B-Cell Chronic Lymphocytic Leukemia
Conditions
Brief summary
The purpose of this study is to determine the safety and efficacy of lenalidomide as a first line therapy in treating patients with B-cell Chronic Lymphocytic Leukemia. This study will compare the effects (good and bad) of lenalidomide with chlorambucil.
Detailed description
After notification from the US Food and Drug Administration (FDA) on 12 July 2013, Celgene agreed to discontinue the lenalidomide treatment for all patients due to an imbalance in the number of deaths in patients treated with lenalidomide versus patients treated with chlorambucil. No specific causality for this imbalance has been identified to date. Investigators were instructed to immediately discontinue all participants from experimental lenalidomide treatment and inform their patients accordingly. Participants on the Chlorambucil arm may continue up to 12 months (13 cycles) with the last participant completing in March 2014. All randomized participants will continue to be followed for overall survival and secondary primary malignancies.
Interventions
DRUGLenalidomide
For patients with normal renal function (defined as CrCl ≥ 60 mL/min), 5 mg once daily on Days 1 through 28 of the first 28-day cycle, 10 mg once daily on Days 1 through 28 starting at the second cycle, 15 mg once daily starting at the third cycle and for the remainder of the study until PD or unacceptable toxicity, whichever occurs first. For patients with moderate renal impairment (defined as CrCl ≥ 30 to \< 60 mL/min), 2.5 mg once daily on Days 1 through 28 of the first 28-day cycle, 5 mg once daily on Days 1 through 28 starting at the second cycle, 7.5 mg once daily starting at the third cycle and for the remainder of the study until PD or unacceptable toxicity, whichever occurs first.
DRUGChlorambucil
Patients assigned to the chlorambucil arm will receive oral chlorambucil tablets at 0.8 mg/kg on Days 1 and 15 of each 28-day cycle for a total duration of 12 months (approximately 13 cycles).
Sponsors
Celgene
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
65 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Must sign an informed consent form. 2. Age ≥ 65 years 3. Must be able to adhere to the study visit schedule and other protocol requirements. 4. Must have a documented diagnosis of B-cell CLL. 5. Must have an Eastern Cooperative Oncology Group (ECOG) performance status score of ≤2. 6. Must agree to follow pregnancy precautions as required by the protocol. 7. Must agree to receive counseling related to teratogenic and other risks of lenalidomide. 8. Must agree not to donate blood or semen as defined by the protocol
Exclusion criteria
1. Prior treatment for B-cell CLL. 2. Any medical condition, that would prevent the subject from signing the informed consent form. 3. Active infections requiring systemic antibiotics. 4. Systemic infection that has not resolved \> 2 months prior to initiating lenalidomide 5. Pregnant or lactating females. 6. Participation in any clinical study or having taken any investigational therapy within 28 days. 7. Known presence of alcohol and/or drug abuse. 8. Central nervous system (CNS) involvement. 9. Prior history of malignancies, other than CLL, unless the subject has been free of the disease for ≥3 years. Exceptions include the following: * Basal cell carcinoma of the skin * Squamous cell carcinoma of the skin * Carcinoma in situ of the cervix * Carcinoma in situ of the breast * Incidental histologic finding of prostate cancer (TNM stage of T1a or T1b) 10. History of renal failure requiring dialysis. 11. Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV) and/or Hepatitis C Virus (HCV) infection. 12. Prior therapy with lenalidomide. 13. Evidence of TLS at screening 14. Presence of specific hematology and/or chemistry abnormalities 15. Uncontrolled hyperthyroidism or hypothyroidism 16. Venous thromboembolism within one year 17. ≥ Grade-2 neuropathy 18. Uncontrolled autoimmune hemolytic anemia or thrombocytopenia 19. Disease transformation \[i.e. Richter's Syndrome (lymphomas) or prolymphocytic leukemia\]
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Kaplan-Meier Estimate of Progression Free Survival (PFS) With a Later Cut-off Date of 14 March 2014 | From randomization to data cut off date of 31 March 2014; median follow up time for all participants was 12.6 months | Progression-free survival was defined as the time from randomization to the first documented progression confirmed per investigator's assessment or death due to any cause on study, whichever occurred first. Progressive disease included lymphadenopathy, an appearance of any new lesion such as enlarged lymph nodes (\> 1.5 cm), splenomegaly, hepatomegaly or other organ infiltrates, an increase by 50% or more in greatest determined diameter of any previous site or an increase by 50% or more in the sum of the product of diameters of multiple nodes. The progression date was assigned to the earliest time when any progression was observed without prior missing assessments. If withdrawal of consent or lost to follow-up occurred before documented progression or death, then these observations were censored at the date when the last complete tumor assessments determined a lack of progression. |
