Haploidentical BMT With Post-Transplant Cyclophosphamide and Bendamustine

Sponsor

University of Arizona (Other)

Overall Status

Recruiting

CT.gov ID

NCT02996773

Collaborator

(none)

Enrollment

Location

Arm

Anticipated Duration (Months)

0.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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 is open for enrollment.

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.

Condition or Disease	Intervention/Treatment	Phase
Acute Lymphoblastic Leukemia Acute Myelogenous Leukemia Myelodysplastic Syndromes Chronic Myelogenous Leukemia Lymphoma,Non-Hodgkin Lymphoma, Hodgkin Lymphoma, Follicular Marginal Zone Lymphoma Large Cell Lymphoma Mantle-Cell Lymphoma Gray Zone Lymphoma Burkitt Lymphoma High Risk Undifferentiated Acute Leukemia	Drug: Bendamustine Drug: Cyclophosphamide	Phase 1/Phase 2

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

38 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Nov 29, 2016

Anticipated Primary Completion Date :

Nov 29, 2022

Anticipated Study Completion Date :

Nov 29, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cyclophosphamide and Bendamustine Experimental: Cyclophosphamide and Bendamustine Control: Cyclophosphamide Interventions: Drug: Bendamustine Drug: Cyclophosphamide	Drug: Bendamustine After transplant, given intravenously on day +4 as part of Phase Ib. Other Names: BEN Drug: Cyclophosphamide After transplant, given intravenously on day +3 as part of Phase 1b. Other Names: CY

Arm

Intervention/Treatment

Experimental: Cyclophosphamide and Bendamustine

Experimental: Cyclophosphamide and Bendamustine Control: Cyclophosphamide Interventions: Drug: Bendamustine Drug: Cyclophosphamide

Drug: Bendamustine

After transplant, given intravenously on day +4 as part of Phase Ib.

Other Names:

BEN

Drug: Cyclophosphamide

After transplant, given intravenously on day +3 as part of Phase 1b.

Other Names:

Outcome Measures

Primary Outcome Measures

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. [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]
Determine the safety of haploidentical BMT using a preparative regimen of Busulfan Fludarabine and Melphalan, or Total Body Irradiation and Fludarabine followed by PT-CY and/or PT-BEN. Demonstrate that the post-transplant regimen is well tolerated and will not result in unacceptable rates of high-grade acute or chronic Graft vs Host Disease (GvHD), graft failure, infections, non-relapse mortality or relapse compared to concurrently treated control patients and published data with PT-CY. Examine the effects of PT-BEN on immune reconstitution following human haploidentical BMT.

Secondary Outcome Measures

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]]
Severity 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]]
Level of donor cell engraftment [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]]
Duration of neutropenia and thrombocytopenia [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 neutropenia and thrombocytopenia [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]]
Requirement for blood product support [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]]
Complete blood count (CBC) will be monitored routinely and patients transfused if Hb is < 8 g/dl and platelets <20,000
Infection risk [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 will be studied prospectively. Viral and fungal prophylaxis and treatment will be done according to our BMT programs guidelines
Infection severity [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 will be studied prospectively. Viral and fungal prophylaxis and treatment will be done according to our BMT programs guidelines
Number of patients relapse free [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 [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]]
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
Length of stay of the protocol [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]]
Cost effectiveness of the protocol [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]]
Reconstituting T-cell subsets change with escalation of PT- BEN and de-escalation of day +4 PT-CY during the phase I trial [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]]
These effects of PT-BEN will be confirmed in all patients enrolled in the phase II component.
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]]
Gather data on Incidence of bacterial, fungal and viral infections/reactivations

Eligibility Criteria

Criteria

Ages Eligible for Study:

4 Years to 30 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.