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Study of HLA-Haploidentical Stem Cell Transplantation to Treat Clinically Aggressive Sickle Cell Disease

Primary Purpose

Sickle Cell Disease

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
ATG
fludarabine
cyclophosphamide
Total body irradiation
Stem cell infusion
Sirolimus
mycophenolate mofetil
Sponsored by
University of Illinois at Chicago
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Sickle Cell Disease

Eligibility Criteria

16 Years - 60 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Patient Eligibility:

  1. Patients with sickle cell disease are eligible if they have any of the following complications:

    1.1 Stroke or central nervous system event lasting longer than 24 hours 1.2 Frequent vaso-occlusive pain episodes, defined as ≥ 3 per year requiring emergency room, acute care center, hospital admissions, or home bedrest leading to absence from work or school. 1.3 Recurrent episodes of priapism, defined as ≥ 2 per year requiring emergency room visits 1.4 Acute chest syndrome with recurrent hospitalizations, defined as ≥ 2 lifetime events 1.5 Red-cell alloimmunization (≥ 2 antibodies) during long-term transfusion therapy 1.6 Bilateral proliferative retinopathy with major visual impairment in at least one eye 1.7 Osteonecrosis of 2 or more joints 1.8 Sickle cell nephropathy, defined by a GFR < 90mL/min/1.73m2 or the presence of macroalbuminuria (urine albumin > 300 mg/g creatinine) 1.9 Pulmonary hypertension, defined by a mean pulmonary arterypressure >25mmHg

  2. Age 16-60 years
  3. Karnofsky performance status of 60 or higher (Appendix A)
  4. Adequate cardiac function, defined as left ventricular ejection fraction ≥ 40%
  5. Adequate pulmonary function, defined as diffusion lung capacity of carbon monoxide ≥ 50% predicted (after adjustment for hemoglobin concentration)
  6. Estimated GFR ≥ 50mL/min/1.73m2 as calculated by the modified MDRD equation
  7. ALT ≤ 3x upper limit of normal
  8. HIV-negative
  9. Patient is not pregnant
  10. Patient is able and willing to sign informed consent
  11. Patient does not have a fully HLA-matched sibling donor
  12. Patient has an HLA-haploidentical relative

Donor Eligibility Relatives (parents, offspring, siblings, aunts/uncles, cousins) will be tested by molecular typing of HLA class I (A, B, and C) and class II (DRB1) at low resolution. Only those that are an HLA-haploidentical match (≥ 4/8) will be considered as a potential donor. NOTE: If during testing, a fully HLA-matched sibling donor is found and is willing to donate his/her stem cells, the potential subject will not be eligible for this protocol.

Donor consent will be obtained as per standard protocol of the bone marrow transplant unit.

Sites / Locations

  • University of Illinois at ChicagoRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Subject treatment

Arm Description

Patients will receive the following conditioning regimen: ATG, fludarabine (6 days before stem cell infusion), cyclophosphamide, and total body irradiation. The stem cell product will be infused according to BMT unit policy. Patients will also receive GVHD prophylaxis which will consist of cyclophosphamide, sirolimus, and mycophenolate mofetil according to the protocol. Post-transplant evaluation will be done as per standard care with study data collected at days 30, 60, 100, 180, 365, and annually thereafter.

Outcomes

Primary Outcome Measures

Estimate the number of patients who engraft by Day +60
Patients who achieve < 5% peripheral blood donor chimerism by Day +30 and do not have a Day +60 measure will be regarded as failing to achieve full donor chimerism by Day +60; patients who achieve > 5% donor chimerism by Day +30 but do not have a Day +60 measure will be considered nonevaluable for the primary endpoint.

