| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Diffuse Large B Cell Lymphoma |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 21.0 |
| 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) |
|
| 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. |
|
| 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
|
|
| 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 andfor
a period after end of study drug therapy
• 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. |
|
| 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
contraindication
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. |
|
| 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. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The final PFS analysis will be realized when a total of 160 progression/death has been reached. The aproximate updated schedule of the final analysis will be 90 months (September 2016 after the first patient randomized). |
|
| 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)
-Progression Free Survival 2 (PFS 2): Time from randomization to objective tumor progression on next-line treatment or death from any cause
-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 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
OS, EFS and PFS2: interim analysis at the time of final analysis of PFS, final analysis at the study closure.
-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 final analysis for PFS will be done
-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 |
|
| 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 |
|
| 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
|
| The end of the trial is defined as : "the last visit of the last subject undergoing the trial". |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 8 |
| E.8.9.1 | In the Member State concerned months | 3 |
| 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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