13 to -10) with pharmacokinetics, followed by fludarabine or fludarabine/cyclophosphamide IV infusions (3 or 5 days depending on the donor) and 200 cGy total body irradiation (TBI) on day -1. HCT will be infused on day 0.
  • Participants with an 8/8 human leukocyte antigen (HLA)-matched related or unrelated donor assigned to Arm A will receive a fludarabine for three days on days -4, -3, and -2.
  • Participants with a 7/8 HLA-matched unrelated donor or a haploidentical related donor assigned to Arm B will receive a fludarabine for five days on days -6, -5, -4, -3, and -2, cyclophosphamide for 2 days on days -6 and -5
  • Post-transplant immunosuppression for Graft Versus Host Disease (GVHD) prophylaxis for recipients of Arms A and B will consist of cyclophosphamide for 2 days on days +3 and +4, along with mycophenolate mofetil from day +5 to approximately day +35 and tacrolimus from day +5 to approximately day +180. If there is no evidence of GVHD, tacrolimus will be stopped or tapered at approximately day +180

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

  • INCLUSION CRITERIA:
  • Age >= 6 and <= 70 years old
  • Germline mutation in the GATA binding protein 2 (GATA2) gene, predicted to be deleterious or previously reported in GATA2 deficiency as determined by targeted GATA2 sequencing performed at the National Institutes of Health (NIH)
  • Clinical manifestation(s) consistent with a diagnosis of GATA2 deficiency, including any of the following (Note: only one clinical manifestation is required):
  • History of severe, disfiguring, and/or recurrent infections
  • Low monocyte (< 190 cells/microL), B cell (< 61 cells/microL) and/or Natural Killer (NK) cell (< 126 cells/microL) counts
  • Myelodysplastic syndrome by World Health Organization (WHO) criteria
  • "Early stage" GATA2 deficiency defined as a hypocellular for age bone marrow with less than 5% blasts and normal cytogenetics or favorable cytogenetics (defined as "good" or "very good" cytogenetics risk groups plus trisomy 8)
  • Availability of an 8/8 HLA-matched related or unrelated donor, a 7/8 HLA-matched unrelated donor or a haploidentical related donor
  • Lansky (for participants < 16 years of age) or Karnofsky (for participants >=16 years of age) performance status of >= 40%
  • Left ventricular ejection fraction > 40%, preferably by 2-D echocardiogram (echo) obtained within 90 days prior to treatment initiation
  • Participants must have adequate organ function as defined below:
  • Total bilirubin <=2.5 x upper limit of normal (ULN)
  • Alanine transaminase (ALT) and aspartate aminotransferase (AST) <= 5 x ULN
  • Creatinine:

Adult participants: <=2.0 mg/dl and creatinine clearance >= 30 ml/min.

Pediatric participants (<18 years old): creatinine <1.5 mg/dL and a creatinine clearance using the Schwartz Formula > 30 mL/min/1.73m^2

  • Pulmonary function tests (PFT)s: Forced expiratory volume in 1 second (FEV1) and adjusted diffusing capacity of the lungs for carbon monoxide (DLCO) >30%. Children who are unable to cooperate for pulmonary function tests (PFTs) due to age are still eligible if no evidence of dyspnea at rest and no need for supplemental oxygen
  • Women of childbearing potential (WOCBP) and men must agree to use highly effective contraception (hormonal, intrauterine device (IUD), abstinence, tubal ligation, partner has had the previous vasectomy) at the study entry, for the duration of study treatment, and for at least one-year post-allogeneic HCT or 12 months after completion of chemotherapy preparative administration if HCT is not performed for women and for 4 months for the same for men.
  • Breastfeeding participants must be willing to discontinue breastfeeding
  • Willingness to remain in the NIH hospital or, if discharged, stay close to the NIH (60 minutes' drive), for a minimum of 100 days after transplant or longer if there are complications. The participants must commit to having an adult caregiver with them during the first 100 days after transplant in case of discharging from the hospital before 100 days verified by social worker
  • Participants with hepatitis B virus (HBV) or hepatitis C virus (HCV) antibody-positive testing are allowed if HBV DNA <100 IU/m or HCV RNA level is undetectable. Additionally, transplantation must be approved by a hepatology consult for these participants
  • Participants or parents/guardians must be able to understand and willing to sign a written informed consent document

