Reduced Intensity Transplantation for Severe Sickle Cell Disease
Primary Purpose
Sickle Cell Disease
Status
Suspended
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
hydroxyurea, azathioprine, alemtuzumab, thioptepa, low dose total body irradiation and sirolimus
hydroxyurea, azathioprine, alemtuzumab, thiotepa, plerixafor, low dose total body irradiation, cyclophosphamide and sirolimus
Sponsored by
About this trial
This is an interventional treatment trial for Sickle Cell Disease
Eligibility Criteria
Inclusion Criteria for Transplant Recipient
- Age less than or equal to 25 years.
- Patients with a suitable HLA-matched sibling donor (MSD) can be enrolled on MSD arm of the trial. Patients with single haplotype matched (≥ 3 of 6) family member donor can be enrolled on HAPLO arm of the trial, if they do not have a suitable HLA-matched sibling donor (MSD) available for progenitor cell donation.
Patients with SCD (any genotype) who meet any ONE of the following criteria:
- 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 the 2-years period preceding enrollment.
- History of two or more SCD pain events requiring treatment with an opiate or IV pain medication (inpatient or outpatient) in the last 12 months.
- History of any hospitalization for SCD pain or ACS while receiving hydroxyurea treatment in the last 12 months.
- 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 for Transplant Recipient
- Karnofsky or Lansky performance score <60.
- Pregnant or breastfeeding patients.
- 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 or positive NAAT for HIV are excluded.
- Serum conjugated (direct) bilirubin >3x upper limit of normal for age or serum ALT >5x upper limit of normal for age as per local laboratory. Participants with hyperbilirubinemia or elevated AST as the result of hyperhemolysis, or a severe drop in hemoglobin post blood transfusion, are not excluded as long as these values downtrend and return to acceptable limits subsequently.
- Left ventricular shortening fraction <25% or ejection fraction <40% by echocardiogram.
- Estimated creatinine clearance less than 50 mL/min/1.73m2.
- Diffusion capacity of carbon monoxide (DLCO) <35% (adjusted for hemoglobin). Baseline oxygen saturation <85% or PaO2 <70.
- History of RBC alloantibodies against donor RBC antigens (even if current antibody screen is negative).
- Presence of high titer anti-donor specific HLA antibodies should be carefully evaluated, and desensitization considered prior to transplantation. HLA antibody presence and specificity will be determined by solid phase immunoassays. An anti-donor specific HLA antibody will be considered positive when the mean fluorescence intensity (MFI) is >1000 for donor specific antibody to HLA-A, -B, and DRB1 and MFI >2000 for HLA-C, DQB1 and DPB1. Patients with borderline elevated anti-donor specific HLA antibodies may be considered for inclusion in consultation with the PIs.
Inclusion Criteria for Donor
- An HLA-matched sibling donor for MSD arm and at least single haplotype matched (≥ 3 of 6) family member for HAPLO arm.
- HIV negative.
- Not pregnant as confirmed by negative serum or urine pregnancy test within 14 days prior to enrollment (if female).
- Not breast feeding.
- Donor should not have clinically significant hemoglobinopathy. Donors with sickle cell trait are acceptable.
Sites / Locations
- St. Jude Children's Research Hospital
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Matched Sibling Donor (MSD)
Haploidentical (HAPLO)
Arm Description
Patients with a suitable HLA matched sibling donor (MSD) will be enrolled on the MSD arm.
Patients without an eligible MSD who have a suitable haploidentical (HAPLO) donor available will be enrolled on the HAPLO arm of the study.
Outcomes
Primary Outcome Measures
Donor T-cell chimerism at 1-year post transplant in each respective arm (MSD, HAPLO) of the trial.
Number of participants who have achieved donor T-cell chimerism greater than 60% by 1-year post transplant will be reported. The rate of success will be checked for in each arm after the first 10 evaluable patients have been enrolled and followed for up to 1 year.
Secondary Outcome Measures
Overall survival and 1-year, 2-year and 3-year post-transplant graft versus host disease (GVHD)-free SCD-free survival.
Graft versus host disease (GVHD)-free SCD-free survival in each arm of the trial will be calculated at 1-year, 2-year and 3-year post-transplant and reported as a percentage of the enrolled patients.
Graft rejection rate.