| Kaplan-Meier Estimate of Progression Free Survival (PFS) | From first dose of study drug to date of data cut-off of 18 Feb 2013; up to approximately 39 months | Progression-free survival was defined as the time from randomization to the first documented progression confirmed per investigator's assessment or death due to any cause on study, whichever occurred first. The progression date was assigned to the earliest time when any progression was observed without prior missing assessments. If withdrawal of consent or lost to follow-up occurred before documented progression or death, then these observations were censored at the date when the last complete tumor assessments determined a lack of progression |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events With a Later Cut-off Date of 31 March 2014 | From randomization to the data cut-off date of 31 March 2014; Up to 53 months; maximum duration of exposure for Lenalidomide was 1140 days and 406 days for Chlorambucil | AEs = any noxious, unintended, or untoward medical occurrence that may appear or worsen during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the participant's health, regardless of cause. Serious AE (SAE) = any AE which results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; constitutes an important medical event. The severity of AEs were graded based upon the participants symptoms according to the Common Terminology Criteria for Adverse Events (CTCAE, Version 4.0); AEs were evaluated for severity according to the following scale: Grade 1 = Mild - transient or mild discomfort; no medical intervention required; Grade 2 = Moderate - mild to moderate limitation in activity; Grade 3 = Severe; Grade 4 = Life threatening; Grade 5 = Death |
| Percentage of Participants With the Best Overall Response Based on the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) Guidelines | Up to data cut-off date of 18 Feb 2013; approximately 39 months | A best overall response rate is a CR, CRi, nPR or PR and is defined as: Complete Remission (CR): * No lymphadenopathy * No hepatomegaly or splenomegaly * Absence of constitutional symptoms * Polymorphonuclear leukocytes ≥ 1500/ul * No circulating clonal B-lymphocytes * Platelets \> 100,000/ul * Hemoglobin \> 11.0 g/dl * Normocellular \<30% lymphocytes, no B-lymphoid nodules; Incomplete Clinical Response (CRi): • CR without bone marrow biopsy confirmation. Nodular Partial Response (nPR): • CR with the presence of residual clonal nodules. Partial Response (PR) requires: * ≥ 50% decrease in peripheral blood lymphocyte count * ≥ 50% reduction in lymphadenopathy * ≥ 50% reduction in size of liver and/or spleen * 1 or more of the following: * Polymorphonuclear leukocytes ≥ 1500/ul * Platelets \>100,000/ul |
| Percentage of Participants With a Best Overall Response Based on IWCLL Guidelines With a Later Cut-off Date of 31 March 2014 | Up to data cut-off of 31 March 2014; approximately 53 months | A best overall response rate is a CR, CRi, nPR or PR and is defined as: Complete Remission (CR): * No lymphadenopathy * No hepatomegaly or splenomegaly * Absence of constitutional symptoms * Polymorphonuclear leukocytes ≥ 1500/ul * No circulating clonal B-lymphocytes * Platelets \> 100,000/ul * Hemoglobin \> 11.0 g/dl * Normocellular \<30% lymphocytes, no B-lymphoid nodules; Incomplete Clinical Response (CRi): • CR without bone marrow biopsy confirmation. Nodular Partial Response: • CR with the presence of residual clonal nodules. Partial Response requires: * ≥ 50% decrease in peripheral blood lymphocyte count * ≥ 50% reduction in lymphadenopathy * ≥ 50% reduction in size of liver and/or spleen * 1 or more of the following: * Polymorphonuclear leukocytes ≥ 1500/ul * Platelets \>100,000/ul |
| Kaplan-Meier Estimate for Duration of Response | Up to data cut-off of 18 Feb 2013; up to approximately 39 months | Duration of response was defined as the time from first nPR, PR, CRi, or CR to PD. Duration of response was censored at the last date that the patient was known to be progression-free for: 1) participants who had not progressed at the time of analysis; 2) participants who had withdrawn consent or were lost to follow-up prior to documentation of progression |
| Kaplan-Meier Estimate for Duration of Response With a Later Cut-off Date of 31 March 2014 | Up to data cut-off of 31 March 2014; up to approximately 53 months | Duration of response was defined as the time from first nPR, PR, CRi, or CR to PD. Duration of response was censored at the last date that the patient was known to be progression-free for: 1) patients who had not progressed at the time of analysis; 2) patients who had withdrawn consent or were lost to follow-up prior to documentation of progression |
| Time to Response | Up to data cut-off of 18 Feb 2013; up to approximately 39 months | Time to response was calculated as the time from randomization to the first nPR, PR, CRi or CR based on IWCLL guidelines |
| Kaplan Meier Estimate of Overall Survival | Up to data cut off of 31 March 2014; median follow-up for all participants was 18.8 months | Overall Survival is defined as the time between randomization and death from any cause. |
| Kaplan Meier Estimate for Overall Survival at the Final Analysis | Up to the last patient last visit date of 19 May 2018; median follow-up for all participants was 46.7 months | Overall Survival is defined as the time between randomization and death from any cause. Overall survival was censored at the last date that the subject was known to be alive for participants who were alive as of the data cutoff date and for participants who were lost to follow-up before death was documented. |
