A First-in-Human Study of HLA-Partially to Fully Matched Allogenic Cryopreserved Deceased Donor Bone Marrow Transplantation for Patients With Hematologic Malignancies

Study Overview
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Brief Summary
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The goal of this clinical trial is to determine the safety and feasibility of allogeneic transplantation with bone marrow from a deceased donor in patients with acute leukemias. Patients will either receive myeloablative conditioning or reduced intensity conditioning regimen prior to the transplant. Patients will be followed for 56 days for safety endpoints and remain in follow-up for one year.

Official Title
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A First-in-Human Study of HLA-Partially to Fully Matched Allogenic Cryopreserved Deceased Donor Bone Marrow Transplantation for Patients With Hematologic Malignancies

Conditions
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Acute Leukemia, Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Acute Biphenotypic Leukemia, Acute Undifferentiated Leukemia

Intervention / Treatment
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* Drug: Busulfan
* Drug: Fludarabine
* Radiation: Total Body Irradiation
* Drug: Cyclophosphamide
* Drug: Mesna
* Procedure: Bone Marrow Transplant
* Drug: Cyclophosphamide
* Drug: Tacrolimus
* Drug: Mycophenolate Mofetil
* Drug: Filgrastim


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient has the ability to provide informed consent according to the applicable regulatory and local institutional requirements Male or female, aged ≥18 and <55 years for patients receiving MAC (Regimen A or Regimen B); aged ≥18 and <70 years for patients receiving RIC (Regimen C in Cohort 2 only) Patient must require allogeneic HCT per the discretion of the treating physician Patient must be high-resolution, HLA partially or fully matched (4-8/8 allele matched at HLA-A, -B, -C, DRB1) to an available Ossium HPC, Marrow product Stated willingness to comply with all study procedures and availability for the duration of the study Diagnosed with acute leukemia [acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute biophenotypic leukemia (ABL), or acute undifferentiated leukemia (AUL)] in the first remission or beyond with ≤5% marrow blasts and no circulating blasts or extra-medullary disease documented by bone marrow assessment within 42 days prior to anticipated start of conditioning Karnofsky performance status score ≥70% (MAC) or ≥60% (RIC) HCT comorbidity index (HCT-CI) <5 Adequate organ function defined as: Cardiac: LVEF at rest ≥45% (RIC) or LVEF at rest ≥40% (MAC) Pulmonary: DLCO, FEV1, FVC ≥50% predicted by pulmonary function tests (PFTs). DLCO value may be corrected for hemoglobin. Hepatic: total bilirubin ≤2.0 mg/dL, and ALT, AST, and ALP <3 x upper limit normal (ULN), unless ALT, AST, and/or ALP are disease related Renal: SCr within 1.5x normal range for age. If SCr is outside normal range for age, CrCl> 60 mL/min/1.73m2 must be obtained (measured by 24-hour urine specimen or nuclear glomerular filtration rate (GFR), or calculated GFR (by Cockcroft-Gault formula)) Exclusion Criteria: Availability of suitable graft from living donor (defined as 7/8 or 8/8 HLA-matched related or unrelated donors, haploidentical donors, or cord blood donors) Prior autologous or allogeneic HCT Pregnancy or lactation Ongoing treatment with an investigational drug used for disease-related treatment within 5 half-lives of the drug Current uncontrolled bacterial, viral or fungal infection defined as currently taking medication with evidence of progression of clinical symptoms or radiologic findings Any condition(s) or diagnosis, both physical or psychological, or physical exam finding that in the investigator's opinion precludes participation