Secondary Outcome Measures

Disease free survival
Using the Kaplan-Meier method, the probability of EFS will be estimated and reported with 90% confidence intervals. The proportion of patients who are alive will also be estimated with a 90% exact binomial confidence interval. Cumulative incidences of transplant related mortality will be estimated separately using Grey's method.
Overall survival
Using the Kaplan-Meier method, the probability of overall survival will be estimated and reported with 90% confidence intervals. The proportion of patients who are alive will also be estimated with a 90% exact binomial confidence interval. Cumulative incidences of transplant related mortality will be estimated separately using Grey's method.
Adverse Effects
The cumulative incidence of acute (grade II-IV, grade III-IV) and chronic GVHD will be estimated through competing-risk analysis using Grey's method, wherein graft failure, and death are competing risks for GVHD. Other selected toxicities (including rates of infection) will be reported descriptively.

Full Information

First Posted
April 14, 2017
Last Updated
October 27, 2022
Sponsor
University of Illinois at Chicago
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1. Study Identification

Unique Protocol Identification Number
NCT03121001
Brief Title
Study of HLA-Haploidentical Stem Cell Transplantation to Treat Clinically Aggressive Sickle Cell Disease
Official Title
A Phase II Study of HLA-Haploidentical Stem Cell Transplantation to Treat Clinically Aggressive Sickle Cell Disease
Study Type
Interventional

2. Study Status

Record Verification Date
October 2022
Overall Recruitment Status
Recruiting
Study Start Date
March 20, 2017 (Actual)
Primary Completion Date
September 12, 2023 (Anticipated)
Study Completion Date
September 12, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Illinois at Chicago

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.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The study is a Phase II clinical trial. Patients will receive intensity modulated total body irradiation (TBI) at a dose of 3 Gy with standard fludarabine/ i.v. cyclophosphamide conditioning prior to human leukocyte antigen (HLA)-haploidentical hematopoietic stem cell transplant (HSCT). The primary objective of the study is to determine the engraftment at Day +60 following HLA-haploidentical hematopoietic stem cell transplant protocol using immunosuppressive agents and low-dose total body irradiation (TBI) for conditioning and post-transplant cyclophosphamide in patients with sickle cell disease.

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
50 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Subject treatment
Arm Type
Experimental
Arm Description
Patients will receive the following conditioning regimen: ATG, fludarabine (6 days before stem cell infusion), cyclophosphamide, and total body irradiation. The stem cell product will be infused according to BMT unit policy. Patients will also receive GVHD prophylaxis which will consist of cyclophosphamide, sirolimus, and mycophenolate mofetil according to the protocol. Post-transplant evaluation will be done as per standard care with study data collected at days 30, 60, 100, 180, 365, and annually thereafter.
Intervention Type
Drug
Intervention Name(s)
ATG
Other Intervention Name(s)
Thymoglobulin®
Intervention Description
0.5 mg/kg IV on day -9, and 2 mg/kg on days -8 and day -7
Intervention Type
Drug
Intervention Name(s)
fludarabine
Intervention Description
30 mg/m2 IVPB daily for day -6 (6 days before stem cell infusion) through day -2
Intervention Type
Drug
Intervention Name(s)
cyclophosphamide
Intervention Description
14.5 mg/kg IV on days -6 and -5 and 50 mg/kg/d on days +3 and +4
Intervention Type
Radiation
Intervention Name(s)
Total body irradiation
Intervention Description
3 Gy on day -1
Intervention Type
Procedure
Intervention Name(s)
Stem cell infusion
Intervention Description
Stem cell product infused according to BMT unit policy on day 0.
Intervention Type
Drug
Intervention Name(s)
Sirolimus
Intervention Description
loading dose of 15 mg followed by 5 mg per day on day +5
Intervention Type
Drug
Intervention Name(s)
mycophenolate mofetil
Intervention Description
1 g every 8 h (until day 35) will be started on day 5
Primary Outcome Measure Information:
Title
Estimate the number of patients who engraft by Day +60
Description
Patients who achieve < 5% peripheral blood donor chimerism by Day +30 and do not have a Day +60 measure will be regarded as failing to achieve full donor chimerism by Day +60; patients who achieve > 5% donor chimerism by Day +30 but do not have a Day +60 measure will be considered nonevaluable for the primary endpoint.
Time Frame
Up to Day +60
Secondary Outcome Measure Information:
Title
Disease free survival
Description
Using the Kaplan-Meier method, the probability of EFS will be estimated and reported with 90% confidence intervals. The proportion of patients who are alive will also be estimated with a 90% exact binomial confidence interval. Cumulative incidences of transplant related mortality will be estimated separately using Grey's method.
Time Frame
Up to Day +60
Title
Overall survival
Description
Using the Kaplan-Meier method, the probability of overall survival will be estimated and reported with 90% confidence intervals. The proportion of patients who are alive will also be estimated with a 90% exact binomial confidence interval. Cumulative incidences of transplant related mortality will be estimated separately using Grey's method.
Time Frame
Up to Day +60
Title
Adverse Effects
Description
The cumulative incidence of acute (grade II-IV, grade III-IV) and chronic GVHD will be estimated through competing-risk analysis using Grey's method, wherein graft failure, and death are competing risks for GVHD. Other selected toxicities (including rates of infection) will be reported descriptively.
Time Frame
Up to Day +60

