Regenerative Medicine to Restore Hematopoiesis and Immune Function in Immunodeficiencies and Inherited Bone Marrow Failures

NCT04232085 | Recruiting Phase 2 DMC FDA Drug

• 2 other identifiers: B19126IRB00227401
• Study Type: interventional
• Target: 27
• Locations: 1 country
• Sites: 1

Brief Summary

Phase II prospective trial to assess the rates of donor engraftment using reduced intensity conditioning (RIC) hematopoietic stem cell transplant (HSCT) and post-transplant cyclophosphamide (PTCy) for patients with primary immune deficiencies (PID), immune dysregulatory syndromes (IDS), inherited bone marrow failure syndromes (IBMFS), short telomere syndromes, Fanconi anemia, and non-Fanconi DNA double-strand break (DNA-dsb) repair disorder.

Conditions

Primary Immune Deficiency Disorder; Immune Deficiency Disease; Bone Marrow Failure; Short Telomere Length; Fanconi Anemia; Non Fanconi DNA-DSB Repair Disorder; Hoyeraal-Hreidarsson Syndrome; Dyskeratosis Congenita; Telomere Biology Disorder; Short Telomere Syndrome

Keywords

Bone Marrow Transplantation

Outcome Measures

Primary Outcomes (1)

• Donor Engraftment

  Rate of donor engraftment ≥95% at day 60 as measured by donor chimerism in whole blood.

  60 Days

Secondary Outcomes (2)

• Number of patients that have survived at 1 year

  1 year

• Disease Free Survival at 1 year

  1 year

Study Arms (3)

PID/IDS/IBMFS

EXPERIMENTAL

Alemtuzumab IV infusion over 2 hours on days -14, -13, and -12. Day -14 3 mg followed by 10 mg. Day -13 15 mg (or 10 mg if \<10 kg). Day -12 20 mg (or 10 mg if \<10 kg). Fludarabine 30 mg/m2/day IV infusion over 2 hours on days -6 to -2. Melphalan 70 mg/m2/day IV infusion over 30-60 minutes on days -3 and -2. (Or may be given as a single infusion of 140 mg/m2/day on day -2.) Total body irradiation (PID/IDS): 200 cGy will be administered in a single fraction on day -1. Bone Marrow will be harvested and infused on day 0. Post-transplantation Cyclophosphamide 50mg/kg will be given on D+3 post-transplant (within 60-72 hr of marrow infusion) and on D+4 post-transplant. Tacrolimus begins on day 5, at least 24 hours after completion of posttransplantation Cy at 0.015mg/kg IBW/dose IV over 4 hours every 12 hours. Mycophenolic acid mofetil (MMF) begins on day 5 at a dose of 15 mg/kg PO TID (based upon actual body weight) with the maximum total daily dose not to exceed 3 grams (1 g PO TID).

Drug: Alemtuzumab; Drug: Fludarabine; Drug: Melphalan; Radiation: Low Dose Total Body Irradiation; Drug: Cyclophosphamide; Drug: Tacrolimus; Drug: Mycophenolate Mofetil

Short Telomere Syndrome

EXPERIMENTAL

Alemtuzumab IV infusion over 2 hours on days -14, -13, and -12. Day -14 3 mg followed by 10 mg. Day -13 15 mg (or 10 mg if \<10 kg). Day -12 20 mg (or 10 mg if \<10 kg). Fludarabine 30 mg/m2/day IV infusion over 2 hours on days -6 to -2. TBI 200 cGY day -1 Bone Marrow will be harvested and infused on day 0. Post-transplantation Cyclophosphamide 25-50mg/kg will be given on D+3 post-transplant (within 60-72 hr of marrow infusion) and on D+4 post-transplant. Starting dose for haplo/MMUD= 50 mg/kg; starting dose for HLA matched= 25 mg/kg Tacrolimus begins on day 5, at least 24 hours after completion of post transplantation Cy at 0.015mg/kg IBW/dose IV over 4 hours every 12 hours. Mycophenolic acid mofetil (MMF) begins on day 5 at a dose of 15 mg/kg PO TID (based upon actual body weight) with the maximum total daily dose not to exceed 3 grams (1 g PO TID).

Drug: Alemtuzumab; Drug: Fludarabine; Radiation: Low Dose Total Body Irradiation; Drug: Cyclophosphamide; Drug: Tacrolimus; Drug: Mycophenolate Mofetil

Fanconi Anemia or DNA-dsb repair

EXPERIMENTAL

Alemtuzumab IV infusion over 2 hours on days -14, -13, and -12. Day -14 3 mg followed by 10 mg. Day -13 15 mg (or 10 mg if \<10 kg). Day -12 20 mg (or 10 mg if \<10 kg). Fludarabine 30 mg/m2/day IV infusion over 2 hours on days -6 to -2. TBI 200 cGY day -1 Bone Marrow will be harvested and infused on day 0. Post-transplantation Cyclophosphamide 25 mg/kg will be given on D+3 post-transplant (within 60-72 hr of marrow infusion) and on D+4 post-transplant. Tacrolimus begins on day 5, at least 24 hours after completion of post transplantation Cy at 0.015mg/kg IBW/dose IV over 4 hours every 12 hours. Mycophenolic acid mofetil (MMF) begins on day 5 at a dose of 15 mg/kg PO TID (based upon actual body weight) with the maximum total daily dose not to exceed 3 grams (1 g PO TID).

