Bendamustine/Lenalidomide/Rituximab: Combination as a Second-Line Therapy for 1st Relapsed-Refractory MCL (R2-B)

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

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.

Study Overview

• Status: Completed
• Conditions: Mantle Cell Lymphoma
• Intervention / Treatment: Drug: Bendamustine, Lenalidomide, Rituximab

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.

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • Alessandria, Italy, 15121
    • SC Ematologia AO SS. Antonio e Biagio e C. Arrigo
  • Ancona, Italy, 60100
    • Clinica di ematologia AOU Umberto I Ospedali Riuniti
  • Brescia, Italy, 25123
    • SC Ematologia Spedali Civili
  • Campobasso, Italy, 86100
    • Ematologia Ospedale Cardarelli ASREM
  • Caserta, Italy, 81100
    • Oncoematologia Ospedale SS. Anna e Sebastiano
  • Catania, Italy, 95100
    • UOC Ematologia Osp. Garibaldi Nesima
  • Catanzaro, Italy, 88100
    • Azienda Ospedaliera Pugliese Ciaccio Dipartimento oncoematologico
  • Genova, Italy, 16132
    • Clinica Ematologica AOU San Martino
  • Genova, Italy, 16132
    • Ematologia AOU S. Martino - IST
  • Latina, Italy, 04100
    • UOC Ematologia Universitaria Polo Pontino Sapienza
  • Messina, Italy, 98100
    • SC Ematologia Azienda Ospedali Riuniti Papardo Piemonte
  • Messina, Italy
    • UOC Ematologia Policlinico Universitario AOU G. Martino
  • Milano, Italy, 20133
    • SC Ematologia - Trapianto di midollo osseo Fond. IRCCS Istituto Nazionale Tumori
  • Milano, Italy, 20162
    • SC Ematologia AO Niguarda Cà Granda
  • Novara, Italy, 28100
    • SCDU Ematologia - Università del Piemonte Orientale
  • Palermo, Italy, 90146
    • Divisione di Ematologia, Azienda Ospedali Riuniti Villa Sofia Cervello
  • Parma, Italy, 43100
    • U.O. Complessa di Ematologia Ospedale di Parma
  • Pavia, Italy, 27100
    • Ematologia Policlinico San Matteo
  • Piacenza, Italy, 29100
    • Unità Ematologia Ospedale Civile di Piacenza
  • Pisa, Italy, 56100
    • UO Ematologia Az Ospedaliera Pisana Ospedale "S.Chiara"
  • Ravenna, Italy, 48100
    • UO Ematologia Ospedale Santa Maria delle Croci
  • Reggio Calabria, Italy, 89124
    • Divisione di Ematologia AO Bianchi Melacrino Morelli
  • Reggio Emilia, Italy, 42123
    • SC Ematologia AO Santa Maria Nuova IRCCS
  • Rimini, Italy, 47900
    • UO Oncoematologia ospedale degli Infermi
  • Roma, Italy, 00144
    • Ematologia Ospedale San Eugenio
  • Roma, Italy, 00144
    • UOC Ematologia e Trapianto Istituto Regina Elena (IFO)
  • Roma, Italy, 00149
    • Ematologia Ospedale S.Camillo Forlanini
  • Roma, Italy, 00161
    • Ematologia Università La Sapienza
  • Roma, Italy, 00184
    • UOC Ematologia AO San Giovanni Addolorata
  • Salerno, Italy, 84131
    • Ematologia e Trapianti A.O. San Giovanni di DIO e Ruggi D'Aragona
  • Taranto, Italy, 74100
    • Ematologia Ospedale SG Moscati
  • Terni, Italy, 05100
    • SC Oncoematologia con autotrapianto AO Santa Maria
  • Torino, Italy, 10126
    • SC Ematologia - AO Città della Salute e della Scienza
  • Torino, Italy, 10126
    • SC Ematologia U - AO Città della Salute e della Scienza
  • Udine, Italy, 33100
    • Clinica Ematologica ASUI Integrata di Udine
  • Varese, Italy, 21100
    • Oncologia Medica Varese Ospedale di Circolo e Fondazione Macchi
  • Varese, Italy, 21100
    • UO Ematologia Ospedale di Circolo e Fondazione Macchi
  • Barletta-Andria-Trani (BT)
    • Trani, Barletta-Andria-Trani (BT), Italy, 76125
      • UOC Ematologia Trani
  • Forlì Cesena
    • Meldola, Forlì Cesena, Italy, 47014
      • Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori IRST Meldola
  • Milano
    • Rozzano, Milano, Italy, 20089
      • Ematologia Istituto Clinico Humanitas
  • Pordenone
    • Aviano, Pordenone, Italy, 33081
      • Centro di riferimento Oncologico CRO Aviano
  • Potenza
    • Rionero in Vulture, Potenza, Italy, 85028
      • IRCCS-Centro di riferimento oncologico UO di ematologia e Trapianto Cellule Staminali
  • Torino
    • Orbassano, Torino, Italy, 10043
      • Medicina Interna 2 ad indirizzo Ematologico AOU San Luigi Gonzaga

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Bendamustina, Lenalidomide, Rituximab; 1 arm for all patients

Drug: Bendamustine, Lenalidomide, Rituximab; 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

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

Collaborators and Investigators

• Sponsor: Fondazione Italiana Linfomi ONLUS
• Investigators: Principal Investigator: Francesco Zaja, M.D., Clinica Ematologica - Udine - Italy

Study record dates

Study Major Dates

• Study Start (Actual): July 31, 2012
• Primary Completion (Actual): July 1, 2014
• Study Completion (Actual): February 2, 2017

Study Registration Dates

• First Submitted: November 27, 2012
• First Submitted That Met QC Criteria: November 28, 2012
• First Posted (Estimate): November 29, 2012

Study Record Updates

• Last Update Posted (Actual): March 9, 2018
• Last Update Submitted That Met QC Criteria: March 8, 2018
• Last Verified: March 1, 2018

More Information

Terms related to this study

• Keywords: MCL; Mantle Cell Lymphoma; RELAPSED-REFRACTORY
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoma, Mantle-Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Lenalidomide; Bendamustine Hydrochloride; Rituximab
• Other Study ID Numbers: FIL R2-B