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Nonmyeloablative Haploidentical Peripheral Blood Mobilized Hematopoietic Precursor Cell Transplantation for Sickle Cell Disease

Primary Purpose

Sickle Cell Disease

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
haploidentical stem cell transplant
sirolimus
campath
pentostatin
cyclophosphamide
Hydroxyurea
Sponsored by
National Heart, Lung, and Blood Institute (NHLBI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Sickle Cell Disease focused on measuring Peripheral Blood Stem Cells, Host-Donor Chimerism, Graft-Versus-Host Disease, Haploidentical, Donor Apheresis

Eligibility Criteria

2 Years - undefined (Child, Adult, Older Adult)All SexesAccepts Healthy Volunteers
  • INCLUSION CRITERIA-RECIPIENTS:

Patients with any type of sickle cell disease who are at high risk for disease-related cerebrovascular morbidity or early mortality, defined by having severe end-organ damage (A, B, C, D, or E):

A. A neurologic event resulting in focal neurologic deficits that lasted >= 24 hours (classical clinical definition of stroke, not requiring imaging studies of the brain) OR a focal neurological event resulting in abnormalities on T2- weighted or FLAIR images using an MRI scan, indicative of an acute infarct, with no other reasonable medical explanation (definition of a stroke supported with MRI imaging scans of the brain), OR both; OR

B. Tricuspid regurgitant jet velocity (TRV) of >= 2.7 m/s at baseline (without vaso- occlusive crisis) and/or pulmonary hypertension; OR

C. Sickle hepatopathy defined as either ferritin >1000 mcg/L and platelet count < 250,000/uL (without vaso-occlusive crisis) OR direct bilirubin > 0.4 mg/dL and platelet count <250,000/uL (without vaso- occlusive crisis)

D. Any acute chest syndrome episode resulting in intensive care admission requiring non- mechanical ventilatory support: simple nasal cannula, face mask that requires oxygen content (venti mask, non-rebreather), continuous positive airway pressure (CPAP), Bilevel positive airway pressure (BiPAP), high flow nasal cannula (HFNC) or invasive mechanical ventilatory support (delivered by endotracheal tube or tracheostomy).

E. Silent cerebral infarct defined as an infarct-like lesion based on an MRI signal abnormality at least 3 mm in one dimension and visible in two planes on FLAIR or T2- weighted images (or similar image with 3D imaging) and documented neurological examination performed by a neurologist demonstrating the participant has a normal neurologic or an abnormality on examination that could not be explained by the location of the brain lesion(s).

Non-disease specific:

A. Age greater than or equal to 18 years

B. Haploidentical relative donor available

C. Ability to comprehend and willing to sign an informed consent

D. Negative serum beta-HCG

E. Ejection fraction greater than or equal to 35%

F. Glomerular filtration rate >60 mL/min/1.73m^2 by cystatin C-based or iothalamate-based or other equivalent GFR testing

G. Adjusted DLCO greater than or equal to 35%

EXCLUSION CRITERIA RECIPIENT: (any of the following would exclude the subject from participating)

  1. Available 6/6 HLA-matched sibling donor
  2. ECOG performance status of 3 or more (See Appendix A)
  3. Evidence of uncontrolled bacterial, viral, or fungal infections (currently taking medication and progression of clinical symptoms) within one month prior to starting the conditioning regimen.
  4. Patients with fever or suspected minor infection should await resolution of symptoms before starting the conditioning regimen.
  5. Major anticipated illness or organ failure incompatible with survival from PBSC transplant
  6. Pregnant or breast-feeding
  7. Donor specific anti-HLA antibodies (DSAs) greater than or equal to 2000 Mean Fluorescence Intensity (MFI)
  8. Patients seronegative for EBV who have EBV seropositive donors

INCLUSION CRITERIA-DONOR:

Haploidentical relative donor deemed suitable and eligible, and willing to donate, per clinical evaluations who are additionally willing to donate blood for research. Related donors will be evaluated in accordance with existing Standard NIH Policies and Procedures for determination of eligibility and suitability for clinical donation. Note that participation in this study is offered to all related donors, but is not required for a do le that not all related donors will enroll onto this study.