Primary and secondary graft rejection rate at 1-year, 2-year and 3-year post- transplant in each arm or the trial will be calculated and reported as a percentage of the enrolled patients.
Incidence and severity of acute and chronic (GVHD).
The incidence and severity of acute and chronic (GVHD) in each arm or the trial will be calculated and reported as a percentage of the enrolled patients.
Incidence of SCD recurrence after transplant.
The incidence of SCD recurrence after transplant in each arm or the trial will be calculated and reported as a percentage of the enrolled patients.
Neutrophil and platelet recovery.
Number of patients who engraft their neutrophils and platelets by 6 months in each arm or the trial will be calculated and reported as a percentage of the enrolled patients.
Full Information
NCT ID
NCT04362293
First Posted
April 13, 2020
Last Updated
August 1, 2023
Sponsor
St. Jude Children's Research Hospital
1. Study Identification
Unique Protocol Identification Number
NCT04362293
Brief Title
Reduced Intensity Transplantation for Severe Sickle Cell Disease
Official Title
Reduced Intensity Related Donor Peripheral Blood Derived Hematopoietic Progenitor Cell Transplantation for Patients With Severe Sickle Cell Disease
Study Type
Interventional
2. Study Status
Record Verification Date
August 2023
Overall Recruitment Status
Suspended
Why Stopped
We are holding enrollment, due to some recent SAEs.
Study Start Date
April 30, 2020 (Actual)
Primary Completion Date
July 1, 2024 (Anticipated)
Study Completion Date
July 1, 2025 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
St. Jude Children's Research Hospital
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
No
5. Study Description
Brief Summary
This study is being done to test a transplant method that may have fewer side effects (or less toxic, less harmful) than conventional high dose chemotherapy conditioning-based transplants for children and young adults with Sickle Cell Disease (SCD). Patients less than or equal to 25 years old with SCD who would likely benefit from allogeneic hematopoietic cell transplantation (HCT) will be included in this study. Patients with a suitable HLA matched sibling donor (MSD) will be enrolled on the MSD arm while patients without an eligible MSD who have a suitable haploidentical (HAPLO) donor available will be enrolled on the HAPLO arm of the study.
Primary Objective
To assess the donor T-cell chimerism at 1-year post transplant in each respective arm (MSD, HAPLO) of the trial.
Secondary Objectives
Assess the overall survival and 1-year, 2-year and 3-year post-transplant graft versus host disease (GVHD)-free SCD-free survival.
Estimate the primary and secondary graft rejection rate at 1-year, 2-year and 3-year post- transplant.
Estimate the incidence and severity of acute and chronic (GVHD).
Estimate the incidence of SCD recurrence after transplant
Assess the neutrophil and platelet recovery kinetics post-transplant.
Exploratory Objectives
Record immune reconstitution parameters, including chimerism analysis, quantitative lymphocyte subsets, T cell receptor excision circle (TREC) analysis, V-beta spectratyping, and lymphocyte phenotype and function.
Conduct longitudinal examination of impact of HCT on patient health-related quality of life (HRQL) and adjustment, and parental adjustment.
Examine impact of HCT on patient cognitive and academic function.
Determine factors that influenced the decision to undergo HCT, explore perceptions of the HCT experience, and assess decisional satisfaction/regret.
Develop and evaluate an objective/quantitative imaging biomarker to assess organ (liver and heart) function/disease status and changes following HCT.
Develop and evaluate an objective/quantitative imaging biomarker to determine cerebral blood flow and oxygen extraction fraction following HCT.
Detailed Description
This is a prospective single center phase II study of a reduced intensity conditioning based hematopoietic cell transplant for patients with sickle cell disease. In this study, patients with SCD who would be expected to benefit from an allogeneic HCT will receive an unmanipulated peripheral blood derived hematopoietic stem and progenitor cell (HSPC) graft from either an MSD or HAPLO donor after a reduced intensity conditioning regimen comprising of alemtuzumab, thiotepa and low dose total body irradiation. All patients will receive a pre-conditioning phase comprising of hydroxyurea and azathioprine to reduce the risk of graft rejection. GVHD prophylaxis will consist of sirolimus. Patients on the HAPLO arm will also receive two doses of post-transplant cyclophosphamide. All patients will receive regularly scheduled low dose donor lymphocyte infusions till donor lymphocyte chimerism reaches at least 90% donor. The main objective of this study is to improve graft function and immune reconstitution after a reduced intensity conditioning based transplant.
