E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Maintenance therapy in subjects with relapsed or refractory B-cell chronic lymphocytic leukemia (CLL) who have achieved at least partial response (PR) to second-line therapy. |
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E.1.1.1 | Medical condition in easily understood language |
Relapse or Refractory B-cell chronic lymphocytic leukemia (CLL) after a
second line therapy with at least a partial response |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10008978 |
E.1.2 | Term | Chronic lymphocytic leukemia refractory |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To compare the efficacy of lenalidomide versus placebo maintenance therapy. |
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E.2.2 | Secondary objectives of the trial |
To evaluate the safety of lenalidomide versus placebo maintenance therapy. |
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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.Must be ≥ 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] Appendix 22.4) 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 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. (see specifics in Appendix 22.10). 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 (see specifics in Appendix 22.10).
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 (See specifics in Appendix 22.9).
•Agree to not donate semen during study drug therapy and for a period after end of study drug therapy (see specifics in Appendix 22.10).
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 (See specifics in Appendix 22.10).
•Agree not to share study medication with another person.
•All subjects must be counseled about pregnancy precautions and risks of fetal exposure (See Appendix 22.10).
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E.4 | Principal 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 (Appendix 22.7) (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.≥ 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.
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E.5 End points |
E.5.1 | Primary end point(s) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Overall Survival [ Time Frame: 8 years ]
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E.5.2 | Secondary end point(s) |
Safety
Progression Free Survival 2 (PFS2) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Safety: ongoing
PFS: Time frame 6 years |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
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 | No |
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 | No |
E.8.1.1 | Randomised | Information not present in EudraCT |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
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) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 90 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Austria |
Canada |
Czech Republic |
Denmark |
France |
Hungary |
Ireland |
Israel |
Italy |
Netherlands |
New Zealand |
Poland |
Romania |
Russian Federation |
Spain |
Sweden |
United Kingdom |
United States |
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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
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LSLV - Subjects will be followed until all subjects in the study have been followed for at least 5 years from the last randomization, October 2020, (or have died/become lost to follow-up before the 5 years).
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. |
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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 |