Exclusion criteria

  • Participants with a Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) score >8
  • Participants who have received any investigational agents within 4 weeks before treatment initiation with the exception of virus-specific T cells for the treatment of viral infection/reactivation prior to allogeneic HCT
  • Participants with a history of hematologic malignancy (e.g., Acute Myeloid Leukemia (AML), Chronic Myelomonocytic Leukemia (CMML). Note: participants with Myelodysplastic Syndromes (MDS) are included
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to agents (fludarabine, cyclophosphamide, tacrolimus, mycophenolate mofetil, granulocyte-colony stimulating factor (G-CSF)) used in the study
  • Presence of active malignancy. Note: participants with malignancy driven by viruses (e.g., human papillomavirus (HPV) or HPV or Epstein-Barr virus (EBV)) are allowed as the immune reconstitution after transplant may control the malignancy and participants with MDS are allowed
  • Human immunodeficiency virus (HIV)-infected participants
  • Pregnancy (confirmed with Beta-Human Chorionic Gonadotropin (HCG) serum or urine pregnancy test performed in WOCBP at screening)
  • Uncontrolled intercurrent illness or social situations (as determined by social work consult) that would limit compliance with study requirements

Treatment and study plan

Mycophenolate mofetil

Drug

15 mg/kg intravenous (IV) three times per day starting on day +5 until approximately day +30 (+/- 2 days)

Other names: CellCept, Myhibbin

Tacrolimus

Drug

0.02 mg/kg intravenous (IV) daily starting on day +5

Other names: Prograf

Post-transplant Cyclophosphamide

Drug

50 mg/kg intravenous (IV) daily on days +3 and +4

Other names: Post-Transplant Cytoxan, Post-Transplant Neosar

Total Body Irradiation

Radiation

200 centigray (cGy) on day -1

Other names: TBI

Hematopoietic Cell Transplant

Procedure

Stem cell transplant on day 0

Other names: HCT

Briquilimab

Drug

Single 0.6 mg/kg intravenous (IV) infusion administered between days -13 and day -10

Other names: JSP191

Cyclophosphamide

Drug

14.5 mg/kg intravenous (IV) daily on days -6 and -5; for 7/8 Unrelated or Haploidentical Donor, prior to transplant.

Other names: Cytoxan, Neosar

Fludarabine

Drug

30 mg/m^2 intravenous (IV) over 30 minutes daily. For 8/8 Matched Related or Unrelated Donor, fludarabine dose will be on days -4, -3, and -2. For 7/8 Unrelated or Haploidentical Donor, fludarabine dose will be on days -6, -5, -4, -3, and -2.

Other names: Fludara

Bone Marrow Biopsy

Procedure

Screening ≤90 days.

Other names: BM Bx

Bone Marrow Aspirate

Procedure

Screening ≤90 days.

Other names: BM aspirate

2D ECHO

Diagnostic Test

Screening ≤90 days.

Other names: Two-dimensional echocardiogram

EKG

Diagnostic Test

Screening ≤90 days.

Other names: Electrocardiogram

PFT's

Procedure

Screening ≤90 days.

Other names: Pulmonary function tests

CT scan of chest, abdomen and pelvis

Diagnostic Test

Baseline ≤28 days.

Other names: Computed tomography of chest, abdomen and pelvis

Primary outcomes

  1. Percentage of Evaluable Participants With GATA-binding Factor 2 (GATA2) Deficiency With Sustained Donor Engraftment by 100 Days Post-transplant Reported Along With a Two-sided 90% Confidence Interval

    Time frame: 100 days

    To determine whether allogeneic hematopoietic cell transplantation with Briquilimab-based conditioning results in sustained donor engraftment by 100 days post-transplant, the percentage of evaluable participants with GATA2 deficiency will be reported along with a two-sided 90% confidence interval. Sustained donor engraftment is defined as neutrophil recovery with ANC ≥ 500/mm^3 for 3 consecutive days associated with >90% myeloid and >10% cluster of differentiation 3 (CD3+) T cell donor chimerism by 100 days post-transplant.

  2. Percentage of Evaluable Participants With GATA-binding Factor 2 (GATA2) Deficiency With Sustained Donor Engraftment by 100 Days Post-transplant Reported Along With a Two-sided 95% Confidence Interval

    Time frame: 100 days

    To determine whether allogeneic hematopoietic cell transplantation with Briquilimab-based conditioning results in sustained donor engraftment by 100 days post-transplant, the percentage of evaluable participants with GATA2 deficiency will be reported along with a two-sided 95% confidence interval. Sustained donor engraftment is defined as neutrophil recovery with ANC ≥ 500/mm^3 for 3 consecutive days associated with >90% myeloid and >10% cluster of differentiation 3 (CD3+) T cell donor chimerism by 100 days post-transplant and restoration of normal hematopoiesis by one-year post-transplant.

