Fludarabine, Bendamustine, and Rituximab in Treating Participants With Lymphoid Cancers Undergoing Stem Cell Transplant

Study Overview
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Brief Summary
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This phase I trial studies the best dose and how well bendamustine works with standard chemotherapy (fludarabine, rituximab) in treating participants with lymphoid cancers undergoing stem cell transplant. Drugs used in chemotherapy, such as fludarabine, bendamustine, and rituximab, 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 before a stem cell transplant helps stop the growth of cancer cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. When the healthy stem cells from a donor are infused into the participant, they may help the participant's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes, the transplanted cells from a donor can make an immune response against the body's normal cells called graft versus host disease. Giving rituximab and methotrexate after the transplant may stop this from happening.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine engraftment and dose limiting toxicity (DLT) of bendamustine in patients with lymphoid malignancies undergoing non-myeloablative allogeneic hematopoietic transplantation. SECONDARY OBJECTIVES: I. To monitor the risk of graft-versus-host disease (GVHD) and clinical responses. OUTLINE: This is a dose escalation study of bendamustine. Participants receive rituximab intravenously (IV) over 5-7 hours on days -13 and -6, fludarabine IV over 1 hour and bendamustine IV over 1 hour on days -5 to -3, and tacrolimus IV starting on day -2 and orally (PO) after hospital discharge for 6 to 8 months. Participants with matched unrelated donor (MUD) receive thymoglobulin on days -2 and -1. Participants undergo allogenic stem cell transplant over 30-45 minutes on day 0. Participants receive rituximab IV over 5-7 hours on days 1 and 8 and methotrexate IV over 30 minutes on days 1, 3, and 6. Participants with MUD also receive methotrexate IV on day 11. Participants receive filgrastim (G-CSF) subcutaneously (SC) once daily starting on day 7 until white blood cell counts recover. After completion of study treatment, participants are followed up every 3 months during year 1 and every 6 months for up to 3 years.

Official Title
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Fludarabine, Bendamustine, and Rituximab (FBR) Non-Myeloablative Allogeneic Conditioning for Patients With Lymphoid Malignancies

Conditions
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CD20 Positive, Chronic Lymphocytic Leukemia, Follicular Lymphoma, Mantle Cell Lymphoma, Marginal Zone Lymphoma, Recurrent Diffuse Large B-Cell Lymphoma, T-Cell Non-Hodgkin Lymphoma

Intervention / Treatment
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* Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
* Biological: Anti-Thymocyte Globulin
* Drug: Bendamustine
* Biological: Filgrastim
* Drug: Fludarabine
* Drug: Methotrexate
* Biological: Rituximab
* Drug: Tacrolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with CD20 + chronic lymphocytic leukemia (CLL), marginal zone, mantle cell and follicular lymphoma or T-cell lymphoid malignancies who are eligible for allogeneic transplantation. Patients with relapsed diffuse large B-cell lymphoma may be included if they were not eligible for autologous transplantation. A fully-matched sibling donor or matched unrelated donor. Left ventricular ejection fraction (EF) > 40% with no uncontrolled arrhythmias or symptomatic heart disease. Forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and diffusion capacity of the lung for carbon monoxide (DLCO) > 40%. Serum creatinine < 1.6 mg/dL. Serum bilirubin < 3 X upper limit of normal. Serum glutamate pyruvate transaminase (SGPT) < 3 X upper limit of normal. Voluntary signed, written Institutional Review Board (IRB)-approved informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care. Men and women of reproductive potential must agree to follow accepted birth control methods for the duration of the study. Female subject is either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study. Male subject agrees to use an acceptable method for contraception for the duration of the study. Exclusion Criteria: Patient with active central nervous system (CNS) disease. Pregnant (positive beta human chorionic gonadotropin [HCG] test in a woman with child bearing potential defined as not post-menopausal for 12 months or no previous surgical sterilization) or currently breast-feeding. Pregnancy testing is not required for post-menopausal or surgically sterilized women. Known infection with human immunodeficiency virus (HIV), human T-lymphotropic virus (HTLV)-I, hepatitis B, or hepatitis C. Patients with other malignancies diagnosed within 2 years prior to study day-13 (except skin squamous or basal cell carcinoma). Active uncontrolled bacterial, viral or fungal infections. History of stroke within 6 months. Myocardial infarction within the past 6 months prior to study day 1, or has New York Heart Association (NYHA) class III or IV heart failure or arrhythmias, unstable angina, uncontrolled congestive heart failure or arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any electrocardiography (ECG) abnormality at screening must be documented by investigator as not medically relevant. A prior allogeneic transplant. Serious medical or psychiatric illness likely to interfere with participation in this clinical study. Patient has received other investigational drugs within 3 weeks before enrollment. Hypersensitivity to bendamustine. Prior known refractoriness to bendamustine.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (chemotherapy, stem cell transplant, rituximab)<br>Participants receive rituximab IV over 5-7 hours on days -13 and -6, fludarabine IV over 1 hour and bendamustine IV over 1 hour on days -5 to -3, and tacrolimus IV starting on day -2 and PO after hospital discharge for 6 to 8 months. Participants with MUD receive thymoglobulin on days -2 and -1. Participants undergo allogenic stem cell transplant over 30-45 minutes on day 0. Participants receive rituximab IV over 5-7 hours on days 1 and 8 and methotrexate IV over 30 minutes on days 1, 3, and 6. Participants with MUD also receive methotrexate IV on day 11. Participants receive G-CSF SC once daily starting on day 7 until white blood cell counts recover. | Procedure: Allogeneic Hematopoietic Stem Cell Transplantation<br>* Undergo ASCT<br>* Other names: HSCT;Biological: Anti-Thymocyte Globulin<br>* Given IV<br>* Other names: Thymoglobulin;Drug: Bendamustine<br>* Given IV<br>* Other names: SDX-105;Biological: Filgrastim<br>* Given IV<br>* Other names: Tevagrastim;Drug: Fludarabine<br>* Given IV<br>* Other names: Fluradosa;Drug: Methotrexate<br>* Given IV<br>* Other names: WR-19039;Biological: Rituximab<br>* Given IV<br>* Other names: RTXM83;Drug: Tacrolimus<br>* Given IV and PO<br>* Other names: Protopic;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose of bendamustine |  | Up to 30 days |