| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Revlimid is indicated for maintenance therapy in high risk patients (age 18 or older) with CLL who have achieved partial or complete response following first line therapy and have either
MRD levels in the peripheral blood at final restaging of >10-2 or
≥10-4 - <10-2 combined with an unmutated IgVH-status or 17p-deletion or TP53 mutation |
|
| E.1.1.1 | Medical condition in easily understood language |
| patients (age 18 or older) with chronic lymphocytic leukemia receive daily lenalidomide tablets shortly after their first chemotherapy if they are in danger to have an early progess of the disease. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10008976 |
| E.1.2 | Term | Chronic lymphocytic leukemia |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | SOC |
| E.1.2 | Classification code | 10029104 |
| E.1.2 | Term | Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10008958 |
| E.1.2 | Term | Chronic lymphocytic leukaemia |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To compare the efficacy of lenalidomide versus placebo maintenance therapy.
|
|
| E.2.2 | Secondary objectives of the trial |
To demonstrate the prolongation of the overall survival (OS) and evaluate the safety of lenalidomide versus placebo maintenance therapy.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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 pentostatin/cyclophosphamid/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 leukemia1) following completion (minimum 4 cycles) of first-line induction therapy prior to randomization (documentation of response status must be available).
and have either:
a. MRD levels in the peripheral blood at final restaging of ≥10-2 or
b. 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 mutation
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 randomization.
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 ≤2.
10. Negative serological Hepatitis B test or negative PCR in case of positive serological test without evidence of an active infection, negative testing of Hepatitis C RNA, negative HIV test within 6 weeks prior to randomization.
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, two reliable forms of effective contraception simultaneously to achieve a PEARL-Index <1 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 study therapy.
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 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.
• Be counseled about pregnancy precautions and risks of fetal exposure.
14. Willingness to inform the general practicioner |
|
| E.4 | Principal exclusion criteria |
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:
a. Basal cell carcinoma of the skin
b. Squamous cell carcinoma of the skin
c. Carcinoma in situ of the cervix
d. Carcinoma in situ of the breast
e. 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:
14. Calculated (method of Cockroft-Gault) creatinine clearance of <60 mL/min
15. Absolute neutrophil count (ANC) < 1,000/μL (1.0 X 109/L)
16. Platelet count < 50,000/μL (50 X 109/L)
17. 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)
18. Serum total bilirubin > 2.0 mg/dL (with the exception of Gilbert’s Syndrome)
19. Uncontrolled hyperthyroidism or hypothyroidism.
20. Venous thromboembolism within one year.
21. ≥ Grade-2 neuropathy.
22. Uncontrolled autoimmune hemolytic anemia or thrombocytopenia.
23. Disease transformation (active) (i.e. Richter’s Syndrome, prolymphocytic leukemia).
24. Known allergy to allopurinol, if the subject has bulky disease
25. Prisoners or subjects who are institutionalized by regulatory or court order or persons who are in dependence to the sponsor or an investigator. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary
• Progression-Free Survival (PFS)
The primary efficacy objective of this study is to demonstrate superiority of lenalidomide over placebo in prolonging Progression-Free Survival (PFS) due to continued therapy, for subjects who have achieved MRD+ partial response or MRD positive complete response following first-line treatment. In addition, it is anticipated that some subjects entering the study, randomized to the lenalidomide arm, will further improve the quality of their response over the first year of treatment in contrast to the subjects randomized into the placebo arm. All subjects, including those subjects who do not improve their response will be treated up to disease progression with lenalidomide maintenance therapy with the objective to demonstrate prolongation of PFS. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
when the total number of 118 events over both treatment arms occurred after approximately 60 months.
The recruitment goal of 200 planned patients might not be reached due to significant lower recruitment rates as planned. Until March 2016, it is assumed to randomize 90 patients approximately. Thus, it would not be possible to perform the planned final analysis after 113 PFS events, so that the study would not be analyzable at the end of recruitment.
Therefore, it was decided to subsequently revise the initial design according to a group sequential design including two interim analyses and one final analysis. Moreover, a revised recruitment rate consisting of two periods was taken into account resulting in a total of 118 PFS events needed instead of 113 beeing observed in 200 patients.
|
|
| E.5.2 | Secondary end point(s) |
• Overall Survival (OS)
• Time to Progression (TTP)
• Safety [type, frequency, and severity of adverse events (AEs) and relationship of AEs to lenalidomide]
• Tumor Response, including evaluation of minimal residual disease (MRD) by flow cytometry (improvement of the quality of response)
• Change in tumor response
• Duration of improved response
• Health-Related Quality of Life by EORTC QLQ C30 and EQ-5D
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| when the total number of 118 events over both treatment arms occurred after approximately 60 months |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.5.1 | Number of sites anticipated in the EEA | 200 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| 60 months from randomization of first patient |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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