Cryopreserved MMUD BM With PTCy for Hematologic Malignancies

Sponsor
Center for International Blood and Marrow Transplant Research (Other)
Overall Status
Not yet recruiting
CT.gov ID
NCT05068401
Collaborator
Ossium Health, Inc. (Industry)
33
Enrollment
3
Arms
24
Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

This is a multi-phase, multi-center, single arm, prospective study designed to establish the safety and efficacy of human leukocyte antigen (HLA)-mismatched unrelated cryopreserved deceased donor bone marrow transplantation (BMT) with post-transplantation cyclophosphamide for patients with hematologic malignancies.

Condition or DiseaseIntervention/TreatmentPhase
Phase 1

Study Design

Study Type:
Interventional
Anticipated Enrollment :
33 participants
Allocation:
Non-Randomized
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Multi-Center Trial of HLA-Mismatched Unrelated Cryopreserved Donor Bone Marrow Transplantation With Post-Transplantation Cyclophosphamide for Patients With Hematologic Malignancies
Anticipated Study Start Date :
Mar 1, 2022
Anticipated Primary Completion Date :
Mar 1, 2024
Anticipated Study Completion Date :
Mar 1, 2024

Arms and Interventions

ArmIntervention/Treatment
Experimental: Regimen A (RIC)

Fludarabine 30 mg/m2/day intravenously (IV) on Days -6, -5, -4, - 3, -2 Cy 14.5 mg/kg/day IV on Days -6, -5 Total body irradiation (TBI) 200 centigray (cGy) on Day -1 Day 0 will be the day of infusion of non-T-cell depleted bone marrow

Procedure: Bone Marrow Hematopoeitic Cell Transplant (HCT)
Bone Marrow stem cell graft is infused from a mismatched unrelated deceased donor on Day 0.
Other Names:
  • Bone Marrow Transplant (BMT)
  • Drug: Fludarabine
    Given IV pre-transplant as part of conditioning regimen.
    Other Names:
  • Fludara
  • Drug: Cyclophosphamide
    Given IV pre-transplant as part of conditioning regimen.
    Other Names:
  • Cytoxan
  • Radiation: Total Body Radiation (TBI)
    Administered pre-transplant as part of conditioning regimen.

    Drug: Mesna
    Mesna is given in divided doses IV 30 min pre- and at 3, 6, and 8 hours post-cyclophosphamide.
    Other Names:
  • Mesnex
  • Drug: Post-Transplantation Cyclophosphamide
    Cyclophosphamide (50 mg/kg) is administered on Day 3 and on Day 4 post-transplant.

    Drug: Sirolimus
    Given at Day 5 with dose adjusted to maintain a level of 5-15 ng/mL through Day 180.

    Drug: Mycophenolate Mofetil
    MMF is given at 15 mg/kg PO TID beginning on Day 5, maximum dose 1g PO TID (maximum daily dose 3g/day) through Day 35
    Other Names:
  • MMF
  • Cellcept
  • Drug: Growth Colony Stimulating Factor
    G-CSF (filgrastim) or a biosimilar begins on Day 5 at a dose of 5 mcg/kg/day (according to actual body weight) IV or SC (rounding to the nearest vial dose is allowed), until the ANC is ≥ 1,000/mm3 over the course of 3 consecutive days.
    Other Names:
  • Filgrastim
  • Experimental: Regimen B (FIC)

    1. Busulfan ≥ 9mg/kg total dose (IV or oral (PO)) on Days -6, -5, -4, -3 2a. Cy 50mg/kg/day IV on Days -2, -1 OR 2b. Fludarabine 30 mg/m2/day IV on Days -6, -5, -4, -3, -2 3. Day 0 will be the day of infusion of non T-cell depleted bone marrow