| Functional Assessment of Cancer Therapy-General to Create the FACT-Leukemia (FACT-Leu) Quality of Life Instrument | Day 1 and once every 8 weeks | The FACT-Leu scale is a valid, reliable, and efficient measure of leukemia-specific health-related quality of life for acute and chronic disease. The FACT-Leu is described as including 27 items that assess 17 physical symptoms (fevers, bleeding, general pain, stomach pain, chills, night sweats, bruising, lymph node swelling, weakness, tiredness, weight loss, appetite, shortness of breath, functional ability, diarrhea, concentration, and mouth sores) and 10 emotional/social concerns (frustration with activity limitation, discouraged by illness, future planning, uncertainty, worry about illness, emotional lability, isolation, infertility concern, family worry, and worry about infections). |
| Euro Quality of Life Five Dimension (EQ-5D) Questionnaire | Day 1 and once every 8 weeks | The standardized extended version of EQ-5D was designed for the collection of health state values using a visual analogue scale (VAS) rating scale - a vertical 20 cm visual analogue scale with the end points labeled best imaginable health state at the top and worst imaginable health state at the bottom having numeric values of 100 and 0 respectively. The participant is asked to indicate his/her health state by ticking (or placing a cross) in the box against the most appropriate statement in each of the 5 dimensions. |
| Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment | Up to the last patient last visit date of 19 May 2018; median follow-up for all participants was 46.7 months | Subsequent anti-cancer therapies administered to participants following the discontinuation of study drug (either Lenalidomide or Chlorambucil) |
| Time to Response for a Later Cut-off Date of 31 March 2014 | Up to data cut-off of 31 March 2014; up to approximately 53 months | Time to response was calculated as the time from randomization to the first nPR, PR, CRi or CR based on IWCLL guidelines |
| Number of Participants With Adverse Events (AEs) | From randomization up to data cut-off of 18 Feb 2013; Up to approximately 39 months; maximum duration of exposure for Lenalidomide was 1086 days and 406 days for Chlorambucil | AEs = any noxious, unintended, or untoward medical occurrence that may appear or worsen during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the participant's health, regardless of cause. Serious AE (SAE) = any AE which results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; constitutes an important medical event. The severity of AEs were graded based upon the participants symptoms according to the Common Terminology Criteria for Adverse Events (CTCAE, Version 4.0); AEs were evaluated for severity according to the following scale: Grade 1 = Mild - transient or mild discomfort; no medical intervention required; Grade 2 = Moderate - mild to moderate limitation in activity; Grade 3 = Severe; Grade 4 = Life threatening; Grade 5 = Death |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Deaths During the Treatment and Survival Follow-Up Phase | From the first dose of study drug up to the last patient last visit date of 19 May 2018; median follow-up for all participants was 46.7 months | The number of study participants deaths during the treatment and follow-up phase |
Countries
Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Croatia, Czechia, Denmark, France, Hungary, Israel, Italy, Netherlands, New Zealand, Poland, Portugal, Romania, Russia, Serbia, Slovakia, South Africa, Spain, United Kingdom, United States
Participant flow
Recruitment details
118 sites randomized participants in Austria, Australia, Belgium, Brazil, Bulgaria, Canada, Chile, Columbia, Croatia, Czech Republic, Denmark, Hungary, Israel, Italy, the Netherlands, New Zealand, Poland, Portugal, Romania, Russia, South Africa, Slovakia, Spain, Serbia, the United Kingdom, and the United States of America
Pre-assignment details
Participants were randomized 1:1 to lenalidomide or chlorambucil and stratified by disease stage, presence of pre-defined co-morbidities and presence of at least one of the following poor prognostic factors: 11q deletion, 17 p deletion, unmutated IgVH and B2M\>4.0 mg/dL.
Participants by arm
| Arm | Count |
|---|---|
| Lenalidomide For participants with normal renal function \[defined as Creatinine Clearance (CrCL ) ≥ 60 mL/min\], 5 mg lenalidomide by mouth (PO) once daily (QD) on Days 1 through 28 of the first 28-day cycle, 10 mg lenalidomide PO QD on Days 1 through 28 starting at cycle 2, 15 mg lenalidomide PO QD starting at cycle 3 and for the remainder of the study until progressive disease (PD) or unacceptable toxicity, whichever occurred first. For participants with moderate renal impairment (defined as CrCL ≥ 30 to \< 60 mL/min), 2.5 mg lenalidomide PO QD on Days 1 through 28 of the first 28-day cycle, 5 mg lenalidomide PO QD on Days 1 through 28 starting at cycle 2, 7.5 mg lenalidomide PO QD starting at cycle 3 and for the remainder of the study until PD or unacceptable toxicity, whichever occurred first. | 225 |
| Chlorambucil Chlorambucil oral tablets at 0.8 mg/kg on Days 1 and 15 of each 28-day cycle for a total duration of 12 months (approximately 13 cycles). | 225 |
| Total | 450 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 63 | 35 |
| Overall Study | Completed 13 cycles of treatment | 0 | 118 |
| Overall Study | Death | 9 | 3 |
| Overall Study | Lost to Follow-up | 2 | 2 |
| Overall Study | Other | 114 | 32 |
| Overall Study | PD with histologic change | 0 | 2 |
