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Haploidentical BMT With Post-Transplant Cyclophosphamide and Bendamustine

Primary Purpose

Acute Lymphoblastic Leukemia, Acute Myelogenous Leukemia, Myelodysplastic Syndromes

Status

Active

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Bendamustine

Cyclophosphamide

About this trial

This is an interventional treatment trial for Acute Lymphoblastic Leukemia focused on measuring high-risk malignancies, Lymphoma, Haploidentical, Bone Marrow Transplant (BMT), Post-transplant, myeloablative (MAC), reduced intensity conditioning (RIC), haploidentical hematopoietic cell transplantation (HHCT), Leukemia

Eligibility Criteria

4 Years - 30 Years (Child, Adult)All SexesDoes not accept 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.

Sites / Locations

The University of Arizona Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Cyclophosphamide and Bendamustine

Arm Description

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

Outcomes

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.

Examine the effects of PT-BEN on immune reconstitution following human haploidentical BMT.

Secondary Outcome Measures

Incidence of regimen-related organ toxicities

Incidence of acute GvHD

Severity of acute GvHD

Incidence of chronic GvHD

Extent of chronic GvHD

Incidence of graft failure

Infection risk

Immune reconstitution will be studied prospectively. Viral and fungal prophylaxis and treatment will be done according to our BMT programs guidelines

Infection severity

Immune reconstitution will be studied prospectively. Viral and fungal prophylaxis and treatment will be done according to our BMT programs guidelines

Overall patient survival

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

Incidence of bacterial, fungal and viral infections/reactivations

Gather data on Incidence of bacterial, fungal and viral infections/reactivations

Full Information

NCT ID

NCT02996773

First Posted

December 1, 2016

Last Updated

July 13, 2023

Sponsor

University of Arizona

1. Study Identification

Unique Protocol Identification Number

NCT02996773

Brief Title

Haploidentical BMT With Post-Transplant Cyclophosphamide and Bendamustine

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

July 2023

Overall Recruitment Status

Active, not recruiting

Study Start Date

November 29, 2016 (Actual)

Primary Completion Date

August 25, 2025 (Anticipated)

Study Completion Date

August 25, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University of Arizona

4. Oversight

Data Monitoring Committee

Yes

5. 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 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

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

Keywords

high-risk malignancies, Lymphoma, Haploidentical, Bone Marrow Transplant (BMT), Post-transplant, myeloablative (MAC), reduced intensity conditioning (RIC), haploidentical hematopoietic cell transplantation (HHCT), Leukemia

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

50 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Cyclophosphamide and Bendamustine

Arm Type

Experimental

Arm Description

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

Intervention Type

Drug

Intervention Name(s)

Bendamustine

Other Intervention Name(s)

BEN

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Cyclophosphamide

Other Intervention Name(s)

Intervention Description

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

Primary Outcome Measure Information:

Title

Description

Examine the effects of PT-BEN on immune reconstitution following human haploidentical BMT.

Time Frame

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 Measure Information:

Title

Incidence of regimen-related organ toxicities

Time Frame