Fludarabine, Bendamustine, and Rituximab (FBR) for Relapsed Chronic Lymphocytic Leukemia (CLL)

A Phase I/II Clinical Trial of Fludarabine, Bendamustine, and Rituximab (FBR) in Previously Treated Patients With Chronic Lymphocytic Leukemia (CLL)

The goal of Phase 1 of this clinical research study is to find the highest tolerable dose of bendamustine, combined with fludarabine and rituximab, that can be given to patients who have CLL that has been treated before. The goal of Phase 2 of this study is to find out if this drug combination can help to control the disease. The safety of this drug combination will also be studied.

The Study Drugs: Fludarabine and bendamustine are designed to damage the DNA (genetic material) of cancer cells, which may cause the cancer cells to die. Rituximab is designed to attach to cancer cells and damage them, which may cause the cancer cells to die. It is also designed to cause the immune system to attack cancer cells. Study Drug Dose Levels: If you are found to be eligible to take part in this study, you will be assigned to a study group based on when you joined this study. One (1) to 8 groups with 3-6 participants will be enrolled in the Phase 1 portion of the study, and up to 58 participants will be enrolled in Phase 2. If you are enrolled in Phase 1, the dose of bendamustine you receive will depend on when you joined this study. The first group will receive the lowest dose. The next group will receive a higher dose, if the number and type of side effects was low or none. The dose of bendamustine will be increased for each new group until the highest tolerable dose is found. If you are enrolled in Phase 2, you will receive bendamustine at the highest dose that was tolerated in Phase 1. All participants in both phases of the study will start out with the same dose levels of fludarabine and rituximab. If side effects occur, the study doctor may decide to lower your doses of study therapy. If you have side effects during a dose, the study staff will observe you for any other problems for 2 hours after the dose. Study Drug Administration: Cycles in this study are 4 weeks. All 3 study drugs are given by vein. Cycle 1: On Days 1-3, bendamustine will be given over 30 minutes. On Days 2-4, fludarabine will be given over 30 minutes. On Day 4, rituximab will be given over 6-8 hours. Cycles 2-6: On Day 1, rituximab will be given at a higher dose than in Cycle 1. If you tolerated the Cycle 1 dose well, your Cycles 2-6 rituximab doses may be given over 2-4 hours. On Days 1-3, fludarabine will be given over 30 minutes. On Days 1-3, bendamustine will be given over 30 minutes. Other Drugs: You will be given Tylenol (acetaminophen) and Benadryl (diphenhydramine hydrochloride) to take by mouth 30-60 minutes before every dose of rituximab (Cycles 1-6). These drugs are given to lower the risk of side effects. Study Visits: Once a week in Cycle 1 and every 2-4 weeks in Cycles 2-6, blood (about 1 tablespoon) will be drawn for routine tests. Before Cycles 1-6, you will also have a physical exam, including measurement of your vital signs. You will be asked about any side effects you may have had. Before Cycle 4, the following tests and procedures will be performed: You will have a physical exam. Blood (about 2 tablespoons) will be drawn for routine tests. You will have a bone marrow aspiration and biopsy to check the status of the disease. If the doctor thinks it is needed, you will have a CT scan of the neck, chest, abdomen, and pelvis to check the status of the disease. Length of Study Participation: You may receive up to 6 cycles of study treatment. The study treatment will be stopped early if the disease gets worse or you experience any intolerable side effects. End-of-Treatment Visit: After Cycle 6 (or earlier if you stop early), the following tests and procedures will be performed: You will have a physical exam. Blood (about 2 tablespoons) will be drawn for routine tests. You will have a bone marrow aspiration and biopsy to check the status of the disease. If the doctor thinks the disease has completely responded, you will have a CT scan of the neck, chest, abdomen, and pelvis to confirm the response. Follow-Up Visits: You will have follow-up visits at the end of Month 6 and Year 1 after your last dose of study drugs, and once a year until you start a new cancer treatment. The same tests will be performed as at the end-of-treatment visit. Starting at Year 3, the follow-up tests and procedures can be done by your local doctor if that is more convenient to you. You should tell your study doctor or staff if you start another cancer treatment after the study. If that occurs, your follow-up in this study will stop. This is an investigational study. Both fludarabine and bendamustine are commercially available and FDA approved to treat CLL. Rituximab is commercially available and FDA approved to treat lymphoma. The use of these drugs together in this study is investigational. Up to 82 patients will take part in this study. All will be enrolled at MD Anderson.

Chronic lymphocytic leukemia, CLL, Bendamustine, Fludarabine, Fludara, Fludarabine Phosphate, Rituximab, Rituxan

Phase 1: Starting Dose of 20 mg/m2 IV on Days 1,2,3 (after fludarabine) Phase 2: 30 mg/m2 by vein (fixed) on Days 1,2,3 (after fludarabine)

Maximum Tolerated Dose (MTD) of Bendamustine Combined With Fixed-Dose Fludarabine and Rituximab (FBR)

MTD defined as highest dose level in which 6 participants have been treated with </= to 1 patient experiencing dose limiting toxicity (DLT). MTD exceeded if 2 or more of 6 patients experience grade 3 or higher, non-hematologic, non-infusion related toxicity a major organ system. DLT defined as treatment-related, grade >/= 3 non-hematologic toxicity. Hematologic toxicity grade >/= 3 that lasts longer than 42 days considered a DLT. Hematologic toxicity graded according to the 2008 IWCLL criteria for grading. Tumor lysis not considered a DLT.

Overall Response is Complete response (CR) + Partial response (PR). Overall response evaluated by 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 for complete or partial response and progressive disease. Complete remission (CR), requiring absence of peripheral blood clonal lymphocytes by immunophenotyping, absence of lymphadenopathy, absence of hepatomegaly or splenomegaly, absence of constitutional symptoms and satisfactory blood counts; positive or negative minimal residual disease (MRD); Partial remission (PR), defined as ≥ 50% fall in lymphocyte count, ≥ 50% reduction in lymphadenopathy or ≥ 50% reduction in liver or spleen, together with improvement in peripheral blood counts;

Overall response assessed 2 months after 6th or last course if participants not able to receive all 6 intended courses of treatment.

Inclusion Criteria: Patients must have a diagnosis of CLL/Small Lymphocytic Lymphoma (SLL) and be previously treated Patients must have an indication for treatment by 2008 IWCLL Criteria Age >/= 16 years Zubrod performance status </= 2 Adequate renal and hepatic function as indicated by all the following: a. serum creatinine </= 2 mg/dL AND; b. alanine aminotransferase (ALT) </= 2.5 times upper limit of normal AND; c. total bilirubin </= 2.5 times upper limit of normal Patients must give written informed consent Patients of childbearing potential must be willing to practice birth control during the study Exclusion Criteria: Pregnant or breast-feeding females Significant co-morbidity indicated by major organ system dysfunction Active, uncontrolled infection, including active hepatitis Uncontrolled autoimmune hemolytic anemia (AIHA) or immune thrombocytopenia purpura (ITP) Treatment including chemotherapy, chemoimmunotherapy, monoclonal antibody therapy, radiotherapy, high-dose corticosteroid therapy (Prednisone >/ 60 mg daily or equivalent), or immunotherapy within 21 days prior to enrollment or concurrent with this trial