| Overall Study | PD without histologic change | 27 | 23 |
| Overall Study | Protocol Violation | 2 | 2 |
| Overall Study | Untreated before cycle 1 | 1 | 2 |
| Overall Study | Withdrawal by Subject | 7 | 5 |
Baseline characteristics
| Characteristic | Lenalidomide | Chlorambucil | Total |
|---|---|---|---|
| Age, Continuous | 73.0 years STANDARD_DEVIATION 5.72 | 73.3 years STANDARD_DEVIATION 5.72 | 73.1 years STANDARD_DEVIATION 5.72 |
| Sex: Female, Male Female | 93 Participants | 83 Participants | 176 Participants |
| Sex: Female, Male Male | 132 Participants | 142 Participants | 274 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 100 / 224 | 93 / 223 |
| other Total, other adverse events | 204 / 224 | 184 / 223 |
| serious Total, serious adverse events | 148 / 224 | 90 / 223 |
Outcome results
Primary
Kaplan-Meier Estimate of Progression Free Survival (PFS)
Progression-free survival was defined as the time from randomization to the first documented progression confirmed per investigator's assessment or death due to any cause on study, whichever occurred first. The progression date was assigned to the earliest time when any progression was observed without prior missing assessments. If withdrawal of consent or lost to follow-up occurred before documented progression or death, then these observations were censored at the date when the last complete tumor assessments determined a lack of progression
Time frame: From first dose of study drug to date of data cut-off of 18 Feb 2013; up to approximately 39 months
Population: This is a smaller population used in this analysis (earlier cut-off date) prior to the last participant enrolled in the study. The ITT population was defined as all participants who were randomized, independent of whether they received study treatment or not.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenalidomide | Kaplan-Meier Estimate of Progression Free Survival (PFS) | 30.8 months |
| Chlorambucil | Kaplan-Meier Estimate of Progression Free Survival (PFS) | 23.0 months |
Comparison: Stratification factors: Disease stage (Binet A or Binet B or Rai I or Rai II versus (VS) Binet C or Rai III or Rai IV); Presence of at least one of the co-morbidities Asparate transaminase (AST)/Alanine transaminase (ALT) ≥ 3.0 times Upper Limits of Normal (ULN,) Creatinine clearance ≥ 30 to \< 60 mL/min, Yes VS No); Presence of at least one 11q deletion, 17p deletion, unmutated Immunoglobulin Heavy-chain Variable-region (IgVH) or Beta-2 Microglobulin (ß2M )\> 4.0 mg/L (Yes versus No VS Unknown)p-value: 0.32390% CI: [0.88, 1.66]stratified log rank
Primary
Kaplan-Meier Estimate of Progression Free Survival (PFS) With a Later Cut-off Date of 14 March 2014
Progression-free survival was defined as the time from randomization to the first documented progression confirmed per investigator's assessment or death due to any cause on study, whichever occurred first. Progressive disease included lymphadenopathy, an appearance of any new lesion such as enlarged lymph nodes (\> 1.5 cm), splenomegaly, hepatomegaly or other organ infiltrates, an increase by 50% or more in greatest determined diameter of any previous site or an increase by 50% or more in the sum of the product of diameters of multiple nodes. The progression date was assigned to the earliest time when any progression was observed without prior missing assessments. If withdrawal of consent or lost to follow-up occurred before documented progression or death, then these observations were censored at the date when the last complete tumor assessments determined a lack of progression.
Time frame: From randomization to data cut off date of 31 March 2014; median follow up time for all participants was 12.6 months
Population: The Intent-to-Treat (ITT) population was defined as all participants who were randomized, independent of whether they received study treatment or not.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenalidomide | Kaplan-Meier Estimate of Progression Free Survival (PFS) With a Later Cut-off Date of 14 March 2014 | 30.8 months |
| Chlorambucil | Kaplan-Meier Estimate of Progression Free Survival (PFS) With a Later Cut-off Date of 14 March 2014 | 21.4 months |
Comparison: Stratification factors: Disease stage (Binet A or Binet B or Rai I or Rai II versus (VS) Binet C or Rai III or Rai IV); Presence of at least one of the co-morbidities Asparate transaminase (AST)/Alanine transaminase (ALT) ≥ 3.0 times Upper Limits of Normal (ULN,) Creatinine clearance ≥ 30 to \< 60 mL/min, Yes VS No); Presence of at least one 11q deletion, 17p deletion, unmutated Immunoglobulin Heavy-chain Variable-region (IgVH) or Beta-2 Microglobulin (ß2M )\> 4.0 mg/L (Yes versus No VS Unknown)p-value: 0.96790% CI: [0.76, 1.29]Log Rank
Secondary
Euro Quality of Life Five Dimension (EQ-5D) Questionnaire
The standardized extended version of EQ-5D was designed for the collection of health state values using a visual analogue scale (VAS) rating scale - a vertical 20 cm visual analogue scale with the end points labeled best imaginable health state at the top and worst imaginable health state at the bottom having numeric values of 100 and 0 respectively. The participant is asked to indicate his/her health state by ticking (or placing a cross) in the box against the most appropriate statement in each of the 5 dimensions.
Time frame: Day 1 and once every 8 weeks
Population: No data were collected for the EQ-5D QOL assessment. The EQ-5D analysis was not conducted due to the discontinuation of the lenalidomide arm.
