Unrelated Donor Transplant Versus Immune Therapy in Pediatric Severe Aplastic Anemia
Unrelated Donor Transplant Versus Immune Therapy in Pediatric Severe Aplastic Anemia
Sponsors
Source
Children's Hospital Los Angeles
Oversight Info
Has Dmc
Yes
Brief Summary
The purpose of this study is to determine the feasibility of comparing outcomes of patients
treated de novo with immunosuppressive therapy (IST) versus matched unrelated donor (MUD)
hematopoietic stem cell transplant (HSCT) for pediatric acquired severe aplastic anemia.
Detailed Description
A major challenge in treating pediatric Severe Aplastic Anemia (SAA) is the determination of
best primary therapy for patients who lack a fully matched related donor for HSCT. Good
survival outcomes have been seen with IST, but initial and late failures, CSA dependence,
persistent cytopenias and secondary Myelodysplastic Syndrome (MDS) / Acute Myeloid Leukemia
(AML) in a portion of patients leave considerable room for improvement. MUD HSCT survival in
SAA has markedly improved, but a direct comparison of this approach with IST is necessary to
determine whether this approach is feasible and will lead to better Event Free Survival. This
trial will address the feasibility of randomization, test whether patients can be evaluated
in a timely fashion and safely begin therapy with MUD HSCT or IST, and give a preliminary
assessment of the safety of up-front MUD HSCT. If successful, this trial will lead to a
future prospective trial comparing directly IST to MUD HSCT in this disease.
Overall Status
Recruiting
Start Date
2016-08-01
Completion Date
2020-05-01
Primary Completion Date
2020-05-01
Phase
N/A
Study Type
Interventional
Primary Outcome
Measure |
Time Frame |
|
Percentage of patients randomized to HSCT that actually complete HSCT |
4 years |
Secondary Outcome
Measure |
Time Frame |
|
Time from screening consent to randomization |
4 years |
|
Number of patients that fail to receive their primary assigned therapy (HSCT or IST). |
4 years |
|
Reasons why patients fail to receive their primary assigned therapy (HSCT or IST). |
4 years |
|
Treatment-related mortality at one year from randomization in both arms |
1 Year |
|
Overall Survival at one year from randomization in both arms |
1 Year |
|
Time from randomization to neutrophil recovery in both arms |
4 years |
|
Time from randomization to platelet recovery in both arms |
4 years |
|
Time from randomization to red blood cell recovery in both arms |
4 years |
|
Time from randomization to cessation of immune suppression recovery in both arms |
4 years |
|
Rates of primary and secondary graft rejection in the MUD HSCT arm |
4 years |
|
Rates of grade II-IV and III-IV acute GVHD, and extensive chronic GVHD in the MUD HSCT arm |
4 years |
|
Rates of IST response |
4 years |
|
Rates of IST relapse |
4 years |
|
Rates of secondary MDS or AML in both treatment arms. |
4 years |
|
Rates of other secondary malignancies in both treatment arms. |
4 years |
|
Development of symptomatic PNH in both treatment arms. |
4 years |
|
Incidence of significant infection in both treatment arms |
4 years |
|
Time to immune reconstitution in the HSCT arm |
4 years |
Enrollment
40
Condition
Intervention
Intervention Type
Drug
Intervention Name
Description
cyclosporine
Arm Group Label
Immunosuppressive Therapy
Matched Unrelated Stem Cell Transplant
Intervention Type
Procedure
Intervention Name
Description
Matched Unrelated Donor (MUD) Hematopoietic Stem Cell Transplantation (HSCT)
Arm Group Label
Matched Unrelated Stem Cell Transplant
Intervention Type
Drug
Intervention Name
Description
horse anti-thymocyte globulin (ATG)
Arm Group Label
Immunosuppressive Therapy
Other Name
ATGAM
Intervention Type
Drug
Intervention Name
Description
rabbit anti-thymocyte globulin (ATG)
Arm Group Label
Matched Unrelated Stem Cell Transplant
Other Name
Thymoglobulin
Intervention Type
Drug
Intervention Name
Description
methotrexate
Arm Group Label
Matched Unrelated Stem Cell Transplant
Intervention Type
Drug
Intervention Name
Description
fludarabine
Arm Group Label
Matched Unrelated Stem Cell Transplant
Intervention Type
Drug
Intervention Name
Description
cyclophosphamide
Arm Group Label
Matched Unrelated Stem Cell Transplant
Intervention Type
Radiation
Intervention Name
Description
low-dose total body irradiation (TBI)
Arm Group Label
Matched Unrelated Stem Cell Transplant
Intervention Type
Procedure
Intervention Name
Description
Immunosuppressive Therapy (IST)
Arm Group Label
Immunosuppressive Therapy
Eligibility
Criteria
Inclusion Criteria:
1. Confirmed diagnosis of idiopathic SAA, defined as:
- Bone marrow cellularity <25%, or <30% hematopoietic cells.
