Relapsed or Refractory Chronic Lymphocytic Leukemia
Conditions
Brief summary
The purpose of this study is to determine the safety and effectiveness of different dose regimens of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia (CLL).
Interventions
DRUGlenalidomide
Depending on the starting dose, subjects will be allocated in a double-blind fashion to three different regimens and will escalate every 28 days, based on individual subject tolerability, as follows: * Treatment Arm 1: 5 mg →10 mg →15 mg →20 mg →25 mg/daily * Treatment Arm 2: 10 mg →15 mg →20 mg →25 mg/daily * Treatment Arm 3: 15 mg →20 mg →25 mg/daily Subjects will continue treatment until disease progression or unacceptable toxicity
Sponsors
Celgene
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age ≥ 18 years at the time of signing the informed consent form * Must be able to adhere to the study visit schedule and other protocol requirements * Must have a documented diagnosis of B-cell CLL * Must be relapsed or refractory to at least 1 regimen for treatment of CLL. At least one of the prior treatments must have included a purine analog-based or bendamustine-based regimen * Must have an Eastern Cooperative Oncology Group (ECOG) performance status score of ≤ 2.
Exclusion criteria
* Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form * Active infections requiring systemic antibiotics * Systemic treatment for B-cell CLL within 28 days of initiation of lenalidomide treatment * Alemtuzumab therapy within 120 days of initiating lenalidomide treatment * Prior therapy with lenalidomide * History of grade 4 rash due to prior thalidomide treatment * Planned autologous or allogeneic bone marrow transplantation * Central nervous system (CNS) involvement as documented by spinal fluid cytology or imaging. * Uncontrolled hyperthyroidism or hypothyroidism * Venous thromboembolism within 12 months * ≥ Grade 2 neuropathy * Uncontrolled autoimmune hemolytic anemia or thrombocytopenia * Disease transformation \[i.e. Richter's Syndrome (lymphomas) or prolymphocytic leukemia\] * Participation in any clinical study or having taken any investigational therapy within 28 days prior to initiating lenalidomide therapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-emergent Adverse Events | From first dose of study drug to 30 days after the last dose; the maximum duration of treatment was 251, 265, and 267 weeks in the 5 mg, 10 mg, and 15 mg treatment groups respectively. | Adverse events (AEs) were graded for severity by the investigator according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0 with the exceptions of hematologic toxicities and tumor lysis syndrome, according to the following scale: Grade 1 = Mild Grade 2 = Moderate Grade 3 = Severe Grade 4 = Life Threatening or disabling AE Grade 5 = Death The investigator determined the relationship of each AE to study drug based on the timing of the AE and whether other medications, therapeutic interventions, or underlying conditions could provide a sufficient explanation for the observed event. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Kaplan-Meier Estimate of Duration of Response | Response was assessed after 3 cycles of therapy (Week 12) and every 4 weeks thereafter until disease progression. Maximum time on study was 91 months. | Duration of response (DOR) was defined as the time from the first visit where PR, CRi, or CR was documented to progressive disease (PD). Duration of response was censored at the last date that the participant was known to be progression-free for participants who had not progressed at the time of analysis or who withdrew consent or were lost to follow-up prior to documentation of progression. |
| Time to Response | Response was assessed after 3 cycles of therapy (Week 12) and every 4 weeks thereafter until disease progression. Maximum time on study was 91 months. | Time to response (TTR) was calculated as the time from randomization to the first documented date of response (PR, CRi or CR) based on iwCLL guidelines for participants with an objective response during the treatment period. |
| Kaplan-Meier Estimate of Time to Progression | From randomization until the end of the study; maximum time on study was 91 months. | Time to progression (TTP) was defined as the time from randomization to the first documented progression. For participants who did not progress during the study, TTP was censored at the last adequate response assessment showing evidence of no disease progression. |
| Overall Response Rate (ORR) | Response was assessed after 3 cycles of therapy (Week 12) and every 4 weeks thereafter until disease progression. Maximum time on study was 91 months. | ORR was defined as the percentage of patients with a complete response (CR), CR with incomplete bone marrow (BM) recovery (CRi) or partial response (PR) during treatment. Response was assessed according to the 2008 International Workshop on Chronic Lymphocytic Leukemia (iwCLL) guidelines. Per the guidelines, a CR required peripheral blood lymphocytes below 4 x 10\^9/L, absence of lymphadenopathy, no hepatomegaly or splenomegaly, absence of disease and blood counts neutrophils \>1.5 x 10\^9/L, platelets \>100 x 10\^9/L, hemoglobin (hgb) \>11g/dL) and BM at least normocellular for age. CRi = CR with incomplete BM recovery. PR = required at least 2 months from end of treatment, a ≥50% decrease in peripheral blood lymphocyte count from the pre-treatment value and either a ≥ 50% reduction in lymphadenopathy or ≥50% reduction of liver enlargement or ≥50% reduction of spleen enlargement plus neutrophils \>1.5 x 10\^9/ or ≥50% increase, platelets \>100 x 10\^9/L or ≥50% increase, hgb 11 g/dL. |