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
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
40 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Matched Sibling Donor (MSD)
Arm Type
Experimental
Arm Description
Patients with a suitable HLA matched sibling donor (MSD) will be enrolled on the MSD arm.
Arm Title
Haploidentical (HAPLO)
Arm Type
Experimental
Arm Description
Patients without an eligible MSD who have a suitable haploidentical (HAPLO) donor available will be enrolled on the HAPLO arm of the study.
Intervention Type
Drug
Intervention Name(s)
hydroxyurea, azathioprine, alemtuzumab, thioptepa, low dose total body irradiation and sirolimus
Intervention Description
The conditioning regimen will consist of hydroxyurea (30mg/Kg) and azathioprine (3mg/Kg) by mouth daily from day -60 to day -8, alemtuzumab subcutaneously daily for 5 days (0.03mg/kg on Day -7, 0.1mg/kg on Day -6, 0.3mg/kg on days -5 to -3), thiotepa intravenously (10mg/Kg) on day -3 and low dose total body irradiation (TBI) 200 cGY on day -2 with gonadal shielding (if possible). The HSCT graft will be G-CSF mobilized PBSCs with minimum CD34+ of 5 x10^6/kg recipient weight.
GVHD prophylaxis will be sirolimus with a loading dose 3 mg/m2 on day -1. Sirolimus dose will be adjusted to maintain a target trough level 5-15 ng/mL. Low dose donor lymphocyte infusions will begin on day +28 and continue till donor lymphocyte chimerism reaches at least 90% donor.
Intervention Type
Drug
Intervention Name(s)
hydroxyurea, azathioprine, alemtuzumab, thiotepa, plerixafor, low dose total body irradiation, cyclophosphamide and sirolimus
Intervention Description
The conditioning regimen will consist of hydroxyurea (30mg/Kg) and azathioprine (3mg/Kg) by mouth daily from day -60 to day -8, alemtuzumab subcutaneously daily for 5 days (0.03mg/kg on Day -7, 0.1mg/kg on Day -6, 0.3mg/kg on days -5 to -3), thiotepa intravenously (10mg/Kg) on day -3, plerixafor (0.24mg/Kg) subcutaneously every 12 hours on days -3 and -2 and low dose total body irradiation (TBI) 200 cGY on days -2 and -1 with gonadal shielding (if possible). The HSCT graft will be G-CSF mobilized PBSCs with minimum CD34+ of 5 x10^6/kg recipient weight.
GVHD prophylaxis will be cyclophosphamide (50mg/Kg) intravenously on days +3 and +4 and sirolimus with a loading dose 3 mg/m2 starting on day +5. Sirolimus dose will be adjusted to maintain a target trough level 5-15 ng/mL. Low dose donor lymphocyte infusions will begin on day +28 and continue till donor lymphocyte chimerism reaches at least 90% donor.
Primary Outcome Measure Information:
Title
Donor T-cell chimerism at 1-year post transplant in each respective arm (MSD, HAPLO) of the trial.
Description
Number of participants who have achieved donor T-cell chimerism greater than 60% by 1-year post transplant will be reported. The rate of success will be checked for in each arm after the first 10 evaluable patients have been enrolled and followed for up to 1 year.
Time Frame
1 year after HCT
Secondary Outcome Measure Information:
Title
Overall survival and 1-year, 2-year and 3-year post-transplant graft versus host disease (GVHD)-free SCD-free survival.
Description
Graft versus host disease (GVHD)-free SCD-free survival in each arm of the trial will be calculated at 1-year, 2-year and 3-year post-transplant and reported as a percentage of the enrolled patients.
Time Frame
Up to 3 years after HCT
Title
Graft rejection rate.
Description
Primary and secondary graft rejection rate at 1-year, 2-year and 3-year post- transplant in each arm or the trial will be calculated and reported as a percentage of the enrolled patients.
Time Frame
Up to 3 years after HCT
Title
Incidence and severity of acute and chronic (GVHD).
Description
The incidence and severity of acute and chronic (GVHD) in each arm or the trial will be calculated and reported as a percentage of the enrolled patients.
Time Frame
Up to 3 years after HCT
Title
Incidence of SCD recurrence after transplant.
Description
The incidence of SCD recurrence after transplant in each arm or the trial will be calculated and reported as a percentage of the enrolled patients.
