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

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

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.

Study Overview

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

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 Type: Interventional
• Enrollment (Estimated): 29
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Stephanie Hyde, CCRP; Phone Number: 314-286-1180; Email: stephanie.day@wustl.edu
• Study Contact Backup: Name: Shalini Shenoy, MD; Phone Number: 314-454-6018; Email: shalinishenoy@wustl.edu

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Recruiting
      • Yale School of Medicine
      • Contact: Niketa Shah, MD
      • Principal Investigator: Niketa Shah, MD
  • Michigan
    • Grand Rapids, Michigan, United States, 49503
      • Recruiting
      • Helen DeVos Children's Hospital
      • Contact: Troy Quigg, DO
      • Principal Investigator: Troy Quigg, DO
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Recruiting
      • Washington University School of Medicine
      • Contact: Lisa Murray, MA, CCRP; Phone Number: 314-454-4240; Email: murraylm@wustl.edu
      • Principal Investigator: Shalini Shenoy, MD
      • Contact: Shalini Shenoy, MD; Phone Number: 314-454-6018; Email: shalinishenoy@wustl.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 day to 21 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: RIC Prep Regimen & GVHD Prophylaxis; Single arm study. All patients receive the same Reduced Intensity Conditioning (RIC) regimen and GVHD prophylaxis regimen

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; Other Names: Transplant Preparative Regimen; Transplant Conditioning Regimen; Drug: 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); Other Names: Graft versus Host Disease prophylaxis regimen

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Donor engraftment	as measured by chimerism	100 days and 1 year post-transplant

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Investigators: Principal Investigator: Shalini Shenoy, MD, Washington University School of Medicine

Publications and helpful links

General Publications

• Ngwube A, Shah N, Godder K, Jacobsohn D, Hulbert ML, Shenoy S. Abatacept is effective as GVHD prophylaxis in unrelated donor stem cell transplantation for children with severe sickle cell disease. Blood Adv. 2020 Aug 25;4(16):3894-3899. doi: 10.1182/bloodadvances.2020002236.

Study record dates

Study Major Dates

• Study Start (Actual): March 20, 2017
• Primary Completion (Estimated): April 1, 2024
• Study Completion (Estimated): April 1, 2026

Study Registration Dates

• First Submitted: April 3, 2017
• First Submitted That Met QC Criteria: April 20, 2017
• First Posted (Actual): April 26, 2017

Study Record Updates

• Last Update Posted (Actual): September 6, 2023
• Last Update Submitted That Met QC Criteria: September 2, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Transplantation; Transplant; Bone marrow transplant; Reduced Intensity; Familial HLA mismatched
• Additional Relevant MeSH Terms: Bone Marrow Diseases; Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia, Sickle Cell; Metabolic Diseases; Immune System Diseases; Hemoglobinopathies; Bone Marrow Failure Disorders; Pancytopenia
• Other Study ID Numbers: 201611172

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No