| Kaplan-Meier Estimate of Progression Free Survival | From randomization until the end of the study; maximum time on study was 91 months. | Progression-free survival (PFS) was calculated as the time from randomization to the first documented progression or death due to any cause during or after the treatment period, whichever occurred first. The progression date was assigned to the earliest time when any progression is observed without prior missing assessments. If withdrawal of consent or loss 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 Overall Survival | From randomization until the end of the study; maximum time on study was 91 months. | Overall survival (OS) was defined as the time from randomization to death from any cause. Overall survival was censored at the last date that the participant was known to be alive for participants who were alive at the time of analysis and for participants who had withdrawn consent or were lost to follow-up before death was documented. |
| Kaplan-Meier Estimate of Event-Free Survival | From randomization until the end of the study; maximum time on study was 91 months. | Event-free survival (EFS) is the interval between the start of treatment to the first sign of disease progression, or treatment for relapse or death (whichever occurred first). If withdrawal of consent or loss 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. |
Countries
Canada, France, Germany, Italy, Spain, Sweden, United Kingdom, United States
Participant flow
Recruitment details
Participants were randomized at 29 sites from North America and Europe.
Pre-assignment details
Participants were randomized (1:1:1) in a double-blind fashion, according to age (\< 65 versus ≥ 65 years) and disease status (relapsed versus refractory) to their last purine-analog or bendamustine-based prior regimen.
Participants by arm
| Arm | Count |
|---|---|
| Lenalidomide 5 mg Participants received a starting dose of 5 mg lenalidomide orally once a day. Lenalidomide dose was escalated by 5 mg in a step-wise manner every 28 days up to a maximum dose of 25 mg daily based on tolerability. | 34 |
| Lenalidomide 10 mg Participants received a starting dose of 10 mg lenalidomide orally once a day. Lenalidomide dose was escalated by 5 mg in a step-wise manner every 28 days up to a maximum dose of 25 mg daily based on tolerability. | 35 |
| Lenalidomide 15 mg Participants received a starting dose of 15 mg lenalidomide orally once a day. Lenalidomide dose was escalated by 5 mg in a step-wise manner every 28 days up to a maximum dose of 25 mg daily based on tolerability. | 35 |
| Total | 104 |
Baseline characteristics
| Characteristic | Lenalidomide 5 mg | Lenalidomide 10 mg | Lenalidomide 15 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 64.0 years STANDARD_DEVIATION 9.46 | 63.3 years STANDARD_DEVIATION 8.31 | 63.7 years STANDARD_DEVIATION 7.56 | 63.6 years STANDARD_DEVIATION 8.39 |
| Age, Customized < 65 years | 16 Participants | 19 Participants | 17 Participants | 52 Participants |
| Age, Customized ≥ 65 years | 18 Participants | 16 Participants | 18 Participants | 52 Participants |
| Race/Ethnicity, Customized Black or African American | 2 Participants | 4 Participants | 2 Participants | 8 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Unknown | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 31 Participants | 30 Participants | 33 Participants | 94 Participants |
| Sex: Female, Male Female | 8 Participants | 13 Participants | 11 Participants | 32 Participants |
| Sex: Female, Male Male | 26 Participants | 22 Participants | 24 Participants | 72 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 24 / 34 | 23 / 34 | 26 / 35 |
| other Total, other adverse events | 34 / 34 | 34 / 34 | 35 / 35 |
| serious Total, serious adverse events | 24 / 34 | 24 / 34 | 27 / 35 |
Outcome results
Primary
Number of Participants With Treatment-emergent Adverse Events
Adverse events (AEs) were graded for severity by the investigator according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0 with the exceptions of hematologic toxicities and tumor lysis syndrome, according to the following scale: Grade 1 = Mild Grade 2 = Moderate Grade 3 = Severe Grade 4 = Life Threatening or disabling AE Grade 5 = Death The investigator determined the relationship of each AE to study drug based on the timing of the AE and whether other medications, therapeutic interventions, or underlying conditions could provide a sufficient explanation for the observed event.
