B-cell Chronic Lymphocytic Leukemia
Conditions
Brief summary
The purpose of this study is to determine if lenalidomide (Revlimid®) is safe and effective as a maintenance therapy at improving further the quality of the response you achieved with your last therapy and at prolonging the duration of your response. This study will compare the effects (good and bad) of lenalidomide with the dummy drug.
Detailed description
This is a phase 3, randomized (computer assigned by chance to treatment arm), study being completed an multiple sites to compare the safety and efficacy (how well a drug works) of lenalidomide maintenance therapy to placebo (dummy capsule that contains no lenalidomide or active substances) maintenance therapy. Patients are assigned by a computer with a 50/50 chance to receive placebo or lenalidomide study treatment. Study drug will be taken once each day until the patient discontinues the study. Patients will remain on study drug until progression of disease. Patients will visit their study doctor every 28 days until disease progression to complete safety and efficacy assessments. Quality of life assessments will be completed every other month. If a patient who discontinue study drug prior to disease progression (i.e. due to an adverse reaction to the study drug), they will continue to visit the study doctor each month to complete the efficacy assessments up to progression of disease. Safety assessments may include laboratory blood tests, ECG tests and questions about any medical conditions or side effects experienced during the study. Efficacy assessments may include laboratory blood tests and focused physical exams. Computed tomography (CT) scans along with blood tests and bone marrow samples will be collected to confirm if a patient has improvement of response while on study. After disease progression, patients will be contacted every 12 weeks for survival information, next CLL treatments and quality of life questions. Subjects currently on lenalidomide treatment will discontinue lenalidomide treatment immediately and complete the Treatment Discontinuation assessment. The subjects will then transition to the survival follow-up period.
Interventions
DRUGLenalidomide
Lenalidomide capsules given orally on days 1-28 of a 28 day cycle
DRUGPlacebo
Placebo capsules given orally on days 1 - 28 of a 28 day cycle
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
1. Must understand and voluntarily sign an informed consent form. 2. Must be greater than or equal to 18 years at the time of signing the informed consent form. 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 (IWCLL guidelines for the diagnosis and treatment of chronic lymphocytic leukemia \[Hallek, 2008\]). 5. Must have been treated with one of the following in first and/or second line: * a purine analog-containing regimen * a bendamustine-containing regimen * an anti-CD20 antibody-containing regimen * a chlorambucil-containing regimen * an alemtuzumab-containing regimen (for those subjects with a 17p deletion) 6. Must have achieved a minimum response of partial response (PR, nPR, CRi, CR, and MRD-negative CR) (IWCLL guidelines for the diagnosis and treatment of chronic lymphocytic leukemia \[Hallek, 2008\]) following completion of second-line induction therapy prior to randomization (documentation of response status must be available). Second-line induction therapy must be documented to have been of sufficient duration. 7. Must have completed last cycle of second-line induction no less than 8 weeks (56 days) and no greater than 20 weeks (140 days) prior to randomization. 8. Must have an ECOG performance status score of less than or equal to 2. 9. Females of childbearing potential (FCBP)† must: * Have two negative medically supervised pregnancy tests prior to starting of study therapy. She must agree to ongoing pregnancy testing during the course of the study, and after end of study therapy. This applies even if the subject practices complete and continued sexual abstinence. * Either commit to continued abstinence from heterosexual contact (which must be reviewed on a monthly basis) or agree to use, and be able to comply with, effective contraception without interruption, 28 days prior to starting study drug, during the study therapy (including dose interruptions), and for 28 days after discontinuation of study therapy. 10. Male subjects must: * Commit to continued abstinence from heterosexual contact or agree to use a condom during sexual contact with a FCBP, even if they have had a vasectomy, throughout study drug therapy, during any dose interruption and after cessation of study therapy. * Agree to not donate semen during study drug therapy and for a period after end of study drug therapy. 11. All subjects must: * Have an understanding that the study drug could have a potential teratogenic risk. * Agree to abstain from donating blood while taking study drug therapy and following discontinuation of study drug therapy. • Agree not to share study medication with another person. * All subjects must be counseled about pregnancy precautions and risks of fetal exposure.
