Early Human Leukocyte Antigen (HLA) Matched Sibling Hematopoietic Stem Cell Transplantation

NCT04018937 | Active Not Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: IRB00093513
• Study Type: interventional
• Target: 43
• Locations: 2 countries
• Sites: 15

Brief Summary

This study aims to enroll 58 pre-adolescent (\<13 years) pediatric participants with sickle cell disease (SCD) who have a pre-adolescent sibling bone marrow donor. All participants will go through a pre-transplant evaluation to find out if there are health problems that will keep them from being able to receive the transplant. It usually takes 2 to 3 months to complete the pre-transplant evaluation and make the arrangements for the transplant. Once they are found to be eligible for transplant, participants will be admitted to the hospital and will start transplant conditioning. Conditioning is the chemotherapy and other medicines given to prepare them to receive donor cells. It prevents the immune system from rejecting donor cells. Conditioning will start 21 days before transplant. Once they complete conditioning, participants will receive the bone marrow transplant. After the transplant, participants will stay in the hospital for 4-6 weeks. After they leave the hospital, participants will be followed closely in the clinic. Outpatient treatment and frequent clinic visits usually last 6 to 12 months. Routine medical care includes at least a yearly examination for many years after transplant by doctors and nurses familiar with sickle cell disease and transplant. The researchers will collect and study information about participants for 2 years after transplant.

Conditions

Sickle Cell Disease

Keywords

Pediatrics; Hematopoietic stem cell transplantation; HLA matched sibling

Outcome Measures

Primary Outcomes (1)

• Immune Suppression-free, Rejection-free Survival

  Immune suppression-free, rejection-free survival is defined as rejection-free survival off all systemic immunosuppressive agents. Participants who are off systemic immune suppression by 2-years post-transplant will be considered as being immune suppression free.

  Year 2

Secondary Outcomes (15)

• Regimen-Related Toxicity

  Day 42

• Number of Neurological Complications

  Up to Year 2

• Neutrophil Recovery

  Up to Year 2

• Platelet Recovery

  Up to Year 2

• Graft Rejection

  Up to Year 2

Study Arms (1)

Reduced Intensity Conditioning with FAM

EXPERIMENTAL

Children with SCD will received reduced intensity conditioning with fludarabine, alemtuzumab and melphalan (FAM) during HSCT with a HLA matched sibling donor

Drug: Alemtuzumab; Drug: Fludarabine; Drug: Melphalan

Interventions

Alemtuzumab DRUG

Alemtuzumab will be administered by either subcutaneous (SQ) injection or IV. A test dose of alemtuzumab, 3 mg, is administered on the first day. If the test dose is tolerated, administration of three treatment doses will begin within 24 hours. The three treatment doses will be administered on consecutive days. On the first day, 10 mg/m2 will be given, 15 mg/m\^2 the second and 20 mg/m\^2 the third. Alemtuzumab will be started between Days -22 and -20, but all doses (test dose and three treatment doses) should be completed by Day -18.

Also known as: Campath

Reduced Intensity Conditioning with FAM

Fludarabine DRUG

Fludarabine will be administered at 30 mg/m\^2 IV daily for five days (Days -7 to -3).

Also known as: Fludara

Reduced Intensity Conditioning with FAM

Melphalan DRUG

Melphalan will be administered at 140 mg/m\^2 IV on Day -3 following fludarabine administration.

Also known as: Alkeran, Evomela

Reduced Intensity Conditioning with FAM

Eligibility Criteria

• Age: 2 Years - 13 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Patients must be at least 2 years and less than 13 years old and have a sickle hemoglobinopathy.
• Patient must have an HLA identical sibling donor who is less than 13 years old. Sibling donors must not have any form of SCD. It is acceptable for the donor to carry a hemoglobinopathy trait.
• Patients must meet criteria for symptomatic SCD as defined below.
• Severe disease:
• Previous clinical stroke, defined as a neurological deficit lasting longer than 24 hours plus new finding on head CT or brain MRI/MRA.
• Progressive silent cerebral infarction, as evidenced by serial MRI scans that demonstrate the development of a succession of lesions (at least two temporally discreet lesions, each measuring at least 3 mm in greatest dimension on the most recent brain MRI/MRA) or the enlargement of a single lesion, initially measuring at least 3 mm). Lesions must be visible on T2-weighted MRI sequences.
• Abnormal TCD testing (confirmed elevated velocities in any single vessel of TAMMV \> 200 cm/sec for non-imaging TCD)
• Significant vasculopathy on MRA (greater than 50% stenosis of \> 2 arterial segments or complete occlusion of any single arterial segment).
• Frequent (at least 3 per year for preceding 2 years) painful vaso-occlusive episodes (defined as episode lasting at least 4 hours and requiring hospitalization or outpatient treatment with parenteral opioids). If patient is on hydroxyurea and its use has been associated with a decrease in the frequency of episodes, the frequency should be gauged from the 2 years prior to the start of hydroxyurea.
• Recurrent (at least 3 in lifetime) acute chest syndrome events which have necessitated erythrocyte transfusion therapy.
• Any combination of at least 3 acute chest syndrome episodes and vaso-occlusive pain episodes (defined as above) yearly for 3 years. If patient is on hydroxyurea and its use has been associated with a decrease in the frequency of episodes, the frequency should be gauged from the 3 years prior to the start of hydroxyurea.
• Less severe disease: to qualify as having less severe disease, patients must not meet criteria for severe disease and must have one of the following:
• Asymptomatic cerebrovascular disease, as evidenced by one the following: Silent cerebral infarction with at least one lesion measuring at least 3 mm in one dimension that is visible on two planes on the most recent brain MRI, or, cerebral arteriopathy, as evidenced by conditional TCD (TAMMV\>170cm/sec but \<200cm/sec) on two separate scans \>2 weeks apart). If patient has a conditional TCD, then a brain MRI/MRA to evaluate for vasculopathy is required.
• or more painful vaso-occlusive episodes (in lifetime) requiring hospitalization or outpatient treatment with parenteral opioids.
• or more episodes of acute chest syndrome (in lifetime) irrespective of SCD modifying therapy administered.