EXCLUSION CRITERIA-DONOR:

None

Sites / Locations

  • National Institutes of Health Clinical CenterRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

recipient

Arm Description

recipient

Outcomes

Primary Outcome Measures

The percentage of patients at 100 days (+/- 1 week) post-transplant with sustained donor type hemoglobin on hemoglobin electrophoresis (HbS less than 50% when donors have sickle cell trait and <10% when donors have normal hemoglobin), who do ...
the absence of graft rejection and no severe GVHD

Secondary Outcome Measures

chimeric status of recipients
1) The level of chimerism required to maintain both graft survival as well as hematologic normalcy

Full Information

First Posted
March 10, 2017
Last Updated
September 22, 2023
Sponsor
National Heart, Lung, and Blood Institute (NHLBI)
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1. Study Identification

Unique Protocol Identification Number
NCT03077542
Brief Title
Nonmyeloablative Haploidentical Peripheral Blood Mobilized Hematopoietic Precursor Cell Transplantation for Sickle Cell Disease
Official Title
Nonmyeloablative Haploidentical Peripheral Blood Mobilized Hematopoietic Precursor Cell Transplantation for Sickle Cell Disease
Study Type
Interventional

2. Study Status

Record Verification Date
July 27, 2023
Overall Recruitment Status
Recruiting
Study Start Date
April 6, 2017 (Actual)
Primary Completion Date
September 30, 2025 (Anticipated)
Study Completion Date
August 31, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Heart, Lung, and Blood Institute (NHLBI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No