Secondary outcomes

  1. Percentage of Evaluated Participants With GATA-binding Factor 2 (GATA2) Deficiency Who Received Allogeneic Hematopoietic Cell Transplantation With Briquilimab-based Conditioning That Results in Restoration of Normal Hematopoiesis by 1-year Post-transplant

    Time frame: 1-year

    To determine whether allogeneic hematopoietic cell transplantation with Briquilimab-based conditioning results in restoration of normal hematopoiesis by one-year post-transplant in participants with GATA2 deficiency the percentage of evaluated participants will be reported along with a 95% two-sided confidence interval. Restoration of normal hematopoiesis is defined as normalization of peripheral blood counts hemoglobin (Hb) >8 g/dL, platelet count > 100,000/µ/L and absolute neutrophil count (ANC)>1,500/µ/L).

  2. Number of Participants With GATA2 Deficiency Conditioned With Briquilimab With Transplant-related Toxicity Reported by Type and Grade of Adverse Event by Arm

    Time frame: 3 years

    By Arm, the participants with transplant-related toxicity will be reported by type and grade of event. Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. Grade 1 is mild. Grade 2 is moderate. Grade 3 is serious. Grade 4 is life-threatening. Grade 5 is death related to adverse event.

  3. 3-year Overall Survival (OS)

    Time frame: 3 years

    OS is defined as time from treatment start date until death from any cause, last follow up or date last known alive. OS was determined by using the Kaplan-Meier method and is reported along with the median value and the 95% confidence interval.

  4. 3-year Event-free Survival (EFS)

    Time frame: 3 years

    EFS is defined as death, receipt of a second transplant, or graft failure. EFS was determined using the Kaplan-Meier method and is reported along with the median value and the 95% confidence interval. Primary graft failure is defined as the lack of donor-derived neutrophil engraftment by day +60 after transplant. Secondary graft failure is defined as initial donor-derived neutrophil engraftment followed by the subsequent loss of donor chimerism to < 10% donor whole blood or myeloid peripheral blood chimerism.

  5. Percentage of Participants With Secondary Graft Failure Within 3 Years After Transplant

    Time frame: 3 years

    Percentage of participants with secondary graft failure at 3 years is reported separately by cohort along with 95% two-sided confidence interval. Secondary graft failure is defined as initial donor-derived neutrophil engraftment followed by the subsequent loss of donor chimerism to < 10% donor whole blood or myeloid peripheral blood chimerism within 3 years after transplant.

  6. Incidence of Grades III-IV Acute and Moderate to Severe Chronic Graft Versus Host Disease (GVHD)

    Time frame: Day 100 (Acute GVHD) and 1-, 2-, and 3-year post-transplant (Chronic GVHD)

    Incidence of grades III-IV acute and moderate to severe chronic graft versus host disease within 3 years after transplant will be reported separately by cohort using simple estimates along with 95% two-sided confidence intervals. In addition, cumulative incidence curves along with 95% two-sided confidence interval. Acute GVHD staging and grading will be assessed according to the 1994 Consensus Conference on Acute GVHD Grading criteria. Grade III liver (bilirubin) stage 2-3 or stage 2.4 gut (stool output per day). Grade IV is stage 4 (skin) or stage 4 liver (bilirubin). Chronic GVHD diagnosis and staging will be assessed according to the 2014 Chronic GVHD Consensus Project. Diagnostic signs and symptoms of chronic GVHD are those that establish the diagnosis of chronic GVHD without need for further testing or evidence of other organ involvement.

  7. Cumulative Incidence of Transplant-related Mortality Reported Along With a 95% Two-sided Confidence Interval

    Time frame: Day 100, 1 year and 2 years

    Cumulative incidence curves accounting for the competing risk of transplant-related mortality will be constructed by cohort, with the values reported at day 100, one, and two years, along with a 95% two-sided confidence interval.

Other outcomes

  1. Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0)

    Time frame: Adverse Events were monitored/assessed from the first study intervention through resolution of event through study completion, up to 2 years

    Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

Sponsors and collaborators

Lead sponsor

National Institutes of Health Clinical Center (CC)

Nih

Collaborators

  • National Cancer Institute (NCI)

Registry information

Official study title

A Phase II Study of Allogeneic Hematopoietic Stem Cell Transplantation With Briquilimab-Based Conditioning in Participants With GATA2 Deficiency

Important dates

Study start
2023
Primary completion
2025
Study completion
2028
First posted
Jun 18, 2023
Registry last updated
Jun 25, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

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This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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