Phase II Study of Age-Adjusted Rituximab, Bendamustine, Cytarabine as Induction Therapy in Older Patients With MCL (FIL-RBAC500)

Phase II Study of Age-Adjusted R-BAC (Rituximab, Bendamustine, Cytarabine) as Induction Therapy in Older Patients With Mantle Cell Lymphoma (MCL)

A phase 2 study of standard R-BAC (rituximab 375 mg/m2, bendamustine 70 mg/m2, ara-c 800 mg/m2) has been recently ultimated at the Vicenza Hematology Department involving several regional centers on both untreated and previously treated patients with Mantle Cell Lymphoma (MCL). An interim analysis conducted on 30 patients showed that rituximab + bendamustine + ara-c combination had very good clinical activity, but a quite relevant hematological toxicity, especially in previously treated and older patients (Visco C, ICML 2011 Lugano Conference, Poster 236).

Objectives:

The primary objective is to determine the activity (complete remission rate according to Cheson 2007 criteria) and safety of age-adjusted Rituximab-Bendamustine-Cytarabine (RBAC500) regimen at the end of treatment in older untreated patients with MCL.

The secondary objectives are to determine:

• The rate of molecular response (characterized by labs of the FIL)
• The progression-free survival (PFS)
• The overall survival (OS)
• The duration of responses (DOR)
• The rate of patients that complete the expected treatment schedule (6 courses)
• The rate of patients that are subject to dose reductions or delays

Study Overview

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

Detailed Description

Study End points Primary efficacy end point of the study is the proportion of CR defined according to Cheson criteria (2007) at the end of treatment (6 or 4 cycles). Primary safety end point is the occurrence of any of the stop treatment criteria or of any episode of relevant toxicity, as above defined.

Secondary end points are MRD defined response, OS, PFS and DOR (Cheson 2007). Molecular response is the proportion of patients with molecular rearrangements at baseline that become negative during treatment, measured by qualitative and quantitative PCR.

OS is measured from enrollment until death from any cause. PFS is measured from the time of enrollment until disease progression, relapse or death from any cause. DOR is measured from the first assessment that documents response (CR or PR) to the date of disease relapse or progression. Minimum follow up required for all patients will be 24 months.