    Procedure: Bone Marrow Hematopoeitic Cell Transplant (HCT)
    Bone Marrow stem cell graft is infused from a mismatched unrelated deceased donor on Day 0.
    Other Names:
  • Bone Marrow Transplant (BMT)
  • Drug: Fludarabine
    Given IV pre-transplant as part of conditioning regimen.
    Other Names:
  • Fludara
  • Drug: Cyclophosphamide
    Given IV pre-transplant as part of conditioning regimen.
    Other Names:
  • Cytoxan
  • Drug: Busulfan
    Given IV or PO pre-transplant as part of conditioning regimen
    Other Names:
  • Busuflex
  • Drug: Mesna
    Mesna is given in divided doses IV 30 min pre- and at 3, 6, and 8 hours post-cyclophosphamide.
    Other Names:
  • Mesnex
  • Drug: Post-Transplantation Cyclophosphamide
    Cyclophosphamide (50 mg/kg) is administered on Day 3 and on Day 4 post-transplant.

    Drug: Sirolimus
    Given at Day 5 with dose adjusted to maintain a level of 5-15 ng/mL through Day 180.

    Drug: Mycophenolate Mofetil
    MMF is given at 15 mg/kg PO TID beginning on Day 5, maximum dose 1g PO TID (maximum daily dose 3g/day) through Day 35
    Other Names:
  • MMF
  • Cellcept
  • Drug: Growth Colony Stimulating Factor
    G-CSF (filgrastim) or a biosimilar begins on Day 5 at a dose of 5 mcg/kg/day (according to actual body weight) IV or SC (rounding to the nearest vial dose is allowed), until the ANC is ≥ 1,000/mm3 over the course of 3 consecutive days.
    Other Names:
  • Filgrastim
  • Experimental: Regimen C (FIC)

    Cy 50mg/kg/day IV on Days -5, -4 TBI 200cGy twice a day on Days -3, -2, -1 Day 0 will be the day of infusion of non- T-cell depleted bone marrow

    Procedure: Bone Marrow Hematopoeitic Cell Transplant (HCT)
    Bone Marrow stem cell graft is infused from a mismatched unrelated deceased donor on Day 0.
    Other Names:
  • Bone Marrow Transplant (BMT)
  • Drug: Cyclophosphamide
    Given IV pre-transplant as part of conditioning regimen.
    Other Names:
  • Cytoxan
  • Radiation: Total Body Radiation (TBI)
    Administered pre-transplant as part of conditioning regimen.

    Drug: Mesna
    Mesna is given in divided doses IV 30 min pre- and at 3, 6, and 8 hours post-cyclophosphamide.
    Other Names:
  • Mesnex
  • Drug: Post-Transplantation Cyclophosphamide
    Cyclophosphamide (50 mg/kg) is administered on Day 3 and on Day 4 post-transplant.

    Drug: Sirolimus
    Given at Day 5 with dose adjusted to maintain a level of 5-15 ng/mL through Day 180.

    Drug: Mycophenolate Mofetil
    MMF is given at 15 mg/kg PO TID beginning on Day 5, maximum dose 1g PO TID (maximum daily dose 3g/day) through Day 35
    Other Names:
  • MMF
  • Cellcept
  • Drug: Growth Colony Stimulating Factor
    G-CSF (filgrastim) or a biosimilar begins on Day 5 at a dose of 5 mcg/kg/day (according to actual body weight) IV or SC (rounding to the nearest vial dose is allowed), until the ANC is ≥ 1,000/mm3 over the course of 3 consecutive days.
    Other Names:
  • Filgrastim
  • Outcome Measures

    Primary Outcome Measures

    1. Graft Failure [Day 35 Post HCT]

      Failed hematopoietic engraftment by Day 35 (primary graft failure) exceeding 5% for first 3 patients

    2. Neutrophil and Platelet Recovery [Day 35 Post HCT]

      Cumulative incidence and kinetics of neutrophil and platelet recovery by Day 35 post-HCT

