NMA Haplo or MUD BMT for Newly Diagnosed Severe Aplastic Anemia

• ClinicalTrials.gov Identifier: NCT02833805
• Recruitment Status: Recruiting
• First Posted: July 14, 2016
• Last Update Posted: July 18, 2019
• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Information provided by (Responsible Party): Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Tracking Information

• First Submitted Date: July 12, 2016
• First Posted Date: July 14, 2016
• Last Update Posted Date: July 18, 2019
• Actual Study Start Date: September 2016
• Estimated Primary Completion Date: August 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 29, 2016)

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.

Original Primary Outcome Measures (submitted: July 13, 2016)

Overall survival at one year after BMT [ Time Frame: 1 year ]

Percentage of participants alive at one year after BMT.

• Change History: Complete list of historical versions of study NCT02833805 on ClinicalTrials.gov Archive Site

Current Secondary Outcome Measures (submitted: August 29, 2016)

• Overall survival at one year [ Time Frame: 1 year ]
  Percentage of participants alive at one year after BMT.
• Probability of neutrophil recovery [ Time Frame: 1 year ]
  Percentage of participants who have recovered neutrophil counts at 1 year.
• Probability of platelet recovery [ Time Frame: 1 year ]
  Percentage of participants who have recovered platelet counts at 1 year.
• Incidence of primary graft failure [ Time Frame: 1 year ]
  Percentage of participants who experience primary graft failure by one year after BMT.
• Incidence of secondary graft failure [ Time Frame: 1 year ]
  Percentage of participants who experience secondary graft failure by one year after BMT.
• 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.
• 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.
• Incidence of chronic GVHD, one year [ Time Frame: 1 year ]
  Percentage of participants who experience chronic GVHD by one year after BMT.
• Estimate full donor chimerism [ Time Frame: Day 60 ]
  Percentage of participants with full donor chimerism at Day 60.
• Estimate GVHD-free relapse-free survival (GRFS) [ Time Frame: 1 year ]
  Percentage of participants alive, without relapse, and without GVHD at 1 year.
• Estimate transplant-related mortality [ Time Frame: 1 year ]
  Percentage of participants deceased for reasons related to BMT at 1 year.

Original Secondary Outcome Measures (submitted: July 13, 2016)

• Probability of engraftment at one year [ Time Frame: 1 year ]
  Percentage of participants alive and engrafted (i.e. without graft failure) at one year after BMT.
• Probability of neutrophil recovery at Day 56 [ Time Frame: Day 56 ]
  Percentage of participants who have recovered neutrophil counts at Day 56.
• Probability of platelet recovery at Day 100 [ Time Frame: Day 100 ]
  Percentage of participants who have recovered platelet counts at Day 100.
• Incidence of primary graft failure [ Time Frame: 1 year ]
  Percentage of participants who experience primary graft failure by one year after BMT.
• Incidence of secondary graft failure [ Time Frame: 1 year ]
  Percentage of participants who experience secondary graft failure by one year after BMT.
• 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.
• 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.
• Incidence of chronic GVHD, one year [ Time Frame: 1 year ]
  Percentage of participants who experience chronic GVHD by one year after BMT.
• Immune reconstitution in first year after BMT [ Time Frame: 1 year ]
  Characterize the pace and quality of immune reconstitution at 3, 6, and 12 months after BMT.
• Infectious complications in first year after BMT [ Time Frame: 1 year ]
  Monitor targeted infections complications (CMV, EBV, and PTLD) in the first year after BMT.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: NMA Haplo or MUD BMT for Newly Diagnosed Severe Aplastic Anemia
• 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
• 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.
• 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
• Study Phase: Phase 2
• Study Design: Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Severe Aplastic Anemia
• Aplastic Anemia
• Bone Marrow Failure
• Immunosuppression

Intervention

• 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

Study Arms

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.

Interventions:

• Drug: Thymoglobulin
• Drug: Fludarabine
• Drug: Cyclophosphamide
• Radiation: Total body irradiation
• Drug: Tacrolimus
• Drug: Mycophenolate mofetil

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: July 13, 2016): 20
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: August 2020
• Estimated Primary Completion Date: August 2020 (Final data collection date for primary outcome measure)

Eligibility 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: Child, Adult, Older Adult
• Accepts Healthy Volunteers: No

Contacts

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

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02833805
• Other Study ID Numbers: J1688; IRB00107139 ( Other Identifier: JHMIRB )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Study Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Collaborators: Not Provided

Investigators

• Principal Investigator: Amy E DeZern, MD; Johns Hopkins University

• PRS Account: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Verification Date: July 2019