Exclusion criteria
1. Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study. 2. Active infections requiring systemic antibiotics. 3. Systemic infection that has not resolved \> 2 months prior to initiating lenalidomide treatment in spite of adequate anti-infective therapy 4. Autologous or allogeneic bone marrow transplant as second-line therapy. 5. Pregnant or lactating females. 6. Systemic treatment for B-cell CLL in the interval between completing the last cycle of second-line induction therapy and randomization. 7. Participation in any clinical study or having taken any investigational therapy for a disease other than CLL within 28 days prior to initiating maintenance therapy. 8. Known presence of alcohol and/or drug abuse. 9. Central nervous system involvement as documented by spinal fluid cytology or imaging. Subjects who have signs or symptoms suggestive of leukemic meningitis or a history of leukemic meningitis must have a lumbar puncture procedure performed within two weeks prior to randomization. 10. Prior history of malignancies, other than CLL, unless the subject has been free of the disease for ≥5 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) 11. History of renal failure requiring dialysis. 12. Known Human Immunodeficiency Virus (HIV), active Hepatitis B Virus (HBV), and/or active Hepatitis C Virus (HCV) infection. 13. Prior therapy with lenalidomide. 14. Evidence of TLS per the Cairo-Bishop definition of laboratory TLS (subjects may be enrolled upon correction of electrolyte abnormalities). 15. Any of the following laboratory abnormalities: * Calculated (method of Cockroft-Gault) creatinine clearance \<60 mL/min. * Absolute neutrophil count (ANC) \<1,000/μL (1.0 X 109/L) * Platelet count \<50,000/μL (50 X 109/L) * Serum aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) or alanine transaminase (ALT)/serum glutamate pyruvate transaminase (SGPT) \> 3.0 x upper limit of normal (ULN) * Serum total bilirubin \>2.0 mg/dL (with the exception of Gilbert's Syndrome) 16. Grade 4 rash due to prior thalidomide treatment 17. Uncontrolled hyperthyroidism or hypothyroidism 18. Venous thromboembolism within one year 19. Greater than or equal to Grade-2 neuropathy 20. Uncontrolled autoimmune hemolytic anemia or thrombocytopenia 21. Disease transformation (active) (ie, Richter's Syndrome, prolymphocytic leukemia) 22. Known allergy to allopurinol for subjects assessed with PR following their second-line induction therapy. 23. Prisoners. 24. More than 2 prior lines of CLL therapy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Up to approximately 11 years | Overall Survival (OS) is defined as the time from randomization to death from any cause. OS will be 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 were lost to follow-up before death was documented. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival 2 (PFS2) | Up to 6 years | Progression Free Survival (PFS2) assessed by investigator is defined as the time from randomization to the second objective disease progression, or death from any cause, whichever occurs first. |
| Number of Participants With Adverse Events (AEs) | From first dose to 30 days post last dose (up to 9 years) | Number of participants with adverse events (AEs) that measure type, frequency and severity of AEs graded by National Cancer Institute Common Terminology Criteria (NCI CTCAE V 3.0) including any grade adverse events (AEs), Grade 3-4 AEs, AEs related to study drug, grade 3-4 AEs related to study drug. |
Countries
Australia, Austria, Belgium, Canada, Colombia, Czechia, Denmark, France, Germany, Hungary, Ireland, Israel, Italy, Mexico, Netherlands, New Zealand, Poland, Portugal, Romania, Russia, South Africa, Spain, Sweden, United Kingdom, United States
Participant flow
Pre-assignment details
317 randomized and 315 treated.