    3. Overall Survival [1-year Post HCT]

    Secondary Outcome Measures

    1. Cumulative incidence of acute GVHD and chronic GVHD [Day 100 Post HCT]

    2. Transplant Related Mortality [1-year Post HCT]

    3. NK, B-, and T-Cell Immune Reconstitution [Day 35 Post HCT]

    4. Progression Free Survival [1-year Post HCT]

    5. Event Free Survival [1-year Post HCT]

    6. GVHD Relapse Free Survival (GRFS) [1-year Post HCT]

    7. Incidence of cytokine release syndrome (CRS) [1-year Post HCT]

    8. Donor Chimerism [Day 35 Post HCT]

    9. Cumulative incidence of BK and cytomegalovirus (CMV) viral infections [Day 100 Post HCT]

    10. Primary Disease Relapse/Progression [1-year Post HCT]

    11. Time to donor identification from search request [1-year Post HCT]

    Other Outcome Measures

    1. Length of Stay in Hospital [Day 100 Post HCT]

    2. Incidence of clinically-significant infections [1-year Post HCT]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    15 Years to 71 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Recipient Inclusion Criteria:
    1. Provision of signed and dated informed consent form

    2. Stated willingness to comply with all study procedures and availability for the duration of the study

    3. Male or female, aged ≥ 15 and < 71 years (Note: HIV-negative subjects with MDS must be aged <50 at the time of signing the informed consent form)

    4. Diagnosed with a. Acute leukemias or T-LBL in 1st of subsequent CR i. ALL or T-LBL as defined by the following:

    5. < 5% blasts in the bone marrow 2. Normal maturation of all cellular components in the bone marrow 3. No currently active extramedullary disease (EMD) (e.g., central nervous system (CNS), soft tissue disease) 4. ANC ≥ 1,000/mm3 ii. AML defined by the following:

    6. < 5% blasts in the bone marrow

    7. No blasts with Auer rods

    8. Normal maturation of all cellular components in the bone marrow

    9. No currently active EMD (e.g., CNS, soft tissue disease)

    10. ANC ≥ 1,000/mm3 iii. ABL/AUL defined by the following:

    11. < 5% blasts in the bone marrow

    12. Normal maturation of all cellular components in the bone marrow

    13. No currently active EMD (e.g., CNS, soft tissue disease)

    14. ANC ≥ 1,000/mm3 b. MDS, fulfilling the following criteria: i. Subjects with de novo MDS who have or have previously had Intermediate-2 or High-risk disease as determined by the IPSS. Current Intermediate-2 or High- risk disease is not a requirement. ii. Subjects must have < 20% bone marrow blasts, assessed within 60 days of informed consent. iii. Subjects may have received prior therapy for the treatment of MDS prior to enrollment

    15. Performance status: Karnofsky or Lansky score ≥ 60%

    16. Adequate organ function defined as:

    17. Cardiac: LVEF at rest ≥ 35% (RIC cohort) or LVEF at rest ≥ 40% (FIC cohort), or LVFS ≥ 25%

    18. Pulmonary: DLCO, FEV1, FVC ≥ 50% predicted by pulmonary function tests (PFTs). DLCO value may be corrected or uncorrected for hemoglobin.

    19. Hepatic: total bilirubin ≤ 2.5 mg/dL, and ALT, AST, and ALP < 5 x ULN (unless ALT, AST, and/or ALP are disease related)

    20. Renal: SCr within normal range for age (see table 5.1A). If SCr is outside normal range for age, CrCl > 40 mL/min/1.73m2 must be obtained (measured by 24-hour (hr) urine specimen or nuclear glomerular filtration rate (GFR), or calculated GFR (by Cockcroft-Gault formula for those aged ≥ 18 years; by Original Schwartz estimate for those < 18 years).

    21. Subjects ≥ 18 years of age must have the ability to give informed consent according to applicable regulatory and local institutional requirements. Legal guardian permission must be obtained for subjects < 18 years of age.