10. Eligibility

Sex
All
Minimum Age & Unit of Time
16 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Patient Eligibility: Patients with sickle cell disease are eligible if they have any of the following complications: 1.1 Stroke or central nervous system event lasting longer than 24 hours 1.2 Frequent vaso-occlusive pain episodes, defined as ≥ 3 per year requiring emergency room, acute care center, hospital admissions, or home bedrest leading to absence from work or school. 1.3 Recurrent episodes of priapism, defined as ≥ 2 per year requiring emergency room visits 1.4 Acute chest syndrome with recurrent hospitalizations, defined as ≥ 2 lifetime events 1.5 Red-cell alloimmunization (≥ 2 antibodies) during long-term transfusion therapy 1.6 Bilateral proliferative retinopathy with major visual impairment in at least one eye 1.7 Osteonecrosis of 2 or more joints 1.8 Sickle cell nephropathy, defined by a GFR < 90mL/min/1.73m2 or the presence of macroalbuminuria (urine albumin > 300 mg/g creatinine) 1.9 Pulmonary hypertension, defined by a mean pulmonary arterypressure >25mmHg Age 16-60 years Karnofsky performance status of 60 or higher (Appendix A) Adequate cardiac function, defined as left ventricular ejection fraction ≥ 40% Adequate pulmonary function, defined as diffusion lung capacity of carbon monoxide ≥ 50% predicted (after adjustment for hemoglobin concentration) Estimated GFR ≥ 50mL/min/1.73m2 as calculated by the modified MDRD equation ALT ≤ 3x upper limit of normal HIV-negative Patient is not pregnant Patient is able and willing to sign informed consent Patient does not have a fully HLA-matched sibling donor Patient has an HLA-haploidentical relative Donor Eligibility Relatives (parents, offspring, siblings, aunts/uncles, cousins) will be tested by molecular typing of HLA class I (A, B, and C) and class II (DRB1) at low resolution. Only those that are an HLA-haploidentical match (≥ 4/8) will be considered as a potential donor. NOTE: If during testing, a fully HLA-matched sibling donor is found and is willing to donate his/her stem cells, the potential subject will not be eligible for this protocol. Donor consent will be obtained as per standard protocol of the bone marrow transplant unit.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Damiano Rondelli, MD
Phone
312 413-3547
Email
drond@uic.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Damiano Rondelli, MD
Organizational Affiliation
University of Illinois at Chicago
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Illinois at Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60612
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Damiano Rondelli, MD
Phone
312-413-3547
Email
drond@uic.edu

12. IPD Sharing Statement

Learn more about this trial

Study of HLA-Haploidentical Stem Cell Transplantation to Treat Clinically Aggressive Sickle Cell Disease

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