Haploidentical BMT With Post-Transplant Cyclophosphamide and Bendamustine

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety of progressively substituting day +3 and +4 post-transplant cyclophosphamide (PT-CY) with post-transplant bendamustine (PT-BEN) in myeloablative (MAC) haploidentical hematopoietic cell transplantation (HHCT) for patients with hematological malignancies. The goal of the Phase 1 component of the study is to evaluate the safety of progressively substituting post-transplant cyclophosphamide (PT-CY) given on Days +3 and +4 with bendamustine (PT-BEN). The Phase I component of the study has been completed. The Phase Ib component of the study will continue to evaluate the safety and efficacy of subjects who receive PT-BEN on Days +3 and +4 at the maximum tolerated dose determined by Phase I. The Phase Ib component of the study has been completed. Approximately, 18-36 subjects will be treated as part of Phase I and 15 as part of Phase Ib. Approximately 18 subjects will be used as controls, subjects that receive no PET-BEN, for direct comparison. Total, approximately 38-56 treatment and control patients and 38-56 donor subjects will be enrolled.

Detailed Description
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This study will follow the standard-of-care bone marrow transplant (BMT), with the only exception being to progressively substitute post-transplant cyclophosphamide (on Days +3 and +4 after BMT) with bendamustine. Six dose levels were planned for the Phase I component of the study, consisting of a combination of sequentially reduced doses of cyclophosphamide (PT-CY) and increased doses of bendamustine (PT-BEN) initially on Day +4 after BMT, followed by the same sequential reduction and increase on Day +3. An interim analysis was performed after cohort 3 was completed in Phase I and included a preliminary comparison between treatment and control groups. Phase Ib will evaluate patients treated with PT-CY on day +3 and PT-BEN on day +4. Control patients will be patients that have declined to participate in the main trial but will receive haploidentical BMT with the current standard of two days of PT-CY (and no PT-BEN) and will be consented for the immune monitoring studies only.

Official Title
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A Phase I/Ib Study of Haploidentical Bone Marrow Transplant With Post-Transplant Cyclophosphamide and/or Bendamustine

Conditions
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Lymphoma, Follicular, Marginal Zone Lymphoma, Acute Lymphoblastic Leukemia, Acute Myelogenous Leukemia, Myelodysplastic Syndromes, Chronic Myelogenous Leukemia, Lymphoma,Non-Hodgkin, Lymphoma, Hodgkin, Large Cell Lymphoma, Mantle-Cell Lymphoma, Gray Zone Lymphoma, Burkitt Lymphoma, High Risk Undifferentiated Acute Leukemia

Intervention / Treatment
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* Drug: Bendamustine
* Drug: Cyclophosphamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be willing and able to provide written consent/assent for the trial. Diagnosed with one of the following high-risk malignancies, which require hematopoietic cell transplantation (HCT) but do not have an available Human Leukocyte Antigen (HLA)-matched related or unrelated donor or acceptable cord blood High risk acute lymphoblastic leukemia (ALL) in 1st complete remission (CR1) or greater High risk acute myelogenous leukemia (AML) in CR1 or greater High risk undifferentiated acute leukemia High risk myelodysplastic syndrome (MDS) Chronic Myelogenous Leukemia (CML) failing or intolerant to Tyrosine Kinase Inhibitors (TKIs) or in accelerated, blastic phase, or in second or subsequent chronic phase Lymphoma, (Hodgkin and Non-Hodgkins Lymphoma including marginal zone, follicular lymphoma, chemotherapy-sensitive large-cell, mantle cell lymphoma, gray zone, and Burkitt's lymphoma in remission). At least one haploidentical related donor is available for bone marrow harvest. Molecular based HLA typing for the HLA-A, -B, -Cw, beta chain (-DRB1) and - DQ Beta 1 Locus (DQB1loci) to the resolution is needed to establish haploidentity. A minimum match of 5/10 is required. No availability of an 8/8 HLA-matched related or unrelated donor or clinical urgency for transplant (e.g., needed within 4-8 weeks) at which time an acceptable unrelated donor will not be available. Exclusion Criteria: Refractory acute leukemia (>5% blasts) or progressive disease Untreated or progressive central nervous system leukemia Refractory to chemotherapy lymphoma Co-morbidities precluding patient's ability to tolerate BMT Aspartate Aminotransferase (AST)/ Alanine Aminotransferase (ALT) > 5 x upper limit of normal (ULN) Bilirubin > 2 x ULN Creatinine greater than >2 x ULN for age or creatinine clearance/glomerular filtration rate (GFR) <40 ml/min/1.73m2 Pulmonary function: Diffusing capacity of the lung for carbon monoxide (DLCO) < 40% of normal or O2 Sat <92% Cardiac: left ventricular ejection fraction <35% Active infection at time of hospital admission of Haplo BMT Documented fungal infection or highly suspected and receiving treatment for presumed fungal infection within 3 months of BMT HIV positive Karnofsky score (adults) < 60% or Lansky score < 50% (pediatrics). Positive pregnancy test for girls post menarche or women of childbearing age. Severe psychiatric illness or mental deficiency making compliance to treatment unlikely and/or informed consent impossible. Any reason, at the investigator's discretion, that the participation of the patient in this protocol would not be in patient's best interest, or where the patient would be unable to adhere to the study requirements.

