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NMA Haplo or MUD BMT for Newly Diagnosed Severe Aplastic Anemia

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ClinicalTrials.gov Identifier: NCT02833805
Recruitment Status : Recruiting
First Posted : July 14, 2016
Last Update Posted : July 26, 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 previously untreated severe aplastic anemia (SAA) patients to be transplanted using non-myeloablative conditioning and post transplantation cyclophosphamide.

Condition or disease Intervention/treatment Phase
Severe Aplastic Anemia Aplastic Anemia Bone Marrow Failure Immunosuppression Drug: Thymoglobulin Drug: Fludarabine Drug: Cyclophosphamide Radiation: Total body irradiation Drug: Tacrolimus Drug: Mycophenolate mofetil Phase 2

Detailed Description:
This is a clinical trial of upfront bone marrow transplantation for patients with SAA who do not have a fully human leukocyte antigen (HLA) matched donor. The trial uses a conditioning regimen which has been successful in the refractory and relapsed setting to maximize engraftment and post transplant therapy to minimize graft versus host disease (GVHD). This would be used here in patients who have not yet undergone immunosuppressive therapy for their SAA or are thought to be unlikely to respond to immunosuppressive therapy for SAA.

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 (NMA) Conditioning and Transplantation of Partially HLA-Mismatched/Haploidentical Related or Matched Unrelated Donor (MUD) Bone Marrow for Newly Diagnosed Patients With Severe Aplastic Anemia
Actual Study Start Date : September 2016
Estimated Primary Completion Date : August 2020
Estimated Study Completion Date : August 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Bone marrow transplant
Non-myeloablative bone marrow transplant with a Thymoglobulin (ATG), fludarabine (Flu), cyclophosphamide (Cy), total body irradiation (TBI) preparative regimen and post-transplant Cy, mycophenolate mofetil (MMF), and tacrolimus as GVHD prophylaxis.
Drug: Thymoglobulin
Day -9: 0.5 mg/kg Days -8 and -7: 2 mg/kg daily
Other Names:
  • Anti-thymocyte globulin
  • ATG

Drug: Fludarabine
Days -6 through -2: 30 mg/m^2 IV daily
Other Name: Fludara

Drug: Cyclophosphamide
Days -6 and -5: 14.5 mg/kg IV daily Days 3 and 4: 50 mg/kg IV daily
Other Names:
  • Cytoxan
  • Cy
  • CTX

Radiation: Total body irradiation
Day -1: 200 centigray (cGy) in a single fraction
Other Name: TBI

Drug: Tacrolimus
Start on Day 5 through Day 365
Other Names:
  • FK-506
  • FK506
  • Prograf

Drug: Mycophenolate mofetil
Days 5 through 35: 15 mg/kg PO three times daily (max 3 g/day)
Other Names:
  • MMF
  • CellCept




Primary Outcome Measures :
  1. Overall survival and engraftment at one year [ Time Frame: 1 year ]
    Percentage of enrolled participants who receive BMT, achieve engraftment, and are alive at one year post BMT.


Secondary Outcome Measures :
  1. Overall survival at one year [ Time Frame: 1 year ]
    Percentage of participants alive at one year after BMT.

  2. Probability of neutrophil recovery [ Time Frame: 1 year ]
    Percentage of participants who have recovered neutrophil counts at 1 year.

  3. Probability of platelet recovery [ Time Frame: 1 year ]
    Percentage of participants who have recovered platelet counts at 1 year.

  4. Incidence of primary graft failure [ Time Frame: 1 year ]
    Percentage of participants who experience primary graft failure by one year after BMT.

  5. Incidence of secondary graft failure [ Time Frame: 1 year ]
    Percentage of participants who experience secondary graft failure by one year after BMT.

  6. Incidence of grades II-IV acute GVHD, Day 100 [ Time Frame: Day 100 ]
    Percentage of participants who experience grade II, III, or IV acute GVHD by Day 100.

  7. Incidence of grades III-IV acute GVHD, Day 100 [ Time Frame: 1 year ]
    Percentage of participants who experience grade III or IV acute GVHD by Day 100.

  8. Incidence of chronic GVHD, one year [ Time Frame: 1 year ]
    Percentage of participants who experience chronic GVHD by one year after BMT.

  9. Estimate full donor chimerism [ Time Frame: Day 60 ]
    Percentage of participants with full donor chimerism at Day 60.

