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Minimizing Toxicity in HLA-identical Related Donor Transplantation for Children With Sickle Cell Disease (SUN)

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ClinicalTrials.gov Identifier: NCT03587272
Recruitment Status : Recruiting
First Posted : July 16, 2018
Last Update Posted : May 23, 2019
Sponsor:
Collaborators:
Alberta Children's Hospital
The Hospital for Sick Children
Levine Children's Hospital
Ann & Robert H Lurie Children's Hospital of Chicago
Information provided by (Responsible Party):
Allistair Abraham, MD, Children's Research Institute

Brief Summary:
This multisite prospective study seeks to determine if HLA-identical sibling donor transplantation using alemtuzumab, low dose total-body irradiation, and sirolimus (Sickle transplant Using a Nonmyeloablative approach, "SUN") can decrease the toxicity of transplant while achieving a high cure rate for children with sickle cell disease (SCD).

Condition or disease Intervention/treatment Phase
Sickle Cell Disease Drug: Alemtuzumab intravenously, low dose total body irradiation, Sirolimus Phase 2

Detailed Description:
This is a prospective, multicenter phase II study of HLA-identical sibling donor HSCT in 30 pediatric patients with SCD using nonmyeloablative conditioning with alemtuzumab, total-body irradiation, and sirolimus. The primary Objective of this study is to determine if the SUN regimen can decrease the incidence of grade II-IV acute graft-versus host disease (GVHD) by day +100 while maintaining similar disease-free survival compared to establish HLA-identical donor hematopoietic stem cell transplant (HSCT) regimens in children with SCD. The secondary Objective is to determine if health-related quality of life (HRQoL) for children undergoing SUN HSCT is preserved during the early post-transplant time period. To determine if the SUN regimen can decrease the number of platelet transfusions compared to established HLA-identical HSCT regimens in children with SCD. The tertiary/Exploratory Objectives: To describe other markers of toxicity (duration of neutropenia, mucositis, length of hospitalization) and indicators of a successful HSCT (HRQoL at 1 year, proportion needing additional immunosuppression during the first year, proportion able to wean sirolimus at 1 year).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Minimizing Toxicity in HLA-identical Related Donor Transplantation for Children With Sickle Cell Disease
Actual Study Start Date : April 17, 2018
Estimated Primary Completion Date : December 2021
Estimated Study Completion Date : November 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: SUN regimen

Alemtuzumab intravenously, low dose total body irradiation, Sirolimus

HLA-identical sibling donor transplantation using alemtuzumab, low dose total-body irradiation, and sirolimus (Sickle transplant Using a Nonmyeloablative approach, "SUN") can decrease the toxicity of transplant while achieving a high cure rate for children with sickle cell disease (SCD).

Drug: Alemtuzumab intravenously, low dose total body irradiation, Sirolimus

The conditioning regimen (SUN regimen) will consist of alemtuzumab intravenously daily for 5 days (0.03mg/kg on Day -7, 0.1mg/kg on Day -6, 0.3mg/kg on Days -5 to -3) and low dose total body irradiation (TBI) 300 cGY on Day -2 with gonadal shielding if possible. The HSCT graft will be G-CSF mobilized PBSCs with minimum CD34+ of 5 x106/kg recipient weight, goal of 10 x 106/kg (no upper limit). A peripheral blood stem cell (PBSC) graft was selected as it engrafts faster than bone marrow and would lead to shorter period of neutropenia and infection and less thrombocytopenia and need for platelet transfusion.

GVHD prophylaxis will be sirolimus with a loading dose 3 mg/m2 on day -1. Sirolimus will be continued at 1 mg/m2/day starting on day 0 and dose adjusted to maintain a target trough level 5-15 ng/mL for the first 3 months and 5-10 ng/mL for the remainder of the first year.





Primary Outcome Measures :
  1. Acute GVHD [ Time Frame: 100 days post transplant ]
    Acute grade II-IV GVHD


Secondary Outcome Measures :
  1. PedsQL 4.0 Measurement model for the Pediatric Quality of Life Inventory [ Time Frame: Day +30, and day +100 post transplant ]
    PedsQL 4.0 assessments of health related quality of life before/after transplant


Other Outcome Measures:
  1. Patient-Reported Outcomes Measurement Information System (PROMIS) [ Time Frame: Day +30, and day +100 post transplant ]
    PROMIS assessments of health related quality of life before/after transplant

  2. Platelet transfusion [ Time Frame: 100 days post transplant ]
    Number of platelet transfusions



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Ages Eligible for Study:   2 Years to 25 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria:

Patients with genotypes hemoglobin SS and Sβ0 thalassemia must have at least one of the following:

  • History of an abnormal transcranial Doppler measurement defined as TCD velocity ≥200 cm/sec by the non-imaging technique (or ≥185 cm/sec by the imaging technique) measured at a minimum of two separate occasions.
  • History of cerebral infarction on brain MRI (overt stroke, or silent stroke if ≥3 mm in one dimension, visible in two planes on fluid-attenuated inversion recovery T2-weighted images).
  • History of two or more episodes of acute chest syndrome (ACS) in lifetime.
  • History of three or more SCD pain events requiring treatment with an opiate or IV pain medication (inpatient or outpatient) in lifetime.
  • History of any hospitalization for SCD pain or ACS while receiving hydroxyurea treatment.
  • History of two or more episodes of priapism (erection lasting ≥4 hours or requiring emergent medical care).
  • Administration of regular RBC transfusions (≥8 transfusions in the previous 12 months).
  • At least two episodes of splenic sequestration requiring red blood cell transfusion or splenectomy after at least one episode of splenic sequestration.

Patients with all other sickle genotypes (hemoglobin SC, Sβ+ thalassemia) must have at least one of the following:

  • Clinically significant neurologic event (overt stroke).
  • History of two or more episodes of ACS in the 2-years period preceding enrollment.
  • History of three or more SCD pain events requiring treatment with an opiate or IV pain medication (inpatient or outpatient) in the 1-year period preceding enrollment.
  • History of any hospitalization for SCD pain or ACS while receiving hydroxyurea treatment.
  • History of two or more episodes of priapism (erection lasting ≥4 hours or requiring emergent medical care).
  • Administration of regular RBC transfusions (≥8 transfusions in the previous 12 months).
  • At least two episodes of splenic sequestration requiring red blood cell transfusion or splenectomy after at least one episode of splenic sequestration.

Exclusion Criteria:

  • • General: Life expectancy less than 6 months. Pregnant or breastfeeding patients.
  • Infection Disease: Uncontrolled bacterial, viral or fungal infections (undergoing appropriate treatment and with progression of clinical symptoms) within 1 month prior to conditioning. Patients with febrile illness or suspected minor infection should await clinical resolution prior to starting conditioning. Patients with confirmed seropositivity for HIV and patients with active Hepatitis B or C determined by serology and/or NAAT are excluded.
  • Liver: Direct (conjugated) bilirubin > 1.5 mg/dL, transaminases >5x upper limit of normal for age.
  • Cardiac: Left ventricular shortening fraction <25% or ejection fraction <50% by ECHO.
  • Kidney: Estimated creatinine clearance less than 60 mL/min/1.73m2.
  • Pulmonary function: Diffusion capacity of carbon monoxide (DLCO) <35% (adjusted for hemoglobin). Baseline oxygen saturation <85% or PaO2 <70.
  • Heme: History of RBC alloantibodies against donor RBC antigens (even if current antibody screen is negative). Major ABO incompatibility with donor.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03587272


Contacts
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Contact: Allistair Abraham, MD 202-476-5000 AAbraham@childrensnational.org
Contact: Robert Nickel, MD 202-476-5000 RNickel@childrensnational.org

Locations
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United States, District of Columbia
Children's National Health System Recruiting
Washington, District of Columbia, United States, 20010
Contact: Jeremy Zack    202-476-6131    jzack@childrensnational.org   
Contact: Fahmida Hoq, MBBS, MS    202-476-3634    fhoq@childrensnational.org   
United States, Illinois
Ann & Robert H. Lurie Children's Hospital of Chicago Recruiting
Chicago, Illinois, United States, 60611
Contact: Olga Jonas    312-227-4871    ojonas@luriechildrens.org   
Contact: Ella Ramsey       dramsey@luriechildrens.org   
Principal Investigator: Sonali Chaudhury, MD         
United States, North Carolina
Levine Children's Hospital Recruiting
Charlotte, North Carolina, United States, 28203
Contact: Janice Hollifield    980-442-2342    Janice.hollifield@atriumhealth.org   
Principal Investigator: Michael Kent, MD         
Sponsors and Collaborators
Allistair Abraham, MD
Alberta Children's Hospital
The Hospital for Sick Children
Levine Children's Hospital
Ann & Robert H Lurie Children's Hospital of Chicago
Investigators
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Principal Investigator: Allistair Abraham, MD Children's National Health System

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Responsible Party: Allistair Abraham, MD, Principal Investigator, Children's Research Institute
ClinicalTrials.gov Identifier: NCT03587272     History of Changes
Other Study ID Numbers: IRB 10322
First Posted: July 16, 2018    Key Record Dates
Last Update Posted: May 23, 2019
Last Verified: May 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Anemia, Sickle Cell
Hematologic Diseases
Genetic Diseases, Inborn
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hemoglobinopathies
Sirolimus
Everolimus
Alemtuzumab
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antineoplastic Agents
Antifungal Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Immunological