Fludarabine, Cyclophosphamide, and Rituximab - High Dose Frontline

Study Overview
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Brief Summary
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Primary Objective: To evaluate the efficacy (combined morphologic and flow remissions) of a combination of fludarabine, cyclophosphamide and multiple dose rituximab as frontline therapy for CLL. Secondary Objective: To evaluate remission duration and survival.

Detailed Description
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DESCRIPTION OF RESEARCH Fludarabine and cyclophosphamide are chemotherapy drugs that are used in the treatment of CLL. Rituximab is a monoclonal antibody that binds to lymphoma cells and causes cell death. Before treatment starts, you will have a complete physical exam and routine blood tests (about 2 teaspoons). A bone marrow sample will be collected. To collect a bone marrow sample, an area of the hip or chest bone is numbed with anesthetic and a small amount of bone marrow is withdrawn through a large needle. Women who are able to have children must have a negative blood or urine pregnancy test. Rituximab will be given through a needle (IV) in a vein on Days 1, 2, and 3. One day after the first dose of rituximab (Day 2), fludarabine and cyclophosphamide will be given through a needle (IV) in a vein daily for 3 days (Days 2, 3, 4). After the first month, all the drugs will be given on Days 1, 2, 3. Other IV fluids such as saline will be given on all of the treatment days for hydration, which means that the daily visit will take about six hours. The combination will be repeated once every 4 to 6 weeks for a total of 6 courses. The drugs acetaminophen (Tylenol) and diphenhydramine hydrochloride (Benadryl) will be given before the dose of rituximab. This will be done to decrease the risk of side effects. If side effects do occur during rituximab treatment, the drug may have to be stopped until the side effects go away and then restarted so the time in the outpatient area may be longer. The first treatment will be given at M. D. Anderson. The other 5 courses can be performed ether at M. D. Anderson or at home with your regular physician. The same doses of all three drugs will be used throughout the study unless side effects become severe. In that case, the dose may be lowered or the treatment may be stopped. You will be taken off study if the disease gets worse. During treatments, patients will have blood samples (about 1 teaspoon each) taken once every 1-2 weeks. Bone marrow studies will be done at the end of the 3rd and 6th chemotherapy courses. After treatment is completed, you will have blood tests (about 2 teaspoons each) done every 3 months for as long as you are in remission. This is an investigational study. The FDA has approved all of the drugs used in this study and they are commercially available. However, their use in this study is investigational. As many as 64 patients will take part in the study. All will be enrolled at M. D. Anderson.

Official Title
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Fludarabine, Cyclophosphamide, and Multiple Dose Rituximab as Frontline Therapy in Chronic Lymphocytic Leukemia (CLL)

Conditions
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Chronic Lymphocytic Leukemia

Intervention / Treatment
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* Drug: Fludarabine Phosphate
* Drug: Cyclophosphamide
* Drug: Rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 16 years or older Untreated CLL with indication for therapy or minimally treated (e.g. less than 1 month of steroids or chemotherapy) are eligible Performance status of 3 or better (Appendix A) Adequate renal and hepatic function (creatinine <2 mg%, bilirubin <2mg%). Patient with renal or liver dysfunction due to organ infiltration by lymphocytes may be eligible after discussion with the study chairman but upper limits for creatinine even under these circumstances would be creatinine < 3 mg% and bilirubin < 6 mg%. Patients with Gilbert's Syndrome may be entered on study with bilirubin 2-7 mg%.. A signed informed consent in keeping with policies of the hospital Exclusion Criteria: 1) None

Ages Eligible for Study
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Minimum Age: 16 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: FCR-Multiple Dose Rituximab<br>Fludarabine phosphate + Cyclophosphamide + Rituximab | Drug: Fludarabine Phosphate<br>* 25 mg/m^2 by vein over 5-30 minutes daily for 3 days (days 2-4)<br>* Other names: Fludarabine;Drug: Cyclophosphamide<br>* 250 mg/m^2 by vein over 60 minutes daily for 3 days (days 2-4)<br>* Other names: Neosar®;Drug: Rituximab<br>* 375 mg/m^2 by vein for dose 1 (given 1 day prior to chemotherapy) and then 500 mg/m^2 on days 2-3<br>* Other names: Rituxan®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Remission (CR) Rate of FCR3 in Treatment-naïve Participants With Chronic Lymphocytic Leukemia (CLL) at 6 Months | CR Rate is defined as number of all treated participants with CR as defined by 2008 IWCLL update of NCI-WG response criteria: 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; Complete remission with incomplete marrow recovery (CRi), defined as CR above, but without normal blood counts; 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; Progressive disease (PD): ≥ 50% rise in lymphocyte count to > 5 x109/L, ≥ 50% increase in lymphadenopathy, ≥ 50% increase in liver or spleen size, Richter's transformation, or new cytopenias due to CLL; Stable disease, defined as not meeting criteria for CR, CRi, PR or PD. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Remission Duration/Time to Progression (TTP) | TTP was defined as time from initiation of treatment to primary refractory disease or CLL progression. TTP was censored for therapy-related myelodysplastic syndrome (t-MDS) or acute myelogenous leukemia (t-AML) and death in remission. TTP calculated using Kaplan-Meier estimates. | 6 months to disease progression, period covered up to 12 years following treatment; Data cutoff for analysis was October 2014. | 
| Overall Survival (OS) Rate | OS was defined as the time from the initiation of treatment to last follow-up date or death. OS were calculated using Kaplan-Meier estimates. | 6 months to disease progression, period covered up to 12 years following treatment; Data cutoff for analysis was October 2014. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Lymphocytic Leukemia, CLL, Leukemia, Fludarabine phosphate, Cyclophosphamide, Rituximab, FCR, Cytoxan®, Neosar®, Rituxan®