Secondary
Functional Assessment of Cancer Therapy-General to Create the FACT-Leukemia (FACT-Leu) Quality of Life Instrument
The FACT-Leu scale is a valid, reliable, and efficient measure of leukemia-specific health-related quality of life for acute and chronic disease. The FACT-Leu is described as including 27 items that assess 17 physical symptoms (fevers, bleeding, general pain, stomach pain, chills, night sweats, bruising, lymph node swelling, weakness, tiredness, weight loss, appetite, shortness of breath, functional ability, diarrhea, concentration, and mouth sores) and 10 emotional/social concerns (frustration with activity limitation, discouraged by illness, future planning, uncertainty, worry about illness, emotional lability, isolation, infertility concern, family worry, and worry about infections).
Time frame: Day 1 and once every 8 weeks
Population: No data were collected for the FACT-Leu QOL assessment. Analysis was not conducted due to the discontinuation of the lenalidomide arm.
Secondary
Kaplan-Meier Estimate for Duration of Response
Duration of response was defined as the time from first nPR, PR, CRi, or CR to PD. Duration of response was censored at the last date that the patient was known to be progression-free for: 1) participants who had not progressed at the time of analysis; 2) participants who had withdrawn consent or were lost to follow-up prior to documentation of progression
Time frame: Up to data cut-off of 18 Feb 2013; up to approximately 39 months
Population: Intent to Treat population with an objective response as of 18 Feb 2013; includes responders
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenalidomide | Kaplan-Meier Estimate for Duration of Response | NA weeks |
| Chlorambucil | Kaplan-Meier Estimate for Duration of Response | 105.3 weeks |
p-value: 0.82690% CI: [0.58, 1.52]Log Rank
Secondary
Kaplan-Meier Estimate for Duration of Response With a Later Cut-off Date of 31 March 2014
Duration of response was defined as the time from first nPR, PR, CRi, or CR to PD. Duration of response was censored at the last date that the patient was known to be progression-free for: 1) patients who had not progressed at the time of analysis; 2) patients who had withdrawn consent or were lost to follow-up prior to documentation of progression
Time frame: Up to data cut-off of 31 March 2014; up to approximately 53 months
Population: Intent to Treat population with an objective response as of 31 March 2014; includes responders.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenalidomide | Kaplan-Meier Estimate for Duration of Response With a Later Cut-off Date of 31 March 2014 | NA weeks |
| Chlorambucil | Kaplan-Meier Estimate for Duration of Response With a Later Cut-off Date of 31 March 2014 | 87.1 weeks |
p-value: 0.14990% CI: [0.48, 1.05]Log Rank
Secondary
Kaplan Meier Estimate for Overall Survival at the Final Analysis
Overall Survival is defined as the time between randomization and death from any cause. Overall survival was censored at the last date that the subject was known to be alive for participants who were alive as of the data cutoff date and for participants who were lost to follow-up before death was documented.
Time frame: Up to the last patient last visit date of 19 May 2018; median follow-up for all participants was 46.7 months
Population: The ITT population was defined as all participants who were randomized, independent of whether they received study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenalidomide | Kaplan Meier Estimate for Overall Survival at the Final Analysis | 74.3 Months |
| Chlorambucil | Kaplan Meier Estimate for Overall Survival at the Final Analysis | 70.5 Months |
p-value: 0.70990% CI: [0.83, 1.34]stratified log rank
Secondary
Kaplan Meier Estimate of Overall Survival
Overall Survival is defined as the time between randomization and death from any cause.
Time frame: Up to data cut off of 31 March 2014; median follow-up for all participants was 18.8 months
Population: The Intent-to-Treat (ITT) population was defined as all participants who were randomized, independent of whether they received study treatment or not.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenalidomide | Kaplan Meier Estimate of Overall Survival | NA Months |
| Chlorambucil | Kaplan Meier Estimate of Overall Survival | 44.0 Months |
p-value: 0.88390% CI: [0.73, 1.46]Log Rank
Secondary
Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment
Subsequent anti-cancer therapies administered to participants following the discontinuation of study drug (either Lenalidomide or Chlorambucil)
Time frame: Up to the last patient last visit date of 19 May 2018; median follow-up for all participants was 46.7 months
Population: The safety population was defined as all randomized participants who received at least 1 dose of the study treatment (either lenalidomide or chlorambucil).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lenalidomide | Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment | Participants receiving plant alkaloids | 22 participants |
| Lenalidomide | Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment | Other Analgesics and Antipyretics | 1 participants |
| Lenalidomide | Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment | Participants receiving therapeutic products | 4 participants |
| Lenalidomide | Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment | Specific Antirheumatic Agents | 1 participants |
| Lenalidomide | Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment | Participants receiving corticosteroids | 27 participants |
| Lenalidomide | Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment | Antiemetics and Antinauseants | 0 participants |
| Lenalidomide | Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment | Participants receiving other unspecified products | 0 participants |
