Allogeneic Hematopoietic Stem Cell Transplant for Patients With Inborn Errors of Immunity

NCT04339777 | Recruiting Phase 2 FDA Drug

• 2 other identifiers: 20007020-C-0070
• Study Type: interventional
• Target: 66
• Locations: 1 country
• Sites: 1

Brief Summary

Background: During a transplant, blood stem cells from one person are given to someone else. The cells grow into the different cells that make up the immune system. This can cure people with certain immunodeficiencies. But transplant has many risks and complications. Objective: To see if stem cell transplant can be successfully performed in people with primary immunodeficiency disease and cure them. Eligibility: People ages 4-69 for whom a primary immunodeficiency (PID) or Primary Immune Regulatory Disorder (PIRD), has caused significant health problems and either standard management has not worked or there are no standard management options, along with their donors Design: Donors will be screened under protocol 01-C-0129. They will donate blood or bone marrow. Participants will be screened with: Medical history Physical exam Blood, urine, and heart tests CT or PET scans Before transplant, participants will have dental and eye exams. They will have a bone marrow biopsy. For this, a needle will be inserted through the skin into the pelvis to remove marrow. Participants will be hospitalized before their transplant. They will have a central catheter put into a vein in their chest or neck. They will get medications through the catheter to prevent complications. Participants will get stem cells through the catheter. They will stay in the hospital for at least 4 weeks. They will give blood, urine, bone marrow, and stool samples. They may need blood transfusions. They may need more scans. They will take more medications. Participants will have visits on days 30, 60, 100, 180, and 360, and 24 months after the transplant. Then they will have visits once a year for about 5 years

Conditions

Lymphoproliferative Disorders; Autoimmune Lymphoproliferative; Immune System Diseases; Common Variable Immunodeficiency; Primary T-cell Immunodeficiency Disorders

Keywords

Autoimmunity; Haploidentical; Opportunistic Infection; Immune Dysregulation; Congenital

Outcome Measures

Primary Outcomes (1)

• Sustained donor engraftment

  neutrophil recovery with ANC \>/= 500/mm\^3 for 3 consecutive days with \>50% or \>75% T-cell and myeloid donor chimerism

  baseline to day +100

Secondary Outcomes (8)

• Reversal of the immunological abnormalities

  1 through 5 years post transplant

• Reversal of the clinical phenotype

  1 and 2 years post transplant

• regimen-related mortality

  +180 and 1 year post transplant

• Overall survival

  1 through 5 years post transplant

• infection and viral reactivation

  +180 and 1 year post transplant

Study Arms (2)

Arm A

ACTIVE COMPARATOR

Low Intensity, Intermediate Intensity and High Intensity Conditioning with or without alemtuzumab

Drug: Busulfan test dose; Drug: Fludarabine; Drug: Busulfan; Drug: Alemtuzumab; Procedure: Allogeneic HSCT; Drug: Tacrolimus (Tacro); Drug: Mycophenolate mofetil (MMF); Drug: Cyclophosphamide (Cytoxan)

Arm B

ACTIVE COMPARATOR

Intermediate Intensity Conditioning with or without Alemtuzumab

Drug: Busulfan test dose; Drug: Fludarabine; Drug: Busulfan; Drug: Alemtuzumab; Radiation: Total body Irradiation; Procedure: Allogeneic HSCT; Drug: Tacrolimus (Tacro); Drug: Mycophenolate mofetil (MMF); Drug: Cyclophosphamide (Cytoxan)

Interventions

Busulfan test dose DRUG

0.8 mg/kg IV infusion over 2 hours

Arm A; Arm B

Fludarabine DRUG

40 mg/m2 IV infusion over 30 min once daily for 4 days

Arm A; Arm B

Busulfan DRUG

AUC Targeted Dose based on busulfan test dose PKs, IV infusion over 3 hours once daily (3.2 mg/kg IV per day will be the default dose) per the below time frame: For 10/10 Matched Related and Unrelated Donor Recipients For the High Intensity Arm, the busulfan dose will be given for 4 days (-6, -5, -4, and -3). For Intermediate Intensity Arm, the busulfan dose will be given for 3 days (-6,-5, and -4). For Low Intensity Arm, the busulfan dose will be given for 2 days on days (-6 and -5). 9/10 HLA Matched Related or Unrelated Donor Recipients For the High Intensity Arm, the busulfan dose will be given for 3 days (-6, -5, and -4). For the the Intermediate Intensity Arm, the busulfan dose will be given for 2 days (-6 and -5). For the Low Intensity Arm, the busulfan dose will be given for 1 day on day (-6).

