| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with first relapsed/refractory mantle cell lymphoma (MCL) |
| Pazienti affetti da linfoma a cellule del mantello (MCL) in prima recidiva o refrattari |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with first relapsed/refractory mantle cell lymphoma (MCL) |
| Pazienti affetti da linfoma a cellule del mantello (MCL) in prima recidiva o refrattari |
|
| 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 | HLT |
| E.1.2 | Classification code | 10026798 |
| E.1.2 | Term | Mantle cell lymphomas |
| E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
|
| 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 |
| 1.To explore the antitumor activity of the association of R2-B in terms of complete response (CR) in patients with relapsed/refractory MCL to a first line of therapy. 2.To evaluate the efficacy of a maintenance treatment with Lenalidomide for 18 months from the end of R2-B (from month 7 to 24) for those responding (CR or PR) to the induction, in terms of progression free survival (maPFS). |
| 1.Esplorare l'attivita' antitumorale dell'associazione di R2-B in termini di risposta completa (CR); 2.Valutare l'efficacia del mantenimento con Lenalidomide per 18 mesi (dal mese 7 al mese 24) nei pazienti che rispondono (CR o PR) alla terapia di induzione e consolidamento, in termini di sopravvivenza libera da progressione (maPFS). |
|
| E.2.2 | Secondary objectives of the trial |
| 1.To evaluate the safety profile; 2.To evaluate the molecular response (MR); 3.To evaluate the overall response (OR); 4.To evaluate the effect of treatment on Progression Free Survival (PFS); 5.To evaluate the effect of treatment on Overall Survival (OS); 6.To estimate the cumulative incidence of second primary malignancies (hematological and not-hematological). |
| 1.Valutare il profilo di sicurezza; 2.Valutare la risposta molecolare (MR); 3.Valutare la risposta globale (OR); 4.Valutare l’effetto del trattamento sulla Progression Free Survival (PFS); 5.Valutare l’effetto del trattamento sulla Overall Survival (OS); 6.Valutare l’incidenza di neoplasie secondarie (ematologiche e non). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| 1-Patient has a diagnosis of MCL according to the WHO classification; 2-Patient age is ≥ 18 years; 3-Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2; 4-Understands and voluntarily signs an informed consent form; 5-Able to adhere to the study visit schedule and other protocol requirements; 6-Patients treated with one prior regimen and relapsed, or refractory to front line therapy; front line consolidation with autologous stem cell transplantation is considered to be part of first line therapy; 7-Patient has at least one site of measurable nodal disease at baseline ≥ 2.0 cm in the longest transverse diameter as determined by CT scan (MRI is allowed only if CT scan can not be performed). Note: Patients with bone marrow involvement are eligible; 8-Adequate haematological counts: ANC > 1.5 x 109/L and platelet count > 75 x 109/L unless due to bone marrow involvement by MCL; 9-Conjugated bilirubin up to 2 x ULN unless due to liver involvement by MCL; 10-Alkaline phosphatase and transaminases up to 2 x ULN unless due to liver involvement by MCL; 11-Creatinine clearance ≥ 30 ml/min; a dose reduction of Lenalidomide for patients with creatinine clearance ≥ 30 mL/min but < 50 mL/min is planned; 12-Written informed consent was obtained from the patient prior to any study-specific screening procedures; 13-Patient has the ability to swallow capsules or tablets; 14-Life expectancy ≥ 6 months; 15-Male and Female patients: accordance to comply with Lenalidomide Risk Management Plan for pregnancy prevention. |
| 1-Pazienti con diagnosi di MCL in base alla classificazione WHO; 2-Pazienti con eta' ≥ 18 anni; 3-Pazienti con ECOG performance status ≤ 2; 4-Firma del consenso informato scritto; 5-Capacita' di aderire al programma delle visite dello studio e agli altri requisiti dello studio; 6-Pazienti recidivati o refrattari alla terapia di prima linea; il consolidamento in prima linea con il trapianto autologo di cellule staminali e' considerata parte della terapia di prima linea. 7-Pazienti che al baseline hanno almeno un sito di malattia misurabile ≥ 2.0 cm nel diametro maggiore determinato con la TAC (RMN e' consentita solo se la TAC con puo' essere eseguita). Nota: i pazienti con coinvolgimento del midollo osseo sono ammissibili 8-Adeguata conta ematologica ANC > 1.5 x 109/L e conta piastrinica > 75 x 109/L tranne in caso di coinvolgimento del midollo osseo da MCL; 9-Bilirubina coniugata fino a 2 x ULN tranne in caso di coinvolgimento del fegato da MCL; 10-Fosfatasi alcalina e transaminasi fino a 2 x ULN tranne in caso di coinvolgimento del fegato da MCL; 11-Clearance della creatinina ≥ 30 ml/min; e' prevista una riduzione di Lenalidomide per pazienti con clearance della creatinina ≥ 30 mL/min ma < 50 mL/min; 12-Consenso informato scritto ottenuto dal paziente prima di qualsiasi procedura di screening prevista dallo studio; 13-Pazienti con capacita' di deglutire capsule o compresse; 14-Aspettativa di vita ≥ 6 mesi; 15-Per i pazienti di sesso maschile e femminile: volonta' di rispettare il piano di gestione del rischio di prevenzione della gravidanza durante il trattamento con Lenalidomide. |
