Cryopreserved MMUD BM With PTCy for Hematologic Malignancies

• Status: Not yet recruiting
• Trial end date: 2024-03-01
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 1
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Center for International Blood and Marrow Transplant Research
• Collaborator: Ossium Health, Inc.
• Treatments: Busulfan; Cyclophosphamide; Fludarabine; Mycophenolic Acid; Sargramostim; Sirolimus

Criteria

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:

1. < 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:

1. < 5% blasts in the bone marrow

2. No blasts with Auer rods

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

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

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

1. < 5% blasts in the bone marrow

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

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

4. 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

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

6. Adequate organ function defined as:

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

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

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

4. 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).

7. 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

8. 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.

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

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

2. 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