| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Diffuse Large B Cell Lymphoma |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10012818 |
| E.1.2 | Term | Diffuse large B-cell lymphoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| 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 |
| The primary objective is to determine the benefit estimated by the progression-free survival associated with lenalidomide maintenance compared to placebo in responding patients treated with R-CHOP for diffuse large B-cell lymphoma. |
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives are to assess:
• percentage of patients who convert from PR to CR
• efficacy according to the response to R-CHOP
• Overall survival in both groups of patients (with and without lenalidomide maintenance)
• The safety of lenalidomide in maintenance
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
For patients registered at the time of initial diagnosis:
• Patient with histologically proven CD20+ diffuse large B-cell lymphoma (DLBCL) (WHO classification 2008) including clinical subtypes (primitive mediastinal, intravascular, etc.). Patients with De Novo Transformed DLBCL from low grade lymphoma (Follicular, other..) may also be included. Patients with DLBCL associated with some small cell infiltration in bone marrow may also be included
- Or CD20+ B-cell lymphoma with intermediate features between DLBCL and Burkitt or with intermediate features between DLBCL and classical Hodgkin lymphoma
- Or CD20+ Follicular lymphoma grade 3B
- Or CD20+ Agressive B-cell lymphoma unclassifiable
• Previously untreated with chemo- or radiotherapy
For patients registered after response evaluation to first line treatment with R-CHOP:
• Patient with histologically proven CD20+ diffuse large B-cell lymphoma (DLBCL) (WHO classification 2008) including clinical subtypes (primitive mediastinal, intravascular, etc.). Patients with De Novo Transformed DLBCL from low grade lymphoma (Follicular, other...) may also be included. Patients with DLBCL associated with some small cell infiltration in bone marrow may also be included
- Or CD20+ B-cell lymphoma with intermediate features between DLBCL and Burkitt or with intermediate features between DLBCL and classical Hodgkin lymphoma
- Or CD20+ Follicular lymphoma grade 3B
- Or CD20+ Agressive B-cell lymphoma unclassifiable
• Have reached a CR or PR (Cheson 2007) after first line treatment with at least 6 cycles of R-CHOP-14 regimens and up to 8 cycles of R-CHOP-21
• Previously untreated with Radiotherapy
For all patients:
• Aged from 60 to 80 years at time of registration
• Ann Arbor stages II-IV at time of initial diagnosis
• aaIPI ≥ 1 at time of initial diagnosis
• Eastern Cooperative Oncology Group [ECOG] performance status 0-2
• Minimum life expectancy of 3 months
• Voluntary signed informed consent before performance of any study related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
• The following laboratory values at screening
Absolute neutrophil count (ANC) ≥ 1 000.106/L and Platelets ≥ 60 000.106/L, unless these abnormalities are related to bone marrow infiltration.
Aspartate transaminase (AST) ≤ 5 x ULN; Alanine transaminase (ALT) ≤ 5 x ULN; Total bilirubin ≤ 1.5 x ULN;
Creatinine clearance > 30 ml/min (as calculated by the Cockcroft-Gault formula)
• Females of childbearing potential (FCBP)† must:
Have a negative medically supervised pregnancy test 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 patient 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, 28 days prior to starting study drug, during the study therapy (including dose interruptions), and for 28 days after discontinuation of study therapy.
• Male patients 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 or sperm during study drug therapy and for a period after end of study drug therapy (see specifics.
• All patients 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. |
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| E.4 | Principal exclusion criteria |
For all patients:
• Any other histological type of lymphoma, Burkitt included.
• Any history of treated or non-treated small B-cell lymphoma
• Central nervous system or meningeal involvement by lymphoma
• Contraindication to any drug contained in the chemotherapy regimen For example: “cardiac contra-indication to anthracyclines (alteration of Left Ventricular Function defined by LVEF<50%) neurological contra-indication to vincristine (peripheral neuropathy of WHO grade ≥ 2).
• Myocardial infarction during last 3 months or unstable coronary disease or uncontrolled chronic symptomatic congestive heart insufficiency NYHA III - IV
• Uncontrolled hypertension
• Uncontrolled diabetes mellitus as defined by the investigator
• Active systemic infection requiring treatment.
• Previously known HIV positive serology
• Active hepatitis B or C
• Prior history of malignancies other than lymphoma within 3 years (except for complete resection of basal cell carcinoma, squamous cell carcinoma of the skin, or in situ malignancy. Patients previously diagnosed with prostate cancer are eligible if (1) their disease was T1-T2a, N0, M0, with a Gleason score ≤ 7, and a prostate specific antigen (PSA) ≤ 10 ng/mL prior to initial therapy, (2) they had definitive curative therapy (ie, prostatectomy or radiotherapy) ≥ 2 years before Day 1 of Cycle 1, and (3) at a minimum 2 years following therapy they had no clinical evidence of prostate cancer, and their PSA was undetectable if they underwent prostatectomy or <1 ng/mL if they did not undergo prostatectomy.
• Serious medical or psychiatric illness likely to interfere with participation in this clinical study.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is the progression-free survival (PFS) associated with lenalidomide maintenance compared to placebo in responding patients treated with R-CHOP for diffuse large B cell lymphoma.
PFS will be measured from the date of randomization to the date of first documented disease progression or death.Progression data will be assigned to the earliest time when any progression is observed without prior missing assessments during the study up to the end of the follow up phase.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The approximate timing of the interim analysis is after 50% (144 events) of the total number of planned events (n=287).
The approximate schedule of the interim and final analyses will be 46 and 75 months after the first patient randomized, respectively.
Given that events rate during the study appeared to be lower than expected, a simulation of analyses timelines has been performed according to the blinded database. The approximate updated schedule of the interim and final analyses will be 59 months (June 2014) and 95 months (June 2017) after the first patient randomized or at the latest when the last patient into the study will finish follow up.
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| E.5.2 | Secondary end point(s) |
Secondary end points are:
-Overall survival (OS) in both groups of patients (lenalidomide or placebo)
-Event-Free Survival (EFS)
-Response rate at the end of maintenance treatment
-Percentage of patients who convert from PR (partial response) to CR (complete response)
-Safety of lenalidomide in maintenance
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
-OS :when 278 deaths have been observed or at least when the number of events for PFS (287) has been reached or at the latest when the last patient into the study will finish follow up
-EFS :when the number of events for PFS (287) has been reached
-Response rate at the end of maintenance will be set when the number of events for PFS (287) has been reached.
-Percentage of patients who were in PR at the end of induction treatment and who were in CR at the end of maintenance treatment will be set when the number of events for PFS (287) has been reached
-safety of lenalidomide in maintenance is from randomization of the first patient to 5 years after the randomization of the last patient. Will be set when the last patient into the study will finish follow up
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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 | 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 | 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 | 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 | Yes |
| 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
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 138 |
| 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 |
| Israel |
| Switzerland |
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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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| The end of the trial is defined as : "the last visit of the last subject undergoing the trial". |
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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 | 7 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 9 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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