Time frame: From first dose of study drug to 30 days after the last dose; the maximum duration of treatment was 251, 265, and 267 weeks in the 5 mg, 10 mg, and 15 mg treatment groups respectively.
Population: Randomized participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Lenalidomide 5 mg | Number of Participants With Treatment-emergent Adverse Events | AE leading to study drug dose interruption only | 25 Participants |
| Lenalidomide 5 mg | Number of Participants With Treatment-emergent Adverse Events | AE leading to discontinuation of study drug | 21 Participants |
| Lenalidomide 5 mg | Number of Participants With Treatment-emergent Adverse Events | Treatment-related Grade 5 adverse events | 2 Participants |
| Lenalidomide 5 mg | Number of Participants With Treatment-emergent Adverse Events | Grade 3/4 adverse events | 33 Participants |
| Lenalidomide 5 mg | Number of Participants With Treatment-emergent Adverse Events | Treatment-related serious adverse events | 15 Participants |
| Lenalidomide 5 mg | Number of Participants With Treatment-emergent Adverse Events | Serious adverse events | 24 Participants |
| Lenalidomide 5 mg | Number of Participants With Treatment-emergent Adverse Events | Any adverse events | 34 Participants |
| Lenalidomide 5 mg | Number of Participants With Treatment-emergent Adverse Events | Treatment-related adverse events (TRAE) | 33 Participants |
| Lenalidomide 5 mg | Number of Participants With Treatment-emergent Adverse Events | AE leading to study drug dose reduction only | 8 Participants |
| Lenalidomide 5 mg | Number of Participants With Treatment-emergent Adverse Events | Treatment-related Grade 3/4 adverse events | 31 Participants |
| Lenalidomide 5 mg | Number of Participants With Treatment-emergent Adverse Events | AE leading to study drug interruption & reduction | 18 Participants |
| Lenalidomide 5 mg | Number of Participants With Treatment-emergent Adverse Events | TRAE leading to discontinuation of study drug | 16 Participants |
| Lenalidomide 5 mg | Number of Participants With Treatment-emergent Adverse Events | Grade 5 adverse events | 4 Participants |
| Lenalidomide 10 mg | Number of Participants With Treatment-emergent Adverse Events | Serious adverse events | 24 Participants |
| Lenalidomide 10 mg | Number of Participants With Treatment-emergent Adverse Events | Any adverse events | 34 Participants |
| Lenalidomide 10 mg | Number of Participants With Treatment-emergent Adverse Events | Treatment-related adverse events (TRAE) | 34 Participants |
| Lenalidomide 10 mg | Number of Participants With Treatment-emergent Adverse Events | Grade 3/4 adverse events | 32 Participants |
| Lenalidomide 10 mg | Number of Participants With Treatment-emergent Adverse Events | Treatment-related Grade 3/4 adverse events | 32 Participants |
| Lenalidomide 10 mg | Number of Participants With Treatment-emergent Adverse Events | Grade 5 adverse events | 4 Participants |
| Lenalidomide 10 mg | Number of Participants With Treatment-emergent Adverse Events | Treatment-related Grade 5 adverse events | 2 Participants |
| Lenalidomide 10 mg | Number of Participants With Treatment-emergent Adverse Events | Treatment-related serious adverse events | 13 Participants |
| Lenalidomide 10 mg | Number of Participants With Treatment-emergent Adverse Events | AE leading to discontinuation of study drug | 17 Participants |
| Lenalidomide 10 mg | Number of Participants With Treatment-emergent Adverse Events | TRAE leading to discontinuation of study drug | 14 Participants |
| Lenalidomide 10 mg | Number of Participants With Treatment-emergent Adverse Events | AE leading to study drug dose reduction only | 6 Participants |
| Lenalidomide 10 mg | Number of Participants With Treatment-emergent Adverse Events | AE leading to study drug dose interruption only | 24 Participants |
| Lenalidomide 10 mg | Number of Participants With Treatment-emergent Adverse Events | AE leading to study drug interruption & reduction | 26 Participants |
