Clinical trial NCT03128996: Reduced Intensity Conditioning and Familial HLA-Mismatched BMT for Non-Malignant Disorders
Official title: A Phase I/II Trial of Reduced Intensity Conditioning and Familial HLA-Mismatched Bone Marrow Transplantation in Children With Non-Malignant Disorders
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Severe Sickle Cell Disease
Bone Marrow Failure Syndromes
Metabolic Disorders
Immunologic Disorders
Hemoglobinopathies
Non-malignant Disorders
Keywords: Bone marrow transplant
Transplant
Transplantation
Reduced Intensity
Familial HLA mismatched
Lead sponsor: Washington University School of Medicine
Sponsor class: OTHER
First posted: 2017-04-26
Enrollment: 29
Sex: ALL
Minimum age (years): 1
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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)

Primary outcomes:
measure: Donor engraftment
timeFrame: 100 days and 1 year post-transplant
Secondary outcomes:
measure: Time to neutrophil engraftment
timeFrame: 100 days post-transplant
measure: Time to platelet engraftment
timeFrame: 100 days post-transplant
measure: Effect of BMT on pulmonary function
timeFrame: 90 days, 1 year, and 2 years post-transplant
measure: Effect of BMT on hepatic function
timeFrame: 90 days, 180 days, 1 year, and 2 years post-transplant
measure: Effect of BMT on neurologic function
timeFrame: 90 days, 1 year, and 2 years post-transplant
measure: Effect of BMT on cardiac function
timeFrame: 90 days, 1 year, and 2 years post-transplant
measure: Effect of BMT on renal function
timeFrame: 90 days, 180 days, 1 year, and 2 years post-transplant
measure: Pharmacokinetics of alemtuzumab
timeFrame: days -19, day 0, day +15, and day +30
measure: Pharmacokinetics of abatacept
timeFrame: days +30, +60, +90, 1 year, 1.5 years, and 2 years post-transplant
measure: Incidence of acute graft-versus-host disease (GVHD)
timeFrame: 1 year post-transplant
measure: Incidence of chronic graft-versus-host disease (GVHD)
timeFrame: 2 years post-transplant
measure: Immune reconstitution
timeFrame: days +30, +60, +90, 1 year, 1.5 years, and 2 years post-transplant
Other outcomes:
Locations:
city: New Haven
country: United States
facility: Yale School of Medicine
state: Connecticut
city: Grand Rapids
country: United States
facility: Helen DeVos Children's Hospital
state: Michigan
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
Study officials:
affiliation: Washington University School of Medicine
name: Shalini Shenoy, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.