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Unrelated Donor Transplant Versus Immune Therapy in Pediatric Severe Aplastic Anemia

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ClinicalTrials.gov Identifier: NCT02845596
Recruitment Status : Recruiting
First Posted : July 27, 2016
Last Update Posted : September 25, 2018
Sponsor:
Information provided by (Responsible Party):
Michael Pulsipher, MD, Children's Hospital Los Angeles

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.

Condition or disease Intervention/treatment Phase
Severe Aplastic Anemia Drug: cyclosporine Procedure: Matched Unrelated Donor Hematopoietic Stem Cell Transplant Drug: horse anti-thymocyte globulin (ATG) Drug: rabbit anti-thymocyte globulin (ATG) Drug: methotrexate Drug: fludarabine Drug: cyclophosphamide Radiation: low-dose total body irradiation (TBI) Procedure: Immunosuppressive Therapy (IST) Not Applicable

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.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Other
Official Title: Unrelated Donor Transplant Versus Immune Therapy in Pediatric Severe Aplastic Anemia
Study Start Date : August 2016
Estimated Primary Completion Date : May 2020
Estimated Study Completion Date : May 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Immunosuppressive Therapy
Patient will receive standard immunosuppressive therapy combination of drugs: horse anti-thymocyte globulin (ATG) and cyclosporine.
Drug: cyclosporine
cyclosporine

Drug: horse anti-thymocyte globulin (ATG)
horse anti-thymocyte globulin (ATG)
Other Name: ATGAM

Procedure: Immunosuppressive Therapy (IST)
Immunosuppressive Therapy (IST)

Active Comparator: Matched Unrelated Stem Cell Transplant
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.
Drug: cyclosporine
cyclosporine

Procedure: Matched Unrelated Donor Hematopoietic Stem Cell Transplant
Matched Unrelated Donor (MUD) Hematopoietic Stem Cell Transplantation (HSCT)

Drug: rabbit anti-thymocyte globulin (ATG)
rabbit anti-thymocyte globulin (ATG)
Other Name: Thymoglobulin

Drug: methotrexate
methotrexate

Drug: fludarabine
fludarabine

Drug: cyclophosphamide
cyclophosphamide

Radiation: low-dose total body irradiation (TBI)
low-dose total body irradiation (TBI)




Primary Outcome Measures :
  1. Percentage of patients randomized to HSCT that actually complete HSCT [ Time Frame: 4 years ]
    Feasibility of comparing outcomes of patients treated de novo with IST versus matched unrelated donor HSCT for pediatric acquired severe aplastic anemia as defined by percentage of patients randomized to HSCT that actually complete HSCT.


Secondary Outcome Measures :
  1. Time from screening consent to randomization [ Time Frame: 4 years ]
    To measure the time from screening consent and randomization of patients to initiation of the preparative regimen of those randomized to HSCT.

  2. Number of patients that fail to receive their primary assigned therapy (HSCT or IST). [ Time Frame: 4 years ]
    Number of patients fail to receive their primary assigned therapy (HSCT or IST).

  3. Reasons why patients fail to receive their primary assigned therapy (HSCT or IST). [ Time Frame: 4 years ]
    Reasons why patients fail to receive their primary assigned therapy (HSCT or IST).

  4. Treatment-related mortality at one year from randomization in both arms [ Time Frame: 1 Year ]
    Number of deaths that are treatment related

  5. Overall Survival at one year from randomization in both arms [ Time Frame: 1 Year ]
    percentage of enrolled patients living at 1 year post randomization

  6. Time from randomization to neutrophil recovery in both arms [ Time Frame: 4 years ]
    Time from randomization to neutrophil recovery in both arms

  7. Time from randomization to platelet recovery in both arms [ Time Frame: 4 years ]
    Time from randomization to platelet recovery in both arms

  8. Time from randomization to red blood cell recovery in both arms [ Time Frame: 4 years ]
    Time from randomization to red blood cell recovery in both arms

  9. Time from randomization to cessation of immune suppression recovery in both arms [ Time Frame: 4 years ]
    Time from randomization to cessation of immune suppression recovery in both arms

  10. Rates of primary and secondary graft rejection in the MUD HSCT arm [ Time Frame: 4 years ]
    Rates of primary and secondary graft rejection in the MUD HSCT arm

  11. Rates of grade II-IV and III-IV acute GVHD, and extensive chronic GVHD in the MUD HSCT arm [ Time Frame: 4 years ]
    Rates of grade II-IV and III-IV acute GVHD, and extensive chronic GVHD in the MUD HSCT arm

  12. Rates of IST response [ Time Frame: 4 years ]
    Rates of IST response

  13. Rates of IST relapse [ Time Frame: 4 years ]
    Rates of IST relapse

  14. Rates of secondary MDS or AML in both treatment arms. [ Time Frame: 4 years ]
    Rates of secondary MDS or AML in both treatment arms.

