Bendamustine With or Without Cyclophosphamide in Preventing GVHD in Patients Undergoing Stem Cell Transplant

Study Overview
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Brief Summary
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This phase I/II trial studies the side effects and best dose of bendamustine when given with or without cyclophosphamide in preventing graft versus host disease (GVHD) in patients undergoing stem cell transplant. Drugs used in chemotherapy, such as bendamustine and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving chemotherapy and total body irradiation before or after a stem cell transplant helps kills cancer cells that are in the body and helps make room in the patient's bone marrow for new blood-forming cells (stem cells) to grow. Sometimes, the transplanted cells from a donor can attack the body's normal cells called GVHD. Giving tacrolimus, mycophenolate mofetil, and filgrastim after the transplant may stop this from happening.

Detailed Description
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PRIMARY OBJECTIVE: I. Evaluate the safety of substituting the standard post-transplant cyclophosphamide (PT-CY) given on day +3 and +4 with post-transplant bendamustine (PT-BEN) in patients undergoing HLA-mismatched hematopoietic cell transplantation. SECONDARY OBJECTIVES: I. To evaluate treatment-related mortality. II. To assess acute and chronic graft-versus-host disease (GVHD). III. To assess overall survival, progression-free survival and relapse rates. IV. To evaluate the risk of acute cystitis. V. To evaluate immune reconstitution after transplantation. OUTLINE: This is a dose-escalation study of bendamustine. Patients are assigned to 1 of 2 treatment schedules. SCHEDULE I (NON-LYMPHOMA): Patients receive fludarabine intravenously (IV) over 1 hour on days -5 to -2, melphalan IV over 30 minutes on days -5 and -4, and undergo total body irradiation (TBI) on day -1 and stem cell transplantation IV over 2-6 hours on day 0. Depending on when the trial was joined, patients receive cyclophosphamide IV over 3 hours or bendamustine IV over 30-60 minutes or cyclophosphamide IV over 3 hours and bendamustine IV over 30-60 minutes on day 3. Patients also receive bendamustine IV over 30-60 minutes on day 4. Beginning day 5, patients receive tacrolimus IV followed by orally (PO) once daily (QD) or twice daily (BID) for 6 months and mycophenolate mofetil PO thrice daily (TID) until day 100. Beginning day 7, patients receive filgrastim-sndz subcutaneously (SC) QD until blood cell levels return to normal. SCHEDULE II (LYMPHOID MALIGNANCIES): Patients receive fludarabine IV over 1 hour, bendamustine IV over 30-60 minutes on days -5 to -3 and undergo TBI on day -1 and stem cell transplantation over 2-6 hours on day 0. Depending on when the trial was joined, patients receive cyclophosphamide IV over 3 hours or bendamustine IV over 30-60 minutes or cyclophosphamide IV over 3 hours and bendamustine IV over 30-60 minutes on day 3. Patients also receive bendamustine IV over 30-60 minutes on day 4. Beginning day 5, patients receive tacrolimus IV followed by PO QD or BID for 6 months and mycophenolate mofetil PO TID until day 100. Beginning day 7, patients receive filgrastim-sndz SC QD until blood cell levels return to normal. CD20+ patients receive rituximab IV over 4-6 hours on days -13, -6, 1, and 8. After completion of study treatment, patients are followed weekly for 3 months, every 3 months in year 1, and every 6 months in year 2.

Official Title
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Post-Transplant Bendamustine (PT-BEN) for GVHD Prophylaxis

Conditions
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Hematopoietic and Lymphoid System Neoplasm

