Reduced Intensity Conditioning and Familial HLA-Mismatched BMT for Non-Malignant Disorders

Hemoglobinopathies Clinical Trial

Official title:

A Phase I/II Trial of Reduced Intensity Conditioning and Familial HLA-Mismatched Bone Marrow Transplantation in Children With Non-Malignant Disorders

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03128996
• Other study ID #: 201611172
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: March 20, 2017
• Est. completion date: April 2026

Study information

• Verified date: September 2023
• Source: Washington University School of Medicine
• Contact: Shalini Shenoy, MD
• Phone: 314-454-6018
• Email: shalinishenoy[@]wustl.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study is designed to estimate the efficacy and toxicity of familial HLA mismatched bone marrow transplants in patients with non-malignant disease who are less than 21 years of age and could benefit from the procedure.

Description:

Patients < 21 years of age with a non-malignant disorder benefited by hematopoietic stem cell transplant will receive a reduced intensity conditioning regimen consisting of hydroxyurea, alemtuzumab, fludarabine, thiotepa, and melphalan. This will be followed by a familial HLA-mismatched bone marrow transplant. The primary objective is to establish safety and donor cell engraftment at 100 days and 1 year post-transplant.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 29
• Est. completion date: April 2026
• Est. primary completion date: April 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Day to 21 Years

Eligibility

Inclusion Criteria:

• Nonmalignant disorder requiring bone marrow transplant including bone marrow failure syndromes, metabolic disorders, immunologic disorders, or hemoglobinopathy
• For patients with sickle cell disease, must have one of the following severe

manifestations:

1. Overt or silent stroke or persistently elevated transcranial doppler velocities despite transfusion therapy

2. Recurrent acute chest syndrome with significant respiratory compromise each time

3. Sickle nephropathy

4. Recurrent admissions for vaso-occlusive episodes resulting in prolonged opioid use and poor quality of life with interrupted school attendance activity

5. Red cell alloimmunization with the need for chronic transfusions

6. Recurrent osteonecrosis or multiple joint involvement from avascular necrosis

• Patients with sickle cell disease must have hemoglobin S < 30% within 30 days prior to beginning alemtuzumab
• Age </= 20.99 years at the time of enrollment
• Performance score >/= 50
• Left ventricular ejection fraction > 40% or left ventricular shortening fraction > 26% by echocardiogram
• DLCO > 40% (corrected for hemoglobin) or pulse oximetry with a baseline O2 saturation of >/= 90% on room air if too young to perform PFTs
• Serum creatinine </= 1.5x upper limit of normal for age and/or GFR > 70 mL/min/1.73m2
• Direct bilirubin < 2x upper limit of normal for age
• ALT and AST < 5x upper limit of normal for age
• Participants who have or are receiving >/= 8 packed red blood cell transfusions for >/= 1 year or >/= 20 packed red blood cell transfusions (lifetime cumulative) will undergo liver MRI for estimation of hepatic iron content.

1. Liver biopsy is indicated for hepatic iron content >/= 7mg Fe/mg liver dry weight by liver MRI. Histologic examination of the liver must document for the absence of cirrhosis, bridging fibrosis, and active hepatitis

• Female subjects of childbearing potential, must agree to practice 2 methods of contraception at the same time from the time of signing of informed consent through 12 months post transplant. Male subjects must agree to practice effective barrier contraception or practice true abstinence from the time of signing informed consent through 12 months post transplant.
• Written informed consent must be obtained from all recipients in accordance with the guidelines of the institution's Human Studies Committee.

Exclusion Criteria:

• Patients who have an HLA-identical sibling who is able and willing to donate bone marrow
• Patients with cirrhosis or established bridging fibrosis of the liver or active hepatitis
• Uncontrolled bacterial, viral, or fungal infection within 6 weeks prior to enrollment
• Evidence of HIV infection or known HIV positive serology
• Patients who have received a previous stem cell transplant
• Patients who have received an investigational drug or device or off-label use of a drug or device within 3 months of enrollment
• Females who are pregnant or breast feeding
• Patients with active autoimmune disease (e.g. sarcoidosis, lupus, scleroderma)

Related Conditions & MeSH terms

• Anemia, Sickle Cell
• Bone Marrow Failure Disorders
• Bone Marrow Failure Syndromes
• Hemoglobinopathies
• Immune System Diseases
• Immunologic Disorders
• Metabolic Diseases
• Metabolic Disorders
• Non-malignant Disorders
• Pancytopenia
• Severe Sickle Cell Disease

Intervention

Drug:
• RIC regimen
Days -60 to -21: hydroxyurea (30mg/kg/day po) >6hrs prior to 1st dose: alemtuzumab (3mg IV) Day -21: alemtuzumab (10mg IV or S/C) Day -20: alemtuzumab (15mg IV or S/C) (10mg if < 10kg) Day -19: alemtuzumab (20mg IV or S/C) (10mg if < 10kg) Days -8 to -4: fludarabine (30mg/m2/day IV) Day -4: thiotepa (8mg/kg IV) Day -3: melphalan (140mg/m2) Days -2 to -1: rest days/no therapy Day 0: bone marrow transplant
• GVHD prophylaxis regimen
Day +3 to +4: cyclophosphamide (50mg/kg/day IV) Day +5: Start of tacrolimus & Start of mycophenolate mofetil (MMF) Days +5, +14, +30, +60, +90: abatacept (IND) (10mg/kg/day IV) Days +120 to +390: abatacept (IND) monthly (5mg/kg/day IV)

Locations

Country	Name	City	State
United States	Helen DeVos Children's Hospital	Grand Rapids	Michigan
United States	Yale School of Medicine	New Haven	Connecticut
United States	Washington University School of Medicine	Saint Louis	Missouri

Sponsors (1)

Lead Sponsor	Collaborator
Washington University School of Medicine

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Donor engraftment	as measured by chimerism	100 days and 1 year post-transplant
Secondary	Time to neutrophil engraftment	as measured by complete blood counts	100 days post-transplant
Secondary	Time to platelet engraftment	as measured by complete blood counts	100 days post-transplant
Secondary	Effect of BMT on pulmonary function	as measured by pulmonary function tests	90 days, 1 year, and 2 years post-transplant
Secondary	Effect of BMT on hepatic function	as measured by laboratory evaluations	90 days, 180 days, 1 year, and 2 years post-transplant
Secondary	Effect of BMT on neurologic function	as measured by cognitive testing and quality of life surveys	90 days, 1 year, and 2 years post-transplant
Secondary	Effect of BMT on cardiac function	as measured by echocardiograms	90 days, 1 year, and 2 years post-transplant
Secondary	Effect of BMT on renal function	as measured by laboratory evaluations	90 days, 180 days, 1 year, and 2 years post-transplant
Secondary	Pharmacokinetics of alemtuzumab	as measured by maximum plasma concentration of alemtuzumab	days -19, day 0, day +15, and day +30
Secondary	Pharmacokinetics of abatacept	as measured by maximum plasma concentration of abatacept	days +30, +60, +90, 1 year, 1.5 years, and 2 years post-transplant
Secondary	Incidence of acute graft-versus-host disease (GVHD)	as measured by protocol grading scale	1 year post-transplant
Secondary	Incidence of chronic graft-versus-host disease (GVHD)	as measured by protocol grading scale	2 years post-transplant
Secondary	Immune reconstitution	as measured by research laboratory evaluations	days +30, +60, +90, 1 year, 1.5 years, and 2 years post-transplant