| Lenalidomide 15 mg | Number of Participants With Treatment-emergent Adverse Events | AE leading to discontinuation of study drug | 16 Participants |
| Lenalidomide 15 mg | Number of Participants With Treatment-emergent Adverse Events | Treatment-related Grade 3/4 adverse events | 30 Participants |
| Lenalidomide 15 mg | Number of Participants With Treatment-emergent Adverse Events | AE leading to study drug dose interruption only | 25 Participants |
| Lenalidomide 15 mg | Number of Participants With Treatment-emergent Adverse Events | TRAE leading to discontinuation of study drug | 13 Participants |
| Lenalidomide 15 mg | Number of Participants With Treatment-emergent Adverse Events | Grade 3/4 adverse events | 34 Participants |
| Lenalidomide 15 mg | Number of Participants With Treatment-emergent Adverse Events | Any adverse events | 35 Participants |
| Lenalidomide 15 mg | Number of Participants With Treatment-emergent Adverse Events | AE leading to study drug dose reduction only | 5 Participants |
| Lenalidomide 15 mg | Number of Participants With Treatment-emergent Adverse Events | Serious adverse events | 27 Participants |
| Lenalidomide 15 mg | Number of Participants With Treatment-emergent Adverse Events | Treatment-related Grade 5 adverse events | 0 Participants |
| Lenalidomide 15 mg | Number of Participants With Treatment-emergent Adverse Events | Treatment-related adverse events (TRAE) | 32 Participants |
| Lenalidomide 15 mg | Number of Participants With Treatment-emergent Adverse Events | Treatment-related serious adverse events | 20 Participants |
| Lenalidomide 15 mg | Number of Participants With Treatment-emergent Adverse Events | Grade 5 adverse events | 3 Participants |
| Lenalidomide 15 mg | Number of Participants With Treatment-emergent Adverse Events | AE leading to study drug interruption & reduction | 19 Participants |
Secondary
Kaplan-Meier Estimate of Duration of Response
Duration of response (DOR) was defined as the time from the first visit where PR, CRi, or CR was documented to progressive disease (PD). Duration of response was censored at the last date that the participant was known to be progression-free for participants who had not progressed at the time of analysis or who withdrew consent or were lost to follow-up prior to documentation of progression.
Time frame: Response was assessed after 3 cycles of therapy (Week 12) and every 4 weeks thereafter until disease progression. Maximum time on study was 91 months.
Population: Randomized participants with an objective response (CR/CRi or PR)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenalidomide 5 mg | Kaplan-Meier Estimate of Duration of Response | 101.1 weeks |
| Lenalidomide 10 mg | Kaplan-Meier Estimate of Duration of Response | 35.1 weeks |
| Lenalidomide 15 mg | Kaplan-Meier Estimate of Duration of Response | 88.8 weeks |
Secondary
Kaplan-Meier Estimate of Event-Free Survival
Event-free survival (EFS) is the interval between the start of treatment to the first sign of disease progression, or treatment for relapse or death (whichever occurred first). If withdrawal of consent or loss 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 until the end of the study; maximum time on study was 91 months.
Population: All randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenalidomide 5 mg | Kaplan-Meier Estimate of Event-Free Survival | 25.6 weeks |
| Lenalidomide 10 mg | Kaplan-Meier Estimate of Event-Free Survival | 31.9 weeks |
| Lenalidomide 15 mg | Kaplan-Meier Estimate of Event-Free Survival | 24.1 weeks |
Secondary
Kaplan-Meier Estimate of Overall Survival
Overall survival (OS) was defined as the time from randomization to death from any cause. Overall survival was censored at the last date that the participant was known to be alive for participants who were alive at the time of analysis and for participants who had withdrawn consent or were lost to follow-up before death was documented.