Time Frame
Up to 3 years after HCT
Title
Neutrophil and platelet recovery.
Description
Number of patients who engraft their neutrophils and platelets by 6 months in each arm or the trial will be calculated and reported as a percentage of the enrolled patients.
Time Frame
Up to 6 months after HCT
10. Eligibility
Sex
All
Minimum Age & Unit of Time
2 Years
Maximum Age & Unit of Time
25 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria for Transplant Recipient
Age less than or equal to 25 years.
Patients with a suitable HLA-matched sibling donor (MSD) can be enrolled on MSD arm of the trial. Patients with single haplotype matched (≥ 3 of 6) family member donor can be enrolled on HAPLO arm of the trial, if they do not have a suitable HLA-matched sibling donor (MSD) available for progenitor cell donation.
Patients with SCD (any genotype) who meet any ONE of the following criteria:
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 the 2-years period preceding enrollment.
History of two or more SCD pain events requiring treatment with an opiate or IV pain medication (inpatient or outpatient) in the last 12 months.
History of any hospitalization for SCD pain or ACS while receiving hydroxyurea treatment in the last 12 months.
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 for Transplant Recipient
Karnofsky or Lansky performance score <60.
Pregnant or breastfeeding patients.
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 or positive NAAT for HIV are excluded.
Serum conjugated (direct) bilirubin >3x upper limit of normal for age as per local laboratory. Participants with hyperbilirubinemia or elevated AST as the result of hyperhemolysis, or a severe drop in hemoglobin post blood transfusion, are not excluded as long as it downtrends and return to acceptable limits subsequently.
Left ventricular shortening fraction <25% or ejection fraction <40% by echocardiogram.
Estimated creatinine clearance less than 50 mL/min/1.73m2.
Diffusion capacity of carbon monoxide (DLCO) <35% (adjusted for hemoglobin). Baseline oxygen saturation <85% or PaO2 <70.
Presence of anti-donor specific HLA antibodies unresponsive to desensitization as defined below.
HLA antibody presence and specificity will be determined by solid phase immunoassays. An anti-donor specific HLA antibody test will be considered positive when the mean fluorescence intensity (MFI) is:
>1,000 for donor specific antibodies to HLA-A, -B, and DRB1. or
>2,000 for donor specific antibodies to HLA-C, DQB1 and DPB1.
A participant with presence of anti-donor specific HLA antibodies may be provisionally enrolled on the study if desensitization (see Appendix H) is begun concurrently with pre-conditioning. Response to desensitization will be defined as:
decreasing anti-donor specific HLA antibody titer with an MFI of less than 5,000 and
negative C1q-binding anti-HLA antibody assay.
Inclusion Criteria for Donor
An HLA-matched sibling donor for MSD arm and at least single haplotype matched (≥ 3 of 6) family member for HAPLO arm.
HIV negative.
Not pregnant as confirmed by negative serum or urine pregnancy test within 14 days prior to enrollment (if female).
Not breast feeding.
Donor should not have clinically significant hemoglobinopathy. Donors with sickle cell trait are acceptable.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Akshay Sharma, MBBS
Organizational Affiliation
St. Jude Children's Research Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
St. Jude Children's Research Hospital
City
Memphis
State/Province
Tennessee
ZIP/Postal Code
38105
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
Individual participant de-identified datasets containing the variables analyzed in the published article will be made available (related to the study primary or secondary objectives contained in the publication). Supporting documents such as the protocol, statistical analyses plan, and informed consent are available through the CTG website for the specific study. Data used to generate the published article will be made available at the time of article publication. Investigators who seek access to individual level de-identified data will contact the computing team in the Department of Biostatistics (ClinTrialDataRequest@stjude.org) who will respond to the data request.
IPD Sharing Time Frame
Data will be made available at the time of article publication.
IPD Sharing Access Criteria
Data will be provided to researchers following a formal request with the following information: full name of requestor, affiliation, data set requested, and timing of when data is needed. As an informational point, the lead statistician and study principal investigator will be informed that primary results datasets have been requested.
Links:
URL
http://www.stjude.org
Description
St. Jude Children's Research Hospital
URL
http://www.stjude.org/protocols
Description
Clinical Trials Open at St. Jude
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Reduced Intensity Transplantation for Severe Sickle Cell Disease
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