- Two out of three of the following (in peripheral blood): neutrophils <0.5 x109/L,
platelets <20 x109/L, reticulocyte count <60 x109/L with hemoglobin <8g/dL.
2. Age ≤25 years old.
3. No suitable fully matched related donor available (minimum 6/6 match for Human
Leukocyte antigen (HLA) -A and B at intermediate or high resolution and DRB1 at high
resolution using DNA based typing).
4. At least two unrelated donors noted on National Marrow Donor Program (NMDP) search who
are well matched (9/10 or 10/10 for HLA-A, B, C, DRB1, and DQB1 using high
resolution).
5. Signed informed consent for the randomized trial by patient and/or legal guardian.
6. Adequate organ function defined as in the judgment of the investigator, there is not
irreversible organ damage that would preclude the patient from meeting the organ
function inclusion criteria for HSCT listed in section 2.3.4 by the intended time of
HSCT (6-8 weeks after randomization) or preclude patients from receiving horse ATG.
Exclusion Criteria:
1. Inherited bone marrow failure syndromes (IBMFS). The diagnosis of Fanconi anemia must
be excluded by diepoxybutane (DEB) or equivalent testing on peripheral blood or
marrow. Telomere length testing should be sent on all patients to exclude Dyskeratosis
congenita, but if results are delayed or unavailable and there are no clinical
manifestations of DC, patients may enroll. If patients have clinical characteristics
suspicious for Shwachman Diamond syndrome, this syndrome must be excluded by
pancreatic isoamylase testing or gene mutation analysis. Note: pancreatic isoamylase
testing is not accurate in children less than 3 years.
2. Clonal cytogenetic abnormalities or fluorescence In Situ Hybridization (FISH) pattern
consistent with pre-myelodysplastic syndrome (pre-MDS) or MDS on marrow examination
(see section 4.2.3.1 for details of the required MDS FISH panel).
3. Known severe allergy to horse ATG.
4. Prior allogeneic stem cell transplant.
5. Prior solid organ transplant.
6. Infection with human immunodeficiency virus (HIV).
7. Active Hepatitis B or C. This should be excluded in patients where there is clinical
suspicion of hepatitis (e.g. elevated LFTs).
8. Female patients who are pregnant or breast-feeding.
9. Prior malignancies except resected basal cell carcinoma or treated cervical carcinoma
in situ.