| Lenalidomide | Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment | Corticosteriods for Systemic Use | 0 participants |
| Lenalidomide | Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment | Participants receiving antimetabolites | 34 participants |
| Lenalidomide | Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment | Immunostimulants | 0 participants |
| Lenalidomide | Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment | Drugs for Peptic ulcer and Gastric Reflex | 1 participants |
| Lenalidomide | Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment | Participants receiving immunosuppressants | 3 participants |
| Lenalidomide | Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment | Participants receiving alkylating agents | 107 participants |
| Lenalidomide | Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment | Immunoglobulins | 1 participants |
| Lenalidomide | Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment | Participants receiving antineoplastic aents | 93 participants |
| Lenalidomide | Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment | Participants receiving cytotoxic antibiotics | 10 participants |
| Lenalidomide | Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment | Antihistamine For Systemic Use | 1 participants |
| Lenalidomide | Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment | Participants receiving additional CLL therapy | 125 participants |
| Chlorambucil | Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment | Antihistamine For Systemic Use | 1 participants |
| Chlorambucil | Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment | Participants receiving antineoplastic aents | 86 participants |
| Chlorambucil | Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment | Participants receiving antimetabolites | 24 participants |
| Chlorambucil | Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment | Participants receiving corticosteroids | 16 participants |
| Chlorambucil | Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment | Participants receiving plant alkaloids | 11 participants |
| Chlorambucil | Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment | Participants receiving cytotoxic antibiotics | 3 participants |
| Chlorambucil | Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment | Participants receiving immunosuppressants | 2 participants |
| Chlorambucil | Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment | Participants receiving therapeutic products | 3 participants |
| Chlorambucil | Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment | Participants receiving other unspecified products | 2 participants |
| Chlorambucil | Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment | Drugs for Peptic ulcer and Gastric Reflex | 0 participants |
| Chlorambucil | Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment | Immunoglobulins | 2 participants |
| Chlorambucil | Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment | Other Analgesics and Antipyretics | 1 participants |
| Chlorambucil | Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment | Specific Antirheumatic Agents | 0 participants |
| Chlorambucil | Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment | Antiemetics and Antinauseants | 1 participants |
| Chlorambucil | Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment | Corticosteriods for Systemic Use | 1 participants |
| Chlorambucil | Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment | Immunostimulants | 1 participants |
| Chlorambucil | Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment | Participants receiving additional CLL therapy | 120 participants |
| Chlorambucil | Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment | Participants receiving alkylating agents | 106 participants |
Secondary
Number of Participants With Adverse Events (AEs)
AEs = any noxious, unintended, or untoward medical occurrence that may appear or worsen during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the participant's health, regardless of cause. Serious AE (SAE) = any AE which results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; constitutes an important medical event. The severity of AEs were graded based upon the participants symptoms according to the Common Terminology Criteria for Adverse Events (CTCAE, Version 4.0); AEs were evaluated for severity according to the following scale: Grade 1 = Mild - transient or mild discomfort; no medical intervention required; Grade 2 = Moderate - mild to moderate limitation in activity; Grade 3 = Severe; Grade 4 = Life threatening; Grade 5 = Death
Time frame: From randomization up to data cut-off of 18 Feb 2013; Up to approximately 39 months; maximum duration of exposure for Lenalidomide was 1086 days and 406 days for Chlorambucil
Population: This is a smaller population used in this analysis (earlier cut-off date) prior to the last participant enrolled in the study. The safety population was defined as all randomized participants who received at least 1 dose of the study treatment (either lenalidomide or chlorambucil) as of the data cut off date of 18 Feb 2013
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lenalidomide | Number of Participants With Adverse Events (AEs) | ≥1 TEAE leading to stopping either study drug | 61 participants |
| Lenalidomide | Number of Participants With Adverse Events (AEs) | ≥ 1 NCI CTC Grade 3-4 TEAE | 173 participants |
| Lenalidomide | Number of Participants With Adverse Events (AEs) | ≥ 1 Serious TEAE | 129 participants |
| Lenalidomide | Number of Participants With Adverse Events (AEs) | ≥ 1 Serious TEAE related to any study drug | 95 participants |
| Lenalidomide | Number of Participants With Adverse Events (AEs) | ≥1 Related TEAE leading to stopping either drug | 39 participants |