5. Study Description

Brief Summary
Background: Peripheral blood stem cell transplantation procedures are used for people with sickle cell disease. Researchers want to improve the success and reduce the complications for these procedures. This might allow more people to have a transplant. Objective: To see if a new transplant regime is effective, safe and well tolerated in people with sickle cell disease. Eligibility: Adults at least 18 years old with sickle cell disease and certain complications. A relative who is a half tissue match. Design: Participants will be screened with medical history, physical exam, and blood tests. Recipients will also have: Heart, lung, and mental health tests Chest x-rays Bone marrow taken from the pelvic bone Eyes and teeth checked Recipients will have a large central line inserted into a vein for up to 6 months. Donors will have their veins tested and have an IV inserted for 1 day or on rare occasions 2 days. Donors will get a drug to activate bone marrow. It will be injected for about 6 days. Donors will have at least 1 five-hour procedure where bone marrow stem cells will be collected. Blood will be taken from a vein in one arm or in rare cases from a groin vein and put through a machine. Some blood will be saved and the rest will be returned. Stem cells will be taken from the saved blood in a lab and frozen until ready to give to the recipient. Recipients will have: Stems cells collected and frozen Hygiene lessons Bone density scans Low-dose radiation Drugs for their immune system Donor cells infused through their central line Transfusions After about 30 days, recipients will leave the hospital. They must stay near NIH for 3 months after the transplant and have frequent visits. After returning home, they will have 8 visits over 5 years, then be contacted yearly. ...
Detailed Description
Nonmyeloablative allogeneic peripheral blood stem cell (PBSC) transplants are currently being investigated in phase I/II trials assessing engraftment, efficacy, and toxicity at a number of transplant centers. Our ongoing protocol for patients with severe congenital anemias, particularly sickle cell disease (SCD), and an HLA-matched sibling donor has had excellent preliminary results. None of the patients who engrafted had sickle-related events or any evidence of graft versus host disease (GVHD). There was no significant toxicity associated with the conditioning regimen. An additional protocol is ongoing for patients with high risk of graft rejection which employs pentostatin and oral cyclophosphamide (PC) pre-transplant to further deplete recipient lymphocytes in an attempt to decrease the rate of graft rejection. Four of 4 patients transplanted remain free of SCD. Our main limitation has been a lack of HLA-matched sibling donors in the majority of patients. We performed a study in which patients with severe SCD who lacked a suitable donor underwent a search for a matched unrelated donor or umbilical cord donor. The vast majority of patients were not found to have an appropriate alternative donor. We therefore seek to develop a safe nonmyeloablative regimen to be applied to the haploidentical setting so that family members can serve as donors and greatly expand the donor pool. We developed a nonmyeloablative haploidentical PBSC transplant protocol which included 3 cohorts, with stopping rules built in for regimen failure, defined as graft rejection or severe GVHD. All included 400 cGy total body irradiation (TBI) in divided doses 1 and 2 days prior to transplant, alemtuzumab, and sirolimus. The first cohort included no cyclophosphamide. The 2nd included one dose of cyclophosphamide given at 50mg/kg on day 3 post-transplant, and the 3rd included 100mg/kg cyclophosphamide given in divided doses on days 3 and 4 post-transplant. The engraftment rate and percentage of patients who remained free of SCD improved with each successive cohort. However, the graft rejection rate in the 3rd cohort remained high at 50%. To attempt to reduce the rate of graft rejection in the haploidentical setting, this protocol will add PC to the conditioning regimen. In this protocol, we propose PBSC transplantation in patients with SCD considered at high risk for complications from or ineligible for standard bone marrow transplantation, with allogeneic peripheral blood stem cells from a haploidentical donor using a novel immunosuppressive regimen without myeloablation in an attempt to further decrease the transplant-related morbidity/mortality. The low intensity nonmyeloablative conditioning regimen will consist of a relatively low radiation dose for therapeutic radiation, Alemtuzumab (Campath ), Sirolimus (Rapamune ), Cyclophosphamide (Cytoxan ), and pentostatin (Nipent ) as a strategy to provide adequate immunosuppression to allow sufficient engraftment for clinical remission with a lower risk of GVHD development. T-cell replete, donor-derived, granulocyte colony-stimulating factor (G-CSF)- mobilized PBSC will be used to establish hematopoietic and lymphoid reconstitution. The primary endpoint of this study is the percentage of patients at 100 days post-transplant who have not rejected their grafts, and who are without severe GVHD (defined as grade 3 and higher acute GVHD and moderate to severe chronic GVHD). Other endpoints include degree of donor-host chimerism necessary for long-term graft survival and disease amelioration, incidence of acute and chronic GVHD, incidence of graft rejection, transplant-related morbidity, as well as disease-free and overall survival.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Sickle Cell Disease
Keywords
Peripheral Blood Stem Cells, Host-Donor Chimerism, Graft-Versus-Host Disease, Haploidentical, Donor Apheresis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
98 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
recipient
Arm Type
Experimental
Arm Description
recipient
Intervention Type
Procedure
Intervention Name(s)
haploidentical stem cell transplant
Intervention Description
haploidentical stem cell transplant
Intervention Type
Drug
Intervention Name(s)
sirolimus
Intervention Description
conditioning regimen
Intervention Type
Drug
Intervention Name(s)
campath
Intervention Description
conditioning regimen
Intervention Type
Drug
Intervention Name(s)
pentostatin
Intervention Description
conditioning regimen
Intervention Type
Drug
Intervention Name(s)
cyclophosphamide
Intervention Description
conditioning regimen
Intervention Type
Drug
Intervention Name(s)
Hydroxyurea
Intervention Description
conditioning regimen
Primary Outcome Measure Information:
Title
The percentage of patients at 100 days (+/- 1 week) post-transplant with sustained donor type hemoglobin on hemoglobin electrophoresis (HbS less than 50% when donors have sickle cell trait and <10% when donors have normal hemoglobin), who do ...
Description
the absence of graft rejection and no severe GVHD
Time Frame
100 days post transplant
Secondary Outcome Measure Information:
Title
chimeric status of recipients
Description
1) The level of chimerism required to maintain both graft survival as well as hematologic normalcy
Time Frame
+30, +60, +100, 6months, 12 months, 18months, 24months annually

