HLA-Mismatched Unrelated Donor Peripheral Blood Stem Cell Transplantation With Reduced Dose Post Transplantation Cyclophosphamide GvHD Prophylaxis

Study Overview
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Brief Summary
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The goal of this clinical trial is to determine the effectiveness of Reduced Dose Post-Transplant Cyclophosphamide (PTCy) in patients with hematologic malignancies after receiving an HLA-Mismatched Unrelated Donor (MMUD) . The main question[s] it aims to answer are: Does a reduced dose of PTCy reduce the occurrence of infections in the first 100 days after transplant? Does a reduced dose of PTCy maintain the same level of protection against Graft Versus Host Disease (GvHD) as the standard dose of PTCy?

Official Title
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A Phase II Study of Reduced Dose Post Transplantation Cyclophosphamide as GvHD Prophylaxis in Adult Patients With Hematologic Malignancies Receiving HLA-Mismatched Unrelated Donor Peripheral Blood Stem Cell Transplantation

Conditions
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Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Acute Leukemia, Myelodysplastic Syndromes, Chronic Myeloid Leukemia, Chronic Lymphocytic Leukemia, Myeloproliferative Neoplasm, Lymphoma, Chronic Myelomonocytic Leukemia, Pro-Lymphocytic Leukemia, Myelofibrosis

Intervention / Treatment
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* Drug: Busulfan
* Drug: Fludarabine
* Procedure: PBSC Hematopoietic Stem Cell Transplantation (HSCT)
* Drug: Post-Transplant Cyclophosphamide
* Drug: Mesna
* Drug: Tacrolimus
* Drug: Mycophenolate Mofetil
* Other: Patient Reported Outcomes
* Drug: Melphalan
* Radiation: Total-body irradiation
* Drug: Cyclophosphamide


Participation Criteria
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Eligibility Criteria
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Stratum 1 Recipient Inclusion Criteria: Age ≥ 18 years and < 66 years (chemotherapy-based conditioning) or < 61 years (total body irradiation [TBI]-based conditioning) at the time of signing informed consent Patient or legally authorized representative has the ability to provide informed consent according to the applicable regulatory and institutional requirements. Stated willingness to comply with all study procedures and availability for the duration of the study. Planned MAC regimen as defined per study protocol Available partially HLA-MMUD (4/8-7/8 at HLA-A, -B, -C, and -DRB1 is required) with age ≥ 18 and ≤ 40 years (≤ 35 preferred). Product planned for infusion is MMUD T-cell replete PBSC allograft HCT-CI < 5. The presence of prior malignancy will not be used to calculate HCT-CI for this trial to allow for the inclusion of patients with secondary or therapy-related AML or MDS. One of the following diagnoses: Acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or other acute leukemia in 1st remission or beyond with ≤ 5% marrow blasts and no circulating blasts or evidence of extra-medullary disease. Documentation of bone marrow assessment will be accepted within 45 days prior to the anticipated start of conditioning. Patients with MDS with no circulating blasts and with < 10% blasts in the bone marrow (higher blast percentage allowed in MDS due to lack of differences in outcomes with < 5% or 5-10% blasts in MDS). Documentation of bone marrow assessment will be accepted within 45 days prior to the anticipated start of conditioning. Cardiac function: Left ventricular ejection fraction ≥ 45% based on most recent echocardiogram or multi-gated acquisition scan (MUGA) results. Estimated creatinine clearance ≥ 45mL/min calculated by equation. Pulmonary function: diffusing capacity of the lungs for carbon monoxide (DLCO) corrected for hemoglobin > 50% and forced expiratory volume in first second (FEV1) predicted > 50% based on most recent pulmonary function test (PFT) results Liver function acceptable per local institutional guidelines KPS of ≥ 70% Stratum 2 Recipient Inclusion Criteria: Age ≥18 years at the time of signing informed consent Patient or legally authorized representative has the ability to provide informed consent according to the applicable regulatory and local institutional requirements. Stated willingness to comply with all study procedures and availability for the duration of the study. Planned NMA/RIC regimen per study protocol Available partially HLA-MMUD (4/8-7/8 at HLA-A, -B, -C, and -DRB1 is required) with age ≥ 18 and ≤ 40 years (≤ 35 preferred). Product planned for infusion is MMUD T-cell replete PBSC allograft One of the following diagnoses: Patients with acute leukemia or chronic myeloid leukemia (CML) with no circulating blasts, no evidence of extramedullary disease, and