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

Sickle Cell Disease Clinical Trial

— SUN  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03587272
• Other study ID #: IRB 10322
• Status: Recruiting
• Phase: Phase 2
• Start date: April 17, 2018
• Est. completion date: November 2025

Study information

• Verified date: December 2023
• Source: Children's National Research Institute
• Contact: Robert Nickel, MD
• Phone: 202-476-5000
• Email: RNickel[@]childrensnational.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 30
• Est. completion date: November 2025
• Est. primary completion date: November 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years to 25 Years

Eligibility

Inclusion criteria:

Patients with genotypes hemoglobin SS and Sß0 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, Sß+ 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.

Related Conditions & MeSH terms

• Anemia, Sickle Cell
• Sickle Cell Disease

Intervention

Drug:
• Alemtuzumab, low dose total body irradiation, Sirolimus
The conditioning regimen (SUN regimen) will consist of alemtuzumab 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.

Locations

Country	Name	City	State
Canada	Alberta Children's Hospital	Calgary	Alberta
Canada	The Hospital for Sick Children	Toronto	Ontario
United States	Levine Children's Hospital	Charlotte	North Carolina
United States	Ann & Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	Children's National Health System	Washington	District of Columbia

Sponsors (8)

Lead Sponsor	Collaborator
Robert Nickel	Alberta Children's Hospital, Ann & Robert H Lurie Children's Hospital of Chicago, Levine Children's Hospital, Morgan Stanley Children's Hospital, Nationwide Children's Hospital, The Children's Hospital at Montefiore, The Hospital for Sick Children

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Patient-Reported Outcomes Measurement Information System (PROMIS)	PROMIS assessments of health related quality of life before/after transplant	Day +30, and day +100 post transplant
Other	Platelet transfusion	Number of platelet transfusions	100 days post transplant
Primary	Acute GVHD	Acute grade II-IV GVHD	100 days post transplant
Secondary	PedsQL 4.0 Measurement model for the Pediatric Quality of Life Inventory	PedsQL 4.0 assessments of health related quality of life before/after transplant	Day +30, and day +100 post transplant