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Transplantation of Partially Mismatched Related or Matched Unrelated Bone Marrow for Patients With Refractory Severe Aplastic Anemia

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ClinicalTrials.gov Identifier: NCT02224872
Recruitment Status : Recruiting
First Posted : August 25, 2014
Last Update Posted : December 20, 2018
Sponsor:
Information provided by (Responsible Party):
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Brief Summary:
Our primary objective is to determine if it is feasible for SAA patients to be transplanted using non-myeloablative conditioning and post transplantation cyclophosphamide with partially HLA-mismatched donors.

Condition or disease Intervention/treatment Phase
Severe Aplastic Anemia Bone Marrow Failure Syndromes Procedure: Bone marrow transplant Drug: Thymoglobulin Drug: Fludarabine Drug: Cyclophosphamide Radiation: TBI Drug: Mesna Drug: Tacrolimus Drug: Mycophenolic acid mofetil Phase 2

Detailed Description:

This research is being done to find out if bone marrow transplantation (BMT) followed by chemotherapy will help people with aplastic anemia who have failed other treatments.

You have a severe, life threatening disease (severe aplastic anemia) in your bone marrow. Your disease has come back or not responded after receiving one or more immunosuppressive treatments. High dose chemotherapy followed by bone marrow transplantation (BMT) has been used to treat blood diseases like yours but complications from Graft vs. Host disease (GVHD) and graft failure have limited the survival for those people.

A small study done at Johns Hopkins has shown that in subjects with other diseases (blood cancers) some immunosuppressive drugs given after the BMT have decreased how often subjects had complications of GVHD and engraftment failure.

People with aplastic anemia who have refractory disease (not responding to standard treatment) may join.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Trial of Non-Myeloablative Conditioning and Transplantation of Partially HLA-Mismatched/Haploidentical Related or Matched Unrelated Bone Marrow for Patients With Refractory Severe Aplastic Anemia and Other Bone Marrow Failure Syndromes
Study Start Date : August 2014
Estimated Primary Completion Date : November 2023
Estimated Study Completion Date : November 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Bone marrow transplant
Thymoglobulin on days -9 to -7 Fludarabine on days -6 to -2 Cyclophosphamide on days -6, -5, 3, 4 TBI on day -1 BMT on day 0 Mesna on days 3, 4 Tacrolimus on days 5-365 Mycophenolic acid mofetil on days 5-35
Procedure: Bone marrow transplant
Day 0

Drug: Thymoglobulin
0.5 mg/kg IV on Day -9 2 mg/kg IV on Days -8, -7

Drug: Fludarabine
30 mg/M2 IV on days -6 to -2

Drug: Cyclophosphamide
14.5 mg/kg IV on days -6, -5, 3, 4
Other Name: CTX

Radiation: TBI
200 cGy on day -1

Drug: Mesna
40 mg/kg IV on days 3, 4

Drug: Tacrolimus
For patients 18 years or older, tacrolimus will be given per institutional standards; may be increased or later changed to a PO BID schedule. Treatment to continue until Day 365 or longer if GVHD present

Drug: Mycophenolic acid mofetil
15 mg/kg PO/IV TID beginning on day 5 through day 35
Other Name: MMF




Primary Outcome Measures :
  1. Is this type of transplantation for SAA feasible and safe? [ Time Frame: 5 years ]
    Feasibility will be met with the following conditions: the patient has the transplant, is assessed for the safety endpoint, and survives one year. The safety monitoring plan is included to monitor graft failure (day 60), grade 2-4 acute graft versus host disease (day100), 6 month mortality (day 180), and chronic graft versus host disease (day 180).


Secondary Outcome Measures :
  1. Number of patients that have survived at one year [ Time Frame: 5 years ]
  2. Number of patients that have acheived full donor chimerism by day 60 after transplant [ Time Frame: 5 years ]
    Donor chimerism will be measured in the peripheral blood around day 30 and day 60. Patients with >5% donor chimerism around day 60 will be considered as having engrafted.

  3. Number of patients that expired due to non-relapsed-related mortality following transplant [ Time Frame: 5 years ]
  4. Major toxicities related to transplant [ Time Frame: 5 years ]
  5. Number of patients that expired due to transplant related mortality [ Time Frame: 5 years ]
  6. Number of patients with primary or secondary graft failure following transplant [ Time Frame: 5 years ]

    Graft failure: < 5% donor chimerism in blood and/or bone marrow on ~Day 30 or after and on all subsequent measurements.

    Primary graft failure: < 5% donor chimerism in blood and/or bone marrow by ~ Day 56 Secondary graft failure: achievement of > 5% donor chimerism, followed by sustained <5% donor chimerism in blood and/or bone marrow.


  7. Number of patients with grade II-IV or grade III-IV acute GVHD [ Time Frame: 5 years ]
  8. Number of patients with chronic GVHD [ Time Frame: 5 years ]
  9. Length of time required for patients to recover ANC and platelet counts after transplant [ Time Frame: 5 years ]
    CBC drawn daily with a WBC differential once the total WBC is greater than 100 until ANC > 500 for three days or two consecutive measurements over a three day period; then CBC drawn weekly with differential.

  10. Length of GVHD free, relapse free survival (GRFS) in patients [ Time Frame: 5 years ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   up to 73 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients with relapsed or refractory SAA or very SAA defined:

    • Bone marrow (< 25% cellular)
    • Peripheral cytopenias (at least 2 of 3)

      • ANC < 500 per ml
      • Platelets < 20,000 per ml
      • Absolute retic < 60,000 or corrected retic < 1%
    • Very severe: as above, but ANC < 200
    • Disease may be designated as acquired or inherited if previous counts known (these other bone marrow failure disorders that are characterized by aplastic anemia may go by additional names such as dyskeratosis congenita or PNH)
    • Failed at least one course of immunosuppressive therapy (if presumed acquired disease). Patients with inherited disease will be characterized as refractory and do not require immunosuppressive first.
  • Age 0- upper age limit as determined by current institutional standards
  • Good performance status (ECOG 0 or 1; Karnofsky and Lansky 70-100)
  • Patients and donors must be able to sign consent forms (or if a minor the parent will sign). Donors should be willing to donate.
  • Patients must be geographically accessible and willing to participate in all stages of treatment.
  • Adequate end-organ function as measured by:

    1. Left ventricular ejection fraction > or = to 35%, or shortening fraction > 25% (For pediatric patients, a normal ejection fraction is required)
    2. Bilirubin ≤ 3.0 mg/dL (unless due to Gilbert's syndrome or hemolysis), and ALT and AST ≤ 5 x ULN
    3. FEV1 and FVC > or = to 40% of predicted; or in pediatric patients, if unable to perform pulmonary function tests due to young age, oxygen saturation >92% on room air

Exclusion Criteria:

  • Patients will not be excluded on the basis of sex, racial or ethnic background.
  • Prior transfusions from selected donor (as this could have cause recipient alloimmunization against the donor)
  • Women of childbearing potential who currently are pregnant (HCG+) or who are not practicing adequate contraception.
  • Patients who have any debilitating medical or psychiatric illness that would preclude their giving informed consent or their receiving optimal treatment and follow up.
  • Uncontrolled viral, bacterial, or fungal infections (HIV infection permitted if viral load undetectable)

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): NCT02224872


Contacts
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Contact: Amy DeZern, MD 410-502-7208 adezern1@jhmi.edu

Locations
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United States, Maryland
The Sidney Kimmel Comprehensive Cancer Center Recruiting
Baltimore, Maryland, United States, 21287
Contact: Amy DeZern, MD    410-502-7208    adezern1@jhmi.edu   
Contact: Clinical Trials Office- SKCCC    410-955-8804    jhcccro@jhmi.edu   
Principal Investigator: Amy DeZern, MD         
United States, Wisconsin
Medical College of Wisconsin/Children's Hospital of Wisconsin Recruiting
Milwaukee, Wisconsin, United States, 53226
Contact: David Margolis, MD    414-337-7066    dmargoli@mcw.edu   
Contact: Monica Thakar, MD    414-955-7546    mthakar@mcw.edu   
Sponsors and Collaborators
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Investigators
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Principal Investigator: Amy DeZern, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
ClinicalTrials.gov Identifier: NCT02224872     History of Changes
Other Study ID Numbers: J1424
IRB00031590 ( Other Identifier: JHMIRB )
First Posted: August 25, 2014    Key Record Dates
Last Update Posted: December 20, 2018
Last Verified: December 2018

Keywords provided by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins:
bone marrow transplant
thymoglobulin
cyclophosphamide
fludarabine
tacrolimus
Mycophenolic Acid Mofetil
chemotherapy
GVHD
haploidentical

Additional relevant MeSH terms:
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Bone Marrow Diseases
Syndrome
Anemia
Anemia, Aplastic
Pancytopenia
Hemoglobinuria, Paroxysmal
Disease
Pathologic Processes
Hematologic Diseases
Anemia, Hemolytic
Myelodysplastic Syndromes
Cyclophosphamide
Tacrolimus
Fludarabine phosphate
Thymoglobulin
Antilymphocyte Serum
Fludarabine
Mycophenolic Acid
Mesna
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Calcineurin Inhibitors
Enzyme Inhibitors