B-Cell Chronic Lymphocytic Leukemia
Conditions
Brief summary
This is a Phase 3, prospective, multicenter, open-label, randomized, controlled study to evaluate and compare the efficacy and safety of fludarabine plus alemtuzumab versus fludarabine alone as second-line therapy for patients with relapsed or refractory B-cell chronic lymphocytic leukemia (B-CLL). Patients who meet all eligibility criteria and sign the informed consent document may be entered on the study.
Interventions
BIOLOGICALFluCAM [Fludara + Campath]
Phase A: Escalating Doses of alemtuzumab (Campath) Alone Day 1: alemtuzumab 3 mg intravenously (IV) over 2 hours. Day 2: alemtuzumab 10 mg IV over 2 hours if 3 mg was tolerated, else repeat 3 mg daily until tolerated. Day 3: alemtuzumab 30 mg IV over 2 hours if 10 mg was tolerated, else repeat 10 mg daily until tolerated. Participants were allowed 3-14 days to escalate to 30 mg. Once 30 mg was tolerated, the participant had to begin Phase B within 7 days. Phase B: FluCAM Cycle 1: Days 1,2,3 fludarabine phosphate administered at 30 mg/m\^2 over 30 minutes IV, followed within 1 hour by alemtuzumab 30 mg IV over 2 hours. A similar schedule is set for Cycles 2 through 6; duration of alemtuzumab infusions vary from 2-6 hours. Each 28-day period is 1 cycle. Fludarabine phosphate dosage is based on participants' body surface area at the beginning of each cycle. FluCAM administered up to a maximum of 6 cycles, based upon participants' response to therapy and toxicity.
BIOLOGICALfludarabine phosphate
Fludarabine phosphate (Fludara) is administered at a dose of 25 mg/m\^2 IV over 15 to 30 minutes daily for 5 consecutive days (days 1 through 5) every 28 days (per package instructions). Each 28-day period is 1 cycle. The dose of fludarabine phosphate will be based on the participant's body surface area as calculated at the beginning of each cycle. Participants treated with fludarabine phosphate up to a maximum of 6 cycles, based upon their response to therapy and toxicity.
Sponsors
Genzyme, a Sanofi Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* A diagnosis of B-cell chronic lymphocytic leukemia (B-CLL); according to the National Cancer Institute Working Group (NCI WG) criteria. * Relapsed or refractory disease after 1 prior regimen except patients who were refractory to (i.e., progressed on) fludarabine or alemtuzumab therapy. Patients who previously responded (complete response or partial response) to fludarabine or alemtuzumab therapy, but who have relapsed at the time of study entry, may be eligible but response to fludarabine or alemtuzumab therapy must have lasted \>12 months (i.e., \>12 months from a documented response to a documented relapse). * Binet stage A, stage B, or stage C or Rai Stage I through IV disease with evidence of progression as evidenced by the presence of one or more of the following: I. Evidence of progressive marrow failure as manifested by: 1) a decrease in hemoglobin to \<11g/dL, or 2) a decrease in platelet count to \<100 x 10\^9/L within the previous 6 months, or 3) a decrease in absolute neutrophil count (ANC) to \<1.0 X 10\^9/L. II. Progressive splenomegaly to \>2 cm below the left costal margin or other organomegaly. III. Progressive lymphadenopathy. IV. Progressive lymphocytosis with an increase of 50% over a 2-month period, or an anticipated doubling time of less than 6 months. * World Health Organization (WHO) performance status (PS) of 0 or 1. * Life expectancy \>12 weeks. * Anti-cancer therapy, major surgery, or irradiation was completed \>3 weeks before randomization in this study. Patient must have recovered from the acute side effects incurred as a result of previous therapy. * Serum creatinine less than or equal to 2.0 x institutional upper limits of normal (ULN) and calculated creatinine clearance (CrCl) greater than or equal to 30mL/min using the Cockroft and Gault formula. * Adequate liver function as indicated by a total bilirubin, AST, and ALT less than or equal to 2 x the institutional ULN value, unless directly attributable to the patient's tumor. * Female patients with childbearing potential must have a negative serum pregnancy test with 2 weeks of first dose of study drug(s). Male and female patients must agree to use an effective contraceptive method while on study treatment, if appropriate, and for a minimum of 6 months following study therapy. * Signed, written informed consent.