| Lenalidomide | Number of Participants With Adverse Events (AEs) | ≥ 1 TEAE | 202 participants |
| Lenalidomide | Number of Participants With Adverse Events (AEs) | Grade 3-4 adverse event related to any study drug | 143 participants |
| Lenalidomide | Number of Participants With Adverse Events (AEs) | ≥ 1 NCI CTC Grade 5 TEAE | 21 participants |
| Lenalidomide | Number of Participants With Adverse Events (AEs) | ≥ Grade 5 adverse event related to any study drug | 6 participants |
| Lenalidomide | Number of Participants With Adverse Events (AEs) | ≥ 1 TEAE related to study drug | 183 participants |
| Chlorambucil | Number of Participants With Adverse Events (AEs) | ≥ 1 Serious TEAE | 76 participants |
| Chlorambucil | Number of Participants With Adverse Events (AEs) | ≥ 1 TEAE related to study drug | 139 participants |
| Chlorambucil | Number of Participants With Adverse Events (AEs) | ≥ 1 TEAE | 186 participants |
| Chlorambucil | Number of Participants With Adverse Events (AEs) | ≥ Grade 5 adverse event related to any study drug | 1 participants |
| Chlorambucil | Number of Participants With Adverse Events (AEs) | ≥ 1 NCI CTC Grade 3-4 TEAE | 117 participants |
| Chlorambucil | Number of Participants With Adverse Events (AEs) | ≥ 1 NCI CTC Grade 5 TEAE | 9 participants |
| Chlorambucil | Number of Participants With Adverse Events (AEs) | ≥ 1 Serious TEAE related to any study drug | 46 participants |
| Chlorambucil | Number of Participants With Adverse Events (AEs) | ≥1 TEAE leading to stopping either study drug | 34 participants |
| Chlorambucil | Number of Participants With Adverse Events (AEs) | Grade 3-4 adverse event related to any study drug | 82 participants |
| Chlorambucil | Number of Participants With Adverse Events (AEs) | ≥1 Related TEAE leading to stopping either drug | 19 participants |
Secondary
Number of Participants With Adverse Events With a Later Cut-off Date of 31 March 2014
AEs = any noxious, unintended, or untoward medical occurrence that may appear or worsen during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the participant's health, regardless of cause. Serious AE (SAE) = any AE which results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; constitutes an important medical event. The severity of AEs were graded based upon the participants symptoms according to the Common Terminology Criteria for Adverse Events (CTCAE, Version 4.0); AEs were evaluated for severity according to the following scale: Grade 1 = Mild - transient or mild discomfort; no medical intervention required; Grade 2 = Moderate - mild to moderate limitation in activity; Grade 3 = Severe; Grade 4 = Life threatening; Grade 5 = Death
Time frame: From randomization to the data cut-off date of 31 March 2014; Up to 53 months; maximum duration of exposure for Lenalidomide was 1140 days and 406 days for Chlorambucil
Population: The safety population was defined as all randomized participants who received at least 1 dose of the study treatment (either lenalidomide or chlorambucil).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lenalidomide | Number of Participants With Adverse Events With a Later Cut-off Date of 31 March 2014 | ≥ 1 TEAE | 216 participants |
| Lenalidomide | Number of Participants With Adverse Events With a Later Cut-off Date of 31 March 2014 | ≥ 1 TEAE related to study drug | 194 participants |
| Lenalidomide | Number of Participants With Adverse Events With a Later Cut-off Date of 31 March 2014 | ≥ 1 NCI CTC Grade 3-4 TEAE | 188 participants |
| Lenalidomide | Number of Participants With Adverse Events With a Later Cut-off Date of 31 March 2014 | Grade 3-4 adverse event related to any study drug | 157 participants |
| Lenalidomide | Number of Participants With Adverse Events With a Later Cut-off Date of 31 March 2014 | ≥ Grade 5 adverse event related to any study drug | 6 participants |
| Lenalidomide | Number of Participants With Adverse Events With a Later Cut-off Date of 31 March 2014 | ≥ 1 NCI CTC Grade 5 TEAE | 21 participants |
| Lenalidomide | Number of Participants With Adverse Events With a Later Cut-off Date of 31 March 2014 | ≥ 1 Serious TEAE | 148 participants |
| Lenalidomide | Number of Participants With Adverse Events With a Later Cut-off Date of 31 March 2014 | ≥ 1 Serious TEAE related to any study drug | 107 participants |
| Lenalidomide | Number of Participants With Adverse Events With a Later Cut-off Date of 31 March 2014 | ≥1 TEAE leading to stopping either study drug | 70 participants |
| Lenalidomide | Number of Participants With Adverse Events With a Later Cut-off Date of 31 March 2014 | ≥1 Related TEAE leading to stopping either drug | 46 participants |
| Chlorambucil | Number of Participants With Adverse Events With a Later Cut-off Date of 31 March 2014 | ≥1 Related TEAE leading to stopping either drug | 23 participants |
| Chlorambucil | Number of Participants With Adverse Events With a Later Cut-off Date of 31 March 2014 | ≥ 1 TEAE | 202 participants |
| Chlorambucil | Number of Participants With Adverse Events With a Later Cut-off Date of 31 March 2014 | ≥ 1 TEAE related to study drug | 155 participants |
| Chlorambucil | Number of Participants With Adverse Events With a Later Cut-off Date of 31 March 2014 | ≥ 1 NCI CTC Grade 3-4 TEAE | 131 participants |
| Chlorambucil | Number of Participants With Adverse Events With a Later Cut-off Date of 31 March 2014 | Grade 3-4 adverse event related to any study drug | 90 participants |
| Chlorambucil | Number of Participants With Adverse Events With a Later Cut-off Date of 31 March 2014 | ≥ 1 NCI CTC Grade 5 TEAE | 11 participants |
| Chlorambucil | Number of Participants With Adverse Events With a Later Cut-off Date of 31 March 2014 | ≥ Grade 5 adverse event related to any study drug | 1 participants |