Drug: Alemtuzumab; Drug: Fludarabine; Radiation: Low Dose Total Body Irradiation; Drug: Cyclophosphamide; Drug: Tacrolimus; Drug: Mycophenolate Mofetil

Interventions

Alemtuzumab DRUG

Preparative regimen

Also known as: Campath

Fanconi Anemia or DNA-dsb repair; PID/IDS/IBMFS; Short Telomere Syndrome

Fludarabine DRUG

Preparative regimen

Fanconi Anemia or DNA-dsb repair; PID/IDS/IBMFS; Short Telomere Syndrome

Melphalan DRUG

Preparative regimen

PID/IDS/IBMFS

Low Dose Total Body Irradiation RADIATION

Preparative regimen

Fanconi Anemia or DNA-dsb repair; PID/IDS/IBMFS; Short Telomere Syndrome

Cyclophosphamide DRUG

GVHD prophylaxis

Also known as: Cytoxan

Fanconi Anemia or DNA-dsb repair; PID/IDS/IBMFS; Short Telomere Syndrome

Tacrolimus DRUG

GVHD prophylaxis

Also known as: FK506, Prograf

Fanconi Anemia or DNA-dsb repair; PID/IDS/IBMFS; Short Telomere Syndrome

Mycophenolate Mofetil DRUG

GVHD prophylaxis

Also known as: MMF, Cellcept

Fanconi Anemia or DNA-dsb repair; PID/IDS/IBMFS; Short Telomere Syndrome

Eligibility Criteria

• Age: 4 Months - 50 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Cohort A:
• Primary Immune Deficiencies with indication for HCT:
• Chronic granulomatous disease (CGD)
• Wiskott-Aldrich syndrome (WAS)
• Hyper-IgM syndrome
• Common variable immunodeficiency (CVID)
• Leukocyte adhesion deficiency-1 (LAD-1)
• Severe Combined Immunodeficiency (SCID)
• CTLA-4 deficiency
• CARD9 deficiency
• DOCK8 deficiency
• Immune Dysregulatory Syndromes:
• Immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome
• Hemophagocytic lymphohistiocytosis (HLH) or related disorder with indication for transplant
• CAEBV: Patients with chronic EBV infection (CAEBV) with indication for BMT:

You may not qualify if:

• Patients will not be excluded on the basis of sex, racial or ethnic background.
• Positive leukocytotoxic crossmatch.
• Prior allogeneic stem cell transplant.
• Uncontrolled bacterial, viral, or fungal infection at the time of enrollment. Uncontrolled is defined as currently taking medication and with progression or no clinical improvement on adequate medical treatment. The investigators recognize that patients with CAEBV may have ongoing EBV viremia at the time of initiating pre-transplant therapy, but other patients should have no uncontrolled bacterial, viral, or fungal infections.
• Diagnosis of idiopathic aplastic anemia
• Seropositivity for the human immunodeficiency virus (HIV)
• Active Hepatitis B or C determined by serology and/or NAT
• Female patients who are diagnosed as pregnant by beta bHCG testing (per institutional practice) or who are breast-feeding.
• Active malignancy or within the timeframe for significant concern for relapse of prior malignancy
• For Cohort B and C: liver biopsy (if performed, not required) with moderate-severe fibrosis/cirrhosis
• Donor Eligibility
• Donor must be medically, socially, and psychologically fit to donate
• Bone marrow is the preferred graft source, however, PBSCs may be requested. In particular, PBSCs may be preferred for patients with active viral reactivations and/or for patients who would benefit from a higher count in the graft. Cord blood is not permitted.
• First-degree relatives should be tested for degree of HLA match, CMV serology, ABO type, and complete blood count (CBC). An unrelated donor search should be initiated at the time the patient is referred for BMT.
• Age ≥5 years

Sponsors & Collaborators

• Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins: lead
• Maryland Stem Cell Research Fund: collaborator

Study Sites (1)

Johns Hopkins University

Baltimore, Maryland, 21287, United States

RECRUITING

Related Publications (1)

• Klein OR, Bapty S, Lederman HM, Younger MEM, Zambidis ET, Jones RJ, Cooke KR, Symons HJ. Reduced Intensity Bone Marrow Transplantation with Post-Transplant Cyclophosphamide for Pediatric Inherited Immune Deficiencies and Bone Marrow Failure Syndromes. J Clin Immunol. 2021 Feb;41(2):414-426. doi: 10.1007/s10875-020-00898-0. Epub 2020 Nov 6.

  PMID: 33159275 DERIVED

MeSH Terms

Conditions

Primary Immunodeficiency Diseases; Immune Deficiency Disease; Bone Marrow Failure Disorders; Fanconi Anemia; Hoyeraal Hreidarsson syndrome; Dyskeratosis Congenita

Interventions

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

Condition Hierarchy (Ancestors)

Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Immunologic Deficiency Syndromes; Immune System Diseases; Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Anemia, Hypoplastic, Congenital; Anemia, Aplastic; Anemia; Congenital Bone Marrow Failure Syndromes; DNA Repair-Deficiency Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Skin Abnormalities; Congenital Abnormalities; Genetic Diseases, X-Linked; Skin Diseases, Genetic; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phenylalanine; Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids; Radiotherapy; Therapeutics; Investigative Techniques; Phosphoramide Mustards; Phosphoramides; Organophosphorus Compounds; Macrolides; Lactones; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids

Study Officials

• Heather J Symons, MD, MHS

  Johns Hopkins University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Heather J Symons, MD, MHS

CONTACT

4105029961; hsymons2@jhmi.edu

Megan Petrycki, RN

CONTACT

4109555068; mpetryc1@jhmi.edu

Study Design

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

Model Details: This is a Phase II prospective trial

Study Record Dates

• First Submitted: December 30, 2019
• First Posted: January 18, 2020
• Study Start: February 12, 2020
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2028
• Last Updated: November 28, 2025

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)