Gender
All
Minimum Age
N/A
Maximum Age
25 Years
Healthy Volunteers
No
Overall Official
Last Name |
Role |
Affiliation |
|
Michael Pulsipher, MD |
Study Chair |
Children's Hospital Los Angeles |
|
David A Williams, MD |
Study Chair |
Boston's Childrens Hospital |
Overall Contact
Location
Facility |
Status |
Contact |
Investigator |
|
Children's Hospital Los Angeles Los Angeles California 90027 United States |
Recruiting |
Last Name: Michael Pulsipher, MD Role: Principal Investigator | |
|
Boston Children's Hospital Boston Massachusetts 02115 United States |
Recruiting |
Last Name: David A Williams, MD Role: Principal Investigator | |
|
Hackensack University Medical Center Hackensack New Jersey 07601 United States |
Recruiting |
Last Name: Alfred Gillio, MD Role: Principal Investigator | |
|
Children's Hospital of Philadelphia Philadelphia Pennsylvania 19104 United States |
Recruiting |
Last Name: Timothy Olson, MD Role: Principal Investigator | |
|
Texas Children's Hospital Houston Texas 77030 United States |
Recruiting |
Last Name: Alison Bertuch, MD Role: Principal Investigator | |
|
Medical College of Wisconsin Milwaukee Wisconsin 53226 United States |
Recruiting |
Last Name: David Margolis, MD Role: Principal Investigator |
Location Countries
Country
United States
Verification Date
2017-10-01
Lastchanged Date
N/A
Firstreceived Date
N/A
Responsible Party
Responsible Party Type
Sponsor-Investigator
Investigator Affiliation
Children's Hospital Los Angeles
Investigator Full Name
Michael Pulsipher, MD
Investigator Title
Principal Investigator
Has Expanded Access
No
Condition Browse
Number Of Arms
2
Intervention Browse
Mesh Term
Cyclophosphamide
Methotrexate
Fludarabine phosphate
Cyclosporins
Cyclosporine
Immunosuppressive Agents
Thymoglobulin
Antilymphocyte Serum
Fludarabine
Arm Group
Arm Group Label
Immunosuppressive Therapy
Arm Group Type
Active Comparator
Description
Patient will receive standard immunosuppressive therapy combination of drugs: horse anti-thymocyte globulin (ATG) and cyclosporine.
Arm Group Label
Matched Unrelated Stem Cell Transplant
Arm Group Type
Active Comparator
Description
Patient will under go matched unrelated donor transplant of hematopoietic stem cells as their therapy using fludarabine, cyclophosphamide, rabbit anti-thymocyte globulin (ATG), and low-dose total body irradiation (TBI) as preparative regimen and cyclosporine and methotrexate for graft versus host disease (GVHD) prevention.
Firstreceived Results Date
N/A
Overall Contact Backup
Patient Data
Sharing Ipd
Undecided
Firstreceived Results Disposition Date
N/A
Study Design Info
Allocation
Randomized
Intervention Model
Parallel Assignment
Primary Purpose
Other
Masking
None (Open Label)
Study First Submitted
May 9, 2016
Study First Submitted Qc
July 22, 2016
Study First Posted
July 27, 2016
Last Update Submitted
October 5, 2017
Last Update Submitted Qc
October 5, 2017
Last Update Posted
October 9, 2017
ClinicalTrials.gov processed this data on August 31, 2018
Conditions
Conditions usually refer to a disease, disorder, syndrome, illness, or injury. In ClinicalTrials.gov,
conditions include any health issue worth studying, such as lifespan, quality of life, health risks, etc.
Interventions
Interventions refer to the drug, vaccine, procedure, device, or other potential treatment being studied.
Interventions can also include less intrusive possibilities such as surveys, education, and interviews.
Study Phase
Most clinical trials are designated as phase 1, 2, 3, or 4, based on the type of questions
that study is seeking to answer:
In Phase 1 (Phase I) clinical trials, researchers test a new drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.
In Phase 2 (Phase II) clinical trials, the study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety.
In Phase 3 (Phase III) clinical trials, the study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.
In Phase 4 (Phase IV) clinical trials, post marketing studies delineate additional information including the drug's risks, benefits, and optimal use.
These phases are defined by the Food and Drug Administration in the Code of Federal Regulations.
In Phase 1 (Phase I) clinical trials, researchers test a new drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.
In Phase 2 (Phase II) clinical trials, the study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety.
In Phase 3 (Phase III) clinical trials, the study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.
In Phase 4 (Phase IV) clinical trials, post marketing studies delineate additional information including the drug's risks, benefits, and optimal use.
These phases are defined by the Food and Drug Administration in the Code of Federal Regulations.