Intervention / Treatment
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* Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
* Drug: Bendamustine
* Drug: Cyclophosphamide
* Biological: Filgrastim-sndz
* Drug: Fludarabine
* Drug: Melphalan
* Drug: Mycophenolate Mofetil
* Biological: Rituximab
* Drug: Tacrolimus
* Radiation: Total-Body Irradiation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient with hematologic malignancies. Donor: Mismatched or haplo-identical. Zubrod performance 0 to 2 or Karnofsky of at least 60. Creatinine less than or equal to 1.6 mg/dL and creatinine clearance >= 30 ml/min. Creatine clearance will be calculated using the Cockcroft-Gault equation. (at time of study entry) Total bilirubin less than < 1.5 x upper limit of normal (UNL). (at time of study entry) Serum glutamate pyruvate transaminase (SGPT) < 2.5 x ULN. (at time of study entry) Ejection fraction >= 40%. (at time of study entry) Forced expiratory volume in one second (FEV1) >= 40%. (at time of study entry) Forced vital capacity (FVC) >= 40%. (at time of study entry) Diffusion capacity of the lung for carbon monoxide (DLCO) >= 40%. (at time of study entry) Exclusion Criteria: Pregnant or nursing women. Known to be human immunodeficiency virus (HIV) positive. Active and uncontrolled disease/infection. Unable or unwilling to sign consent. Current active hepatic or biliary disease (with exception of Gilbert's syndrome). Active hepatitis B or C. Toxicities (grade > 1) unresolved from prior treatment (including chemotherapy, targeted therapy, immunotherapy, experimental agents radiation, or surgery. Patients with standard risk acute leukemia in first complete remission and patients with chronic myeloid leukemia in first chronic will be excluded during escalated phase.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Schedule I (non-lymphoma)<br>Patients receive fludarabine IV over 1 hour on days -5 to -2, melphalan IV over 30 minutes on days -5 and -4, and undergo TBI on day -1 and stem cell transplantation IV over 2-6 hours on day 0. Depending on when the trial was joined, patients receive cyclophosphamide IV over 3 hours or bendamustine IV over 30-60 minutes or cyclophosphamide IV over 3 hours and bendamustine IV over 30-60 minutes on day 3. Patients also receive bendamustine IV over 30-60 minutes on day 4. Beginning day 5, patients receive tacrolimus IV followed by PO QD or BID for 6 months and mycophenolate mofetil PO TID until day 100. Beginning day 7, patients receive filgrastim-sndz SC QD until blood cell levels return to normal. | Procedure: Allogeneic Hematopoietic Stem Cell Transplantation<br>* Undergo stem cell transplantation<br>* Other names: Stem Cell Transplantation, Allogeneic;Drug: Bendamustine<br>* Given IV<br>* Other names: SDX-105;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Biological: Filgrastim-sndz<br>* Given SC<br>* Other names: Zarxio;Drug: Fludarabine<br>* Given IV<br>* Other names: Fluradosa;Drug: Melphalan<br>* Given IV<br>* Other names: WR-19813;Drug: Mycophenolate Mofetil<br>* Given PO<br>* Other names: MMF;Drug: Tacrolimus<br>* Given IV and PO<br>* Other names: Protopic;Radiation: Total-Body Irradiation<br>* Undergo TBI<br>* Other names: Whole-Body Irradiation;|
| Experimental: Schedule II (lymphoid malignancies)<br>Patients receive fludarabine IV over 1 hour, bendamustine IV over 30-60 minutes on days -5 to -3 and undergo TBI on day -1 and stem cell transplantation over 2-6 hours on day 0. Depending on when the trial was joined, patients receive cyclophosphamide IV over 3 hours or bendamustine IV over 30-60 minutes or cyclophosphamide IV over 3 hours and bendamustine IV over 30-60 minutes on day 3. Patients also receive bendamustine IV over 30-60 minutes on day 4. Beginning day 5, patients receive tacrolimus IV followed by PO QD or BID for 6 months and mycophenolate mofetil PO TID until day 100. Beginning day 7, patients receive filgrastim-sndz SC QD until blood cell levels return to normal. CD20+ patients receive rituximab IV over 4-6 hours on days -13, -6, 1, and 8. | Procedure: Allogeneic Hematopoietic Stem Cell Transplantation<br>* Undergo stem cell transplantation<br>* Other names: Stem Cell Transplantation, Allogeneic;Drug: Bendamustine<br>* Given IV<br>* Other names: SDX-105;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Biological: Filgrastim-sndz<br>* Given SC<br>* Other names: Zarxio;Drug: Fludarabine<br>* Given IV<br>* Other names: Fluradosa;Drug: Mycophenolate Mofetil<br>* Given PO<br>* Other names: MMF;Biological: Rituximab<br>* Given IV<br>* Other names: Truxima;Drug: Tacrolimus<br>* Given IV and PO<br>* Other names: Protopic;Radiation: Total-Body Irradiation<br>* Undergo TBI<br>* Other names: Whole-Body Irradiation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose level (MTDL) (Phase I) | Will employ the time-to-event Bayesian optimal interval design to find the MTDL. After the trial is completed, the MTDL will be selected based on isotonic regression as specified in Yuan et al. Specifically, MTDL will be selected as the dose for which the isotonic estimate of the toxicity rate is closest to the target toxicity rate. If there are ties, the higher dose level when the isotonic estimate is lower than the target toxicity rate will be selected and the lower dose level when the isotonic estimate is greater than or equal to the target toxicity rate will be selected. | Up to 30 days | 
| Dose-limiting toxicity (Phase I) |  | Up to 100 days | 
| Incidence of adverse events (Phase II) | The trial is continuously monitored for toxicity per the statistical design. | Up to 2 years |