Chronic Lymphocytic Leukemia
Conditions
Keywords
Chronic Lymphocytic Leukemia, CLL, Leukemia, Fludarabine phosphate, Cyclophosphamide, Rituximab, FCR, Cytoxan®, Neosar®, Rituxan®
Brief summary
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
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a bone marrow sample, an area of the hip or chest bone is numbed with anesthetic and a small amount of bone marrow is withdrawn through a large needle.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.
Interventions
DRUGFludarabine Phosphate
25 mg/m\^2 by vein over 5-30 minutes daily for 3 days (days 2-4)
DRUGCyclophosphamide
250 mg/m\^2 by vein over 60 minutes daily for 3 days (days 2-4)
DRUGRituximab
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
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
Age
16 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. 16 years or older 2. Untreated CLL with indication for therapy or minimally treated (e.g. less than 1 month of steroids or chemotherapy) are eligible 3. Performance status of 3 or better (Appendix A) 4. 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%.. 5. A signed informed consent in keeping with policies of the hospital
Exclusion criteria
1\) None
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Complete Remission (CR) Rate of FCR3 in Treatment-naïve Participants With Chronic Lymphocytic Leukemia (CLL) at 6 Months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Remission Duration/Time to Progression (TTP) | 6 months to disease progression, period covered up to 12 years following treatment; Data cutoff for analysis was October 2014. | 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. |
| Overall Survival (OS) Rate | 6 months to disease progression, period covered up to 12 years following treatment; Data cutoff for analysis was October 2014. | 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. |
Countries
United States
Participant flow
Recruitment details
Recruitment Period: All recruitment done at The University of Texas MD Anderson Cancer Center.
Participants by arm
| Arm | Count |
|---|---|
| FCR-Multiple Dose Rituximab Fludarabine phosphate 25 mg/m\^2 intravenous (IV) daily for 3 days (days 2-4) + Cyclophosphamide 250 mg/m\^2 IV daily for 3 days (days 2-4)+ Rituximab 375 mg/m\^2 IV for dose 1 (given 1 day prior to chemotherapy) then 500 mg/m\^2 on days 2-3 | 66 |
| Total | 66 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 11 |
| Overall Study | Ineligible/Screen Failure | 1 |
| Overall Study | Resistant Disease | 2 |
| Overall Study | Secondary Malignancies | 2 |
Baseline characteristics
| Characteristic | FCR-Multiple Dose Rituximab |
|---|---|
| Age, Continuous | 58 years |
| Region of Enrollment United States | 66 participants |
| Sex: Female, Male Female | 13 Participants |
| Sex: Female, Male Male | 53 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 63 / 65 |
| serious Total, serious adverse events | 30 / 65 |
Outcome results
Primary
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.
Time frame: 6 months
Population: Of the 66 participants registered, one participant failed screening and therefore was not evaluable for toxicity or response. One of the 65 participants was not assessed for response to therapy therefore is not included in analysis. The participant went off study after two months of treatment and was not evaluable for response.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FCR-Multiple Dose Rituximab | Complete Remission (CR) Rate of FCR3 in Treatment-naïve Participants With Chronic Lymphocytic Leukemia (CLL) at 6 Months | 75 Percentage of Participants |
Secondary
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.
Time frame: 6 months to disease progression, period covered up to 12 years following treatment; Data cutoff for analysis was October 2014.
Population: Of the 66 participants registered, one participant failed screening and therefore was not evaluable for toxicity or response. One of the 65 participants is not included in analysis, the participant went off study after two months of treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FCR-Multiple Dose Rituximab | Overall Survival (OS) Rate | 58 Percentage of Participants |
Secondary
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.
Time frame: 6 months to disease progression, period covered up to 12 years following treatment; Data cutoff for analysis was October 2014.
Population: Of the 66 participants registered, one participant failed screening and therefore was not evaluable for toxicity or response. One of the 65 participants was not assessed for response to therapy therefore is not included in analysis. The participant went off study after two months of treatment and was not evaluable for response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| FCR-Multiple Dose Rituximab | Remission Duration/Time to Progression (TTP) | 81 Months |