with < 5% blasts in the bone marrow. Documentation of bone marrow assessment will be accepted within 45 days prior to the anticipated start of conditioning. Patients with MDS with no circulating blasts and with < 10% blasts in the bone marrow (higher blast percentage allowed in MDS due to lack of differences in outcomes with < 5% or 5-10% blasts in MDS.) Documentation of bone marrow assessment will be accepted within 45 days prior to the anticipated start of conditioning. Patients with chronic lymphocytic leukemia (CLL) or other leukemias (including prolymphocytic leukemia) with chemosensitive disease at time of transplantation Higher risk CMML according to CMML-specific prognostic scoring system or high risk MDS/MPN not otherwise specified are eligible, provided there is no evidence of high-grade bone marrow fibrosis or massive splenomegaly at the time of enrollment. Patients with lymphoma with chemosensitive disease at the time of transplantation Cardiac function: Left ventricular ejection fraction ≥ 40% based on most recent echocardiogram or MUGA results with no clinical evidence of heart failure Estimated creatinine clearance ≥ 45mL/min calculated by equation Pulmonary function: DLCO corrected for hemoglobin > 50% and FEV1 predicted >50% based on most recent PFT results Liver function acceptable per local institutional guidelines KPS of ≥ 60% Stratum 3 Recipient Inclusion Criteria: Age ≥18 years at the time of signing informed consent Patient or legally authorized representative has the ability to provide informed consent according to the applicable regulatory and local institutional requirements. Stated willingness to comply with all study procedures and availability for the duration of the study. Planned NMA/RIC regimen per study protocol Available partially HLA-MMUD (4/8-7/8 at HLA-A, -B, -C, and -DRB1 is required) with age ≥ 18 and ≤ 40 years (≤ 35 preferred). Product planned for infusion is MMUD T-cell replete PBSC allograft Diagnosis of primary myelofibrosis with risk features making them eligible for HCT. Myelofibrosis secondary to essential thrombocythemia, polycythemia vera, or MDS with grade 4 fibrosis are also eligible. Patients with a myelofibrosis diagnosis require sponsor approval before enrolling. Cardiac function: Left ventricular ejection fraction ≥ 40% based on most recent echocardiogram or MUGA results with no clinical evidence of heart failure Estimated creatinine clearance ≥ 45 mL/min calculated by equation Pulmonary function: DLCO corrected for hemoglobin > 50% and FEV1 predicted >50% based on most recent PFT results Liver function acceptable per local institutional guidelines KPS of ≥ 60% Donor Inclusion Criteria (note: donors are not research subjects): Must be unrelated to the subject and high-resolution HLA-matched at 4/8, 5/8, 6/8, or 7/8 (HLA-A, -B, -C, and -DRB1. Donor must be typed at high-resolution for a minimum of HLA-A, -B, -C, -DQB1, and -DPB1. Age ≥ 18 years and ≤ 40 years at the time of signing informed consent for PBSC donation. Note: donors are preferred to be ≤ 35. Meet the donor registries' medical suitability requirements for PBSC donation. Must undergo eligibility screening according to current Food and Drug Administration (FDA) requirements. Donors who do not meet one or more of the donor screening requirements may donate under urgent medical need. Must agree to donate PBSC. Must have the ability to give informed consent according to standard (non-study) informed consent according to applicable donor regulatory requirements. Recipient Exclusion Criteria (Strata 1, 2, and 3): Suitable HLA-matched related or 8/8 high-resolution matched unrelated donor available Subject unwilling or unable to give informed consent, or unable to comply with the protocol including required follow-up and testing Subjects with a prior allogeneic transplant Subjects with an autologous transplant within the past 3 months Females who are breast-feeding or pregnant Uncontrolled bacterial, viral, or fungal infection at the time of the transplant preparative regimen Concurrent enrollment on a preventative GvHD and/or infectious disease prevention clinical trial. Subjects who undergo desensitization to reduce anti-donor HLA antibody levels prior to transplant. Patients who are HIV+ with persistently positive viral load. HIV-infected patients on effective anti-retroviral therapy (ART) with undetectable viral load within 6 months are eligible for this trial. Patients with well controlled HIV are eligible provided resistance panels are negative, the patient is compliant with ART, and their disease remains well controlled. Donor Exclusion Criteria: Donor unwilling or unable to donate. 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 prior to donor mobilization and initiation of recipient preparative regimen.

