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Fludarabine Based RIC for Bone Marrow Failure Syndromes

Primary Purpose

Bone Marrow Failure Syndromes

Status
Recruiting
Phase
Early Phase 1
Locations
United States
Study Type
Interventional
Intervention
MRD-BMT with Fludarabine-based RIC for Acquired AA
MRD-BMT with Fludarabine-based RIC for iBMF with trilineage aplasia
MRD-BMT with Fludarabine-based RIC for iBMF without trilineage aplasia
Sponsored by
Children's Hospital of Philadelphia
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Bone Marrow Failure Syndromes focused on measuring Acquired aplastic anemia, Inherited bone marrow failure

Eligibility Criteria

undefined - 22 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Children's Hospital of PhiladelphiaRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

Acquired Aplastic Anemia (AA)

Inherited Bone Marrow Failure Syndrome + Trilineage Aplasia

Inherited Bone Marrow Failure Syndrome no Trilineage Aplasia

Arm Description

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.

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.

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.

Outcomes

Primary Outcome Measures

Rate of graft failure
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
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

Secondary Outcome Measures

Rate of overall survival
Rate of disease free survival

Full Information

First Posted
October 7, 2016
Last Updated
March 8, 2023
Sponsor
Children's Hospital of Philadelphia
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1. Study Identification

Unique Protocol Identification Number
NCT02928991
Brief Title
Fludarabine Based RIC for Bone Marrow Failure Syndromes
Official Title
Fludarabine-Based Conditioning for Matched Related Donor Bone Marrow Transplantation in Patients With Bone Marrow Failure Syndromes
Study Type
Interventional

2. Study Status

Record Verification Date
March 2023
Overall Recruitment Status
Recruiting
Study Start Date
April 2015 (undefined)
Primary Completion Date
December 2024 (Anticipated)
Study Completion Date
December 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Children's Hospital of Philadelphia

4. Oversight

Data Monitoring Committee
No

5. 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).
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Bone Marrow Failure Syndromes
Keywords
Acquired aplastic anemia, Inherited bone marrow failure

7. Study Design

Primary Purpose
Treatment
Study Phase
Early Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
75 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Acquired Aplastic Anemia (AA)
Arm Type
Experimental
Arm Description
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.
Arm Title
Inherited Bone Marrow Failure Syndrome + Trilineage Aplasia
Arm Type
Experimental
Arm Description
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.
Arm Title
Inherited Bone Marrow Failure Syndrome no Trilineage Aplasia
Arm Type
Experimental
Arm Description
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 Type
Other
Intervention Name(s)
MRD-BMT with Fludarabine-based RIC for Acquired AA
Intervention Description
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
Intervention Type
Other
Intervention Name(s)
MRD-BMT with Fludarabine-based RIC for iBMF with trilineage aplasia
Intervention Description
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
Intervention Type
Other
Intervention Name(s)
MRD-BMT with Fludarabine-based RIC for iBMF without trilineage aplasia
Intervention Description
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
Primary Outcome Measure Information:
Title
Rate of graft failure
Description
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 Frame
Up to 1 year post transplant
Title
Time to neutrophil engraftment
Description
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.
Time Frame
Up to 1 year post transplant
Title
Transplant-related mortality
Time Frame
Up to 100 days post transplant
Secondary Outcome Measure Information:
Title
Rate of overall survival
Time Frame
Up to 1 year post transplant
Title
Rate of disease free survival
Time Frame
Up to 1 year post transplant

10. Eligibility

Sex
All
Maximum Age & Unit of Time
22 Years
Accepts Healthy Volunteers
No
Eligibility 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: Ages 0-22 years at time of enrollment 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 Lansky or Karnofsky performance >60 HLA matched related donor available. No active untreated infection 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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Timothy Olson, MD, PhD
Email
OLSONT@chop.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Timothy Olson, MD, PhD
Organizational Affiliation
Children's Hospital of Philadelphia
Official's Role
Principal Investigator
Facility Information:
Facility Name
Children's Hospital of Philadelphia
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Timothy Olson, MD, PhD
Email
OLSONT@chop.edu
First Name & Middle Initial & Last Name & Degree
Barbara McGlynn, RN, BSN
Email
MCGLYNN@chop.edu
First Name & Middle Initial & Last Name & Degree
Timothy Olson, MD

12. IPD Sharing Statement

Plan to Share IPD
No

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Fludarabine Based RIC for Bone Marrow Failure Syndromes

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