10. Eligibility

Sex
All
Minimum Age & Unit of Time
2 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
INCLUSION CRITERIA-RECIPIENTS: Patients with any type of sickle cell disease who are at high risk for disease-related cerebrovascular morbidity or early mortality, defined by having severe end-organ damage (A, B, C, D, or E): A. A neurologic event resulting in focal neurologic deficits that lasted >= 24 hours (classical clinical definition of stroke, not requiring imaging studies of the brain) OR a focal neurological event resulting in abnormalities on T2- weighted or FLAIR images using an MRI scan, indicative of an acute infarct, with no other reasonable medical explanation (definition of a stroke supported with MRI imaging scans of the brain), OR both; OR B. Tricuspid regurgitant jet velocity (TRV) of >= 2.7 m/s at baseline (without vaso- occlusive crisis) and/or pulmonary hypertension; OR C. Sickle hepatopathy defined as either ferritin >1000 mcg/L and platelet count < 250,000/uL (without vaso-occlusive crisis) OR direct bilirubin > 0.4 mg/dL and platelet count <250,000/uL (without vaso- occlusive crisis) D. Any acute chest syndrome episode resulting in intensive care admission requiring non- mechanical ventilatory support: simple nasal cannula, face mask that requires oxygen content (venti mask, non-rebreather), continuous positive airway pressure (CPAP), Bilevel positive airway pressure (BiPAP), high flow nasal cannula (HFNC) or invasive mechanical ventilatory support (delivered by endotracheal tube or tracheostomy). E. Silent cerebral infarct defined as an infarct-like lesion based on an MRI signal abnormality at least 3 mm in one dimension and visible in two planes on FLAIR or T2- weighted images (or similar image with 3D imaging) and documented neurological examination performed by a neurologist demonstrating the participant has a normal neurologic or an abnormality on examination that could not be explained by the location of the brain lesion(s). Non-disease specific: A. Age greater than or equal to 18 years B. Haploidentical relative donor available C. Ability to comprehend and willing to sign an informed consent D. Negative serum beta-HCG E. Ejection fraction greater than or equal to 35% F. Glomerular filtration rate >60 mL/min/1.73m^2 by cystatin C-based or iothalamate-based or other equivalent GFR testing G. Adjusted DLCO greater than or equal to 35% EXCLUSION CRITERIA RECIPIENT: (any of the following would exclude the subject from participating) Available 6/6 HLA-matched sibling donor ECOG performance status of 3 or more (See Appendix A) Evidence of uncontrolled bacterial, viral, or fungal infections (currently taking medication and progression of clinical symptoms) within one month prior to starting the conditioning regimen. Patients with fever or suspected minor infection should await resolution of symptoms before starting the conditioning regimen. Major anticipated illness or organ failure incompatible with survival from PBSC transplant Pregnant or breast-feeding Donor specific anti-HLA antibodies (DSAs) greater than or equal to 2000 Mean Fluorescence Intensity (MFI) Patients seronegative for EBV who have EBV seropositive donors INCLUSION CRITERIA-DONOR: Haploidentical relative donor deemed suitable and eligible, and willing to donate, per clinical evaluations who are additionally willing to donate blood for research. Related donors will be evaluated in accordance with existing Standard NIH Policies and Procedures for determination of eligibility and suitability for clinical donation. Note that participation in this study is offered to all related donors, but is not required for a do le that not all related donors will enroll onto this study. EXCLUSION CRITERIA-DONOR: None
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Julia M Varga
Phone
(301) 402-3595
Email
julia.varga@nih.gov
First Name & Middle Initial & Last Name or Official Title & Degree
Courtney F Joseph, M.D.
Phone
(301) 402-6496
Email
courtney.fitzhugh@nih.gov
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Courtney F Joseph, M.D.
Organizational Affiliation
National Heart, Lung, and Blood Institute (NHLBI)
Official's Role
Principal Investigator
Facility Information:
Facility Name
National Institutes of Health Clinical Center
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)
Phone
800-411-1222
Ext
TTY8664111010
Email
prpl@cc.nih.gov

12. IPD Sharing Statement

Links:
URL
https://clinicalstudies.info.nih.gov/cgi/detail.cgi?A_2017-H-0069.html
Description
NIH Clinical Center Detailed Web Page

Learn more about this trial

Nonmyeloablative Haploidentical Peripheral Blood Mobilized Hematopoietic Precursor Cell Transplantation for Sickle Cell Disease

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