    Recipient Exclusion Criteria:
    1. Suitable HLA-matched related or 8/8 allele matched (HLA-A, -B, -C, -DRB1) unrelated donor available that is not an Ossium product 2. Autologous HCT < 3 months prior to the time of signing the informed consent form 3. Pregnancy or lactation 4. Treatment with an investigational drug or other interventional GVHD clinical trials 5. Current uncontrolled bacterial, viral or fungal infection (currently taking medication with evidence of progression of clinical symptoms or radiologic findings) 6. Prior allogeneic HCT 7. Primary myelofibrosis or myelofibrosis secondary to essential thrombocythemia or polycythemia vera
    2. Subjects with MDS may not receive RIC and must be < 50 years of age at the time of signing the informed consent form 9. Any condition(s) or diagnosis, both physical or psychological, or physical exam finding that in the investigator's opinion precludes participation
    Donor Inclusion Criteria:
    1. Those who donated after brain death (DBD) or after circulatory death (DCD)

    2. Sex and Age: Both male and female donors age 7-55 years old who have consented for organ and tissue procurement for research purposes.

    3. Maximum warm ischemia time: 8 hours

    4. Maximum cold ischemia time: 50 hours (defined as all the time after vertebral bodies are placed on wet ice)

    5. Must undergo eligibility screening procedures, including an evaluation of medical history and relevant social behavior, per 21 CFR 1271 and the FDA's Guidance for Industry: Eligibility Determination for Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) (2007)

    Donor Exclusion Criteria:
    1. Evidence of septicemia, viremia, or bacteremia at time of death or positive blood culture 2. Sexually transmitted infections acquired, treated, or untreated within the last 12 months 3. Active or past history of neurological diseases such as Alzheimer's disease, dementia, or Creutzfeldt-Jakob disease (CJD) 4. Rabies 5. If the colon or esophagus was perforated during recovery 6. A positive/reactive result on the infectious disease panel (see serology requirements)

    The serology testing requirements for donor eligibility for the infectious disease organisms:

    • Hepatitis B Surface Antigen (HBsAg)

    • Hepatitis B Core Antibody (HBc Ab)

    • Human T-Lymphotropic Virus Type I & II (HTLV I/II)

    • Human Immunodeficiency Virus 1 and 2 Plus O Antibody (HIV 1/2 +O Ab)

    • Hepatitis C Virus Antibody (Anti-HCV)

    • Syphilis (RPR or STS)

    • HIV1/HCV/HBV Nucleic Acid Testing (NAT)

    • West Nile Virus (WNV) Nucleic Acid Testing

    • Trypanosoma cruzi (T. cruzi) Anti-T. cruzi Assay (Chagas)

    • Cytomegalovirus

    • Epstein-Barr Virus (EBV VCA IgG or EBNA)

    • Toxoplasmosis (IgG)

    Donors must have negative or nonreactive results to all tests except for HBc Ab, CMV or EBV, where a reactive or nonreactive result is conditionally acceptable. However, donors may be ruled out if they pose a significant risk to researchers or the processing environment.

    1. Recipient positive anti-donor HLA antibodies against a mismatched HLA in the selected donor determined by either:

    2. a positive crossmatch test of any titer (by complement-dependent cytotoxicity or flow cytometric testing) or

    3. the presence of anti-donor HLA antibody to any HLA locus (HLA-A, -B, -C, - DRB1, -DQB1, -DQA1, -DPB1, -DPA1) with mean fluorescence intensity (MFI) >3000 by solid phase immunoassay

    Contacts and Locations

    Locations

    No locations specified.

    Sponsors and Collaborators

    • Center for International Blood and Marrow Transplant Research
    • Ossium Health, Inc.

    Investigators

    • Study Chair: Jeffery Auletta, MD, Study Protocol Officer

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Center for International Blood and Marrow Transplant Research
    ClinicalTrials.gov Identifier:
    NCT05068401
    Other Study ID Numbers:
    • OSSM-BC01
    First Posted:
    Oct 5, 2021
    Last Update Posted:
    Oct 5, 2021
    Last Verified:
    Sep 1, 2021

    Study Results

    No Results Posted as of Oct 5, 2021