E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
|
E.1.1.1 | Medical condition in easily understood language |
|
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 | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10061275 |
E.1.2 | Term | Mantle 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 of the trial is to evaluate whether the addition of lenalidomide to rituximab-maintenance improves progression free survival (PFS) compared to standard rituximab maintenance after response to induction chemotherapy in older patients with mantle cell lymphoma not suitable for autologous stem cell transplantation |
|
E.2.2 | Secondary objectives of the trial |
The secondary efficacy objectives are: • to compare efficacy and safety of the maintenance regimens in terms of secondary endpoints • to evaluate whether the introduction of cytarabine into induction improves clinical outcome compared to standard R-CHOP in older patients with mantle cell lymphoma not suitable for autologous stem cell transplantation
|
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
The principle inclusion criteria are:
• signed informed consent form • Biopsy-proven mantle cell lymphoma according to WHO classification, including evidence of cyclin D1 overexpression or the translocation t(11;14)(q13;q32), • ≥ 60 years of age and ineligible for autologous transplant • Ann Arbor stage II-IV • previously untreated (except for patients randomized directly for maintenance treatment who will receive 8 RCHOP before registration in the trial) • ECOG performance status ≤ 2 • Male subjects must: - agree to use a condom during sexual contact with a woman of childbearing potential, even if they have had a vasectomy, throughout lenalidomide therapy - agree to not donate semen during lenalidomide therapy. • All subjects must: - have an understanding that the lenalidomide could have a potential teratogenic risk. - agree to abstain from donating blood while taking lenalidomide therapy - agree not to share study medication with another person. - be counselled about pregnancy precautions and risks of foetal exposure.
Additional inclusion criteria for randomization in maintenance phase :
- CR, CRu or PR after induction treatment, determined as per Cheson 1999 criteria by investigator - During the run-in period of 6 months starting from the date of the first patient randomized in the trial: in case of direct randomization into maintenance phase, patient must have been treated in first line by 6-8 cycles of R-CHOP.
|
|
E.4 | Principal exclusion criteria |
The principle exclusion criteria are:
• Female of child-bearing potential (without natural menopause for at least 24 consecutive months, a hysterectomy or bilateral oophorectomy) • Any of the following laboratory abnormalities, if not related to lymphoma: - Absolute neutrophils count (ANC) <1,000 /mm3 (1.0 x 109/L) if not result of a BM infiltration. - Platelet counts < 75,000/mm3 (75 x 109/L) if not result of a BM infiltration. - Serum aspartate transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT) >3.0 x upper limit of normal (ULN). - Serum total bilirubin > 1.5 ULN (except if due to Gilbert’s syndrome) • Calculated creatinine clearance (Cockcroft-Gault formula or MDRD) < 30 mL /min. • Central nervous system involvement by lymphoma • Contraindication for medicamentous DVT prophylaxis for patients at high risk for DVT • Prior history of malignancies other than MCL unless the subject has been free of the disease for ≥ 5 years (Exceptions: Basal or squamous cell carcinoma of the skin, Carcinoma in situ of the cervix or of the breast, Incidental histologic finding of prostate cancer (TNM stage of T1a or T1b). • Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the patient to receive the study medication as planned. • Poor cardiac function (LVEF < 50%) on echocardiography • Seropositivity for human immunodeficiency virus (HIV, mandatory test) Seropositivity for hepatitis C virus (HCV, mandatory test), Active viral infection with hepatitis B virus (HBV, mandatory test): - HBsAg positive - HBsAg negative, anti-HBs positive and anti-HBc positive Patients with prior Hepatitis B must be given antiviral prophylaxis and HBV DNA monitored Note: Patients who are HBsAg negative, anti-HBs positive and/or anti- HBc positive but viral DNA negative are eligible. • Uncontrolled illness including, but not limited to: - Active infection requiring parenteral antibiotics - Uncontrolled diabetes mellitus - Chronic symptomatic congestive heart failure (Class NYHA III or IV). - Unstable angina pectoris, angioplasty, stenting, or myocardial infarction within 6 months - Clinically significant cardiac arrhythmia that is symptomatic or requires treatment, or asymptomatic sustained ventricular tachycardia. • Prior ≥ Grade 3 allergic hypersensitivity to thalidomide. • Prior ≥ Grade 3 rash or any desquamating (blistering) rash while taking thalidomide. • Subjects with ≥ Grade 2 neuropathy. • Known anti-murine antibody (HAMA) reactivity or known hypersensitivity to murine antibodies • Prior use of lenalidomide. • Participation in another clinical trial within three weeks before randomization in this study.
Additional exclusion criteria for randomization in maintenance phase:
- SD or PD after induction treatment determined as per Cheson 1999 criteria assessed by investigator. - Patients who had not received at least 6 cycles of R-CHOP21 or 2 cycles of R-CHOP21 / 2 cycles of R-HAD28 (alternating) - Patients with serious underlying medical conditions, which could impair the ability to receive maintenance treatment - Calculated creatinine clearance (Cockcroft-Gault formula or MDRD) of < 30 mL /min at screening for maintenance. - ANC < 1,000 cells/mm³ (1.0 X 109/L) at screening for maintenance; - Platelet count < 50,000 cells/mm³ (50 X 109/L) at screening for maintenance. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
progression free survival (PFS). |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
From randomization for maintenance to progression or death from any cause. Tumor assessment (clinical examination, laboratory tests, CT scan, bone marrow examination) will be performed at baseline, at the end of induction and of maintenance and every 6 months during maintenance and follow-up period. |
|
E.5.2 | Secondary end point(s) |
• Time to event : - overall survival from induction randomization to death from any cause - overall survival from maintenance randomization to death from any cause - time to treatment failure, progression-free survival from induction randomization, remission duration • PR/CRu to CR and PR to CRu conversion during maintenance • Minimal residual disease (MRD) status and levels in peripheral blood and bone marrow at midterm and at the end of induction, after one and two years from end of induction and during follow-up until progression or up to 2.5 years of follow-up whichever comes first • complete and overall response rates (based on Cheson 1999 criteria) at midterm and end of induction, • safety according to NCI CTCAE (v 4.0) • secondary primary malignancies rates after lenalidomide vs. no lenalidomide • Exploratory : response assessment according to Cheson 2007 criteria including FDG-PET evaluation |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
• investigator-assessed progression free survival: from randomization for maintenance • overall survival: from first randomization to death from any cause • remission rates, time to treatment failure, remission duration: all duration of the study • minimal residual disease (MRD) levels: at end of induction, after one and two years of maintenance • safety according to NCI CTCAE (v 4.0): all duration of the study • PR to CR conversion: during maintenance • the rates of secondary neoplasias after lenalidomide vs. no lenalidomide: after starting maintenance treatment |
|
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 | 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) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 4 |
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 | 25 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 180 |
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
|
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 | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 8 |