| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| stage II-IV follicular lymphoma grade 1-3a not previously treated |
| lymphome folliculaire grade 1 à 3a, de stade II à IV non antérieurement traité |
|
| E.1.1.1 | Medical condition in easily understood language |
| follicular lymphoma in need of treatment |
| lymphome folliculaire nécessitant un traitement |
|
| 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 | PT |
| E.1.2 | Classification code | 10016908 |
| E.1.2 | Term | Follicle centre lymphoma, follicular grade I, II, III stage II |
| 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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10016910 |
| E.1.2 | Term | Follicle centre lymphoma, follicular grade I, II, III stage IV |
| 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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10016909 |
| E.1.2 | Term | Follicle centre lymphoma, follicular grade I, II, III stage III |
| 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 of the study is to compare the efficacy of rituximab plus lenalidomide to rituximab plus chemotherapy followed by rituximab in patients with previously untreated follicular lymphoma. Efficacy determination will be based upon the co-primary endpoints of complete response (CR/CRu) rate at 120 weeks and PFS assessed by the IRC using the IWG (Cheson, 1999) criteria. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are:
To compare the efficacy of rituximab plus lenalidomide versus rituximab
plus chemotherapy followed by rituximab using other parameters of
efficacy:
o Complete Response (CR) at 120 weeks by IWG 1999, Event
Free Survival (EFS) by IWG 1999, Time to Next Anti-Lymphoma
Treatment (TTNLT), and Overall Survival (OS).
To compare the safety of rituximab plus lenalidomide versus rituximab
plus chemotherapy followed by rituximab |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
The exploratory objectives of the study are:
• CR rate at 120 weeks, Overall Response Rate at 120 weeks by IWG 1999 Criteria and PFS by 2007 Revised Response Criteria for
Malignant Lymphoma incorporating FDG-PET (Cheson, 2007)
• Time to Treatment Failure (TTF)
• Time to Next Chemotherapy Treatment (TTNCT)
• Histological transformation rate at first progression
• To explore the relationship between lenalidomide exposure and
response (hematology, biomarkers, and other clinical outcomes as
appropriate).
• To compare the effects of rituximab plus lenalidomide versus
rituximab plus chemotherapy followed by rituximab on minimal residual
disease using PCR detection of the t(14;18) translocation in peripheral
blood or other MRD assays.
• To compare the effects of rituximab plus lenalidomide versus
rituximab plus chemotherapy followed by rituximab on immune
competence
• Evaluate Fc-gamma receptor polymorphisms in blood samples
collected pre-treatment and correlate with clinical outcomes
• To investigate potential predictive biomarkers of clinical response or
resistance to rituximab plus lenalidomide, including, but not limited to,
gene expression, analysis of acquired chromosomal aberrations
(translocations, gains, deletions, single nucleotide polymorphisms,
mutations), microRNA and protein expression in archival diagnostic or
fresh tumor samples
• Health related quality of life as measured by the EORTC QLQ-C30
To examine utility during the active, maintenance, and follow-up phases
using the EQ-5D for the purpose of collecting information on the
treatment regimens to support cost-effectiveness analyses and
modeling. |
|
| E.3 | Principal inclusion criteria |
-Histologically confirmed CD20+ follicular lymphoma grade 1, 2 or 3a
-Have no prior systemic treatment for lymphoma.
-Must be in need of treatment
-Bi-dimensionally measurable disease with at least one mass lesion > 2 cm that was not previously irradiated.
-Stage II, III or IV disease.
-Must be ≥ 18 years and sign an informed consent.
-Performance status ≤ 2 on the ECOG scale.
-Adequate hematological function
-Females of childbearing potential (FCBP) receiving lenalidomide must
have two negative pregnancy tests . She must agree to ongoing pregnancy testing during the course of the study, and after end of study
therapy.
-Male patients receiving lenalidomide must practice complete abstinence or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 28 days following study drug
discontinuation
-All patients receiving lenalidomide must have an understanding that the
study drug could have a potential teratogenic risk.
