Clinical Trial 23284

• Overview

  Study Title:

  A Phase II Trial of Non-Myeloablative Conditioning and Transplantation of Haploidentical Related, Partially HLA-Mismatched, or Matched Unrelated Bone Marrow for Newly Diagnosed Patients with Severe Aplastic Anemia

  Objective:

  Primary: Estimate GVHD-free failure-free survival (GFFS) (a composite end point of survival without Grade III-IV aGVHD, cGVHD requiring immunosuppression, or primary or secondary graft failure requiring second definitive therapy) at 1 year after initiation of conditioning. GFFS will be evaluated separately for each transplant cohort. Secondary: 1. Estimate OS at 1 year after initiation of conditioning. 2. Estimate FFS (a composite end point of survival without initiation of treatment with a second definitive therapy for curative intent) at 1 year after initiation of conditioning. 3. Estimate the probability of being engrafted (i.e., without primary or secondary graft failure) and alive at 1 year after initiation of conditioning. 4. Estimate the cumulative incidences of neutrophil recovery at Day +28 and Day +56 post-HSCT, platelet recovery at Day +100 post-HSCT, and red blood cell recovery at Day +100, Day +180, and Day +365 post-HSCT. 5. Estimate the cumulative incidences of primary, secondary, and any graft failure at 1 year post-HSCT. 6. Estimate the hematologic response classification according to the NIH criteria at Day +100, Day +180, and Day +365 post-HSCT. 7. Estimate the cumulative incidences of Grade II-IV and Grade III-IV aGVHD at Day +100 post-HSCT. 8. Estimate the cumulative incidences of all cGVHD and cGVHD requiring immunosuppression at 1 year post-HSCT.

• Treatments

  Therapies:

  Bone Marrow Transplant; Chemotherapy (NOS); Radiotherapy

  Medications:

  Cellcept (Mycophenolate Mofetil); FK506 (Tacrolimus); MESNA (); Mycophenolate Mofetil (); Radiotherapy (); Tacrolimus (); Thymoglobulin (); cyclophosphamide (); cytoxan (cyclophosphamide); fludarabine (Fludarabine phosphate)

• Inclusion Criteria

  Key Inclusion Criteria:
  • Age 3 years to 75 years.
  • Confirmed diagnosis of acquired SAA defined as: a) a. Bone marrow cellularity > No suitable fully matched related donor as per Investigator’s discretion (6/6 match for HLA-A and B at intermediate or high-resolution and DRB1 at high-resolution using deoxyribonucleic acid [DNA]-based typing) available.
  • Available donor per Section 2.4.
  • Participant and/or legal guardian must sign informed consent.
  • Adequate organ function defined by institutional transplant standards.
  • Karnofsky or Lansky performance status ≥ 60%.
  • Females and males of childbearing potential must agree to practice 2 effective methods of contraception at the same time or agree to abstinence.
  • Other inclusion criteria may apply.

• Exclusion Criteria

  Key Exclusion Criteria:
  • Inherited bone marrow failure syndromes such as Fanconi anemia and short telomere syndromes must be ruled out according to center standards. It is recommended that functional testing for Fanconi Anemia (di-epoxybutane [DEB] chromosomal breakage analysis) and telomere length assessment be performed. If available, genetic panels for inherited bone marrow failure syndromes can be considered as an alternative to functional testing.
  • Clonal cytogenetic abnormalities consistent with pre-MDS or MDS on marrow examination (e.g., monosomy 7 and other MDS-defining changes per recent pathology guidelines).
  • Formal diagnosis of MDS by World Health Organization (WHO) 2022 or International Consensus Classification (ICC).
  • Recipient positive for HLA antibodies against a mismatched HLA in the selected donor determined by the presence of donor specific HLA antibodies (DSA) to any mismatched HLA allele/antigen at any of the following loci (HLA-A, -B, -C, –DRB1, DRB3, DRB4, DRB5, -DQA1, -DQB1, -DPA1, -DPB1) with median fluorescence intensity (MFI) >3000 by microarray-based single antigen bead testing. In patients receiving red blood cell or platelet transfusions, DSA evaluation must be performed or repeated post-transfusion and immediately prior to initiation of recipient preparative regimen to ensure there is confirmation of no DSA to the selected donor when conditioning starts.
  • Prior desensitization attempt for HLA antibodies to chosen donor. Any intervention with the sole intent to reduce the level of HLA DSA, (e.g., plasmapheresis, intravenous immunoglobulin [IVIG], MMF, etc.) would constitute a desensitization attempt.
  • Prior treatment for SAA (e.g., immunosuppressive therapy using ATG, calcineurin inhibitors [CNIs], thrombopoietin receptor agonists or androgens). Short courses of steroids or IVIG that were not explicitly administered for SAA therapy will be allowed.
  • Prior allogeneic stem cell transplant.
  • Prior solid organ transplant.
  • Known life-threatening reaction (i.e., anaphylaxis) to Thymoglobulin® (Sanofi) that would prohibit use for the participant as this study requires use of the Thymoglobulin® (Sanofi) preparation of ATG.
  • Uncontrolled bacterial, viral, or fungal infection at the time of enrollment. Uncontrolled is defined as currently taking medication and with progression or no clinical improvement on adequate medical treatment.
  • Female participants who are pregnant, as detected using a pregnancy test as per institutional practice, or breast-feeding.
  • Prior malignancies except resected basal cell carcinoma or treated cervical carcinoma in situ. Cancer treated with curative intent > 5 years previously will be allowed. Cancer treated with curative intent ≤ 5 years previously will not be allowed unless approved by the Protocol Chairs and/or Protocol Officer.
  • Other exclusion criteria may apply.

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