  10. Estimate GVHD-free relapse-free survival (GRFS) [ Time Frame: 1 year ]
    Percentage of participants alive, without relapse, and without GVHD at 1 year.

  11. Estimate transplant-related mortality [ Time Frame: 1 year ]
    Percentage of participants deceased for reasons related to BMT at 1 year.



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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Confirmed diagnosis of inherited or acquired severe aplastic anemia (SAA)
  • One of the following available donors:

    1. HLA-haploidentical relative
    2. If recipient is >= 40 years old, may use HLA-matched related donor
    3. For recipients with inherited bone marrow failure syndromes (IBMFS) with clear evidence of same disorder in potential related donors, may use 10/10 matched unrelated donor
  • Recipient and/or legal guardian must sign protocol informed consent
  • Donor must be willing to donate bone marrow
  • Left ventricular ejection fraction (LVEF) >= 40%. For recipients < 13 years old, shortening fraction >= 26% may be used instead.
  • Bilirubin < 3 x upper limit of normal (ULN) for age, unless patient has Gilbert's disease
  • aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 5 x ULN for age
  • For patients >= 13 years old: estimated creatinine clearance > 50 mL/min using Cockcroft-Gault formula and actual body weight
  • For patients >= 1 but < 13 years old: glomerular filtration rate (GFR) estimated by updated Schwartz formula >= 90 mL/min/1.73 m^2. If estimated GFR is < 90 mL/min/1.73 m^2, 24-hour measured creatinine clearance must be > 50 mL/min/1.73 m^2.
  • For patients >= 8 years old, diffusing capacity of the lung for carbon monoxide (DLCO) (corrected for hemoglobin) > 40%; forced expiratory volume at one second (FEV1) > 50%; forced vital capacity (FVC) > 50%
  • For patients < 8 years old or unable to undergo pulmonary function testing: no evidence of dyspnea at rest; no need for supplemental oxygen; oxygen saturation > 92% on room air
  • Karnofsky/Lansky status (depending on age) >= 70%
  • Females and males of childbearing potential must agree to practice 2 effective methods of contraception at the same time. If unwilling, they must agree to complete abstinence.

Exclusion Criteria:

  • Previous administration of immunosuppressive therapy for SAA.
  • Fanconi anemia. At minimum, this diagnosis must be excluded by diepoxybutane (DEB) or equivalent testing on peripheral blood or marrow in patients < 30 years old.
  • Clonal cytogenetic abnormalities consistent with pre-myelodysplastic syndrome (pre-MDS) or MDS on bone marrow examination
  • Presence of anti-donor antibodies
  • Prior allogeneic stem cell transplant
  • Prior solid organ transplant
  • Uncontrolled bacterial, viral, or fungal infection
  • HIV seropositivity
  • Active hepatitis B or C infection determined by serology and/or nucleic acid testing (NAT)
  • Pregnancy or active breastfeeding
  • Prior malignancies except: resected basal carcinoma or treated cervical carcinoma in situ; cancer treated with curative intent > 5 years previously. Other prior cancers will not be allowed unless approved by the PI.

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): NCT02833805


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

Locations
United States, Maryland
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Recruiting
Baltimore, Maryland, United States, 21287
Contact: Amy E DeZern, MD    410-502-7208    adezern1@jhmi.edu   
Sponsors and Collaborators
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Investigators
Principal Investigator: Amy E DeZern, MD Johns Hopkins University

Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
ClinicalTrials.gov Identifier: NCT02833805     History of Changes
Other Study ID Numbers: J1688
IRB00107139 ( Other Identifier: JHMIRB )
First Posted: July 14, 2016    Key Record Dates
Last Update Posted: July 26, 2018
Last Verified: July 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins:
immunosuppression
nonmyeloablative
non-myeloablative
allogeneic
tacrolimus
bone marrow
bone marrow transplant
cyclophosphamide
thymoglobulin
ATG
fludarabine

Additional relevant MeSH terms:
Anemia
Anemia, Aplastic
Pancytopenia
Hematologic Diseases
Bone Marrow Diseases
Cyclophosphamide
Tacrolimus
Fludarabine phosphate
Thymoglobulin
Antilymphocyte Serum
Fludarabine
Mycophenolic Acid
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
Antimetabolites, Antineoplastic
Antimetabolites
Antibiotics, Antineoplastic
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents