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Haploidentical BMT With Post-Transplant Cyclophosphamide and Bendamustine

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ClinicalTrials.gov Identifier: NCT02996773
Recruitment Status : Recruiting
First Posted : December 19, 2016
Last Update Posted : June 29, 2018
Sponsor:
Information provided by (Responsible Party):
University of Arizona

Brief Summary:

The purpose of this study is to evaluate the safety and efficacy of substituting day +4 cyclophosphamide with post-transplant bendamustine in myeloablative (MAC) or reduced intensity conditioning (RIC) haploidentical hematopoietic cell transplantation (HHCT) for advanced leukemia and lymphoma patients.

The phase I component of the study is to evaluate the safety of completely substituting the second dose of post-transplant cyclophosphamide (PT-CY) given on day +4 with bendamustine (PT-BEN).

The phase II component of the study will continue to evaluate the safety and efficacy of subjects who receive PT-CY on day +3 and PT-BEN on day +4.

Approximately, a total of 32 subjects will be treated under this protocol. Approximately 12 to 15 subjects will be used as control, subjects that receive no PT-BEN, for direct comparison.


Condition or disease Intervention/treatment Phase
Acute Lymphoblastic Leukemia Acute Myelogenous Leukemia Myelodysplastic Syndromes Chronic Myelogenous Leukemia Juvenile Myelomonocytic Leukemia Lymphoma,Non-Hodgkin Lymphoma, Hodgkin Lymphoma, Follicular Marginal Zone Lymphoma Large Cell Lymphoma Mantle-Cell Lymphoma Gray Zone Lymphoma Burkitt Lymphoma 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 gradually substitute post-transplant cyclophosphamide (on day +4 after BMT) with bendamustine. Three dose levels are planned for the phase I component of the study, consisting of a combination of sequentially reduced doses of cyclophosphamide and increased doses of bendamustine (on day +4 after BMT) with the full dose cyclophosphamide on day +3 after BMT remaining unchanged.

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 Type : Interventional  (Clinical Trial)
Estimated Enrollment : 32 participants
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 : November 29, 2016
Estimated Primary Completion Date : April 2022
Estimated Study Completion Date : April 2022


Arm Intervention/treatment
Experimental: Cyclophosphamide and Bendamustine
Several dose levels are planned to gradually decrease cyclophosphamide and replace with bendamustine on Day 4+ post-transplant.
Drug: Bendamustine

After transplant, on day +4, Cyclophosphamide and Bendamustine will be given intravenously

Dose level 1: 20 mg/m2 Dose Level 2: 60 mg/m2 Dose Level 3: 100 mg/m2

Other Name: BEN

Drug: Cyclophosphamide

After transplant, on day +4, Cyclophosphamide and Bendamustine will be given intravenously

Dose level 1: 40 mg/kg Dose Level 2: 20 mg/kg Dose Level 3: 0 mg/kg

Other Name: CY




Primary Outcome Measures :
  1. Safety in regards to engraftment, incidence and grade of acute and chronic graft versus host disease and toxicity/non-relapse mortality post-haploidentical bone marrow transplantation. [ Time Frame: Change from baseline to 3 years ]
    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 this regimen is well tolerated and will not result in unacceptable rates of high-grade acute or chronic graft vs host disease (GvHD), graft failure, non-relapse mortality (NRM) or relapse compared to published data with PT-CY.


Secondary Outcome Measures :
  1. Incidence of regimen-related organ toxicities [ Time Frame: Change from baseline to 3 years ]
  2. Severity of regimen-related organ toxicities [ Time Frame: Change from baseline to 3 years ]
  3. Incidence of acute GvHD [ Time Frame: Change from baseline to 3 years ]
  4. Severity of acute GvHD [ Time Frame: Change from baseline to 3 years ]
  5. Incidence of chronic GvHD [ Time Frame: Change from baseline to 3 years ]
  6. Extent of chronic GvHD [ Time Frame: Change from baseline to 3 years ]
  7. Incidence of graft failure [ Time Frame: Change from baseline to 3 years ]
  8. Level of donor cell engraftment [ Time Frame: Change from baseline to 3 years ]
  9. Duration of neutropenia and thrombocytopenia [ Time Frame: Change from baseline to 3 years ]
  10. Severity of neutropenia and thrombocytopenia [ Time Frame: Change from baseline to 3 years ]
  11. Requirement for blood product support [ Time Frame: Change from baseline to 3 years ]
    Complete blood count (CBC) will be monitored routinely and patients transfused if Hb is < 8 g/dl and platelets <20,000

  12. Infection risk [ Time Frame: Change from baseline to 3 years ]
    Immune reconstitution will be studied prospectively. Viral and fungal prophylaxis and treatment will be done according to our BMT programs guidelines

  13. Infection severity [ Time Frame: Change from baseline to 3 years ]
    Immune reconstitution will be studied prospectively. Viral and fungal prophylaxis and treatment will be done according to our BMT programs guidelines

  14. Number of patients relapse free [ Time Frame: Change from baseline to 3 years ]
  15. Overall patient survival [ Time Frame: Change from baseline to 3 years ]
  16. Immune reconstitution following haploidentical BMT [ Time Frame: Change from baseline to 6 months post-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

  17. Length of stay of the protocol [ Time Frame: Change from baseline to 3 years ]
  18. Cost effectiveness of the protocol [ Time Frame: Change from baseline to 3 years ]
  19. Reconstituting T-cell subsets change with escalation of PT- BEN and de-escalation of day +4 PT-CY during the phase I trial [ Time Frame: Change from baseline to 3 years ]
    These effects of PT-BEN will be confirmed in all patients enrolled in the phase II component.



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Ages Eligible for Study:   8 Years to 65 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
  • Juvenile Myelomonocytic Leukemia (JMML)
  • 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 within 3 months of BMT
  • HIV positive
  • Karnofsky score (adults) < 60% or Lansky score < 50% (pediatrics).
  • Positive pregnancy test for 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02996773


Contacts
Contact: Olga Ambriz (520) 694-4767 oambriz@email.arizona.edu
Contact: Emmanuel Katsanis, MD (520) 626-7053 katsanis@peds.arizona.edu

Locations
United States, Arizona
The University of Arizona Cancer Center Recruiting
Tucson, Arizona, United States, 85724
Contact: Olga Ambriz    (520) 694-4767    oambriz@email.arizona.edu   
Principal Investigator: Emmanuel Katsanis, MD         
Sub-Investigator: Faiz Anwer, MD         
Sub-Investigator: Daniel Persky, MD         
Sub-Investigator: Soham Puvvada, MD         
Sub-Investigator: Ali McBride, PharmD, MS, BCPS         
Sub-Investigator: Denise J. Roe, DrPH         
Sub-Investigator: Murali Kodali, MD         
Sub-Investigator: Lisa Kopp, DO         
Sub-Investigator: Ravitharan Krishnadasan, MD         
Sub-Investigator: Sandra Kurtin, NPC         
Sub-Investigator: Laura McPheeters, NP         
Sub-Investigator: Jana Montez, NP         
Sub-Investigator: Lauren Nichols, MD         
Sub-Investigator: Luz Pelayo-Katsanis, RN, PNP         
Sub-Investigator: Lauren Sapp, NP         
Sub-Investigator: Katherine Whitney, NP         
Sub-Investigator: Andrew Yeager, MD         
Sub-Investigator: Yi Zeng, MD         
Sponsors and Collaborators
University of Arizona
Investigators
Principal Investigator: Emmanuel Katsanis, MD The University of Arizona Cancer Center

Responsible Party: University of Arizona
ClinicalTrials.gov Identifier: NCT02996773     History of Changes
Other Study ID Numbers: 1609876907
First Posted: December 19, 2016    Key Record Dates
Last Update Posted: June 29, 2018
Last Verified: March 2018

Keywords provided by University of Arizona:
high-risk malignancies
Lymphoma
Haploidentical
Bone Marrow Transplant (BMT)
Post-transplant
myeloablative (MAC)
reduced intensity conditioning (RIC)
haploidentical hematopoietic cell transplantation (HHCT)
Leukemia

Additional relevant MeSH terms:
Epstein-Barr Virus Infections
Lymphoma
Leukemia
Myelodysplastic Syndromes
Preleukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Leukemia, Myeloid
Lymphoma, Mantle-Cell
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Lymphoma, B-Cell, Marginal Zone
Burkitt Lymphoma
Leukemia, Myeloid, Acute
Lymphoma, Non-Hodgkin
Leukemia, Myelomonocytic, Juvenile
Lymphoma, Follicular
Hodgkin Disease
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Myeloproliferative Disorders
Lymphoma, B-Cell
Herpesviridae Infections
DNA Virus Infections