You may not qualify if:

• Bridging (portal to portal) fibrosis or cirrhosis of the liver.
• Parenchymal lung disease stemming from SCD or other process defined as a diffusing capacity of the lungs for carbon monoxide (DLCO; corrected for hemoglobin) or forced vital capacity of less than 45% of predicted. Children unable to perform pulmonary function testing will be excluded if they require daytime oxygen supplementation.
• Renal dysfunction with an estimated glomerular filtration rate (GFR) \< 50% of predicted normal for age.
• Cardiac dysfunction with shortening fraction \< 25%.
• Neurologic impairment other than hemiplegia, defined as full-scale intelligence quotient (IQ) of less than or equal to 70, quadriplegia or paraplegia, or inability to ambulate.
• Lansky functional performance score \< 70%.
• Patient is HIV infected.
• Donor is HIV infected.
• Patient with unspecified chronic toxicity serious enough to detrimentally affect the patient's capacity to tolerate HSCT.
• Patient's parent(s) or legal guardian is unable to understand the nature and the risks inherent in the HSCT process.
• History of lack of adherence with medical care that would jeopardize transplant course.
• Donor who for psychological, physiologic, or medical reasons is unable to tolerate a bone marrow harvest or receive general anesthesia.
• Active viral, bacterial, fungal or protozoal infection.
• Patients with viral upper respiratory tract infections should be asymptomatic for at least 7 days prior to enrollment. PCR testing for respiratory viruses (nasopharyngeal sample) should be negative at the start of the conditioning regimen. Exceptions may be made in patients with prolonged carriage (repeatedly positive over many weeks) of rhinovirus. These exceptions should be discussed with and approved by both study co-chairs and STAR Medical Director.

Sponsors & Collaborators

• Emory University: lead

Study Sites (15)

Children's Hospital of Alabama

Birmingham, Alabama, 35233, United States

Location

Phoenix Children's

Phoenix, Arizona, 85016, United States

Location

Yale University, Yale Cancer Center

New Haven, Connecticut, 06520, United States

Location

Children's National Hospital

Washington D.C., District of Columbia, 20010, United States

Location

Children's Healthcare of Altanta

Atlanta, Georgia, 30322, United States

Location

University of Chicago

Chicago, Illinois, 60637, United States

Location

Riley Children's Health/Indiana University

Indianapolis, Indiana, 46202, United States

Location

Dana-Farber Cancer Institute/Boston Children's Hospital

Boston, Massachusetts, 02215, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Hackensack University Medical Center

Hackensack, New Jersey, 07601, United States

Location

University of North Carolina Medical Center

Chapel Hill, North Carolina, 27514, United States

Location

Atrium Health Levine Cancer Institute

Charlotte, North Carolina, 28204, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

Cancercare Manitoba/Winnipeg Children's Hospital

Winnipeg, Manitoba, Canada

Location

Centre Hospitalier Universitaire Sainte-Justine

Montreal, Quebec, Canada

Location

Related Publications (1)

• Leonard A, Furstenau D, Abraham A, Darbari DS, Nickel RS, Limerick E, Fitzhugh C, Hsieh M, Tisdale JF. Reduction in vaso-occlusive events following stem cell transplantation in patients with sickle cell disease. Blood Adv. 2023 Jan 24;7(2):227-234. doi: 10.1182/bloodadvances.2022008137.

  PMID: 36240296 DERIVED

MeSH Terms

Conditions

Anemia, Sickle Cell

Interventions

Alemtuzumab; fludarabine; fludarabine phosphate; Melphalan

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

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

Study Officials

• Ann Haight, MD

  Emory University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: July 10, 2019
• First Posted: July 15, 2019
• Study Start: March 22, 2019
• Primary Completion (Estimated): November 1, 2026
• Study Completion (Estimated): November 1, 2026
• Last Updated: November 25, 2024

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (13); CA (2)