CLLM1-Protocol of the German CLL-Study Group (GCLLSG) A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group Study of the Efficacy and Safety of Lenalidomide (Revlimid®) as Maintenance Therapy for High-risk Patients With Chronic Lymphocytic Leukemia Following First-line Therapy
1. Must understand and voluntarily sign an informed consent form.
2. Age ≥ 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 CLL (IWCLL guidelines for the diagnosis and
treatment of chronic lymphocytic leukemia1).
5. Must have been treated with one of the first line induction therapies:
fludarabine/cyclophosphamide/rituximab, or bendamustine/rituximab or
fludarabine/rituximab or fludarabine/cyclophosphamide,(in case of hypersensitivity
reactions to Rituximab).
6. Must have achieved a response of at least PR (IWCLL guidelines for the diagnosis and
treatment of chronic lymphocytic leukemia [Hallek, 2008]) following completion
(minimum 4 cycles) of first-line induction therapy prior to randomization
(documentation of response status must be available).
and have either:
- MRD levels in the peripheral blood at final restaging of ≥ 10-2 or
- MRD levels in the peripheral blood ≥ 10-4 - < 10-2 combined with at least one of
the following factors:
- an unmutated IGHV-status
- 17p-deletion or
- TP53 mutation1
7. Must have completed last cycle of at least 4 cycles of first-line induction no less
than 8 weeks (56 days) and no greater than 20 weeks (140 days) prior to
8. Subjects who completed first line induction treatment with less than 6 but at least 4
cycles should document reason for early discontinuation
9. Must have an Eastern Cooperative Oncology Group (ECOG) performance status score of ≤
10. Negative serological Hepatitis B test, negative testing of Hepatitis C RNA, negative
HIV test within 6 weeks prior to registration.
11. 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 intercourse (which must
be reviewed on a monthly basis) or agree to use, and be able to comply with,
effective contraception without interruption (Highly effective methods:
Intrauterine device (IUD), Hormonal (birth control pills, injections, implants),
Tubal ligation, Partner's vasectomy, Additional effective methods: Male condom,
Diaphragm, Cervical Cap), 28 days prior to starting study drug, during the study
therapy (including dose interruptions), and for 28 days after discontinuation of
12. Male subjects must:
- 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.
13. All subjects must:
- Have an understanding that the study drug could have a potential teratogenic
- 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.
- Be counseled about pregnancy precautions and risks of fetal exposure.
1. A CIRS Score of more than 6 or a single score of 4 for an organ system limiting the
ability to receive an intensive therapy for CLL
2. Active infections requiring systemic antibiotics.
3. Systemic infection CTC grade 3 or 4 that has not resolved > 2 months prior to
randomization in spite of adequate anti-infective therapy.
4. Autologous or allogeneic bone marrow transplant as first line therapy.
5. Pregnant or lactating females.
6. Systemic treatment for CLL in the interval between completing the last cycle of
first-line induction therapy and randomization.
7. Participation in any clinical study or having taken any investigational therapy which
would interfere with the study drug 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 (CNS) 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 histological finding of prostate cancer (TNM stage of T1a or T1b)
11. History of renal failure requiring dialysis.
12. Prior therapy with lenalidomide.
13. Any of the following laboratory abnormalities:
- Calculated (method of Cockroft-Gault) creatinine clearance of < 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)
14. Uncontrolled hyperthyroidism or hypothyroidism
15. Venous thromboembolism within one year
16. ≥ Grade-2 neuropathy
17. Uncontrolled autoimmune hemolytic anemia or thrombocytopenia
18. Disease transformation (active) (i.e. Richter's Syndrome, prolymphocytic leukemia)
19. Known allergy to allopurinol, if the subject has bulky disease
20. Prisoners or subjects who are institutionalized by regulatory or court order