Time frame: From randomization until the end of the study; maximum time on study was 91 months.
Population: All randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenalidomide 5 mg | Kaplan-Meier Estimate of Overall Survival | 161.0 weeks |
| Lenalidomide 10 mg | Kaplan-Meier Estimate of Overall Survival | 106.7 weeks |
| Lenalidomide 15 mg | Kaplan-Meier Estimate of Overall Survival | 154.6 weeks |
Secondary
Kaplan-Meier Estimate of Progression Free Survival
Progression-free survival (PFS) was calculated as the time from randomization to the first documented progression or death due to any cause during or after the treatment period, whichever occurred first. The progression date was assigned to the earliest time when any progression is observed without prior missing assessments. If withdrawal of consent or loss 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 until the end of the study; maximum time on study was 91 months.
Population: All randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenalidomide 5 mg | Kaplan-Meier Estimate of Progression Free Survival | 31.4 weeks |
| Lenalidomide 10 mg | Kaplan-Meier Estimate of Progression Free Survival | 45.1 weeks |
| Lenalidomide 15 mg | Kaplan-Meier Estimate of Progression Free Survival | 66.3 weeks |
Secondary
Kaplan-Meier Estimate of Time to Progression
Time to progression (TTP) was defined as the time from randomization to the first documented progression. For participants who did not progress during the study, TTP was censored at the last adequate response assessment showing evidence of no disease progression.
Time frame: From randomization until the end of the study; maximum time on study was 91 months.
Population: All randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenalidomide 5 mg | Kaplan-Meier Estimate of Time to Progression | 96.3 weeks |
| Lenalidomide 10 mg | Kaplan-Meier Estimate of Time to Progression | 47.6 weeks |
| Lenalidomide 15 mg | Kaplan-Meier Estimate of Time to Progression | 66.3 weeks |
Secondary
Overall Response Rate (ORR)
ORR was defined as the percentage of patients with a complete response (CR), CR with incomplete bone marrow (BM) recovery (CRi) or partial response (PR) during treatment. Response was assessed according to the 2008 International Workshop on Chronic Lymphocytic Leukemia (iwCLL) guidelines. Per the guidelines, a CR required peripheral blood lymphocytes below 4 x 10\^9/L, absence of lymphadenopathy, no hepatomegaly or splenomegaly, absence of disease and blood counts neutrophils \>1.5 x 10\^9/L, platelets \>100 x 10\^9/L, hemoglobin (hgb) \>11g/dL) and BM at least normocellular for age. CRi = CR with incomplete BM recovery. PR = required at least 2 months from end of treatment, a ≥50% decrease in peripheral blood lymphocyte count from the pre-treatment value and either a ≥ 50% reduction in lymphadenopathy or ≥50% reduction of liver enlargement or ≥50% reduction of spleen enlargement plus neutrophils \>1.5 x 10\^9/ or ≥50% increase, platelets \>100 x 10\^9/L or ≥50% increase, hgb 11 g/dL.
Time frame: Response was assessed after 3 cycles of therapy (Week 12) and every 4 weeks thereafter until disease progression. Maximum time on study was 91 months.
Population: All randomized participants (intent-to-treat population)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lenalidomide 5 mg | Overall Response Rate (ORR) | 47.1 percentage of participants |
| Lenalidomide 10 mg | Overall Response Rate (ORR) | 37.1 percentage of participants |
| Lenalidomide 15 mg | Overall Response Rate (ORR) | 40.0 percentage of participants |
Secondary
Time to Response
Time to response (TTR) was calculated as the time from randomization to the first documented date of response (PR, CRi or CR) based on iwCLL guidelines for participants with an objective response during the treatment period.
Time frame: Response was assessed after 3 cycles of therapy (Week 12) and every 4 weeks thereafter until disease progression. Maximum time on study was 91 months.
Population: Randomized participants with an objective response (CR/CRi or PR)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenalidomide 5 mg | Time to Response | 16.9 weeks |
| Lenalidomide 10 mg | Time to Response | 12.6 weeks |
| Lenalidomide 15 mg | Time to Response | 12.7 weeks |