Exclusion criteria
* Previously treated with \>1 prior regimen for B-CLL. * Previously treated with a fludarabine plus alemtuzumab (FluCAM) regimen for B-CLL. * Positive Coombs test and actively hemolyzing. * Absolute neutrophil count (ANC) \<1.5 x 10\^9/L or platelet count \<75 x 10\^9/L, unless due to bone marrow involvement. * Medical condition requiring chronic use of pharmacologic doses of oral corticosteroids, i.e. anything other than replacement dose levels. * History of anaphylaxis following exposure to monoclonal antibodies. * Use of investigational agents within 6 weeks prior to study randomization. * Active infection or history of severe infection (grade 4) within 3 months prior to study randomization. * Known to be human immunodeficiency virus (HIV) positive. * Autoimmune thrombocytopenia. * Active second malignancy. * Known central nervous system (CNS) involvement with B-CLL. * Other severe, concurrent diseases, including tuberculosis, mental disorders, serious cardiac functional capacity (Class III or IV as defined by the New York Heart Association Classification), severe diabetes, severe hypertension, pulmonary disease (chronic obstructive pulmonary disease \[COPD\] with hypoxemia), or major organ malfunction (liver, kidney) that could interfere with the patient's ability to participate in the study. * Pregnant or nursing women. * Patients that have progressed with more aggressive B-cell cancers such as Richter's syndrome. * Active hepatitis or a history of prior viral hepatitis B or hepatitis C, or positive hepatitis B serologies without prior immunization.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Kaplan-Meier Estimates for Progression-free Survival (PFS) Based on Independent Response Review Panel (IRRP) Assessment | Up to 6 years | Progression-free survival was defined as the number of days from the date of randomization to the date of first objective documentation of progressive disease (PD) as determined by the treatment-blinded IRRP, or death due to any cause. Results are expressed in months. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean EQ-5D™ Index Scores to Measure Quality of Life at Baseline | Day 0 (baseline) | EQ-5D™ is a trademark of the EuroQol Group. EQ-5D™ is a standardized instrument for use as a measure of health outcome. The questionnaire asks about health status along 5 dimensions: mobility, self care, usual activities, pain/discomfort, and anxiety/depression, which are rated at three possible levels (no problems, some problems, extreme problems). The score ranges from best (+1) to worst (-0.59). |
| Total Volume of Distribution (Vss) of Fludarabine | month 4 (cycle 4): first day of dosing (pre-dose, 0.5 hr end of infusion), second day of dosing (pre-dose, 0.5 hr end of infusion), third day of dosing (pre-dose, 0.25 hr, 0.5 hr end of infusion, 1,2,3,4,6,24,48,72 hr after start of fludarabine infusion) | The total volume of distribution (Vss) is the apparent volume in which fludarabine is distributed immediately after it has been injected intravenously and equilibrated between plasma and the surrounding tissues. Total volume of distribution (Vss) of fludarabine is derived from plasma concentration versus time data. |
| Area Under the Curve (AUC) of Fludarabine From (AUC 0-tau) | month 4 (cycle 4): first day of dosing (pre-dose, 0.5 hr end of infusion), second day of dosing (pre-dose, 0.5 hr end of infusion), third day of dosing (pre-dose, 0.25 hr, 0.5 hr end of infusion, 1,2,3,4,6,24,48,72 hr after start of fludarabine infusion) | AUC (0-tau) is the area under the plasma concentration curve for fludarabine over the dosage interval (tau). |
| Maximum Plasma Concentration (Cmax) of Fludarabine | month 4 (cycle 4): first day of dosing (pre-dose, 0.5 hr end of infusion), second day of dosing (pre-dose, 0.5 hr end of infusion), third day of dosing (pre-dose, 0.25 hr, 0.5 hr end of infusion, 1,2,3,4,6,24,48,72 hr after start of fludarabine infusion) | Cmax is the maximum plasma concentration of fludarabine observed. |
| Participants With Minimal Residual Disease (MRD) | up to 9 months | MRD negativity in this report was defined by the absence of tumor cells in bone marrow, using 4-color flow cytometry. MRD was assessed in participants with a clinical complete response (CR) or partial response (PR) without recovery of blood counts. MRD represents a very positive outcome. |
| Mean Systemic Clearance (CL) of Fludarabine | month 4 (cycle 4): first day of dosing (pre-dose, 0.5 hr end of infusion), second day of dosing (pre-dose, 0.5 hr end of infusion), third day of dosing (pre-dose, 0.25 hr, 0.5 hr end of infusion, 1,2,3,4,6,24,48,72 hr after start of fludarabine infusion) | Clearance of drug from plasma is affected by the absorption, distribution, metabolism and elimination of the drug. Mean systemic clearance of fludarabine is derived from plasma concentration versus time data. |
| Participant Best Response to Treatment Assessed by the Independent Response Review Panel (IRRP) | Up to 9 months | Participants were evaluated by the IRRP according to National Cancer Institute (NCI) 1996 response criteria. The best response observed during the study is summarized. Response categories include Complete Response (CR) with normal physical exam, marrow cells and blood values, Partial Response (PR) with a \>= 50% decrease from baseline in lymphocytes, lymphadenopathy and liver or spleen exam, Stable Disease (SD) without significant progression from baseline, or Progressive Disease (PD) with increased size/number of nodes, size of liver or spleen, increase in lymphocytes, aggressive histology. |
| Kaplan-Meier Estimates of Overall Survival Time | Up to 6 years | Overall survival was defined as the time in days from the date of randomization to the date of death due to any cause plus 1 day for all participants. Results are stated in months. |
| Kaplan Meier Estimates for Time to Disease Progression Assessed by the Independent Response Review Panel (IRRP) | Up to 6 years | Time to disease progression was defined as the number of days from the date of randomization to the date of first objective documentation of progressive disease as determined by IRRP. Results are stated in months. |
| Kaplan-Meier Estimates for Duration of Response Assessed by the Independent Response Review Panel (IRRP) | Up to 6 years | Duration of response was analyzed for participants who achieved a complete response (CR) or partial response (PR) and was defined as the number of days from the first date of documented response to the date of progressive disease as determined by IRRP or death due to any cause. Results are stated in months. |
| Kaplan-Meier Estimates for Time to Alternative Therapy | Up to 6 years | Time to alternative therapy was defined as the number of days from the date of randomization to the date of first alternative therapy for chronic lymphocytic leukemia (CLL) or death resulting from any cause. Participants who had not received alternative therapy as of the data cutoff date were censored at the last follow-up visit assessment date plus 1 day. Results are stated in months. |
| Mean EQ-5D™ Index Scores to Measure Quality of Life at End of Treatment | up to month 6 (end of treatment) | EQ-5D™ is a trademark of the EuroQol Group. EQ-5D™ is a standardized instrument for use as a measure of health outcome. The questionnaire asks about health status along 5 dimensions: mobility, self care, usual activities, pain/discomfort, and anxiety/depression, which are rated at three possible levels (no problems, some problems, extreme problems). The score ranges from best (+1) to worst (-0.59). |
| Mean EuroQol Visual Analogue Scale (EQ-VAS) Scores to Measure Quality of Life at Baseline | Day 0 (baseline) | The EuroQol Visual Analogue Scale (EQ-VAS) was also used to capture the self-rating of current health status using a visual thermometer with the end points of 100 (best imaginable health state) at the top and zero (worst imaginable health state) at the bottom. |
| Mean EuroQol Visual Analogue Scale (EQ-VAS) Scores to Measure Quality of Life at End of Treatment | up to month 6 (end of treatment) | The EuroQol Visual Analogue Scale (EQ-VAS) was also used to capture the self-rating of current health status using a visual thermometer with the end points of 100 (best imaginable health state) at the top and zero (worst imaginable health state) at the bottom. |
| Summary of Participants With Adverse Experiences (AEs) | Up to 6 years | Number of participants with adverse events (AEs). AEs were graded by the investigator using the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 and were assessed for relatedness to study treatment (4 point scale from 'not related' to 'definitely related'). Categories reported include participant counts for treatment-emergent AEs, AEs for infections, serious AEs, AEs causing discontinuation of study drug(s), and deaths. Related AEs for the combination arm can be related to either fludarabine or alemtuzumab. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Kaplan-Meier Estimates of Overall Survival Time for Participants With Rai Stage I-II | Up to 6 years | Overall survival was defined as the time in days from the date of randomization to the date of death due to any cause plus 1 day for all participants. Results are stated in months and include participants with Rai Stage I or II. |
| Kaplan-Meier Estimates of Overall Survival Time for Participants With Rai Stage III-IV | Up to 6 years | Overall survival was defined as the time in days from the date of randomization to the date of death due to any cause plus 1 day for all participants. Results are stated in months and include participants with Rai Stage III or IV. |
| Kaplan-Meier Estimates for Progression-free Survival (PFS) Based on Independent Response Review Panel (IRRP) for Participants With Rai Stage I-II | Up to 6 years | Progression-free survival was defined as the number of days from the date of randomization to the date of first objective documentation of progressive disease (PD) as determined by the treatment-blinded IRRP, or death due to any cause. Results are expressed in months and include participants with Rai stage I or II. |
| Kaplan-Meier Estimates for Progression-free Survival (PFS) Based on Independent Response Review Panel (IRRP) for Participants With Rai Stage III-IV | Up to 6 years | Progression-free survival was defined as the number of days from the date of randomization to the date of first objective documentation of progressive disease (PD) as determined by the treatment-blinded IRRP, or death due to any cause. Results are expressed in months and include participants with Rai stage III or IV. |
Countries
Austria, Bulgaria, Canada, Croatia, France, Germany, Greece, Italy, Poland, Portugal, Romania, Russia, Sweden, Ukraine, United States
Participant flow
Pre-assignment details
Treatment was from initiation of study drug(s) to 4 weeks after last administration of study drug. Follow-up was for those without disease progression and ended upon disease progression or primary endpoint analysis whichever came first. Observation included those with disease progression who were observed for alternative rx and overall survival.
Participants by arm
| Arm | Count |
|---|---|
| Combination Arm (FluCAM) Participants received both fludarabine (Fludara) and alemtuzumab (Campath) intravenously. Initial escalation of alemtuzumab from 3 to 30 mg (escalation can take up to 14 days). Up to six cycles of fludarabine 30 mg/m\^2 intravenous (IV) followed by alemtuzumab 30 mg IV on the first 3 days of each 28 day cycle. | 168 |
| Fludarabine Alone Participants received fludarabine monotherapy 25 mg/m\^2 IV daily for the first 5 days of each 28 day cycle for up to 6 cycles. | 167 |
| Total | 335 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Follow-up Period | AE - not related | 1 | 0 |
| Follow-up Period | Death | 13 | 7 |
| Follow-up Period | Disease progression | 72 | 99 |
| Follow-up Period | Other | 7 | 6 |
| Follow-up Period | Physician Decision | 0 | 1 |
| Follow-up Period | Unable to comply with protocol | 5 | 0 |
| Follow-up Period | Withdrawal by Subject | 6 | 6 |
| Observation Period | Death | 33 | 55 |
| Observation Period | Other | 8 | 7 |
| Observation Period | Unable to comply with protocol | 1 | 1 |
| Observation Period | Withdrawal by Subject | 4 | 2 |
| Treatment Period | AE - not treatment related | 7 | 7 |
| Treatment Period | Anemia or thrombocytopenia | 1 | 4 |
| Treatment Period | Death | 5 | 7 |
| Treatment Period | Disease progression | 9 | 8 |
| Treatment Period | Other | 5 | 3 |
| Treatment Period | Physician Decision | 13 | 7 |
| Treatment Period | Toxicity - treatment related | 15 | 15 |
| Treatment Period | Unable to comply with protocol | 3 | 1 |
| Treatment Period | Withdrawal by Subject | 7 | 8 |
Baseline characteristics
| Characteristic | Fludarabine Alone | Combination Arm (FluCAM) | Total |
|---|---|---|---|
| Age, Continuous | 60.8 years STANDARD_DEVIATION 9.34 | 60.0 years STANDARD_DEVIATION 9.25 | 60.4 years STANDARD_DEVIATION 9.29 |
| Binet Stage Binet Stage A | 25 participants | 27 participants | 52 participants |
| Binet Stage Binet Stage B | 89 participants | 89 participants | 178 participants |
| Binet Stage Binet Stage C | 53 participants | 52 participants | 105 participants |
| Body Surface Area (BSA) | 1.90 meters^2 STANDARD_DEVIATION 0.218 | 1.87 meters^2 STANDARD_DEVIATION 0.213 | 1.88 meters^2 STANDARD_DEVIATION 0.216 |
| Disease Status Refractory | 66 participants | 67 participants | 133 participants |
| Disease Status Relapsed | 101 participants | 101 participants | 202 participants |
| Height | 169.4 centimeters STANDARD_DEVIATION 9.3 | 169.0 centimeters STANDARD_DEVIATION 8.88 | 169.2 centimeters STANDARD_DEVIATION 9.08 |
| Maximum Lymph Node Size <5 centimeters | 136 participants | 134 participants | 270 participants |
| Maximum Lymph Node Size >= 5 centimeters | 31 participants | 34 participants | 65 participants |
| Race/Ethnicity, Customized Other | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized White | 167 participants | 167 participants | 334 participants |
| Rai Stage Group Rai Stage 0 | 2 participants | 2 participants | 4 participants |
| Rai Stage Group Rai Stage I - II | 102 participants | 104 participants | 206 participants |
| Rai Stage Group Rai Stage III - IV | 63 participants | 62 participants | 125 participants |
| Sex: Female, Male Female | 59 Participants | 59 Participants | 118 Participants |
| Sex: Female, Male Male | 108 Participants | 109 Participants | 217 Participants |
| Summary of Prior Therapy by Type of Therapy Fludarabine-containing therapy | 26 participants | 25 participants | 51 participants |
| Summary of Prior Therapy by Type of Therapy Non-fludarabine-containing therapy | 141 participants | 143 participants | 284 participants |
| World Health Organization (WHO) Performance Status WHO Performance Status = 0 | 72 participants | 81 participants | 153 participants |
| World Health Organization (WHO) Performance Status WHO Performance Status = 1 | 95 participants | 87 participants | 182 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 160 / 164 | 147 / 165 |
| serious Total, serious adverse events | 54 / 164 | 41 / 165 |
Outcome results
Primary
Kaplan-Meier Estimates for Progression-free Survival (PFS) Based on Independent Response Review Panel (IRRP) Assessment
Progression-free survival was defined as the number of days from the date of randomization to the date of first objective documentation of progressive disease (PD) as determined by the treatment-blinded IRRP, or death due to any cause. Results are expressed in months.
Time frame: Up to 6 years
Population: Full analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Combination Arm (FluCAM) | Kaplan-Meier Estimates for Progression-free Survival (PFS) Based on Independent Response Review Panel (IRRP) Assessment | 23.65 months |
| Fludarabine Alone | Kaplan-Meier Estimates for Progression-free Survival (PFS) Based on Independent Response Review Panel (IRRP) Assessment | 16.48 months |
p-value: <0.00195% CI: [0.467, 0.795]Regression, Cox
Secondary
Area Under the Curve (AUC) of Fludarabine From (AUC 0-tau)
AUC (0-tau) is the area under the plasma concentration curve for fludarabine over the dosage interval (tau).
Time frame: month 4 (cycle 4): first day of dosing (pre-dose, 0.5 hr end of infusion), second day of dosing (pre-dose, 0.5 hr end of infusion), third day of dosing (pre-dose, 0.25 hr, 0.5 hr end of infusion, 1,2,3,4,6,24,48,72 hr after start of fludarabine infusion)
Population: Pharmacokinetic population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Combination Arm (FluCAM) | Area Under the Curve (AUC) of Fludarabine From (AUC 0-tau) | 8203 ng*h/mL | Standard Deviation 6531 |
| Fludarabine Alone | Area Under the Curve (AUC) of Fludarabine From (AUC 0-tau) | 5669 ng*h/mL | Standard Deviation 3888 |
Secondary
Kaplan-Meier Estimates for Duration of Response Assessed by the Independent Response Review Panel (IRRP)
Duration of response was analyzed for participants who achieved a complete response (CR) or partial response (PR) and was defined as the number of days from the first date of documented response to the date of progressive disease as determined by IRRP or death due to any cause. Results are stated in months.
Time frame: Up to 6 years
Population: Full analysis set of participants who achieved a complete response or a partial response as determined by the IRRP.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Combination Arm (FluCAM) | Kaplan-Meier Estimates for Duration of Response Assessed by the Independent Response Review Panel (IRRP) | 25.10 months |
| Fludarabine Alone | Kaplan-Meier Estimates for Duration of Response Assessed by the Independent Response Review Panel (IRRP) | 19.14 months |
Secondary
Kaplan-Meier Estimates for Time to Alternative Therapy
Time to alternative therapy was defined as the number of days from the date of randomization to the date of first alternative therapy for chronic lymphocytic leukemia (CLL) or death resulting from any cause. Participants who had not received alternative therapy as of the data cutoff date were censored at the last follow-up visit assessment date plus 1 day. Results are stated in months.
Time frame: Up to 6 years
Population: Full analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Combination Arm (FluCAM) | Kaplan-Meier Estimates for Time to Alternative Therapy | 25.43 months |
| Fludarabine Alone | Kaplan-Meier Estimates for Time to Alternative Therapy | 22.01 months |
p-value: 0.02195% CI: [0.543, 0.951]Regression, Cox
Secondary
Kaplan Meier Estimates for Time to Disease Progression Assessed by the Independent Response Review Panel (IRRP)
Time to disease progression was defined as the number of days from the date of randomization to the date of first objective documentation of progressive disease as determined by IRRP. Results are stated in months.
Time frame: Up to 6 years
Population: Full analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Combination Arm (FluCAM) | Kaplan Meier Estimates for Time to Disease Progression Assessed by the Independent Response Review Panel (IRRP) | 27.96 months |
| Fludarabine Alone | Kaplan Meier Estimates for Time to Disease Progression Assessed by the Independent Response Review Panel (IRRP) | 18.68 months |
p-value: <0.00195% CI: [0.42, 0.752]Regression, Cox
Secondary
Kaplan-Meier Estimates of Overall Survival Time
Overall survival was defined as the time in days from the date of randomization to the date of death due to any cause plus 1 day for all participants. Results are stated in months.
Time frame: Up to 6 years
Population: Full analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Combination Arm (FluCAM) | Kaplan-Meier Estimates of Overall Survival Time | NA months |
| Fludarabine Alone | Kaplan-Meier Estimates of Overall Survival Time | 52.93 months |
p-value: 0.04295% CI: [0.449, 0.937]Regression, Cox
Secondary
Maximum Plasma Concentration (Cmax) of Fludarabine
Cmax is the maximum plasma concentration of fludarabine observed.
Time frame: month 4 (cycle 4): first day of dosing (pre-dose, 0.5 hr end of infusion), second day of dosing (pre-dose, 0.5 hr end of infusion), third day of dosing (pre-dose, 0.25 hr, 0.5 hr end of infusion, 1,2,3,4,6,24,48,72 hr after start of fludarabine infusion)
Population: Pharmacokinetic population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Combination Arm (FluCAM) | Maximum Plasma Concentration (Cmax) of Fludarabine | 4084 ng/mL | Standard Deviation 6089 |
| Fludarabine Alone | Maximum Plasma Concentration (Cmax) of Fludarabine | 1847 ng/mL | Standard Deviation 1637 |
Secondary
Mean EQ-5D™ Index Scores to Measure Quality of Life at Baseline
EQ-5D™ is a trademark of the EuroQol Group. EQ-5D™ is a standardized instrument for use as a measure of health outcome. The questionnaire asks about health status along 5 dimensions: mobility, self care, usual activities, pain/discomfort, and anxiety/depression, which are rated at three possible levels (no problems, some problems, extreme problems). The score ranges from best (+1) to worst (-0.59).
Time frame: Day 0 (baseline)
Population: Full analysis dataset. Participants who provided valid answers on questionnaires are included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Combination Arm (FluCAM) | Mean EQ-5D™ Index Scores to Measure Quality of Life at Baseline | 0.7959 units on a scale | Standard Deviation 0.1868 |
| Fludarabine Alone | Mean EQ-5D™ Index Scores to Measure Quality of Life at Baseline | 0.7822 units on a scale | Standard Deviation 0.2023 |
Secondary
Mean EQ-5D™ Index Scores to Measure Quality of Life at End of Treatment
EQ-5D™ is a trademark of the EuroQol Group. EQ-5D™ is a standardized instrument for use as a measure of health outcome. The questionnaire asks about health status along 5 dimensions: mobility, self care, usual activities, pain/discomfort, and anxiety/depression, which are rated at three possible levels (no problems, some problems, extreme problems). The score ranges from best (+1) to worst (-0.59).
Time frame: up to month 6 (end of treatment)
Population: Full analysis dataset. Participants who provided valid answers on questionnaires are included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Combination Arm (FluCAM) | Mean EQ-5D™ Index Scores to Measure Quality of Life at End of Treatment | 0.8049 units on a scale | Standard Deviation 0.2752 |
| Fludarabine Alone | Mean EQ-5D™ Index Scores to Measure Quality of Life at End of Treatment | 0.7749 units on a scale | Standard Deviation 0.2569 |
Secondary
Mean EuroQol Visual Analogue Scale (EQ-VAS) Scores to Measure Quality of Life at Baseline
The EuroQol Visual Analogue Scale (EQ-VAS) was also used to capture the self-rating of current health status using a visual thermometer with the end points of 100 (best imaginable health state) at the top and zero (worst imaginable health state) at the bottom.
Time frame: Day 0 (baseline)
Population: Full analysis set. Participants who provided valid answers on questionnaires are included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Combination Arm (FluCAM) | Mean EuroQol Visual Analogue Scale (EQ-VAS) Scores to Measure Quality of Life at Baseline | 70.9 units on a scale | Standard Deviation 18.01 |
| Fludarabine Alone | Mean EuroQol Visual Analogue Scale (EQ-VAS) Scores to Measure Quality of Life at Baseline | 70.2 units on a scale | Standard Deviation 17.24 |
Secondary
Mean EuroQol Visual Analogue Scale (EQ-VAS) Scores to Measure Quality of Life at End of Treatment
The EuroQol Visual Analogue Scale (EQ-VAS) was also used to capture the self-rating of current health status using a visual thermometer with the end points of 100 (best imaginable health state) at the top and zero (worst imaginable health state) at the bottom.
Time frame: up to month 6 (end of treatment)
Population: Full analysis set. Participants who provided valid answers on questionnaires are included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Combination Arm (FluCAM) | Mean EuroQol Visual Analogue Scale (EQ-VAS) Scores to Measure Quality of Life at End of Treatment | 77.1 units on a scale | Standard Deviation 19.41 |
| Fludarabine Alone | Mean EuroQol Visual Analogue Scale (EQ-VAS) Scores to Measure Quality of Life at End of Treatment | 75.7 units on a scale | Standard Deviation 17.98 |
Secondary
Mean Systemic Clearance (CL) of Fludarabine
Clearance of drug from plasma is affected by the absorption, distribution, metabolism and elimination of the drug. Mean systemic clearance of fludarabine is derived from plasma concentration versus time data.
Time frame: month 4 (cycle 4): first day of dosing (pre-dose, 0.5 hr end of infusion), second day of dosing (pre-dose, 0.5 hr end of infusion), third day of dosing (pre-dose, 0.25 hr, 0.5 hr end of infusion, 1,2,3,4,6,24,48,72 hr after start of fludarabine infusion)
Population: Pharmacokinetic population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Combination Arm (FluCAM) | Mean Systemic Clearance (CL) of Fludarabine | 9.46 liters/hour | Standard Deviation 4.31 |
| Fludarabine Alone | Mean Systemic Clearance (CL) of Fludarabine | 9.54 liters/hour | Standard Deviation 3.1 |
Secondary
Participant Best Response to Treatment Assessed by the Independent Response Review Panel (IRRP)
Participants were evaluated by the IRRP according to National Cancer Institute (NCI) 1996 response criteria. The best response observed during the study is summarized. Response categories include Complete Response (CR) with normal physical exam, marrow cells and blood values, Partial Response (PR) with a \>= 50% decrease from baseline in lymphocytes, lymphadenopathy and liver or spleen exam, Stable Disease (SD) without significant progression from baseline, or Progressive Disease (PD) with increased size/number of nodes, size of liver or spleen, increase in lymphocytes, aggressive histology.