  15. Rates of other secondary malignancies in both treatment arms. [ Time Frame: 4 years ]
    Rates of other secondary malignancies in both treatment arms.

  16. Development of symptomatic PNH in both treatment arms. [ Time Frame: 4 years ]
    Development of symptomatic PNH in both treatment arms.

  17. Incidence of significant infection in both treatment arms [ Time Frame: 4 years ]
    Incidence of significant infection in both treatment arms

  18. Time to immune reconstitution in the HSCT arm [ Time Frame: 4 years ]
    Time to immune reconstitution in the HSCT arm



Information from the National Library of Medicine

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Ages Eligible for Study:   up to 25 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

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): NCT02845596


Contacts
Contact: Kim Arieli 323-361-5744 karieli@chla.usc.edu
Contact: Maggie Malsch, MSN 617-355-4685 maggie.malsch@childrens.harvard.edu

Locations
United States, California
Children's Hospital Los Angeles Recruiting
Los Angeles, California, United States, 90027
Contact: Nini Huynh    323-361-5286    huhuynh@chla.usc.edu   
Principal Investigator: Michael Pulsipher, MD         
United States, Colorado
Children's Hospital Colorado Recruiting
Aurora, Colorado, United States, 80045
Contact: Wendy Moore    720-777-6353    Wendy.moore2@childrenscolorado.org   
Principal Investigator: Taizo Nakano, MD         
United States, Massachusetts
Boston Children's Hospital Recruiting
Boston, Massachusetts, United States, 02115
Contact: Maggie Malsch, MSN       maggie.malsch@childrens.harvard.edu   
Contact: Leah Cheng       leah.cheng@childrens.harvard.edu   
Principal Investigator: David A Williams, MD         
United States, New Jersey
Hackensack University Medical Center Recruiting
Hackensack, New Jersey, United States, 07601
Contact: Jeanette Haugh    551-996-3457    jeanette.haugh@hackensackmeridian.org   
Principal Investigator: Alfred Gillio, MD         
United States, Pennsylvania
Children's Hospital of Philadelphia Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Barbara McGlynn    215-590-1303    mcglynn@email.chop.edu   
Principal Investigator: Timothy Olson, MD         
United States, Texas
Texas Children's Hospital Recruiting
Houston, Texas, United States, 77030
Contact: Margaret Nagel    832-824-1538    menagel@texaschildrens.org   
Principal Investigator: Alison Bertuch, MD         
United States, Washington
Fred Hutchinson Cancer Research Center Recruiting
Seattle, Washington, United States, 98109
Contact: Bernie McLaughlin    206-667-4916    bmclaugh@fredhutch.org   
Principal Investigator: Lauri Burroughs, MD         
Sponsors and Collaborators
Michael Pulsipher, MD
Investigators
Study Chair: Michael Pulsipher, MD Children's Hospital Los Angeles
Study Chair: David A Williams, MD Boston's Childrens Hospital

Responsible Party: Michael Pulsipher, MD, Principal Investigator, Children's Hospital Los Angeles
ClinicalTrials.gov Identifier: NCT02845596     History of Changes
Other Study ID Numbers: TransIT NMD 1601
First Posted: July 27, 2016    Key Record Dates
Last Update Posted: September 25, 2018
Last Verified: September 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Additional relevant MeSH terms:
Anemia
Anemia, Aplastic
Hematologic Diseases
Bone Marrow Diseases
Cyclophosphamide
Methotrexate
Fludarabine phosphate
Cyclosporins
Cyclosporine
Immunosuppressive Agents
Thymoglobulin
Antilymphocyte Serum
Fludarabine
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Antimetabolites, Antineoplastic
Antimetabolites
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Nucleic Acid Synthesis Inhibitors