Chronic Lymphocytic Leukemia
Conditions
Keywords
Chronic Lymphocytic Leukemia, Fludarabine, Cyclophosphamide, Rituximab, Bevacizumab, CLL
Brief summary
The goal of this clinical research study is to learn if the combination of fludarabine, cyclophosphamide, rituximab, and bevacizumab is effective in treating chronic lymphocytic leukemia in patients who have already been treated with chemotherapy. The safety of this treatment will also be studied.
Detailed description
During the study, you will have up to 6 cycles of treatment. A cycle is made up of treatment with the study drugs for 3-4 days and then about 3-1/2 weeks (25 days) of no treatment (about 4 weeks total). Treatment with the study drugs will be given for 4 days in a row on the first cycle, and 3 days in a row on Cycles 2-6. On Day 1 of each cycle, you will receive rituximab through a needle in a vein. On Cycle 1, since it is your first exposure to rituximab, it must be given slowly, so it may take 6-8 hours to complete. On the cycles after that, it can be given more rapidly, over 3-4 hours. Cyclophosphamide and fludarabine will be given separately through a needle in a vein on Days 2-4 of Cycle 1 and Days 1-3 of Cycles 2-6. Cyclophosphamide and fludarabine will each be given over 30 minutes. Bevacizumab will be given through a needle in a vein over 90 minutes on Day 3 of Cycle 1. If it is well tolerated, the next dose of Bevacizumab will be given over 60 minutes on Day 2 of Cycle 2. If the Cycle 2 dose is well tolerated, the next doses of Bevacizumab will be given over 30 minutes on Day 2 of Cycles 2-6. In addition to the study drugs, you may also be given fluids by vein to help flush the kidneys, to help prevent possible kidney damage. You may receive up to 6 cycles of treatment. Treatment will be given on an outpatient basis. The injections for each daily treatment visit should take less than 6 hours. Up to 66 patients will take part in the study. All will be enrolled at M.D. Anderson.
Interventions
DRUGFludarabine
25 mg/m\^2 IV over 30 minutes daily for 3 days
DRUGCyclophosphamide
250 mg/m\^2 IV over 30 minutes daily for 3 days
DRUGRituximab
375 mg/m\^2 IV on Day 1 by prolonged infusion. All subsequent doses 500 mg/m\^2 IV 30-minute infusion.
DRUGBevacizumab
10 mg/Kg IV on Day 3, course 1 over 30-90 minutes
Sponsors
Genentech, Inc.
M.D. Anderson Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
* Diagnosis of B-cell CLL * Relapsed, fludarabine-sensitive (duration of response \> 6 months as assessed by prior treating physician) or fludarabine-naive patients * Rai Stage III or IV, or Rai Stage I or II if determined to have disease progression as evidenced by rapid doubling of peripheral lymphocyte count, progressive lymphadenopathy, progressive splenomegaly, or B symptoms. * Prestudy WHO Performance Status \</= 2. * Signed, written Institutional Review Board (IRB)approved informed consent. * Men and women of reproductive potential must agree to follow accepted birth control methods during treatment and for 3 months after completion of treatment. * Acceptable liver function: Bilirubin \</= 2.0 mg/dL (26 umol/L), AST (SGOT) and/or ALT (SGPT) \</= 2 times upper limit of normal. * Acceptable hematologic status: Platelet count \>/= 50 x 10\^9/L., absolute neutrophil count (ANC) \>/= 1 x 10\^9/L. * Acceptable renal function: Serum creatinine \</= 2.0 mg/dL
Exclusion criteria