Time frame: Up to 9 months
Population: Full analysis set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Combination Arm (FluCAM) | Participant Best Response to Treatment Assessed by the Independent Response Review Panel (IRRP) | Overall Response (CR+PR) | 137 participants |
| Combination Arm (FluCAM) | Participant Best Response to Treatment Assessed by the Independent Response Review Panel (IRRP) | Complete Response (CR) | 21 participants |
| Combination Arm (FluCAM) | Participant Best Response to Treatment Assessed by the Independent Response Review Panel (IRRP) | Partial Response (PR) | 116 participants |
| Combination Arm (FluCAM) | Participant Best Response to Treatment Assessed by the Independent Response Review Panel (IRRP) | Progressive Disease (PD) | 6 participants |
| Combination Arm (FluCAM) | Participant Best Response to Treatment Assessed by the Independent Response Review Panel (IRRP) | Stable Disease (SD) | 12 participants |
| Combination Arm (FluCAM) | Participant Best Response to Treatment Assessed by the Independent Response Review Panel (IRRP) | Not Evaluable (NE) | 13 participants |
| Fludarabine Alone | Participant Best Response to Treatment Assessed by the Independent Response Review Panel (IRRP) | Stable Disease (SD) | 21 participants |
| Fludarabine Alone | Participant Best Response to Treatment Assessed by the Independent Response Review Panel (IRRP) | Overall Response (CR+PR) | 126 participants |
| Fludarabine Alone | Participant Best Response to Treatment Assessed by the Independent Response Review Panel (IRRP) | Progressive Disease (PD) | 9 participants |
| Fludarabine Alone | Participant Best Response to Treatment Assessed by the Independent Response Review Panel (IRRP) | Complete Response (CR) | 7 participants |
| Fludarabine Alone | Participant Best Response to Treatment Assessed by the Independent Response Review Panel (IRRP) | Not Evaluable (NE) | 11 participants |
| Fludarabine Alone | Participant Best Response to Treatment Assessed by the Independent Response Review Panel (IRRP) | Partial Response (PR) | 119 participants |
Comparison: Comparison of Overall Response.p-value: 0.17895% CI: [-0.03, 0.15]Cochran-Mantel-Haenszel
Comparison: Comparison of complete response (CR).p-value: 0.01895% CI: [0.02, 0.15]Cochran-Mantel-Haenszel
Secondary
Participants With Minimal Residual Disease (MRD)
MRD negativity in this report was defined by the absence of tumor cells in bone marrow, using 4-color flow cytometry. MRD was assessed in participants with a clinical complete response (CR) or partial response (PR) without recovery of blood counts. MRD represents a very positive outcome.
Time frame: up to 9 months
Population: Full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combination Arm (FluCAM) | Participants With Minimal Residual Disease (MRD) | 6 participants |
| Fludarabine Alone | Participants With Minimal Residual Disease (MRD) | 0 participants |
p-value: 0.01495% CI: [0.01, 0.08]Cochran-Mantel-Haenszel
Secondary
Summary of Participants With Adverse Experiences (AEs)
Number of participants with adverse events (AEs). AEs were graded by the investigator using the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 and were assessed for relatedness to study treatment (4 point scale from 'not related' to 'definitely related'). Categories reported include participant counts for treatment-emergent AEs, AEs for infections, serious AEs, AEs causing discontinuation of study drug(s), and deaths. Related AEs for the combination arm can be related to either fludarabine or alemtuzumab.
Time frame: Up to 6 years
Population: Safety population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Combination Arm (FluCAM) | Summary of Participants With Adverse Experiences (AEs) | At least 1 drug-related infection | 44 participants |
| Combination Arm (FluCAM) | Summary of Participants With Adverse Experiences (AEs) | Discontinuation of study drug due to AE | 37 participants |
| Combination Arm (FluCAM) | Summary of Participants With Adverse Experiences (AEs) | At least 1 treatment-emergent infection | 67 participants |
| Combination Arm (FluCAM) | Summary of Participants With Adverse Experiences (AEs) | Discontinuation of study drug due to related AE | 32 participants |
| Combination Arm (FluCAM) | Summary of Participants With Adverse Experiences (AEs) | At least 1 serious AE | 54 participants |
| Combination Arm (FluCAM) | Summary of Participants With Adverse Experiences (AEs) | Deaths | 10 participants |
| Combination Arm (FluCAM) | Summary of Participants With Adverse Experiences (AEs) | At least 1 related treatment emergent AE | 159 participants |
| Combination Arm (FluCAM) | Summary of Participants With Adverse Experiences (AEs) | Patients who died due to a related AE | 7 participants |
| Combination Arm (FluCAM) | Summary of Participants With Adverse Experiences (AEs) | At least 1 related serious AE | 47 participants |
| Combination Arm (FluCAM) | Summary of Participants With Adverse Experiences (AEs) | Patients who died within 30 days of the last dose | 4 participants |
| Combination Arm (FluCAM) | Summary of Participants With Adverse Experiences (AEs) | At least 1 treatment emergent AE | 161 participants |
| Fludarabine Alone | Summary of Participants With Adverse Experiences (AEs) | Patients who died within 30 days of the last dose | 7 participants |
| Fludarabine Alone | Summary of Participants With Adverse Experiences (AEs) | At least 1 treatment emergent AE | 149 participants |
| Fludarabine Alone | Summary of Participants With Adverse Experiences (AEs) | At least 1 related treatment emergent AE | 125 participants |
| Fludarabine Alone | Summary of Participants With Adverse Experiences (AEs) | At least 1 treatment-emergent infection | 58 participants |
| Fludarabine Alone | Summary of Participants With Adverse Experiences (AEs) | At least 1 drug-related infection | 30 participants |
| Fludarabine Alone | Summary of Participants With Adverse Experiences (AEs) | At least 1 serious AE | 41 participants |
| Fludarabine Alone | Summary of Participants With Adverse Experiences (AEs) | At least 1 related serious AE | 28 participants |
| Fludarabine Alone | Summary of Participants With Adverse Experiences (AEs) | Discontinuation of study drug due to AE | 32 participants |
| Fludarabine Alone | Summary of Participants With Adverse Experiences (AEs) | Discontinuation of study drug due to related AE | 24 participants |
| Fludarabine Alone | Summary of Participants With Adverse Experiences (AEs) | Deaths | 12 participants |
| Fludarabine Alone | Summary of Participants With Adverse Experiences (AEs) | Patients who died due to a related AE | 6 participants |
Secondary
Total Volume of Distribution (Vss) of Fludarabine
The total volume of distribution (Vss) is the apparent volume in which fludarabine is distributed immediately after it has been injected intravenously and equilibrated between plasma and the surrounding tissues. Total volume of distribution (Vss) of fludarabine is derived from plasma concentration versus time data.