Ages Eligible for Study
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Minimum Age: 18 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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Regimen A (MAC: Busulfan and Fludarabine, PBSC HCT; Reduce Dose PTCy<br>Patients Receive: Patients receive: Busulfan (≥ 9 mg/kg total dose) IV or PO on days -6 to -3 Fludarabine (150 mg/m2 total dose) IV on days -6 to -2 Patients receive a peripheral blood stem cell (PBSC) graft infusion from a mismatched unrelated donor on Day 0. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. | Drug: Busulfan<br>* Given IV or PO pre-transplant as part of conditioning regimen<br>* Other names: Busulfex®;Drug: Fludarabine<br>* Given IV pre-transplant as part of conditioning regimen<br>* Other names: Fludara®;Procedure: PBSC Hematopoietic Stem Cell Transplantation (HSCT)<br>* Peripheral blood stem cell graft is infused from a mismatched unrelated donor on Day 0<br>* Other names: PBSCT;Drug: Post-Transplant Cyclophosphamide<br>* Cyclophosphamide (25mg/kg) is administered on Day 3 and Day 4 post-transplant as an IV infusion over 1-2 hours.<br>* Other names: PTCy;Drug: Tacrolimus<br>* Tacrolimus is given at a dose of 0.05 mg/kg PO or an IV dose of 0.03 mg/kg of ideal body weight (IBW) starting on Day +5 post-transplant with taper recommended at Day + 90 and finished by Day +180.<br>Drug: Mycophenolate Mofetil<br>* Mycophenolate mofetil (MMF) is given at a dose of 15 mg/kg three times daily IV or PO from Day +5 to Day +35 post-transplant.<br>* Other names: Cellcept®;Other: Patient Reported Outcomes<br>* Survey assessments will be administered to study participants pre transplant, at Day + 100, Day + 180, and Day +365 post transplant.<br>* Other names: PRO;|
| Experimental: Regimen B (MAC: Fludarabine and TBI, PBSC HCT; Reduce Dose PTCy<br>Patients receive: Fludarabine (90 mg/m2 total dose) IV on days -7 to -5 Total body irradiation (TBI) (1200 cGy total dose) on days -4 to -1 Patients receive a peripheral blood stem cell (PBSC) graft infusion from a mismatched unrelated donor on Day 0. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. | Drug: Fludarabine<br>* Given IV pre-transplant as part of conditioning regimen<br>* Other names: Fludara®;Procedure: PBSC Hematopoietic Stem Cell Transplantation (HSCT)<br>* Peripheral blood stem cell graft is infused from a mismatched unrelated donor on Day 0<br>* Other names: PBSCT;Drug: Post-Transplant Cyclophosphamide<br>* Cyclophosphamide (25mg/kg) is administered on Day 3 and Day 4 post-transplant as an IV infusion over 1-2 hours.<br>* Other names: PTCy;Drug: Tacrolimus<br>* Tacrolimus is given at a dose of 0.05 mg/kg PO or an IV dose of 0.03 mg/kg of ideal body weight (IBW) starting on Day +5 post-transplant with taper recommended at Day + 90 and finished by Day +180.<br>Drug: Mycophenolate Mofetil<br>* Mycophenolate mofetil (MMF) is given at a dose of 15 mg/kg three times daily IV or PO from Day +5 to Day +35 post-transplant.<br>* Other names: Cellcept®;Other: Patient Reported Outcomes<br>* Survey assessments will be administered to study participants pre transplant, at Day + 100, Day + 180, and Day +365 post transplant.<br>* Other names: PRO;Radiation: Total-body irradiation<br>* Administered pre-transplant as part of conditioning regimen<br>* Other names: TBI;|
| Experimental: Regimen C (RIC: Fludarabine and Busulfan; PBSCT HCT; Reduced Dose PTCy<br>Patients receive: Fludarabine (150-180 mg/m2 total dose) IV on days -6 to -2 Busulfan (less than or equal to 8 mg/kg PO or 6.4 mg/kg IV) on days -5 and -4 Patients receive a peripheral blood stem cell (PBSC) graft infusion from a mismatched unrelated donor on Day 0. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. | Drug: Busulfan<br>* Given IV or PO pre-transplant as part of conditioning regimen<br>* Other names: Busulfex®;Drug: Fludarabine<br>* Given IV pre-transplant as part of conditioning regimen<br>* Other names: Fludara®;Procedure: PBSC Hematopoietic Stem Cell Transplantation (HSCT)<br>* Peripheral blood stem cell graft is infused from a mismatched unrelated donor on Day 0<br>* Other names: PBSCT;Drug: Post-Transplant Cyclophosphamide<br>* Cyclophosphamide (25mg/kg) is administered on Day 3 and Day 4 post-transplant as an IV infusion over 1-2 hours.