-For all patients receiving Rituximab Women must not breast feed and
must use effective contraception must not be pregnant and agree not to become pregnant during participation in the trial and during the 6 months thereafter. Men must agree not to father a child during
participation in the trial and during the 6 months thereafter. |
|
| E.4 | Principal exclusion criteria |
-Clinical evidence of transformed lymphoma by investigator assessment
-Grade 3b follicular lymphoma
-Patients taking corticosteroids during the last 4 weeks
-Major surgery within 28 days prior to signing informed consent
-Seropositive for or active viral infection with hepatitis B virus (HBV)
-Known seropositive for, or active infection hepatitis C virus (HCV)
-Known seropositive for, or active viral infection with HIV
-Life expectancy < 6 months
-Known sensitivity or allergy to murine products
-Prior history of malignancies, unless the subject has been free of the
disease for ≥ 10 years. Exceptions include a history of previously treated Localized non-melanoma skin cancer or Carcinoma in situ of the cervix
-Prior use of lenalidomide
-Neuropathy > Grade 1
-Presence or history of CNS involvement by lymphoma
-Patients who are at a high risk for a thromboembolic event and are not
willing to take venous thromboembolic (VTE) prophylaxis
-Uncontrolled intercurrent illness
-Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form.
-Pregnant or lactating females
-Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study, or which confounds the ability to interpret data from the study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The tumor response data will be assessed by the IRC using the IWG ( Cheson 1999) criteria. Based on the CT/MRI schedule, any assessments in a time window of 120 weeks +/-4 weeks are qualified as the 120 weeks assessments. If two of more assessments are performed in this time window, the assessment wtih the least favorable response will be used. PFS is an accepted endpoint of clinical benefit for previously untreated FL patient and was the basis for the recent approval of rituximab maintenance in this population ( Salles 2011). The disease progression status will be assessed by IRC using the IWG (cheson 1999) criteria.
PFS is defined as the time from randomization into the study to the first observation of documented disease progression or death due to any cause. If a subject has not progressed or died, PFS will be censored at the time of laste visit with adequate assessement. if a subject received other anti-cancer treatment for follicular lymphoma before progression, the CT/MRI assessments should continue as scheduled until disease progression or death which will be counted as events. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
(CR/CRu) rate at 120 weeks
- First interim analysis when the first 200 patients have their response
assessment done at 6 months
- Second interim analysis when the first 200 patients have their
response assessment done at 120 weeks
- Primary analysis will be performed when all randomized patients have
their response assessment done at 120 weeks
PFS:
- interim analysis at the time-point when the co-primary endpoint
CR/CRu rate at 120 weeks is reported, i.e. when all randomized patients
have their response assessment done at 120 weeks
- final analysis at the time-point when the required 456
progression/relapse/death events have occurred among all randomized
patients or at the latest up when 9.5 years of median follow-up have been reached, whichever occurs first |
|
| E.5.2 | Secondary end point(s) |
•Complete Response (CR)
•Event Free Survival (EFS)
•Time to Next Anti-Lymphoma Treatment (TTNLT),
•Overall Survival (OS) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
(CR) at 120 weeks
(EFS) will be measured from the date of randomization to the date of
first documented progression, relapse, and initiation of a new antilymphoma treatment or death by any cause.
(TTNLT) will be measured from the date of randomization to the date of
first documented administration of any new anti-lymphoma treatment
(chemotherapy, radiotherapy, radio-immunotherapy, immunotherapy).
(OS) will be measured from date of randomization to the date of death.
Patients who die, regardless of the cause of death, will be considered to
have had an event. Patients who withdraw consent for the study will be
considered censored at the time of withdrawal. |
|
| 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 | Yes |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| 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 | 18 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 120 |
| 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 |
| Canada |
| Belgium |
| France |
| Germany |
| Italy |
| Portugal |
| Spain |
|
| 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
|
| 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 | 13 |
| 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 | 13 |
| 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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