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Haploidentical Bone Marrow Transplantation in Sickle Cell Patients (BMT CTN 1507)

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ClinicalTrials.gov Identifier: NCT03263559
Recruitment Status : Recruiting
First Posted : August 28, 2017
Last Update Posted : June 12, 2018
Sponsor:
Collaborators:
National Heart, Lung, and Blood Institute (NHLBI)
National Cancer Institute (NCI)
Blood and Marrow Transplant Clinical Trials Network
National Marrow Donor Program
Information provided by (Responsible Party):
Medical College of Wisconsin

Tracking Information
First Submitted Date  ICMJE August 24, 2017
First Posted Date  ICMJE August 28, 2017
Last Update Posted Date June 12, 2018
Actual Study Start Date  ICMJE October 3, 2017
Estimated Primary Completion Date December 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 24, 2017)
Two-Year Post-Transplant Event Free Survival (EFS) [ Time Frame: 2 years ]
EFS is defined as survival without a qualifying event. Primary graft rejection, secondary graft rejection, second infusion of hematopoietic cells or death will count as events for this endpoint.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03263559 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: August 24, 2017)
  • Overall Survival [ Time Frame: 1 and 2 years ]
    Death from any cause will be the event and patients will be censored at the date of last contact or two years post-transplant whichever comes first.
  • One-Year Post-Transplant EFS [ Time Frame: 1 year ]
    EFS is defined as survival without a qualifying event, Primary graft rejection, secondary graft rejection, second infusion of hematopoietic cells or death will count as events for this endpoint.
  • Graft Rejection [ Time Frame: Day 42 ]
    Graft rejection is defined as not having engraftment on or before Day 42 post-transplant. Engraftment is defined as having greater than or equal to 5% donor cells post-transplant, from any molecular chimerism assessment (e.g., unsorted, myeloid, or T-cell) on a peripheral blood or bone marrow aspirate sample.
  • Chimerism [ Time Frame: Days 28, 100, and 180 and at 1 and 2 years ]
    Characterize donor hematopoietic chimerism in peripheral blood will be assessed.
  • Disease Recurrence [ Time Frame: 2 years ]
    Disease recurrence is defined as the return of sickle erythropoiesis (in the absence of red blood count transfusion, Hb S level > 70%), or primary or secondary graft rejection, as defined above, or second infusion of hematopoietic cells.
  • Patient Reported Quality of Life (QoL) [ Time Frame: 1 and 2 years ]
    Health-Related QoL will be measured using patient reported surveys.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Haploidentical Bone Marrow Transplantation in Sickle Cell Patients (BMT CTN 1507)
Official Title  ICMJE Reduced Intensity Conditioning for Haploidentical Bone Marrow Transplantation in Patients With Symptomatic Sickle Cell Disease
Brief Summary This is a Phase II, single arm, multi-center trial, designed to estimate the efficacy and toxicity of haploidentical bone marrow transplantation (BMT) in patients with sickle cell disease (SCD). Based on their age and entry criteria patients are stratified into two groups: (1) children with SCD with strokes; and (2) adults with severe SCD.
Detailed Description This study is designed as a Phase II multi-center trial to determine the feasibility of achieving a high rate of event-free survival (EFS) at 2 years post transplant using pre-conditioning hydroxyurea (HU) with a conditioning regimen that consists of a combination of Thymoglobulin/Cyclophosphamide/Fludarabine/Thiotepa with post-grafting high-dose cyclophosphamide in patients with severe SCD who have HLA-haploidentical donors. EFS is defined as survival without a qualifying event. This is a single arm study in which participants will be enrolled into one of two strata. The first stratum will be restricted to children who have stroke and 40 children will be enrolled in this stratum. The second stratum will consist of adult patients with severe sickle cell disease and 40 participants will be enrolled in this stratum.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Sickle Cell Disease
Intervention  ICMJE
  • Procedure: Haploidentical Bone Marrow Transplantation
    Eligible patients with a first degree Human Leukocyte Antigen (HLA)- haploidentical donor will undergo Haploidentical bone marrow transplantation at Day 0 with non T-cell depleted bone marrow. For Graft-vs-Host Disease (GVHD) prophylaxis, patients will be given sirolimus and mycophenolate mofetil beginning on Day +5.
  • Drug: Hydroxyurea
    HU will be given daily at 30mg/kg from Day -70 through Day -10.
    Other Names:
    • Hydrea
    • Droxia
  • Drug: Rabbit-ATG
    Rabbit-ATG (rATG) will be given at 0.5mg/kg on Day -9, and at 2.0mg/kg on Day -8 and Day -7.
    Other Name: Thymoglobulin
  • Drug: Thiotepa
    Thiotepa will be given at 10mg/kg on Day -7
    Other Name: Chemo
  • Drug: Fludarabine
    Fludarabine will be given at 30mg/m2 from Day -6 to Day -2
    Other Name: Fludara
  • Drug: Cyclophosphamide
    Cyclophosphamide will be given at 14.5mg/kg on Day -6 and Day -5, and at 50 mg/kg on Days +3 and +4.
    Other Name: Cytoxan®
  • Radiation: Total Body Irradiation
    Total Body Irradiation will be given at 200cGy on Day -1
    Other Name: TBI
  • Drug: Mesna
    Mesna will be given at 40mg/kg on Days +3 and +4
    Other Name: Mesnex
Study Arms  ICMJE Experimental: Haploidentical Transplantation
A conditioning regimen with Hydroxyurea, rabbit-ATG, Thiotepa, Fludarabine, Cyclophosphamide, Total Body Irradiation, and Mesna will be administered prior to Haploidentical Bone Marrow Transplantation.
Interventions:
  • Procedure: Haploidentical Bone Marrow Transplantation
  • Drug: Hydroxyurea
  • Drug: Rabbit-ATG
  • Drug: Thiotepa
  • Drug: Fludarabine
  • Drug: Cyclophosphamide
  • Radiation: Total Body Irradiation
  • Drug: Mesna
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: August 24, 2017)
80
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2024
Estimated Primary Completion Date December 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

Adequate physical function as measured by all of the following:

  1. A Karnofsky/Lansky performance score of ≥ 60.
  2. Cardiac function: Left ventricular ejection fraction (LVEF) > 40%; or LV shortening fraction > 26% by cardiac echocardiogram or by Multi Gated Acquisition Scan (MUGA) scan.
  3. Pulmonary function: Pulse oximetry with a baseline O2 saturation of ≥ 85% and Diffusing capacity of the lung for carbon monoxide (DLCO) > 40% (corrected for hemoglobin).
  4. Renal function: Serum creatinine ≤ 1.5 x upper limit of normal for age and estimated or measured creatinine clearance ≥ 70 mL/min/1.73 m²
  5. Hepatic function:

    1. Serum conjugated (direct) bilirubin < 2x upper limit of normal for age as per local laboratory. Participants with hyperbilirubinemia as the result of hyperhemolysis, or a severe drop in hemoglobin post blood transfusion, are not excluded.
    2. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 5x upper limit of normal as per local laboratory.
  6. Liver MRI using a validated methodology per institutional preference (T2* or R2* or by ferriscan [R2 MRI]) for estimation of hepatic iron content is required for participants who are currently receiving ≥8 packed red blood cell transfusions per year for ≥1 year or have received ≥20 packed red blood cell transfusions (lifetime cumulative). Participants who have hepatic iron content ≥ 10 mg Fe/g liver dry weight by liver MRI must have a Gastroenterology/hepatology consultation with liver biopsy and histological examination including documentation of the absence of cirrhosis, bridging fibrosis, and active hepatitis.
  7. Participants must be HLA typed at high resolution using DNA based typing at HLA-A, -B, -C, DRB1, and have available:

    An HLA haploidentical first degree relative donor (parents, siblings or half siblings, or children) with 2, 3, or 4 (out of 8) HLA-mismatches who is willing and able to donate bone marrow. A unidirectional mismatch in either the graft versus host or host versus graft direction is considered a mismatch. The donor and recipient must be HLA identical for at least one antigen (using high resolution DNA based typing) at the following genetic loci: HLA-A, HLA-B, HLA-C, and HLA-DRB1. Fulfillment of this criterion shall be considered sufficient evidence that the donor and recipient share one HLA haplotype, and typing of additional family members is not required. Confirmatory donor HLA typing must be completed < 100 days prior to Segment A enrollment

  8. Umbilical cord blood or peripheral blood stem cell donors will not be accepted.

Inclusion Criteria for Stratum 1: Children Ages 5.00 - 14.99 years of age at enrollment

  1. Age 5.00 - 14.99 years at Segment A enrollment
  2. Participants (Hb SS or Sß° Thalassemia) with overt stroke ischemia based on neuroimaging, clinical evidence of permanent neurological injury lasting for 24 hours, or both.
  3. A neurological 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 a 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.
  4. Lack of clinical or radiologic evidence of a recent cerebral infarct by cerebral MRI/MRA within 30 days prior to enrollment. Participants with clinical or radiologic evidence or a recent cerebral infarct will be deferred for ≥ 6 months with repeat cerebral MRI/MRA to ensure stabilization of the neurologic event prior to proceeding to transplantation.

Inclusion Criteria for Stratum 2: Adults Ages 15.00 - 45.99 at enrollment

Participants with sickle cell anemia (Hb SS or Sß° Thalassemia) who are 15.00 - 45.99 years of age at enrollment AND who have one or more of the following:

  1. Age 15.00 - 45.99 years at Segment A enrollment
  2. Participants with sickle cell anemia (Hb SS or Sß° Thalassemia) who have one or more of the following:

    1. A neurological 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 a 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.
    2. History of two or more episodes of acute chest syndrome (ACS) in the 2-year period preceding enrollment despite the institution of supportive care measures (i.e. asthma therapy and/or hydroxyurea);
    3. History of three or more severe vaso-occlusive pain crises per year in the 2-year period preceding enrollment despite the institution of supportive care measures (i.e. a pain management plan and/or treatment with hydroxyurea); painful episodes related to priapism, osteonecrosis or any sickle-related complication are acceptable;
    4. Administration of regular RBC transfusion therapy, defined as receiving ≥8 packed red blood cell transfusions per year for ≥1 year in the 12 months before enrollment to prevent vaso-occlusive clinical complications (i.e. pain, stroke, and acute chest syndrome);
    5. An echocardiographic finding of tricuspid valve regurgitant jet velocity (TRJV) ≥ 2.7 m/sec.

Exclusion Criteria:

  1. Participants who have an HLA-matched sibling who is able and willing to donate bone marrow. Patients with a HLA-matched unrelated donor are not excluded.
  2. Uncontrolled bacterial, viral or fungal infection in the 6 weeks before enrollment (currently taking medication with evidence of progression of clinical symptoms or radiologic findings).
  3. Evidence of HIV infection or known HIV positive serology.
  4. Participants who have received a previous hematopoetic cell transplant (HCT).
  5. Participants who have received a prior solid organ transplant
  6. Participants who have participated in another clinical trial in which the patient received an investigational or off-label use of a drug or device within 3 months of enrollment.
  7. Females who are pregnant or breastfeeding.
  8. Participants with clinically significant, uncontrolled autoimmune disease, requiring active medical management (immunosuppressive therapy or chemotherapy), which, in the judgment of the local Principal Investigator, indicates that the patient could not tolerate transplantation.
  9. Females of child bearing potential (to include all female participants > 10 years of age, unless postmenopausal for a minimum of 1 year before the time of consent or surgically sterilized), who do not agree to practice two (2) effective methods of contraception at the same time, or do not agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject, from the time of signing of informed consent through 12 months post-transplant.
  10. Males (even if surgical sterilized) who do not agree to practice effective barrier contraception, or who do not agree to practice true abstinence from the time of signing informed consent through 12 months post-transplant.
  11. Presence of anti-donor specific HLA antibodies. 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 higher than the cut-off defined by each institution. Recommended cut-off values are MFI >1000 for donor specific antibody to HLA-A, -B, and DRB1 and MFI >2000 for HLA-C, DQB1 and DPB1. This must be measured before the final donor selection, and < 100 days before enrollment in Segment A (preferably < 30 days before Segment A enrollment). If MFI >1000 for donor specific antibody to HLA-A, -B, DRB1 and/or MFI >2000 for HLA-C, DQB1 and DPB1, documentation must be submitted to the DCC coordinator for review and approval by a Protocol Chair and/or Protocol Officer prior to enrollment
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 5 Years to 45 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Brianne Allison 301-251-1161 ballison@emmes.com
Contact: Adam Mendizabal, PhD amendizabal@emmes.com
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03263559
Other Study ID Numbers  ICMJE BMTCTN1507
2U10HL069294-11 ( U.S. NIH Grant/Contract )
5U24CA076518 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Results will be published in a manuscript and supporting information submitted to NIH BioLINCC (including data dictionaries, case report forms, data submission documentation, documentation for outcomes dataset, etc where indicated).
Supporting Materials: Study Protocol
Supporting Materials: Informed Consent Form (ICF)
Time Frame: Within 6 months of official study closure at participating sites.
Access Criteria: Available to the public
URL: https://biolincc.nhlbi.nih.gov/home/
Responsible Party Medical College of Wisconsin
Study Sponsor  ICMJE Medical College of Wisconsin
Collaborators  ICMJE
  • National Heart, Lung, and Blood Institute (NHLBI)
  • National Cancer Institute (NCI)
  • Blood and Marrow Transplant Clinical Trials Network
  • National Marrow Donor Program
Investigators  ICMJE
Study Director: Mary Horowitz, MD Center for International Blood and Marrow Transplant Research
PRS Account Medical College of Wisconsin
Verification Date June 2018

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