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Unrelated Donor Transplant Versus Immune Therapy in Pediatric Severe Aplastic Anemia

Unrelated Donor Transplant Versus Immune Therapy in Pediatric Severe Aplastic Anemia



Sponsors

Lead Sponsor

 Michael Pulsipher, MD


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

 Severe Aplastic Anemia

Intervention

Intervention Type

Drug

Intervention Name

 cyclosporine

Description

cyclosporine

Arm Group Label

Immunosuppressive Therapy

Matched Unrelated Stem Cell Transplant



Intervention Type

Procedure

Intervention Name

 Matched Unrelated Donor Hematopoietic Stem Cell Transplant

Description

Matched Unrelated Donor (MUD) Hematopoietic Stem Cell Transplantation (HSCT)

Arm Group Label

Matched Unrelated Stem Cell Transplant


Intervention Type

Drug

Intervention Name

 horse anti-thymocyte globulin (ATG)

Description

horse anti-thymocyte globulin (ATG)

Arm Group Label

Immunosuppressive Therapy

Other Name

ATGAM


Intervention Type

Drug

Intervention Name

 rabbit anti-thymocyte globulin (ATG)

Description

rabbit anti-thymocyte globulin (ATG)

Arm Group Label

Matched Unrelated Stem Cell Transplant

Other Name

Thymoglobulin


Intervention Type

Drug

Intervention Name

 methotrexate

Description

methotrexate

Arm Group Label

Matched Unrelated Stem Cell Transplant


Intervention Type

Drug

Intervention Name

 fludarabine

Description

fludarabine

Arm Group Label

Matched Unrelated Stem Cell Transplant


Intervention Type

Drug

Intervention Name

 cyclophosphamide

Description

cyclophosphamide

Arm Group Label

Matched Unrelated Stem Cell Transplant


Intervention Type

Radiation

Intervention Name

 low-dose total body irradiation (TBI)

Description

low-dose total body irradiation (TBI)

Arm Group Label

Matched Unrelated Stem Cell Transplant


Intervention Type

Procedure

Intervention Name

 Immunosuppressive Therapy (IST)

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

Last Name

Elena Eckroth

Phone

323-361-3158

Email

[email protected]


Location

Facility

Status

Contact

Investigator

Children's Hospital Los Angeles
Los Angeles California 90027 United States
Recruiting
Last Name: Elena Eckroth
Email: [email protected]
Last Name: Michael Pulsipher, MD
Role: Principal Investigator
Boston Children's Hospital
Boston Massachusetts 02115 United States
Recruiting
Last Name: Maggie Malsch, MSN
Email: [email protected]
Last Name: David A Williams, MD
Role: Principal Investigator
Hackensack University Medical Center
Hackensack New Jersey 07601 United States
Recruiting
Last Name: Jeanette Haugh
Email: [email protected]
Last Name: Alfred Gillio, MD
Role: Principal Investigator
Children's Hospital of Philadelphia
Philadelphia Pennsylvania 19104 United States
Recruiting
Last Name: Barbara McGlynn
Email: [email protected]
Last Name: Timothy Olson, MD
Role: Principal Investigator
Texas Children's Hospital
Houston Texas 77030 United States
Recruiting
Last Name: Margaret Nagel
Email: [email protected]
Last Name: Alison Bertuch, MD
Role: Principal Investigator
Medical College of Wisconsin
Milwaukee Wisconsin 53226 United States
Recruiting
Last Name: Adam Fielbelkorn
Email: [email protected]
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

 Anemia,  Anemia, Aplastic

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

Last Name

Maggie Malsch, MSN

Phone

617-355-4685

Email

[email protected]


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

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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

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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.

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