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: All patients will receive Ossium HPC, Marrow product. Study arms will be based on conditioning regimen.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Regimen A (MAC)<br>Pre-transplant conditioning treatment with Busulfan and Fludarabine Bone Marrow Transplant with Ossium HPC, Marrow Post-Transplant treatment with Cyclophosphamide, Tacrolimus, Mycophenolate Mofetil, and Filgrastim | Drug: Busulfan<br>* pre-transplant conditioning treatment<br>* Other names: Busuflex;Drug: Fludarabine<br>* pre-transplant conditioning treatment<br>* Other names: Fludara;Procedure: Bone Marrow Transplant<br>* Bone marrow transplant with Ossium HPC, product<br>* Other names: Hematopoetic Cell Transplantation;Drug: Cyclophosphamide<br>* post-transplant treatment<br>* Other names: Cytoxan;Drug: Tacrolimus<br>* post-transplant treatment<br>Drug: Mycophenolate Mofetil<br>* post-transplant treatment<br>* Other names: MMF;Drug: Filgrastim<br>* post-transplant treatment<br>* Other names: G-CSF;|
| Experimental: Regimen B (MAC)<br>Pre-transplant conditioning treatment with Fludarabine and Total Body Irradiation Bone Marrow Transplant with Ossium HPC, Marrow Post-Transplant treatment with Cyclophosphamide, Tacrolimus, Mycophenolate Mofetil, and Filgrastim | Drug: Fludarabine<br>* pre-transplant conditioning treatment<br>* Other names: Fludara;Radiation: Total Body Irradiation<br>* pre-transplant conditioning treatment<br>* Other names: TBI;Procedure: Bone Marrow Transplant<br>* Bone marrow transplant with Ossium HPC, product<br>* Other names: Hematopoetic Cell Transplantation;Drug: Cyclophosphamide<br>* post-transplant treatment<br>* Other names: Cytoxan;Drug: Tacrolimus<br>* post-transplant treatment<br>Drug: Mycophenolate Mofetil<br>* post-transplant treatment<br>* Other names: MMF;Drug: Filgrastim<br>* post-transplant treatment<br>* Other names: G-CSF;|
| Experimental: Regimen C (RIC)<br>Pre-transplant conditioning treatment with Fludarabine, Cyclophosphamide, and Total Body Irradiation Bone Marrow Transplant with Ossium HPC, Marrow Post-Transplant treatment with Cyclophosphamide, Tacrolimus, Mycophenolate Mofetil, and Filgrastim | Drug: Fludarabine<br>* pre-transplant conditioning treatment<br>* Other names: Fludara;Radiation: Total Body Irradiation<br>* pre-transplant conditioning treatment<br>* Other names: TBI;Drug: Cyclophosphamide<br>* pre-transplant conditioning treatment<br>* Other names: Cytoxan;Drug: Mesna<br>* given with Cyclophosphamide<br>* Other names: Mesnex;Procedure: Bone Marrow Transplant<br>* Bone marrow transplant with Ossium HPC, product<br>* Other names: Hematopoetic Cell Transplantation;Drug: Cyclophosphamide<br>* post-transplant treatment<br>* Other names: Cytoxan;Drug: Tacrolimus<br>* post-transplant treatment<br>Drug: Mycophenolate Mofetil<br>* post-transplant treatment<br>* Other names: MMF;Drug: Filgrastim<br>* post-transplant treatment<br>* Other names: G-CSF;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neutrophil Engraftment | Neutrophil engraftment is defined as achieving an absolute neutrophil count (ANC) of greater than or equal to 500/µL for 3 consecutive measurements on 3 different days by Day 28. | Day 28 | 
| Serious Adverse Events | Occurrence of any event classified as SAE. The time of occurrence of each serious adverse event will be recorded. | Day 56 | 
| CTCAE Grade 3/4 Adverse Events (AEs) | Occurrence of any event classified as grade 3/4 AE attributed to Ossium HPC, Marrow per the CTCAE v5.0 guidelines. The time of the occurrence of each event will be recorded. | Day 56 | 
| CTCAE Grade 3/4 Adverse Events (AEs) | Occurrence of any event classified as grade 3 or higher attributed to Ossium HPC, Marrow per the CTCAE v5.0 guidelines as defined in Section 8.5. The time of the occurrence will be recorded. | Day 28 | 
| Death | The time of death will be recorded for each expired patient. | Day 56 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative incidences of neutrophil engraftment | Neutrophil engraftment in defined as achieving an absolute neutrophil count (ANC) of greater than or equal to 500/µL for 3 consecutive measurements on different days by Day 28. | Day 28 | 
| Cumulative incidences of platelet recovery | Platelet recovery is defined as platelets greater than or equal to 20,000/µL for 3 consecutive days in the absence of transfusion for 7 consecutive days by Day 56. | Day 56 | 
| Cumulative incidence of disease relapses | The cumulative incidence of relapse is measured from the date of transplant (Day 0) until the date of relapse or progression; patients not known to have relapsed are censored on the date they were last examined; patients who died without relapse are counted as a competing cause of failure. | Day 365 | 
| Transplant-related mortality (TRM) | TRM is defined as death without evidence of disease progression or recurrence. | Day 100 and Day 365 | 
| Cumulative incidences of acute (aGVHD) Graft Versus Host Disease | aGVHD is defined as any skin, gastrointestinal or liver abnormalities fulfilling the criteria of grades II-IV or grades III-IV. | Day 100, Day 180, and Day 365 | 
| Cumulative incidences of chronic (cGVHD) Graft Versus Host Disease | cGVHD is defined per National Institutes of Health (NIH) Consensus Criteria and includes organ involvement and severity, and overall global composite score (mild/moderate/severe). | Day 100, Day 180, and Day 365 | 
| Incidence of clinically-significant infections | A clinically significant infection is defined as any microbiologic or radiographic infection for which antimicrobial therapy was administered. | Day 100 and Day 365 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Leukemia, Hematologic Diseases, ALL, AML, ABL, AUL, Bone Marrow Transplant