Participants by arm
| Arm | Count |
|---|---|
| Lenalidomide 2.5mg QD PO with escalation after 28 days to 5mg QD PO x 28 days, only if the 2.5mg dose was tolerated. Participants could be escalated to 10mg QD PO x 28 days, but only after 5 continuous cycles at 5mg and only if 5mg was well tolerated and if those participants had not achieved MRD-negative CR | 160 |
| Placebo 2.5mg QD PO with escalation after 28 days to 5mg QD PO x 28 days, only if the 2.5mg dose was tolerated. Participants could be escalated to 10mg QD PO x 28 days, but only after 5 continuous cycles at 5mg and only if 5mg was well tolerated and if those participants had not achieved MRD-negative CR | 157 |
| Total | 317 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Pre-treatment | Other reasons | 2 | 0 |
| Treatment | Adverse Event | 61 | 15 |
| Treatment | Death | 4 | 0 |
| Treatment | Lost to Follow-up | 1 | 1 |
| Treatment | Other Reasons | 32 | 26 |
| Treatment | Progressive Disease with histologic transformation | 4 | 2 |
| Treatment | Progressive Disease without histologic transformation | 51 | 111 |
| Treatment | Withdrawal by Subject | 5 | 2 |
Baseline characteristics
| Characteristic | Placebo | Total | Lenalidomide |
|---|---|---|---|
| Age, Continuous | 62.5 Years STANDARD_DEVIATION 8.85 | 62.7 Years STANDARD_DEVIATION 8.46 | 62.9 Years STANDARD_DEVIATION 8.08 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 7 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 156 Participants | 309 Participants | 153 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 5 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 5 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) White | 150 Participants | 304 Participants | 154 Participants |
| Sex: Female, Male Female | 44 Participants | 89 Participants | 45 Participants |
| Sex: Female, Male Male | 113 Participants | 228 Participants | 115 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 78 / 158 | 80 / 157 |
| other Total, other adverse events | 152 / 158 | 140 / 157 |
| serious Total, serious adverse events | 99 / 158 | 49 / 157 |
Outcome results
Primary
Overall Survival (OS)
Overall Survival (OS) is defined as the time from randomization to death from any cause. OS will be 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 were lost to follow-up before death was documented.
Time frame: Up to approximately 11 years
Population: All randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenalidomide | Overall Survival (OS) | 95.09 Months |
| Placebo | Overall Survival (OS) | 73.28 Months |
p-value: 0.27695% CI: [0.61, 1.15]Log Rank
Secondary
Number of Participants With Adverse Events (AEs)
Number of participants with adverse events (AEs) that measure type, frequency and severity of AEs graded by National Cancer Institute Common Terminology Criteria (NCI CTCAE V 3.0) including any grade adverse events (AEs), Grade 3-4 AEs, AEs related to study drug, grade 3-4 AEs related to study drug.
Time frame: From first dose to 30 days post last dose (up to 9 years)
Population: All treated participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lenalidomide | Number of Participants With Adverse Events (AEs) | Adverse Events (AEs) | 155 Participants |
| Lenalidomide | Number of Participants With Adverse Events (AEs) | Grade 3-4 AEs | 136 Participants |
| Lenalidomide | Number of Participants With Adverse Events (AEs) | AEs related to Study drugs | 143 Participants |
| Lenalidomide | Number of Participants With Adverse Events (AEs) | Grade 3-4 AEs related to Study drugs | 117 Participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Grade 3-4 AEs related to Study drugs | 41 Participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Adverse Events (AEs) | 149 Participants |
| Placebo | Number of Participants With Adverse Events (AEs) | AEs related to Study drugs | 98 Participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Grade 3-4 AEs | 73 Participants |
Secondary
Progression Free Survival 2 (PFS2)
Progression Free Survival (PFS2) assessed by investigator is defined as the time from randomization to the second objective disease progression, or death from any cause, whichever occurs first.
Time frame: Up to 6 years
Population: All randomized evaluable participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenalidomide | Progression Free Survival 2 (PFS2) | NA Months |
| Placebo | Progression Free Survival 2 (PFS2) | 35.9 Months |