<br>* Other names: PTCy;Drug: Tacrolimus<br>* Tacrolimus is given at a dose of 0.05 mg/kg PO or an IV dose of 0.03 mg/kg of ideal body weight (IBW) starting on Day +5 post-transplant with taper recommended at Day + 90 and finished by Day +180.<br>Drug: Mycophenolate Mofetil<br>* Mycophenolate mofetil (MMF) is given at a dose of 15 mg/kg three times daily IV or PO from Day +5 to Day +35 post-transplant.<br>* Other names: Cellcept®;Other: Patient Reported Outcomes<br>* Survey assessments will be administered to study participants pre transplant, at Day + 100, Day + 180, and Day +365 post transplant.<br>* Other names: PRO;|
| Experimental: Regimen D (RIC: Fludarabine and Melphalan; PBSCT HCT; Reduced Dose PTCy<br>Patients receive: Fludarabine (125-150 mg/m2 total dose) IV on days -7 to -3 Melphalan (100-140 mg/m2) IV on day -1 Patients receive a PBSC graft infusion from a mismatched unrelated donor on Day 0. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. | Drug: Fludarabine<br>* Given IV pre-transplant as part of conditioning regimen<br>* Other names: Fludara®;Procedure: PBSC Hematopoietic Stem Cell Transplantation (HSCT)<br>* Peripheral blood stem cell graft is infused from a mismatched unrelated donor on Day 0<br>* Other names: PBSCT;Drug: Post-Transplant Cyclophosphamide<br>* Cyclophosphamide (25mg/kg) is administered on Day 3 and Day 4 post-transplant as an IV infusion over 1-2 hours.<br>* Other names: PTCy;Drug: Tacrolimus<br>* Tacrolimus is given at a dose of 0.05 mg/kg PO or an IV dose of 0.03 mg/kg of ideal body weight (IBW) starting on Day +5 post-transplant with taper recommended at Day + 90 and finished by Day +180.<br>Drug: Mycophenolate Mofetil<br>* Mycophenolate mofetil (MMF) is given at a dose of 15 mg/kg three times daily IV or PO from Day +5 to Day +35 post-transplant.<br>* Other names: Cellcept®;Other: Patient Reported Outcomes<br>* Survey assessments will be administered to study participants pre transplant, at Day + 100, Day + 180, and Day +365 post transplant.<br>* Other names: PRO;Drug: Melphalan<br>* Given IV pre transplant as part of conditioning regimen<br>|
| Experimental: Regimen E (NMA: Fludarabine, Cyclophosphamide, and TBI; PBSCT HCT; Reduced Dose PTCy<br>Patients receive: Fludarabine (150mg/m2 total dose) IV on days -6 to -2 Cyclophosphamide (29-50mg/kg) IV on days -6 and -5 TBI (200cGy) on day -1 Patients receive a PBSC graft infusion from a mismatched unrelated donor on Day 0. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. | Drug: Fludarabine<br>* Given IV pre-transplant as part of conditioning regimen<br>* Other names: Fludara®;Procedure: PBSC Hematopoietic Stem Cell Transplantation (HSCT)<br>* Peripheral blood stem cell graft is infused from a mismatched unrelated donor on Day 0<br>* Other names: PBSCT;Drug: Post-Transplant Cyclophosphamide<br>* Cyclophosphamide (25mg/kg) is administered on Day 3 and Day 4 post-transplant as an IV infusion over 1-2 hours.<br>* Other names: PTCy;Drug: Mesna<br>* Mesna is given in divided doses IV 30 min pre- and at 3, 6, and 8 hours post cyclophosphamide.<br>* Other names: Mesnex®;Drug: Tacrolimus<br>* Tacrolimus is given at a dose of 0.05 mg/kg PO or an IV dose of 0.03 mg/kg of ideal body weight (IBW) starting on Day +5 post-transplant with taper recommended at Day + 90 and finished by Day +180.<br>Drug: Mycophenolate Mofetil<br>* Mycophenolate mofetil (MMF) is given at a dose of 15 mg/kg three times daily IV or PO from Day +5 to Day +35 post-transplant.<br>* Other names: Cellcept®;Other: Patient Reported Outcomes<br>* Survey assessments will be administered to study participants pre transplant, at Day + 100, Day + 180, and Day +365 post transplant.<br>* Other names: PRO;Radiation: Total-body irradiation<br>* Administered pre-transplant as part of conditioning regimen<br>* Other names: TBI;Drug: Cyclophosphamide<br>* Given IV pre-transplant as part of conditioning regimen<br>* Other names: Cytoxan®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Infection Free Survival | Survival at 100 days without grades 2-3 infections (per BMT CTN grading criteria) | 100 days post-HCT | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Defined as time interval between date of transplant and death from any cause | 1-year post-HCT | 
