Bendamustine/Lenalidomide/Rituximab: Combination as a Second-Line Therapy for 1st Relapsed-Refractory MCL

Study Overview
=================
Brief Summary
-----------------
This is a prospective, multicenter phase II trial designed to evaluate the safety and activity of the combination of Bendamustine, Lenalidomide and Rituximab (R2-B) in patients with first relapsed/refractory mantle cell lymphoma (MCL) and the efficacy and safety of a maintenance treatment with Lenalidomide for 18 months from the end of R2-B (from month 7 to 24) for those responding to the induction.

Detailed Description
-----------------
This is a phase II study, non randomized, multicenter. Patients with MCL refractory to front line therapy or in first relapse will be enrolled. The study includes an induction phase, a consolidation phase, a maintenance phase and a follow up phase.

Official Title
-----------------
Bendamustine, Lenalidomide and Rituximab (R2-B) Combination as a Second-Line Therapy for First Relapsed-Refractory Mantle Cell Lymphomas: A Phase II Study

Conditions
-----------------
Mantle Cell Lymphoma

Intervention / Treatment
-----------------
* Drug: Bendamustine, Lenalidomide, Rituximab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patient has a diagnosis of MCL according to the WHO classification; Patient age is ≥ 18 years; Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2; Understands and voluntarily signs an informed consent form; Able to adhere to the study visit schedule and other protocol requirements; 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; 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; Adequate haematological counts: ANC > 1.5 x 109/L and platelet count > 75 x 109/L unless due to bone marrow involvement by MCL; Conjugated bilirubin up to 2 x ULN unless due to liver involvement by MCL; Alkaline phosphatase and transaminases up to 2 x ULN unless due to liver involvement by MCL; Creatinine clearance ≥ 30 ml/min; a dose reduction of Lenalidomide for patients with creatinine clearance ≥ 30 mL/min but < 50 mL/min is planned; Written informed consent was obtained from the patient prior to any study-specific screening procedures; Patient has the ability to swallow capsules or tablets; Life expectancy ≥ 6 months; Disease free of prior malignancies (a part MCL) with the exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma in situ of the cervix or breast; Exclusion Criteria: 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 non-treatment studies is allowed, if it will not interfere with participation in this study; Patient has a history of CNS involvement with lymphoma; Patients with previous history of malignancies (a part MCL) ≤ 3 years 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; History of clinically relevant liver or renal insufficiency; significant cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic, rheumatologic, hematologic, psychiatric, or metabolic disturbances; 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; Creatinine clearance < 30 ml/min; Patient has a known history of HIV seropositivity; 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 + 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 Patients have received previous treatment with either Bendamustine and/or Lenalidomide.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bendamustina, Lenalidomide, Rituximab<br>1 arm for all patients | Drug: Bendamustine, Lenalidomide, Rituximab<br>* INDUCTION PHASE (COURSE 1-4) Bendamustine: 70 mg/m2 on day 2 and 3 every 28 Lenalidomide: 10 mg/daily on day 1 to 14 of a 28 days course Rituximab: 375 mg/m2 on day 1 every 28 days; only for the first cycle in the induction phase will start on day 8 CONSOLIDATION PHASE (courses 5-6) Patients in CR and PR at the end of the induction phase Lenalidomide: 15 mg/daily on day 1 to 21 of a 28 days course. Rituximab: 375 mg/m2 on day 1 every 28 days MAINTENANCE PHASE (courses 7-24) Patients in CR or PR at the end of the consolidation treatment with Lenalidomide until disease progression or unacceptable toxicity up to 18 months (from month 7 to month 24) - Lenalidomide: 15 mg/daily on day 1 to 21 of a 28 days<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response (CR) rate | Proportion of CR according to the Cheson2007 response criteria | At the end of the consolidation phase (6 months) | 
| Maintenance Progression Free Survival (maPFS) | maPFS will be defined in the maintenance cohort as the time between the date of CR/PR and the date of disease progression or death from any cause. | 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity | Incidence of grade 3 or higher Toxicity measured by CTCAE v.4 during induction and maintenance therapy | 24 months | 
| Overall Response Rate (ORR) | ORR at the end of the consolidation treatment is defined as Complete Response(CR) or Partial Response according to the Cheson 2007 response criteria | at the end of the consolidation phase (6 months) | 
| Progression Free Survival (PFS) in all patients | PFS will be measured from the day of enrolment and of disease progression or death from any cause | 42 months | 
| Overall Survival (OS) | OS will be defined as the date of enrolment and the date of recurrence/disease progression or death from any cause | 36 months | 
| Molecular response rate | rate of conversion to molecular remission measured by PCR | 24 months | 
| Molecular relapse rate during study period | rate of conversion to molecular relapse measured by PCR | 42 months | 
| Disease kinetics of minimal residual disease (MRD) during study period | measured by real time PCR in the bone marrow and peripheral blood | up to 42 months | 
| Cumulative incidence of second primary malignancies | incidence of any second primary malignancies (haematological and not haematological) diagnosed after the conclusion of induction phase | up to 42 months | 
| To evaluate the possible relationship between Cereblon expression and response to therapy | Possible relationship between Cereblon expression and response to therapy | 6 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
MCL, Mantle Cell Lymphoma, RELAPSED-REFRACTORY