Arm A; Arm B

Alemtuzumab DRUG

Alemtuzumab will be given if there is evidence of immune dysregulation 10 mg/m2 SC divided over three days (-14, -13, and -12)

Arm A; Arm B

Total body Irradiation RADIATION

200 cGy Transplant Day -1 (Only for 9/10 HLA Matched Related or Unrelated Donor Recipients )

Arm B

Allogeneic HSCT PROCEDURE

Stem cell transplant

Arm A; Arm B

Tacrolimus (Tacro) DRUG

Tacrolimus 0.02 mg/kg IV continuous infusion over 24 hours starting on day +5

Arm A; Arm B

Mycophenolate mofetil (MMF) DRUG

Mycophenolate mofetil 15 mg/kg IV over 2 hours three times a day starting on day +5 will continue until Approximately+35 (+/- two days)

Arm A; Arm B

Cyclophosphamide (Cytoxan) DRUG

Cyclophosphamide: 50 mg/kg IV once daily over 2 hours on days +3 and +4, dosed according to ideal body weight

Arm A; Arm B

Eligibility Criteria

• Age: 4 Years - 69 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Age \>= 4 years and \<=69 yo with Weight \>=12 kilograms
• Mutation in a known monogenic (IEI) gene performed by a CLIA certified laboratory, who have failed standard medical management, or when no standard medical management is available.
• Availability of an 8/8, 7/8, or 6/8 HLA-matched related or unrelated donor (if the mismatch is at DQ this will be considered an 8/8 matched donor), or a haploidentical related donor. Karnofsky or Lansky performance status of \>= 40%
• Adequate end-organ function, as measured by:
• Left ventricular ejection fraction \> 40%, preferably by 2-D echocardiogram (ECHO) obtained within 60 days prior to enrollment.
• Creatinine: Adult patients: \<= 2.0 mg/dl and creatinine clearance \>= 30 ml/min; Pediatric patients (\<18 years old): creatinine \< 1.5 mg/dL and a creatinine clearance, using the Schwartz Formula \> 30 mL/min/1.73m\^2.
• Serum conjugated bilirubin \< 2.5 mg/dl; serum ALT and AST \<= 5 times upper
• limit of normal.
• Pulmonary function tests: FEV1 \> 30% and DLCO \>30%. Children who are unable to have DLCO assessed due to age, are still eligible if no evidence of dyspnea at rest and no need for supplemental oxygen.
• Ability of subject or parent/guardian to understand and the willingness to sign a written informed consent document. For subjects \<18 years old, their legal guardian must give informed consent. Pediatric patients will provide assent.
• As therapeutic agents used in this trial may be harmful to a fetus, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for at least one year post-allo HCT. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in the study, she should inform her treating physician immediately.
• Willingness to remain in the NIH hospital or, if discharged, stay close to the NIH, for a minimum of 100 days after transplant or longer, if there are complications. If outpatient in the first 100 days after transplant, patient must commit to having an adult caregiver with them at all times.

You may not qualify if:

• Patients who are receiving any other investigational agents (with the exception of virus-specific therapy e.g. cytotoxic T-cells for the treatment of viral infection/reactivation prior to allo HCT).
• Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
• HIV-positive patients are ineligible because these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to agents (steroids, cyclophosphamide, busulfan, tacrolimus, sirolimus, MMF, G-CSF, alemtuzumab) used in the study
• Active psychiatric disorder which is deemed by the PI to have significant risk of compromising compliance with the transplant protocol or which does not allow for appropriate informed consent
• Pregnant women are excluded from this study because the study agents have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with the study agents, breastfeeding should be discontinued if the mother is treated with the study agents.
• Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

RECRUITING

Related Publications (1)

• Arnold DE, Kaviany S, Aluri J, Calvo KR, Mehta SS, Tobin JM, Schuettpelz LG, Saucier N, Schmitz EG, Murguia-Favela L, Wright NAM, De Ravin SS, Rao VK, Holland SM, Bleesing JJ, Loughran TP Jr, Feith DJ, Powell J, Ratan A, Warren JT, Pai SY, Bednarski JJ, Connelly JA, Cooper MA. Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function. Blood Adv. 2026 Mar 24;10(6):1967-1976. doi: 10.1182/bloodadvances.2025016338.

  PMID: 41370196 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Lymphoproliferative Disorders; Immune System Diseases; Common Variable Immunodeficiency; T cell immunodeficiency primary; Autoimmune Diseases; Opportunistic Infections

Interventions

fludarabine; Busulfan; Alemtuzumab; Whole-Body Irradiation; Tacrolimus; Mycophenolic Acid; Cyclophosphamide

Condition Hierarchy (Ancestors)

Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immunologic Deficiency Syndromes; Infections

Intervention Hierarchy (Ancestors)

Butylene Glycols; Glycols; Alcohols; Organic Chemicals; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Hydrocarbons; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Radiotherapy; Therapeutics; Investigative Techniques; Macrolides; Lactones; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds

Study Officials

• Sung-Yun Pai, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Shannon L Knight, R.N.

CONTACT

(240) 921-5872; shannon.knight@nih.gov

Sung-Yun Pai, M.D.

CONTACT

(240) 858-7284; sung-yun.pai@nih.gov

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 8, 2020
• First Posted: April 9, 2020
• Study Start: September 22, 2020
• Primary Completion (Estimated): October 1, 2026
• Study Completion (Estimated): November 30, 2027
• Last Updated: May 4, 2026

Record last verified: 2026-04-30

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Clinical data available during the study and indefinitely.
• Access Criteria: Clinical data will be made available via subscription to BTRIS and with the permission of the study PI.

Locations

US (1)