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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 : November 1, 2017
Sponsor:
Information provided by (Responsible Party):

Study Description
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).

Condition or disease Intervention/treatment Phase
Bone Marrow Failure Syndromes Other: MRD-BMT with Fludarabine-based RIC for Acquired AA Other: MRD-BMT with Fludarabine-based RIC for iBMF with trilineage aplasia Other: MRD-BMT with Fludarabine-based RIC for iBMF without trilineage aplasia Early Phase 1

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 Design

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 25 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Fludarabine-Based Conditioning for Matched Related Donor Bone Marrow Transplantation in Patients With Bone Marrow Failure Syndromes
Study Start Date : April 2015
Estimated Primary Completion Date : April 2020
Estimated Study Completion Date : April 2020


Arms and Interventions

Arm Intervention/treatment
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.
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

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.
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

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.
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 Days: -7, -6, -5, -4

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

Bone marrow infusion: Day 0



Outcome Measures

Primary Outcome Measures :
  1. 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%.

  2. 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.

  3. Transplant-related mortality [ Time Frame: Up to 100 days post transplant ]

Secondary Outcome Measures :
  1. Rate of overall survival [ Time Frame: Up to 1 year post transplant ]
  2. Rate of disease free survival [ Time Frame: Up to 1 year post transplant ]

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   up to 22 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02928991


Contacts
Contact: Timothy Olson, MD, PhD OLSONT@email.chop.edu

Locations
United States, Pennsylvania
Children's Hospital of Philadelphia Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Timothy Olson, MD, PhD       OLSONT@email.chop.edu   
Contact: Barbara McGlynn, RN, BSN       MCGLYNN@email.chop.edu   
Principal Investigator: Timothy Olson, MD         
Sponsors and Collaborators
Children's Hospital of Philadelphia
Investigators
Principal Investigator: Timothy Olson, MD, PhD Children's Hospital of Philadelphia
More Information

Responsible Party: Timothy Olson, Assistant Professor, Children's Hospital of Philadelphia
ClinicalTrials.gov Identifier: NCT02928991     History of Changes
Other Study ID Numbers: 14-011465
14BT057 ( Other Identifier: Children's Hospital of Philadelphia )
First Posted: October 10, 2016    Key Record Dates
Last Update Posted: November 1, 2017
Last Verified: October 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Timothy Olson, Children's Hospital of Philadelphia:
Acquired aplastic anemia
Inherited bone marrow failure

Additional relevant MeSH terms:
Anemia, Aplastic
Anemia
Anemia, Hemolytic
Syndrome
Pancytopenia
Hemoglobinuria, Paroxysmal
Disease
Pathologic Processes
Hematologic Diseases
Bone Marrow Diseases
Myelodysplastic Syndromes
Cyclophosphamide
Fludarabine phosphate
Thymoglobulin
Fludarabine
Vidarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic
Antimetabolites
Antiviral Agents
Anti-Infective Agents