* Cancer radiotherapy, radioimmunotherapy, biological therapy, chemotherapy, or other investigational therapy within 4 weeks prior to Study Day 1. * Known infection with HIV, hepatitis B, or hepatitis C * Transformation to aggressive B-cell malignancy (e.g., large B-cell lymphoma, Richter's Syndrome, or prolymphocyte leukemia \[PLL\]). * Patients with secondary malignancy requiring active treatment (except hormonal therapy). * Active uncontrolled bacterial, viral, or fungal infections. * New York Heart Association Class II-IV cardiac disease or myocardial infarction within the past 6 months prior to Study Day 1. * Pregnant or currently breast-feeding. * Current, recent (within 4 weeks of the first infusion of this study), or planned participation in an experimental drug study other than a Genentech-sponsored bevacizumab cancer study. * Blood pressure of \> 150/100 mmHg * Unstable angina * History of stroke within 6 months * Clinically significant peripheral vascular disease * Evidence of bleeding diathesis or coagulopathy * Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 1, anticipation of need for major surgical procedure during the course of the study. * Minor surgical procedures, fine needle aspirations or core biopsies within 7 days prior to Day 1. * Urine protein:creatinine ratio \>/= 1.0 at screening. * History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to Day 1. * Serious, non-healing wound, ulcer, or bone fracture.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) Rate | Baseline up to 5 years | Progression free survival (PFS) was defined as the time from the start of treatment to progression, which included treatment failure, relapse, or death. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Complete or Partial Response to Fludarabine, Cyclophosphamide, Rituximab, and Bevacizumab Therapy in Previously Treated Chronic Lymphocytic Leukemia (CLL) | Response assessed after three 4-week courses and after six courses, up to 24 weeks | Response criteria for Complete response (CR) - Nodes: None; Liver/Spleen Size: Not palpable; Symptoms: None; polymorphonuclear leukocytes (PMN): \>1,500/μl; Platelets \>100,000/μl; Hemoglobin (untransfused): \>11,0 g/dl; Lymphocytes: \<4,000/μl; Bone Marrow aspirate: \<30% lymphocytes; Biopsy: No lymphocyte infiltrate; and for Partial Response (PR), Nodes: \>/= 50% decrease; Liver/Spleen Size: \>/= 50% decrease; Symptoms: None; Platelets \>100,000/μl or \> 50% improvement from baseline; Hemoglobin (untransfused): \>11.0 g/dl or \>50% improvement from baseline; Lymphocytes: \>50% decrease; Biopsy: \<30% lymphocytes with residual disease on biopsy for nodular PR (NPR). |
| Overall Response Rate (ORR) to Fludarabine, Cyclophosphamide, Rituximab, and Bevacizumab Therapy in Previously Treated CLL | Response assessed after three 4-week courses and after six courses, up to 24 weeks | ORR defined as CR and PR response where response criteria for Complete response (CR) - Nodes: None; Liver/Spleen Size: Not palpable; Symptoms: None; polymorphonuclear leukocytes (PMN): \>1,500/μl; Platelets \>100,000/μl; Hemoglobin (untransfused): \>11,0 g/dl; Lymphocytes: \<4,000/μl; Bone Marrow aspirate: \<30% lymphocytes; Biopsy: No lymphocyte infiltrate; and for Partial Response (PR), Nodes: \>/= 50% decrease; Liver/Spleen Size: \>/= 50% decrease; Symptoms: None; Platelets \>100,000/μl or \> 50% improvement from baseline; Hemoglobin (untransfused): \>11.0 g/dl or \>50% improvement from baseline; Lymphocytes: \>50% decrease; Biopsy: \<30% lymphocytes with residual disease on biopsy for nodular PR (NPR). |
Countries
United States
Participant flow
Recruitment details
Recruitment Period: February 23, 2007 to November 17, 2010. All recruitment done at The University of Texas MD Anderson Cancer Center.