| Progression-free survival | Defined as disease relapse or progression, or death by any cause | 1-year post-HCT | 
| Infection-free survival | Defined as death and grades II-III infection (per BMT CTN criteria) | 1-year post-HCT | 
| Graft versus host disease relapse free survival | Defined as relapse or progression of underling disease (by 1 year), grade III-IV acute GvHD (by 6 months), chronic GvHD requiring systemic immune suppression (by 1 year), or death by any cause (by 1 year). | 1-year post-HCT | 
| Non-relapse mortality | Defined as death without evidence of disease progression or recurrence | 1-year post-HCT | 
| Cumulative incidence of neutrophil recovery | Defined as achieving an absolute neutrophil count (ANC) greater than or equal to 500/mm3 for three consecutive measurements on three different days | Day 28 post-HCT | 
| Cumulative incidence of platelet recovery | Defined as platelet count ≥20,000/mm^3 or ≥50,000/mm^3 with no platelet transfusions within seven days. | Day 28 post-HCT | 
| Cumulative incidence of primary and secondary graft failure | Primary graft failure is defined as no neutrophil recovery to ≥ 500 cells/mm3 by Day 28 post HCT. Secondary graft failure is defined as as initial neutrophil count recovery followed by subsequent decline in absolute neutrophil counts <500 cells/mm3, unresponsive to growth factor therapy, but cannot be explained by infection, disease relapse, or medications. | Day 28 and 1-year post-HCT | 
| Donor T-Cell Chimerism | Defined as percent of donor chimerism via peripheral blood | Day 28, 100 and 365 post-HCT | 
| Cumulative incidence of acute GvHD | Defined as cumulative incidence of grades II-IV acute GvHD | Day 100 and Day 180 post-HCT | 
| Cumulative incidence of chronic GvHD |  | 1-year post-HCT | 
| Cumulative incidence of grade 2-3 bacterial, fungal, and viral infections | Defined as grades 2-3 infection as defined by BMT CTN grading criteria. | Day 100 and 1-year post-HCT | 
| Cumulative incidence of grades 2-3 BK virus hemorrhagic cystitis | Defined as incidence of BK virus hemorrhagic cystitis per BMT CTN grading criteria | 1-year post-HCT | 
| Cumulative incidence of relapse/progression | Defined as disease relapse or progression from Day 0 to 1-year post-HCT | 1-year post-HCT | 
| Overall Toxicity | To tabulate adverse events (AEs, experienced by recipients, defined as grade 3-5 unexpected and grade 5 expected AEs according to CTCAE v5 | 1-year post-HCT | 
| Incidence and Severity of cytokine release syndrome | Defined and graded using the ASTCT grading criteria. | within 14 days post-HCT | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lymphoma, Leukemia, Hematologic Diseases, Myelodysplastic Syndromes, Preleukemia, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Leukemia , Lymphocytic, Chronic, B-Cell, Leukemia, Myeloid, Acute, Leukemia, Biphenotypic, Acute, Neoplasms by Histologic Type, Neoplasms, Lymphoproliferative Disorders, Lymphatic Diseases, Immunoproliferative Disorders, Immune System Disorders, Bone Marrow Diseases, Precancerous Conditions, Leukemia, Lymphoid, Leukemia, B-Cell, Leukemia, Myeloid, Cyclophosphamide, Mesna, Tacrolimus, Busulfan, Fludarabine, Total Body Irradiation, Melphalan, Mycophenolate mofetil, Reduced Dose Cyclophosphamide, Immunosuppressive Agents, Immunologic Factors, Physiological Effects of Drugs, Hematopoietic Stem Cell Transplantation, Peripheral Blood Stem Cells, Unrelated Donors