| Chlorambucil | Number of Participants With Adverse Events With a Later Cut-off Date of 31 March 2014 | ≥ 1 Serious TEAE | 90 participants |
| Chlorambucil | Number of Participants With Adverse Events With a Later Cut-off Date of 31 March 2014 | ≥ 1 Serious TEAE related to any study drug | 53 participants |
| Chlorambucil | Number of Participants With Adverse Events With a Later Cut-off Date of 31 March 2014 | ≥1 TEAE leading to stopping either study drug | 42 participants |
Secondary
Percentage of Participants With a Best Overall Response Based on IWCLL Guidelines With a Later Cut-off Date of 31 March 2014
A best overall response rate is a CR, CRi, nPR or PR and is defined as: Complete Remission (CR): * No lymphadenopathy * No hepatomegaly or splenomegaly * Absence of constitutional symptoms * Polymorphonuclear leukocytes ≥ 1500/ul * No circulating clonal B-lymphocytes * Platelets \> 100,000/ul * Hemoglobin \> 11.0 g/dl * Normocellular \<30% lymphocytes, no B-lymphoid nodules; Incomplete Clinical Response (CRi): • CR without bone marrow biopsy confirmation. Nodular Partial Response: • CR with the presence of residual clonal nodules. Partial Response requires: * ≥ 50% decrease in peripheral blood lymphocyte count * ≥ 50% reduction in lymphadenopathy * ≥ 50% reduction in size of liver and/or spleen * 1 or more of the following: * Polymorphonuclear leukocytes ≥ 1500/ul * Platelets \>100,000/ul
Time frame: Up to data cut-off of 31 March 2014; approximately 53 months
Population: The Intent-to-Treat population was defined as all participants who were randomized, independent of whether they received study treatment or not
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lenalidomide | Percentage of Participants With a Best Overall Response Based on IWCLL Guidelines With a Later Cut-off Date of 31 March 2014 | 60.9 percentage of participants with response |
| Chlorambucil | Percentage of Participants With a Best Overall Response Based on IWCLL Guidelines With a Later Cut-off Date of 31 March 2014 | 70.2 percentage of participants with response |
p-value: 0.04795% CI: [0.45, 0.98]Fisher Exact
Secondary
Percentage of Participants With the Best Overall Response Based on the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) Guidelines
A best overall response rate is a CR, CRi, nPR or PR and is defined as: Complete Remission (CR): * No lymphadenopathy * No hepatomegaly or splenomegaly * Absence of constitutional symptoms * Polymorphonuclear leukocytes ≥ 1500/ul * No circulating clonal B-lymphocytes * Platelets \> 100,000/ul * Hemoglobin \> 11.0 g/dl * Normocellular \<30% lymphocytes, no B-lymphoid nodules; Incomplete Clinical Response (CRi): • CR without bone marrow biopsy confirmation. Nodular Partial Response (nPR): • CR with the presence of residual clonal nodules. Partial Response (PR) requires: * ≥ 50% decrease in peripheral blood lymphocyte count * ≥ 50% reduction in lymphadenopathy * ≥ 50% reduction in size of liver and/or spleen * 1 or more of the following: * Polymorphonuclear leukocytes ≥ 1500/ul * Platelets \>100,000/ul
Time frame: Up to data cut-off date of 18 Feb 2013; approximately 39 months
Population: This is a smaller population used in this analysis (earlier cut-off date) prior to the last participant enrolled in the study. The Intent-to-Treat (ITT) population was defined as all participants who were randomized, independent of whether they received study treatment or not.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lenalidomide | Percentage of Participants With the Best Overall Response Based on the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) Guidelines | 51.9 percentage of participants |
| Chlorambucil | Percentage of Participants With the Best Overall Response Based on the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) Guidelines | 62.3 percentage of participants |
p-value: 0.03295% CI: [0.44, 0.96]Fisher Exact
Secondary
Time to Response
Time to response was calculated as the time from randomization to the first nPR, PR, CRi or CR based on IWCLL guidelines
Time frame: Up to data cut-off of 18 Feb 2013; up to approximately 39 months
Population: ITT participants with an objective response as of 18 February 2013
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenalidomide | Time to Response | 8.6 weeks |
| Chlorambucil | Time to Response | 8.1 weeks |
Secondary
Time to Response for a Later Cut-off Date of 31 March 2014
Time to response was calculated as the time from randomization to the first nPR, PR, CRi or CR based on IWCLL guidelines
Time frame: Up to data cut-off of 31 March 2014; up to approximately 53 months
Population: ITT participants who had not progressed at the time of analysis; or those who had withdrawn consent or were lost to follow-up prior to documentation of progression.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenalidomide | Time to Response for a Later Cut-off Date of 31 March 2014 | 10.4 weeks |
| Chlorambucil | Time to Response for a Later Cut-off Date of 31 March 2014 | 8.1 weeks |
Other Pre-specified
Number of Participants Deaths During the Treatment and Survival Follow-Up Phase
The number of study participants deaths during the treatment and follow-up phase
Time frame: From the first dose of study drug up to the last patient last visit date of 19 May 2018; median follow-up for all participants was 46.7 months
Population: ITT population includes all participants who were randomized, independent of whether they received study treatment or not
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lenalidomide | Number of Participants Deaths During the Treatment and Survival Follow-Up Phase | 101 Participants |
| Chlorambucil | Number of Participants Deaths During the Treatment and Survival Follow-Up Phase | 95 Participants |