Participants by arm
| Arm | Count |
|---|---|
| FCR + Bevacizumab FCR = Fludarabine 25 mg/m\^2 intravenous (IV) , Cyclophosphamide 250 mg/m\^2 IV daily for 3 days, Rituximab 375 mg/m\^2 IV Day 1, followed by 500 mg/m\^2 IV. FCR daily for 3 days. Bevacizumab 10 mg/Kg IV on Day 3, course 1. | 64 |
| Total | 64 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 2 |
| Overall Study | Disease progression | 1 |
| Overall Study | Insurance Issues | 1 |
| Overall Study | Withdrawal by Subject | 3 |
Baseline characteristics
| Characteristic | FCR + Bevacizumab |
|---|---|
| Age, Continuous | 62 years |
| Region of Enrollment United States | 64 participants |
| Sex: Female, Male Female | 13 Participants |
| Sex: Female, Male Male | 51 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 62 / 62 |
| serious Total, serious adverse events | 33 / 62 |
Outcome results
Primary
Progression Free Survival (PFS) Rate
Progression free survival (PFS) was defined as the time from the start of treatment to progression, which included treatment failure, relapse, or death. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions
Time frame: Baseline up to 5 years
Population: Five participants of the 62 treated participants were not evaluable for response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| FCR + Bevacizumab | Progression Free Survival (PFS) Rate | 13.5 Months |
Secondary
Number of Participants With Complete or Partial Response to Fludarabine, Cyclophosphamide, Rituximab, and Bevacizumab Therapy in Previously Treated Chronic Lymphocytic Leukemia (CLL)
Response criteria for Complete response (CR) - Nodes: None; Liver/Spleen Size: Not palpable; Symptoms: None; polymorphonuclear leukocytes (PMN): \>1,500/μl; Platelets \>100,000/μl; Hemoglobin (untransfused): \>11,0 g/dl; Lymphocytes: \<4,000/μl; Bone Marrow aspirate: \<30% lymphocytes; Biopsy: No lymphocyte infiltrate; and for Partial Response (PR), Nodes: \>/= 50% decrease; Liver/Spleen Size: \>/= 50% decrease; Symptoms: None; Platelets \>100,000/μl or \> 50% improvement from baseline; Hemoglobin (untransfused): \>11.0 g/dl or \>50% improvement from baseline; Lymphocytes: \>50% decrease; Biopsy: \<30% lymphocytes with residual disease on biopsy for nodular PR (NPR).
Time frame: Response assessed after three 4-week courses and after six courses, up to 24 weeks
Population: Five participants of the 62 treated participants were not evaluable for response.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FCR + Bevacizumab | Number of Participants With Complete or Partial Response to Fludarabine, Cyclophosphamide, Rituximab, and Bevacizumab Therapy in Previously Treated Chronic Lymphocytic Leukemia (CLL) | Complete Response (CR) | 13 participants |
| FCR + Bevacizumab | Number of Participants With Complete or Partial Response to Fludarabine, Cyclophosphamide, Rituximab, and Bevacizumab Therapy in Previously Treated Chronic Lymphocytic Leukemia (CLL) | Partial Response (PR) | 24 participants |
| FCR + Bevacizumab | Number of Participants With Complete or Partial Response to Fludarabine, Cyclophosphamide, Rituximab, and Bevacizumab Therapy in Previously Treated Chronic Lymphocytic Leukemia (CLL) | Nodular Partial Response (NPR) | 8 participants |
Secondary
Overall Response Rate (ORR) to Fludarabine, Cyclophosphamide, Rituximab, and Bevacizumab Therapy in Previously Treated CLL
ORR defined as CR and PR response where response criteria for Complete response (CR) - Nodes: None; Liver/Spleen Size: Not palpable; Symptoms: None; polymorphonuclear leukocytes (PMN): \>1,500/μl; Platelets \>100,000/μl; Hemoglobin (untransfused): \>11,0 g/dl; Lymphocytes: \<4,000/μl; Bone Marrow aspirate: \<30% lymphocytes; Biopsy: No lymphocyte infiltrate; and for Partial Response (PR), Nodes: \>/= 50% decrease; Liver/Spleen Size: \>/= 50% decrease; Symptoms: None; Platelets \>100,000/μl or \> 50% improvement from baseline; Hemoglobin (untransfused): \>11.0 g/dl or \>50% improvement from baseline; Lymphocytes: \>50% decrease; Biopsy: \<30% lymphocytes with residual disease on biopsy for nodular PR (NPR).
Time frame: Response assessed after three 4-week courses and after six courses, up to 24 weeks
Population: Five participants of the 62 treated participants were not evaluable for response.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FCR + Bevacizumab | Overall Response Rate (ORR) to Fludarabine, Cyclophosphamide, Rituximab, and Bevacizumab Therapy in Previously Treated CLL | 79 percentage of participants |