Ages Eligible for Study
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Minimum Age: 4 Years
Maximum Age: 30 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cyclophosphamide and Bendamustine<br>Experimental: Cyclophosphamide and Bendamustine Control: Cyclophosphamide Interventions: Drug: Bendamustine Drug: Cyclophosphamide | Drug: Bendamustine<br>* After transplant, given intravenously on day +4 as part of Phase Ib.<br>* Other names: BEN;Drug: Cyclophosphamide<br>* After transplant, given intravenously on day +3 as part of Phase 1b.<br>* Other names: CY;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety in regards to engraftment, incidence and grade of acute and chronic graft-versus-host-disease, graft failure, infections, relapse, and non-relapse mortality post-haploidentical bone marrow transplantation. | Examine the effects of PT-BEN on immune reconstitution following human haploidentical BMT. | Change from baseline to 3 years. Interim analysis will be performed after cohort 3 and cohort 6 in Phase 1, and include preliminary evaluation of treatment and control groups | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of regimen-related organ toxicities |  | Change from baseline to 3 years. Interim analysis will be performed after cohort 3 and cohort 6 in Phase 1, and include preliminary evaluation of treatment and control groups] | 
| Incidence of acute GvHD |  | Change from baseline to 3 years. Interim analysis will be performed after cohort 3 and cohort 6 in Phase 1, and include preliminary evaluation of treatment and control groups] | 
| Severity of acute GvHD |  | Change from baseline to 3 years. Interim analysis will be performed after cohort 3 and cohort 6 in Phase 1, and include preliminary evaluation of treatment and control groups] | 
| Incidence of chronic GvHD |  | Change from baseline to 3 years. Interim analysis will be performed after cohort 3 and cohort 6 in Phase 1, and include preliminary evaluation of treatment and control groups] | 
| Extent of chronic GvHD |  | Change from baseline to 3 years. Interim analysis will be performed after cohort 3 and cohort 6 in Phase 1, and include preliminary evaluation of treatment and control groups] | 
| Incidence of graft failure |  | Change from baseline to 3 years. Interim analysis will be performed after cohort 3 and cohort 6 in Phase 1, and include preliminary evaluation of treatment and control groups] | 
| Infection risk | Immune reconstitution will be studied prospectively. Viral and fungal prophylaxis and treatment will be done according to our BMT programs guidelines | Change from baseline to 3 years. Interim analysis will be performed after cohort 3 and cohort 6 in Phase 1, and include preliminary evaluation of treatment and control groups] | 
| Infection severity | Immune reconstitution will be studied prospectively. Viral and fungal prophylaxis and treatment will be done according to our BMT programs guidelines | Change from baseline to 3 years. Interim analysis will be performed after cohort 3 and cohort 6 in Phase 1, and include preliminary evaluation of treatment and control groups] | 
| Overall patient survival |  | Change from baseline to 3 years. Interim analysis will be performed after cohort 3 and cohort 6 in Phase 1, and include preliminary evaluation of treatment and control groups] | 
| Immune reconstitution following haploidentical BMT | T cell immune reconstitution (CD4, cluster of differentiation 8 (CD8), Treg, NK), B cell and myeloid cell reconstitution will be evaluated serially until 6 months post-BMT | Change from baseline to 3 years. Interim analysis will be performed after cohort 3 and cohort 6 in Phase 1, and include preliminary evaluation of treatment and control groups] | 
| Incidence of bacterial, fungal and viral infections/reactivations | Gather data on Incidence of bacterial, fungal and viral infections/reactivations | Change from baseline to 3 years. Interim analysis will be performed after cohort 3 and cohort 6 in Phase 1, and include preliminary evaluation of treatment and control groups] | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Leukemia, high-risk malignancies, Lymphoma, Haploidentical, Bone Marrow Transplant (BMT), Post-transplant, myeloablative (MAC), reduced intensity conditioning (RIC), haploidentical hematopoietic cell transplantation (HHCT)