Working…
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov.

Get the latest research information from NIH: https://www.nih.gov/coronavirus.
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03077542
Recruitment Status : Recruiting
First Posted : March 13, 2017
Last Update Posted : June 5, 2020
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )

Tracking Information
First Submitted Date  ICMJE March 10, 2017
First Posted Date  ICMJE March 13, 2017
Last Update Posted Date June 5, 2020
Actual Study Start Date  ICMJE April 6, 2017
Estimated Primary Completion Date September 30, 2025   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 11, 2018)
The percentage of patients at 100 days (+/- 1 week) post-transplantwith 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 d... [ Time Frame: 100 days post transplant ]
The absence of graft rejection and no severe GVHD
Original Primary Outcome Measures  ICMJE
 (submitted: March 10, 2017)
The percentage of patients at 100 days (+/- 1 week) post-transplantwith 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 d... [ Time Frame: 100 days post transplant ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 24, 2019)
Chimeric Status of Recipients [ Time Frame: +30, +60, +100, 6months, 12 months, 18months, 24months annually ]
The level of chimerism required to maintain both graft survival as well as hematologic normalcy
Original Secondary Outcome Measures  ICMJE
 (submitted: March 10, 2017)
The level of chimerism required to maintain both graft survival as wellas hematologic normalcy. [ Time Frame: 100 days post transplant ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Nonmyeloablative Haploidentical Peripheral Blood Mobilized Hematopoietic Precursor Cell Transplantation for Sickle Cell Disease
Official Title  ICMJE Nonmyeloablative Haploidentical Peripheral Blood Mobilized Hematopoietic Precursor Cell Transplantation for Sickle Cell Disease
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), 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Sickle Cell Disease
Intervention  ICMJE
  • Procedure: haploidentical stem cell transplant
    haploidentical stem cell transplant
  • Drug: sirolimus
    conditioning regimen
  • Drug: campath
    conditioning regimen
  • Drug: pentostatin
    conditioning regimen
  • Drug: cyclophosphamide
    conditioning regimen
Study Arms  ICMJE Experimental: recipient
recipient
Interventions:
  • Procedure: haploidentical stem cell transplant
  • Drug: sirolimus
  • Drug: campath
  • Drug: pentostatin
  • Drug: cyclophosphamide
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: September 14, 2019)
88
Original Estimated Enrollment  ICMJE
 (submitted: March 10, 2017)
84
Estimated Study Completion Date  ICMJE August 31, 2026
Estimated Primary Completion Date September 30, 2025   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE
  • INCLUSION CRITERIA-RECIPIENTS:

Patients with any type of sickle cell disease who are at high risk for disease-related morbidity or mortality, defined by having severe end-organ damage (A, B, or C) or potentially modifiable complication(s) not ameliorated by hydroxyurea (D):

A. Stroke defined as a clinically significant neurologic event that is accompanied by an infarct or hemorrhage on cerebral MRI or cerebral arteriopathy requiring chronic transfusion therapy; OR

B. Tricuspid regurgitant jet velocity (TRV) of greater than or equal to 2.5 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 one of the below complications:

  • Complication-Vaso-occlusive crises; Eligible for hydroxyurea*-At least 3 hospital admissions in the last year; Eligible for HSCT-Recurrent vaso-occlusive pain crises (at least 2 per year for the last 2 years) despite hydroxyurea
  • Complication-Acute chest syndrome; Eligible for hydroxyurea*-2 prior ACS; Eligible for HSCT-any ACS while on hydroxyurea.

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 othalamate-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
  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 lactating
  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:

1. 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 donor to make a stem cell donation, so it is possible that not all related donors will enroll onto this study.

EXCLUSION CRITERIA-DONOR:

None

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 2 Years to 80 Years   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE
Contact: Courtney D Fitzhugh, M.D. (301) 402-6496 courtney.fitzhugh@nih.gov
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03077542
Other Study ID Numbers  ICMJE 170069
17-H-0069
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )
Study Sponsor  ICMJE National Heart, Lung, and Blood Institute (NHLBI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Courtney D Fitzhugh, M.D. National Heart, Lung, and Blood Institute (NHLBI)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date June 1, 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP