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Trial record 6 of 1807 for:    "bone marrow" | Recruiting, Not yet recruiting Studies

Fludarabine Based RIC for Bone Marrow Failure Syndromes

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ClinicalTrials.gov Identifier: NCT02928991
Recruitment Status : Recruiting
First Posted : October 10, 2016
Last Update Posted : January 10, 2019
Sponsor:
Information provided by (Responsible Party):
Timothy Olson, Children's Hospital of Philadelphia

Tracking Information
First Submitted Date  ICMJE October 7, 2016
First Posted Date  ICMJE October 10, 2016
Last Update Posted Date January 10, 2019
Study Start Date  ICMJE April 2015
Estimated Primary Completion Date April 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 27, 2016)
  • Rate of graft failure [ Time Frame: Up to 1 year post transplant ]
    Combined rate of primary and secondary graft failure. Primary graft failure is defined as no evidence of neutrophil engraftment by day +28 after stem cell infusion. Secondary graft failure is defined as an ANC<100 for >7-10 days after initial engraftment occurs and is confirmed by hypocellular bone marrow biopsy and donor engraftment <20%.
  • Time to neutrophil engraftment [ Time Frame: Up to 1 year post transplant ]
    The time from the day of transplant until neutrophil engraftment, which is defined as the first day of ANC >500/ul for the first of 3 consecutive days.
  • Transplant-related mortality [ Time Frame: Up to 100 days post transplant ]
Original Primary Outcome Measures  ICMJE
 (submitted: October 7, 2016)
Time to neutrophil engraftment [ Time Frame: Up to 1 year post transplant ]
The time from the day of transplant until neutrophil engraftment, which is defined as the first day of ANC >500/ul for the first of 3 consecutive days.
Change History Complete list of historical versions of study NCT02928991 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: October 27, 2016)
  • Rate of overall survival [ Time Frame: Up to 1 year post transplant ]
  • Rate of disease free survival [ Time Frame: Up to 1 year post transplant ]
Original Secondary Outcome Measures  ICMJE
 (submitted: October 7, 2016)
  • Rate of overall survival [ Time Frame: Up to 1 year post transplant ]
    To determine the rate of overall survival with stable donor engraftment at one year for patients with defined iBMF syndromes receiving MRD-BMT with fludarabine-based, disease-specific conditioning.
  • Time to stable engraftment [ Time Frame: Up to 1 year post transplant ]
    The time from the day of transplant until stable engraftment which is defined as donor chimerism >20% following initial neutrophil engraftment
  • Incidence of primary graft failure [ Time Frame: Up to 28 days after transplant ]
    Primary graft failure is defined as no evidence of neutrophil engraftment by day +28 after stem cell infusion
  • Incidence of secondary graft failure [ Time Frame: Up to 1 year post transplant ]
    Secondary graft failure is defined as an ANC<100 for >7-10 days after initial engraftment occurs and is confirmed by hypocellular bone marrow biopsy and donor engraftment <20%
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Fludarabine Based RIC for Bone Marrow Failure Syndromes
Official Title  ICMJE Fludarabine-Based Conditioning for Matched Related Donor Bone Marrow Transplantation in Patients With Bone Marrow Failure Syndromes
Brief Summary This is a pilot study to determine whether fludarabine-based reduced intensity conditioning (RIC) regimens facilitate successful donor engraftment of patients with acquired aplastic anemia (AA) and Inherited bone marrow failure (iBMF) syndromes undergoing Matched related donor bone marrow transplant (MRD-BMT).
Detailed Description Acquired AA patients will receive the experimental regimen of fludarabine with dose-reduced cyclophosphamide, with results in this prospective single arm experimental group evaluated in the context of our institutional historical experience using HD Cy regimens as well as published outcomes using both fludarabine and high-dose cyclophosphamide-based regimens for MRD-BMT in aplastic anemia. iBMF syndrome patients will receive one of two fludarabine-containing regimens based on disease characteristics, and our outcomes will be compared to previously published data using a variety of regimens. Graft versus host disease (GvHD) prophylaxis will consist of cyclosporine/tacrolimus alone for patients with acquired AA or cyclosporine/tacrolimus plus mycophenolate for patients with iBMF syndromes. For both acquired AA and iBMF syndrome patients, donor chimerism will be assessed at scheduled intervals following BMT and will be used to define patients with full donor or mixed chimerism for comparisons of survival, graft failure, cytogenetic, GvHD, and immune reconstitution outcomes.
Study Type  ICMJE Interventional
Study Phase  ICMJE Early Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Bone Marrow Failure Syndromes
Intervention  ICMJE
  • Other: MRD-BMT with Fludarabine-based RIC for Acquired AA

    Fludarabine: Dose: 30mg/m2/day (<10kg will receive 1mg/kg/day) Days: -7, -6, -5, -4, -3

    Cyclophosphamide: Dose: 60mg/kg/day Days: -5, -4

    Thymoglobulin: Dose: 3mg/kg/day Days: -4, -3, -2

    Bone marrow infusion: Day 0

  • Other: MRD-BMT with Fludarabine-based RIC for iBMF with trilineage aplasia

    Fludarabine: Dose: 30mg/m2/day (<10kg will receive 1mg/kg/day) Days: -7, -6, -5, -4, -3

    Cyclophosphamide: Dose: 10 mg/kg/day Days: -6, -5, -4, -3

    Thymoglobulin: Dose: 3mg/kg/day Days: -4, -3, -2

    Bone marrow infusion: Day 0

  • Other: MRD-BMT with Fludarabine-based RIC for iBMF without trilineage aplasia

    Fludarabine: Dose: 30mg/m2/day (<10kg will receive 1mg/kg/day) Days: -6, -5, -4, -3, -2

    Busulfan: Dose: every 6 hours for a total of 12 doses with dosing adjustments to achieve a steady state concentration of 900-1200ng/mL OR daily for a total of 3 doses targeting AUC 3600-6000 (micromole/liter)*minute Days: -7, -6, -5, -4

    Thymoglobulin: Dose: 3mg/kg/day Days: -10, -9, -8

    Bone marrow infusion: Day 0

Study Arms  ICMJE
  • Experimental: Acquired Aplastic Anemia (AA)
    Patients with severe or very severe acquired aplastic anemia (AA). Patients will receive a matched related donor bone marrow transplant following reduced intensity conditioning (RIC) including thymoglobulin (ATG), fludarabine and dose-reduced cyclophosphamide.
    Intervention: Other: MRD-BMT with Fludarabine-based RIC for Acquired AA
  • Experimental: Inherited Bone Marrow Failure Syndrome + Trilineage Aplasia
    Patients with inherited bone marrow failure (iBMF) syndromes with trilineage aplasia includes those with diagnoses of Fanconi Anemia, Dyskeratosis Congenita, and related conditions. Patients will receive a matched related donor bone marrow transplant following conditioning with fludarabine, cyclophosphamide, thymoglobulin.
    Intervention: Other: MRD-BMT with Fludarabine-based RIC for iBMF with trilineage aplasia
  • Experimental: Inherited Bone Marrow Failure Syndrome no Trilineage Aplasia
    Patients with inherited bone marrow failure (iBMF) syndromes without trilineage aplasia includes those with diagnoses of Severe Congenital Neutropenia, Diamond-Blackfan Anemia, and related conditions. Patients will receive a matched related donor bone marrow transplant following conditioning with thymoglobulin, busulfan and fludarabine.
    Intervention: Other: MRD-BMT with Fludarabine-based RIC for iBMF without trilineage aplasia
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: October 7, 2016)
25
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE April 2020
Estimated Primary Completion Date April 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Patients 0-22 years with acquired aplastic anemia or a diagnosed inherited bone marrow failure syndrome, and a fully Human leukocyte antigen (HLA)-matched (10/10) related donor.

Inclusion Criteria:

Patient:

  1. Ages 0-22 years at time of enrollment
  2. Diseases:

    • Patients with severe or very severe acquired AA, defined by:

      • Bone marrow biopsy demonstrating cellularity of <25% (at least 2 weeks from last dose of G-CSF), in addition to 2 of the following: absolute neutrophil count (ANC) <500/µL, platelets < 20,000/µL and absolute reticulocytes <40,000/µL
      • Negative evaluation for inherited bone marrow failure conditions and negative evaluation for dysplasia or cytogenetic abnormalities associated with myelodysplastic syndromes
      • Patients with concurrent paroxysmal nocturnal hemoglobinuria (PNH) clones are eligible, as long as they meet criteria for severe or very severe aplastic anemia as defined above
    • Patients with clinically diagnosed and/or genetically proven iBMF syndromes, resulting in chronic red blood cell or platelet-transfusion dependence and/or an absolute neutrophil count <500/µL. These disorders include, but are not limited to:

      • Fanconi Anemia
      • Dyskeratosis Congenita
      • Severe Congenital Neutropenia
      • Diamond-Blackfan Anemia
      • Congenital Dyserythropoietic/Sideroblastic Anemias
      • Congenital Amegakaryocytic Thrombocytopenia
      • Shwachman-Diamond Syndrome
  3. Lansky or Karnofsky performance >60
  4. HLA matched related donor available.
  5. No active untreated infection
  6. Females of childbearing potential must have negative pregnancy test.

Organ Function:

  • Serum creatinine <1.5xupper limit of normal for age Hepatic: Transaminases <5x normal
  • Cardiac shortening fraction >27%
  • Bilirubin <2.5x normal (unless elevation due to Gilberts disease).

Donor Selection Criteria:

  • Donor selection will comply with U.S. Food and Drug Administration's Code of Federal Regulations
  • Fully HLA-matched related donor.
  • Donor must be at least 6 months of age
  • Donor suitable for bone marrow collection and meets eligibility for donation, including fulfilling infectious disease criteria as per SOP, including HIV, Hepatitis B, Hepatitis C Polymerase chain reaction (PCR) negative.
  • If subject has confirmed iBMF syndrome, donor must be evaluated for this disorder and testing must be negative
  • Children's Hospital of Philadelphia (CHOP) bone marrow transplant (BMT) procedures apply for determining donor eligibility, including donor screening and testing for relevant communicable disease agents and diseases.
  • Donor evaluation and collection procedure as per CHOP Standard Operating Procedures (SOP)

Exclusion Criteria:

  • Uncontrolled bacterial, viral or fungal infections
  • HLA matched related donor unable to donate bone marrow.
  • No eligible fully HLA-matched related donor
  • Pregnant females
  • Patients with a clinical diagnosis of Myelodysplastic syndrome (MDS) defined by combination of bone marrow dysplasia and classic cytogenetic lesion (Monosomy 7, Trisomy 8 eg.), with or without excess blasts.
  • Patients with PNH without underlying bone marrow aplasia
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 22 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Timothy Olson, MD, PhD OLSONT@email.chop.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02928991
Other Study ID Numbers  ICMJE 14-011465
14BT057 ( Other Identifier: Children's Hospital of Philadelphia )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Timothy Olson, Children's Hospital of Philadelphia
Study Sponsor  ICMJE Children's Hospital of Philadelphia
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Timothy Olson, MD, PhD Children's Hospital of Philadelphia
PRS Account Children's Hospital of Philadelphia
Verification Date January 2019

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