• Study Type: Interventional
• Enrollment (Actual): 57
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • Alessandria, Italy, 15121
    • A.O. SS. Antonio e Biagio e C. Arrigo
  • Bolzano, Italy, 39100
    • Comprensorio Sanitario di Bolzano
  • Campobasso, Italy, 86100
    • Ospedale Cardarelli
  • Catanzaro, Italy, 88100
    • A.O. Pugliese-Ciacci
  • Meldola, Italy, 47014
    • IRST
  • Novara, Italy, 28100
    • Università del Piemonte Orientale - Novara
  • BA
    • Bari, BA, Italy, 70124
      • A.O. Policlinico Consorziale
    • Bari, BA, Italy, 70124
      • IRCCS Ospedale Oncologico
  • BS
    • Brescia, BS, Italy, 25100
      • A.O. Spedali Civili
  • BT
    • Trani, BT, Italy, 70031
      • U.O.C. Ematologia Ospedale "San Nicola Pellegrino" ASL BAT
  • CA
    • Cagliari, CA, Italy, 09121
      • Ospedale Businco
  • CO
    • Como, CO, Italy, 22100
      • AO Valduce
  • CT
    • Catania, CT, Italy, 95125
      • U.O.C. Garibaldi Nesima
  • FI
    • Firenze, FI, Italy, 50134
      • AOU Careggi
  • GE
    • Genova, GE, Italy, 16132
      • A.O.U. San Martino
  • LE
    • Lecce, LE, Italy, 73100
      • PO Vito Fazzi
    • Tricase, LE, Italy, 73039
      • Ospedale Cardinale G. Panico
  • MC
    • Civitanova Marche, MC, Italy, 62012
      • Asur - Zona Territoriale 8
  • ME
    • Messina, ME, Italy, 98100
      • U.O.C. Ematologia - Policlinico Universitario
  • MI
    • Milano, MI, Italy, 20162
      • A.O. Niguarda
    • Milano, MI, Italy, 20122
      • Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico
    • Milano, MI, Italy, 20153
      • A.O. S. Carlo Borromeo di Milano Unità Semplice di Trapianto Midollo - A.O.S.Carlo Borromeo
    • Monza, MI, Italy, 20052
      • Osp. San Gerardo
    • Rozzano, MI, Italy, 20089
      • Istituto Clinico Humanitas
  • MO
    • Modena, MO, Italy, 41100
      • Centro Oncologico Modenese (COM)
  • PA
    • Palermo, PA, Italy, 90146
      • Ospedali Riuniti Villa Sofia - Cervello
    • Palermo, PA, Italy, 90146
      • "La Maddalena"
  • PC
    • Piacenza, PC, Italy, 29121
      • Ospedale Civile Guglielmo da Saliceto
  • PD
    • Padova, PD, Italy, 35128
      • Universita di Padova
  • PE
    • Pescara, PE, Italy, 65124
      • Presidio Ospedaliero di Pescara
  • PN
    • Aviano, PN, Italy, 33081
      • CRO Aviano
  • PV
    • Pavia, PV, Italy, 27100
      • Fondazione IRCCS Policlinico San Matteo,
  • RA
    • Ravenna, RA, Italy, 48121
      • Osp. S. Maria delle Croci
  • RC
    • Reggio Calabria, RC, Italy, 89125
      • Azienda Ospedaliera "Bianchi Melacrino Morelli"
  • RE
    • Reggio Emilia, RE, Italy, 42100
      • Azienda Ospedaliera Arcispedale "S.Maria Nuova"
  • RM
    • Roma, RM, Italy, 00152
      • A.O. San Camillo Forlanini
    • Roma, RM, Italy, 00153
      • Nuovo Regina Margherita
    • Roma, RM, Italy, 00161
      • Università "La Sapienza"
    • Roma, RM, Italy, 00184
      • A.O. S. Giovanni Addolorata
  • RN
    • Rimini, RN, Italy, 47900
      • Ospedale degli Infermi di Rimini
  • RO
    • Rovigo, RO, Italy, 45100
      • Azienda ULSS 18
  • SA
    • Nocera Inferiore, SA, Italy, 84014
      • Osp. Umberto I
    • Salerno, SA, Italy, 84131
      • A.O.U. San Giovanni di Dio e Ruggi d'Aragona
  • SI
    • Siena, SI, Italy, 53100
      • Az. Ospedaliera Univ. Senese
  • TO
    • Ciriè-Ivrea-Chivasso, TO, Italy, 10043
      • ASL TO4
    • Orbassano, TO, Italy, 10043
      • Ospedale S. Luigi Gonzaga,
    • Torino, TO, Italy, 10126
      • A.O.U. S. Giovanni Battista -Ematologia 2
    • Torino, TO, Italy, 10126
      • AOU San Giovanni Battista-Ematologia 1
  • TR
    • Terni, TR, Italy, 05100
      • A.O. S. Maria di Terni
  • UD
    • Udine, UD, Italy, 33100
      • Azienda Ospedaliero - Universitaria di Udine
  • VA
    • Varese, VA, Italy, 21100
      • Ospedale di Circolo e Fondazione Macchi - Ematologia
    • Varese, VA, Italy, 21100
      • Ospedale di Circolo e Fondazione Macchi - Oncologia
  • VC
    • Vercelli, VC, Italy, 13100
      • Osp. S. Andrea Vercelli
  • VE
    • Mirano, VE, Italy, 30035
      • Ospedale Civile di Mirano
  • VI
    • Vicenza, VI, Italy, 36100
      • Ospedale San Bortolo
  • VR
    • Verona, VR, Italy, 37126
      • Ospedale Policlinico G.B. Rossi (Borgo Roma) di Verona

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 65 years and older (OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Previously untreated patients with MCL aged > 65 years if they are FIT according to the geriatric CGA assessment.
• age 60-65 years not eligible to high-dose chemotherapy plus transplantation, FIT or UNFIT according to the geriatric CGA assessment.
• ECOG performance status ≤ 2.
• Positivity for cyclin D1 and SOX11 [the latter being mandatory in cases lacking cyclin D1- or t(11;14)-negative], CD20 and CD5.
• Adequate renal function (Creatinine clearance > 40 mL/min), with preserved diuresis.
• Adequate liver function: alanine aminotransferase (ALT)/aspartate aminotransferase (AST) < 2.5 x upper limit of normal (ULN) value, total bilirubin < 2 mg/dL, unless directly attributable to the patient's tumor.
• Hepatitis B core antibody (HBcAb) positive/HBsAg negative/HBV-DNA negative patients may be enrolled if correct antiviral prophylaxis is administered at least 2 weeks before initiating protocol treatment.
• Written informed consent.