Time frame: month 4 (cycle 4): first day of dosing (pre-dose, 0.5 hr end of infusion), second day of dosing (pre-dose, 0.5 hr end of infusion), third day of dosing (pre-dose, 0.25 hr, 0.5 hr end of infusion, 1,2,3,4,6,24,48,72 hr after start of fludarabine infusion)
Population: Pharmacokinetic population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Combination Arm (FluCAM) | Total Volume of Distribution (Vss) of Fludarabine | 117 liters | Standard Deviation 64.3 |
| Fludarabine Alone | Total Volume of Distribution (Vss) of Fludarabine | 172 liters | Standard Deviation 91.3 |
Other Pre-specified
Kaplan-Meier Estimates for Progression-free Survival (PFS) Based on Independent Response Review Panel (IRRP) for Participants With Rai Stage I-II
Progression-free survival was defined as the number of days from the date of randomization to the date of first objective documentation of progressive disease (PD) as determined by the treatment-blinded IRRP, or death due to any cause. Results are expressed in months and include participants with Rai stage I or II.
Time frame: Up to 6 years
Population: Full analysis set of participants with Rai stage I or II
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Combination Arm (FluCAM) | Kaplan-Meier Estimates for Progression-free Survival (PFS) Based on Independent Response Review Panel (IRRP) for Participants With Rai Stage I-II | 23.75 months |
| Fludarabine Alone | Kaplan-Meier Estimates for Progression-free Survival (PFS) Based on Independent Response Review Panel (IRRP) for Participants With Rai Stage I-II | 20.76 months |
p-value: 0.10295% CI: [0.531, 1.059]Regression, Cox
Other Pre-specified
Kaplan-Meier Estimates for Progression-free Survival (PFS) Based on Independent Response Review Panel (IRRP) for Participants With Rai Stage III-IV
Progression-free survival was defined as the number of days from the date of randomization to the date of first objective documentation of progressive disease (PD) as determined by the treatment-blinded IRRP, or death due to any cause. Results are expressed in months and include participants with Rai stage III or IV.
Time frame: Up to 6 years
Population: Full analysis set of participants with Rai stage III or IV
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Combination Arm (FluCAM) | Kaplan-Meier Estimates for Progression-free Survival (PFS) Based on Independent Response Review Panel (IRRP) for Participants With Rai Stage III-IV | 20.53 months |
| Fludarabine Alone | Kaplan-Meier Estimates for Progression-free Survival (PFS) Based on Independent Response Review Panel (IRRP) for Participants With Rai Stage III-IV | 11.51 months |
p-value: <0.00195% CI: [0.292, 0.671]Regression, Cox
Other Pre-specified
Kaplan-Meier Estimates of Overall Survival Time for Participants With Rai Stage I-II
Overall survival was defined as the time in days from the date of randomization to the date of death due to any cause plus 1 day for all participants. Results are stated in months and include participants with Rai Stage I or II.
Time frame: Up to 6 years
Population: Full analysis set of participants with Rai Stage I or II
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Combination Arm (FluCAM) | Kaplan-Meier Estimates of Overall Survival Time for Participants With Rai Stage I-II | NA months |
| Fludarabine Alone | Kaplan-Meier Estimates of Overall Survival Time for Participants With Rai Stage I-II | NA months |
p-value: 0.81995% CI: [0.619, 1.836]Regression, Cox
Other Pre-specified
Kaplan-Meier Estimates of Overall Survival Time for Participants With Rai Stage III-IV
Overall survival was defined as the time in days from the date of randomization to the date of death due to any cause plus 1 day for all participants. Results are stated in months and include participants with Rai Stage III or IV.
Time frame: Up to 6 years
Population: Full analysis set of participants with Rai Stage III or IV
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Combination Arm (FluCAM) | Kaplan-Meier Estimates of Overall Survival Time for Participants With Rai Stage III-IV | NA months |
| Fludarabine Alone | Kaplan-Meier Estimates of Overall Survival Time for Participants With Rai Stage III-IV | 23.52 months |
p-value: <0.00195% CI: [0.25, 0.69]Regression, Cox