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

Phase 1

Recruiting

• Conditions: Severe Sickle Cell Disease; Bone Marrow Failure Syndromes; Metabolic Disorders; Immunologic Disorders; Hemoglobinopathies; Non-malignant Disorders
• Interventions: Drug: RIC regimen; Drug: GVHD prophylaxis regimen

• Registration Number: NCT03128996
• Lead Sponsor: Washington University School of Medicine

Brief 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.

Detailed 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.

Study Timeline

• Study Start: 2017-03-20
• Study First Submitted: 2017-04-03
• Study First Submitted QC: 2017-04-20
• Study First Posted: 2017-04-26
• Status Verified: 2024-07
• Last Update Submitted: 2024-07-22
• Last Update Posted: 2024-07-23
• Primary Completion: 2026-04
• Study Completion: 2031-04

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 29

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.

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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)

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
RIC Prep Regimen & GVHD Prophylaxis	RIC regimen	Single arm study. All patients receive the same Reduced Intensity Conditioning (RIC) regimen and GVHD prophylaxis regimen
RIC Prep Regimen & GVHD Prophylaxis	GVHD prophylaxis regimen	Single arm study. All patients receive the same Reduced Intensity Conditioning (RIC) regimen and GVHD prophylaxis regimen

Primary Outcome Measures

Name	Time	Method
Donor engraftment	100 days and 1 year post-transplant	as measured by chimerism

Secondary Outcome Measures

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

Trial Locations

Locations (3)

Helen DeVos Children's Hospital; 🇺🇸 Grand Rapids, Michigan, United States

Washington University School of Medicine; 🇺🇸 Saint Louis, Missouri, United States

Yale School of Medicine; 🇺🇸 New Haven, Connecticut, United States