Exclusion Criteria:

• Human immunodeficiency virus (HIV) positive.
• Previous treatment for lymphoma
• Medical conditions or organ injuries that could interfere with administration of therapy.
• Active bacterial, viral, or fungal infection requiring systemic therapy.
• Seizure disorders requiring anticonvulsant therapy.
• Severe chronic obstructive pulmonary disease with hypoxemia.
• History of severe cardiac disease: New York Heart Association (NYHA) functional class III-IV, myocardial infarction within 6 months, ventricular tachyarrhythmias, dilatative cardiomyopathy, or unstable angina.
• Uncontrolled diabetes mellitus.
• Active secondary malignancy.
• Known hypersensitivity or anaphylactic reactions to murine antibodies and proteins, to Bendamustine or mannitol.
• Major surgery within 4 weeks of study Day 1.
• HBsAg+
• HCVAb+ patients with active viral replication (HCV-RNA+ with AST > 2 x normal limit)
• Any co-existing medical or psychological condition that would preclude participation in the study or compromise the patient's ability to give informed consent, or that may affect the interpretation of the results, or render the patient at high risk from treatment complications.
• CNS involvement (a diagnostic lumbar puncture will be performed in patients with the blastoid variant of MCL)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: One arm for all patients.; Rituximab, Bendamustine, Cytarabine	Drug: Rituximab, Bendamustine, Cytarabine.; 6 cycles of 28 days with Rituximab, Bendamustine and Cytarabine (R-BAC). Rituximab 375mg/mq; Bendamustine 70mg/mq; Cytarabine 500mg/mq.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
complete remission rate at the end of treatment	The primary objective is to determine the activity [complete remission rate (CR) according to Cheson 2007 criteria]	6 months
Toxicity will be represented by the occurrence of any of the stop treatment criteria or of any episode of relevant toxicity	Relevant toxicity: Grade 4 cytopenia lasting for more than 6 days or Grade 3-4 non-hematologic toxicity or Febrile neutropenia lasting for more than 3 consecutive days. Stop treatment criteria: Occurrence of relevant toxicity for two subsequent or consecutive cycles.; Grade 3-4 hematological or non-hematological toxicity on day +28 of a cycle not resolving within two weeks.; Grade 3-4 hematological or non-hematological toxicity on day +28 of a cycle after 25% dose reduction.; Patient refusal to procede with further cycles due to perceived excessive toxicity.; Any unpredictable drug related event that suggests against study continuation	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
the rate of molecular response	the rate of molecular response (characterized by labs of the FIL)	6 months
the progression-free survival (PFS)	the progression-free survival (PFS)is defined as the time from enrollment to complete remission with disappearance of all evidence of disease, disease progression or relapse or death from any cause.	30 months
the overall survival (OS)	the overall survival (OS) is defined as the time from enrollment to death from any cause	30 months
the duration of responses (DOR)	the duration of responses (DOR)	30 months
the rate of completion of treatment	the rate of patients that complete the expected treatment schedule (6 courses)	6 months
the rate of dose reductions or delays	the rate of patients that are subject to dose reductions or delays	6 months

Collaborators and Investigators

• Sponsor: Fondazione Italiana Linfomi ONLUS
• Investigators: Principal Investigator: Carlo Visco, MD, Ospedale ULSS 6 di Vicenza - Ematologia

Publications and helpful links

General Publications

• Visco C, Chiappella A, Nassi L, Patti C, Ferrero S, Barbero D, Evangelista A, Spina M, Molinari A, Rigacci L, Tani M, Rocco AD, Pinotti G, Fabbri A, Zambello R, Finotto S, Gotti M, Carella AM, Salvi F, Pileri SA, Ladetto M, Ciccone G, Gaidano G, Ruggeri M, Martelli M, Vitolo U. Rituximab, bendamustine, and low-dose cytarabine as induction therapy in elderly patients with mantle cell lymphoma: a multicentre, phase 2 trial from Fondazione Italiana Linfomi. Lancet Haematol. 2017 Jan;4(1):e15-e23. doi: 10.1016/S2352-3026(16)30185-5. Epub 2016 Dec 5.

Study record dates

Study Major Dates

• Study Start (ACTUAL): March 20, 2012
• Primary Completion (ACTUAL): August 1, 2014
• Study Completion (ACTUAL): September 11, 2017

Study Registration Dates

• First Submitted: June 26, 2012
• First Submitted That Met QC Criteria: August 7, 2012
• First Posted (ESTIMATE): August 10, 2012

Study Record Updates

• Last Update Posted (ACTUAL): August 9, 2022
• Last Update Submitted That Met QC Criteria: August 8, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Keywords: MCL; Mantle Cell Lymphoma; Older
• 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; Anti-Infective Agents; Antiviral Agents; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Antineoplastic Agents, Immunological; Bendamustine Hydrochloride; Rituximab; Cytarabine
• Other Study ID Numbers: FIL-RBAC500