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

Primary Purpose

Sickle Cell Disease

Status

Recruiting

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

Alemtuzumab intravenously, low dose total body irradiation, Sirolimus

About this trial

This is an interventional treatment trial for Sickle Cell Disease

Eligibility Criteria

2 Years - 25 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Children's National Health SystemRecruiting
Ann & Robert H. Lurie Children's Hospital of ChicagoRecruiting
Levine Children's HospitalRecruiting
Nationwide Children's HospitalRecruiting
Alberta Children's HospitalRecruiting
The Hospital for Sick ChildrenRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

SUN regimen

Arm Description

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).

Outcomes

Primary Outcome Measures

Acute GVHD

Acute grade II-IV GVHD

Secondary Outcome Measures

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

Full Information

NCT ID

NCT03587272

First Posted

June 6, 2018

Last Updated

March 2, 2022

Sponsor

Allistair Abraham, MD

Collaborators

Alberta Children's Hospital, The Hospital for Sick Children, Levine Children's Hospital, Ann & Robert H Lurie Children's Hospital of Chicago

1. Study Identification

Unique Protocol Identification Number

NCT03587272

Brief Title

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

Acronym

SUN

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

March 2022

Overall Recruitment Status

Recruiting

Study Start Date

April 17, 2018 (Actual)

Primary Completion Date

December 2024 (Anticipated)

Study Completion Date

November 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Allistair Abraham, MD

Collaborators

Alberta Children's Hospital, The Hospital for Sick Children, Levine Children's Hospital, Ann & Robert H Lurie Children's Hospital of Chicago

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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).

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Sickle Cell Disease

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

30 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

SUN regimen

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Alemtuzumab intravenously, low dose total body irradiation, Sirolimus

Intervention Description

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 Measure Information:

Title

Acute GVHD

Description

Acute grade II-IV GVHD

Time Frame

100 days post transplant

Secondary Outcome Measure Information:

Title

PedsQL 4.0 Measurement model for the Pediatric Quality of Life Inventory

Description

PedsQL 4.0 assessments of health related quality of life before/after transplant

Time Frame

Day +30, and day +100 post transplant

Other Pre-specified Outcome Measures:

Title

Patient-Reported Outcomes Measurement Information System (PROMIS)

Description

PROMIS assessments of health related quality of life before/after transplant

Time Frame

Day +30, and day +100 post transplant

Title

Platelet transfusion

Description

Number of platelet transfusions

Time Frame

100 days post transplant

10. Eligibility

Sex

All

Minimum Age & Unit of Time

2 Years

Maximum Age & Unit of Time

25 Years

Accepts Healthy Volunteers

Eligibility 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.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Allistair Abraham, MD

Phone

202-476-5000

AAbraham@childrensnational.org

First Name & Middle Initial & Last Name or Official Title & Degree

Robert Nickel, MD

Phone

202-476-5000

RNickel@childrensnational.org

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Allistair Abraham, MD

Organizational Affiliation

Children's National Health System

Official's Role

Principal Investigator

Facility Information:

Facility Name

Children's National Health System

City

Washington

State/Province

District of Columbia

ZIP/Postal Code

20010

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Vivitha Mani

Phone

202-476-6131

vmani@childrensnational.org

First Name & Middle Initial & Last Name & Degree

Fahmida Hoq, MBBS, MS

Phone

202-476-3634

fhoq@childrensnational.org

Facility Name

Ann & Robert H. Lurie Children's Hospital of Chicago

City

Chicago

State/Province

Illinois

ZIP/Postal Code

60611

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Olga Jonas

Phone

312-227-4871

ojonas@luriechildrens.org

First Name & Middle Initial & Last Name & Degree

Ella Ramsey

dramsey@luriechildrens.org

First Name & Middle Initial & Last Name & Degree

Sonali Chaudhury, MD

Facility Name

Levine Children's Hospital

City

Charlotte

State/Province

North Carolina

ZIP/Postal Code

28203

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Janice Hollifield

Phone

980-442-2342

Janice.hollifield@atriumhealth.org

First Name & Middle Initial & Last Name & Degree

Michael Kent, MD

Facility Name

Nationwide Children's Hospital

City

Columbus

State/Province

Ohio

ZIP/Postal Code

43205

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Hemalatha Rangarajan

Phone

614-355-1689

Hemalatha.Rangarajan@nationwidechildrens.org

First Name & Middle Initial & Last Name & Degree

Hemalatha Rangarajan, MD

Facility Name

Alberta Children's Hospital

City

Calgary

State/Province

Alberta

ZIP/Postal Code

T3B 6A8

Country

Canada

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Gregory Guilcher

Phone

1-403-955-7272

Greg.Guilcher@AHS.ca

First Name & Middle Initial & Last Name & Degree

Gregory Guilcher, MD

Facility Name

The Hospital for Sick Children

City

Toronto

State/Province

Ontario

ZIP/Postal Code

M5G 1X8

Country

Canada

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Brandon Rothberg

Phone

416-813-7654

Ext

202042

brandon.rothberg@sickkids.ca

First Name & Middle Initial & Last Name & Degree

KY Chiang, MD

12. IPD Sharing Statement

Learn more about this trial

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

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