|
| E.4 | Principal exclusion criteria |
| 1-Patients who have received an experimental drug or used an experimental medical device within 4 weeks before the planned start of treatment. Concurrent participation in nontreatment studies is allowed, if it will not interfere with participation in this study; 2-Patient has a history of CNS involvement with lymphoma; 3-Patients with previous history of malignancies (a part MCL) ≤ 3 before study accrual with the exception of currently treated basal cell and squamous cell carcinoma of the skin, or carcinoma “in situ” of the cervix; 4-History of clinically relevant liver or renal insufficiency; significant cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic, rheumatologic, hematologic, psychiatric, or metabolic disturbances; 5-Patient has any other concurrent severe and/or uncontrolled medical condition(s) (e.g., uncontrolled diabetes mellitus, active or uncontrolled infection) that could cause unacceptable safety risks or compromise compliance with the protocol; 6-Creatinine clearance < 30 ml/min; 7-Patient has a known history of HIV seropositivity; 8-Patient has active HBV hepatitis. The following categories of HBV positive patients but with non evidence of active hepatitis may be considered for the study and treated with R2-B (see also Section 8.1.8): - patient is HBsAg + with HBV DNA < 2000 UI/ml (inactive carriers); HBV DNA > 2000 UI/ml is criteria of exclusion; - patient is HBsAg – HBsAb +; - patient is HBsAg – but HBcAb + 9-Patients with HCV active hepatitis are excluded from the study. Patient with no evidence of active hepatitis and/or advanced chronic liver disease according to liver biopsy or fibro-scan evaluation may be included into the study (see also Section 8.1.9); 10-Patients have received previous treatment with either Bendamustine and/or Lenalidomide. |
| 1-I pazienti che hanno ricevuto un farmaco sperimentale o utilizzato un dispositivo medico sperimentale nelle 4 settimane precedenti l'inizio previsto del trattamento. La partecipazione simultanea ad altri studi che non prevedono una fase di trattamento e' consentita, se non interferira' con la partecipazione in questo studio; 2-Pazienti con una storia di coinvolgimento del CNS con linfoma; 3-Pazienti con anamnesi positiva per una seconda neoplasia ≤ 3 anni prima dell’arruolamento, escluse neoplasie cutanee diverse dal melanoma e il carcinoma in situ della cervice uterina. 4-Storia di insufficienza renale o epatica clinicamente significativa; patologie cardiache, vascolari, polmonari, gastrointestianali, endocrine, neurologiche, reumatologiche, ematologiche, psichiatriche clinicamente significative o disturbi metabolici. 5-Presenza di altre severe e incontrollate patologie (ad esempio: diabete mellito non controllato, infezioni attive o non controllate) che potrebbero causare inaccettabili rischi per la sicurezza o compromettere la conformita' al protocollo; 6-Clearance della creatinina < 30 ml/min; 7-Pazienti con una storia di HIV sieropositivita'; 8-Pazienti con epatite da HBV attiva. Le seguenti categorie di pazienti HBV positivi che non hanno evidenza di epatite attiva possono essere considerati per lo studio e trattati con R2-B (si veda anche sezione 8.1.8): - pazienti HBsAg + con HBV DNA < 2000 UI/ml (portatori inattivi); la presenza di HBV DNA > 2000 UI/ml e' invece un criterio di esclusione; - pazienti HBsAg – HBsAb + - pazienti BsAg – ma HBcAb + 9-I pazienti con epatite attiva da HCV sono esclusi dallo studio. I pazienti senza evidenza di epatite attiva e/o malattia cronica avanzata del fegato documentata con biopsia epatica o valutazione fibro-scan possono essere inclusi nello studio. 10-Pazienti che hanno ricevuto un trattamento precedente con Bendamustina e/o Lenalidomide. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 1-the complete response (CR) rate after consolidation in all included patients according to Cheason Criteria; 2-the maPFS in the subset of patients with CR or PR, receiving the maintenance regimen. maPFS in the maintenance cohort will be defined as the time between the date of CR/PR and the date of disease progression or death from any cause. Patients without events will be censored at the last follow up visit. |
| 1-proporzione di Risposte Complete (CR), definite secondo i criteri di Cheson, al termine della fase di consolidamento in tutti i soggetti arruolati; 2-PFS nel sottogruppo di pazienti in CR o PR, che ricevono il regime di mantenimento. PFS nella coorte sottoposta a regime di mantenimento sara' definita come l’intervallo tra la data di risposta (CR/PR) e la data di recidiva/progressione o la data di morta per qualsiasi causa. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 1-the complete response (CR) rate after consolidation in all included patients; 2-the maPFS in the subset of patients with CR or PR, receiving the maintenance regimen. maPFS in the maintenance cohort will be defined as the time between the date of CR/PR and the date of disease progression or death from any cause. Patients without events will be censored at the last follow up visit. |
| 1-proporzione di Risposte Complete (CR)al termine della fase di consolidamento in tutti i soggetti arruolati; 2-maPFS nel sottogruppo di pazienti in CR o PR, che ricevono il regime di mantenimento. maPFS nella coorte sottoposta a regime di mantenimento sara' definita come l’intervallo tra la data di risposta (CR/PR) e la data di recidiva/progressione o la data di morta per qualsiasi causa. |
|
| E.5.2 | Secondary end point(s) |
| 1-Any grade III or higher toxicities will be recorded and classified according to the definitions of NCI Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 (October 1, 2009). Toxicity events will be determined by the incidence of severe, life- threatening (CTCAE grade 3, 4 and 5) and/or serious adverse events commencing after the first induction dose or at any time during maintenance therapy; 2-Overall response rate (CR+PR) will be assessed at the end of the consolidation treatment; 3-Progression Free Survival (PFS) in all patients will be defined as the time between the date of enrolment and the date of recurrence/disease progression or death from any cause. Patients without events will be censored at the last follow up visit; 4-Overall Survival (OS) will be defined as the time between the date of enrollement (or the date of the end of consolidation for the maintenance cohort) and the date of death from any cause. Patients alive at the end of follow-up will be censored at the last follow up visit; 5-Rate of conversion to molecular remission, rate of molecular relapse, disease kinetics by real time PCR in the BM and PB will be assessed to evaluate the activity of Lenalidomide maintenance on MRD; 6-The cumulative incidence (in the maintenance cohort) of any second primary malignancies (hematological and not-hematological), diagnosed after the conclusion of the induction phase, will be analysed considering deaths as competing events. |
| 1-qualsiasi tossicita' di grado III o superiore secondo NCI Common Terminology Criteria for Adverse Events (CTCAE), version 4.0; 2-tasso di risposte complessivo (CR + PR) dopo la fase di induzione e consolidamento (in tutti i pazienti); 3-PFS (in tutti i pazienti arruolati) sara' definita come l’intervallo tra la data di arruolamento e la data di recidiva/progressione o la data di morta per qualsiasi causa; 4-sopravvivenza complessiva (OS) (in tutti i pazienti arruolati e nella coorte sottoposta a regime di mantenimento) sara' definita come l’intervallo tra la data di arruolamento (o di CR/PR) e la data di morta per qualsiasi causa; 5-tasso di remissione molecolare, tasso di ricaduta molecolare, cinetica nel midollo e nel sangue periferico durante la fase di mantenimento (real time PCR); 6-incidenza cumulativa (nella coorte sottoposta a regime di mantenimento) di qualsiasi ulteriore neoplasia (ematologia e non), diagnosticata dopo il termine della fase di induzione, considerando il decesso come un evento competitivo. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 1-Any grade III or higher toxicities (CTCAE 4.0) 2-CR+PR at the end of the consolidation treatment; 3-PFS in all patients between date of enrolment and date of recurrence/disease progression or death from any cause; 4-OS between date of enrollement (or date of the end of consolidation for the maintenance cohort) and the date of death from any cause. 5-Rate of conversion to molecular remission, rate of molecular relapse, disease kinetics by real time PCR in the BM and PB will be assessed to evaluate the activity of Lenalidomide maintenance on MRD; 6-The cumulative incidence (in the maintenance cohort) of any SPM (hematological and not-hematological), diagnosed after the conclusion of the induction phase, will be analysed considering deaths as competing events. |
| 1-tossicita' di grado III o superiore (CTCAE 4.0); 2-tasso di CR + PR dopo induzione e consolidamento; 3-PFS (tutti pz arruolati) tra data di arruolamento e data di recidiva/progressione o data di morte per qualsiasi causa; 4-OS (in tutti i pazienti arruolati e nella coorte sottoposta a mantenimento) definita come intervallo tra data di arruolamento (o di CR/PR) e data di morte per qualsiasi causa; 5-tasso remissione molecolare, tasso ricaduta molecolare, cinetica nel midollo e nel sangue periferico durante il mantenimento; 6-incidenza cumulativa (nella coorte in regime di mantenimento) di qualsiasi ulteriore neoplasia (ematologia e non), diagnosticata dopo il termine della fase di induzione, considerando il decesso come un evento competitivo. |
|
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| 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.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 56 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 | No |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 60 |
| E.8.9.1 | In the Member State concerned days | 0 |
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