Clinical trial NCT01662050: Phase II Study of Age-Adjusted Rituximab, Bendamustine, Cytarabine as Induction Therapy in Older Patients With MCL
Official title: Phase II Study of Age-Adjusted R-BAC (Rituximab, Bendamustine, Cytarabine) as Induction Therapy in Older Patients With Mantle Cell Lymphoma (MCL)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Mantle Cell Lymphoma
Keywords: MCL
Mantle Cell Lymphoma
Older
Lead sponsor: Fondazione Italiana Linfomi - ETS
Sponsor class: OTHER
First posted: 2012-08-10
Enrollment: 57
Sex: ALL
Minimum age (years): 65
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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

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.

Eligibility criteria: 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)

Primary outcomes:
measure: complete remission rate at the end of treatment
timeFrame: 6 months
measure: Toxicity will be represented by the occurrence of any of the stop treatment criteria or of any episode of relevant toxicity
timeFrame: 6 months
Secondary outcomes:
measure: the rate of molecular response
timeFrame: 6 months
measure: the progression-free survival (PFS)
timeFrame: 30 months
measure: the overall survival (OS)
timeFrame: 30 months
measure: the duration of responses (DOR)
timeFrame: 30 months
measure: the rate of completion of treatment
timeFrame: 6 months
measure: the rate of dose reductions or delays
timeFrame: 6 months
Other outcomes:
Locations:
city: Bari
country: Italy
facility: A.O. Policlinico Consorziale
state: BA
city: Bari
country: Italy
facility: IRCCS Ospedale Oncologico
state: BA
city: Brescia
country: Italy
facility: A.O. Spedali Civili
state: BS
city: Trani
country: Italy
facility: U.O.C. Ematologia Ospedale "San Nicola Pellegrino" ASL BAT
state: BT
city: Cagliari
country: Italy
facility: Ospedale Businco
state: CA
city: Como
country: Italy
facility: AO Valduce
state: CO
city: Catania
country: Italy
facility: U.O.C. Garibaldi Nesima
state: CT
city: Firenze
country: Italy
facility: AOU Careggi
state: FI
city: Genova
country: Italy
facility: A.O.U. San Martino
state: GE
city: Lecce
country: Italy
facility: PO Vito Fazzi
state: LE
city: Tricase
country: Italy
facility: Ospedale Cardinale G. Panico
state: LE
city: Civitanova Marche
country: Italy
facility: Asur - Zona Territoriale 8
state: MC
city: Messina
country: Italy
facility: U.O.C. Ematologia - Policlinico Universitario
state: ME
city: Milano
country: Italy
facility: Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico
state: MI
city: Milano
country: Italy
facility: A.O. S. Carlo Borromeo di Milano Unità Semplice di Trapianto Midollo - A.O.S.Carlo Borromeo
state: MI
city: Milano
country: Italy
facility: A.O. Niguarda
state: MI
city: Monza
country: Italy
facility: Osp. San Gerardo
state: MI
city: Rozzano
country: Italy
facility: Istituto Clinico Humanitas
state: MI
city: Modena
country: Italy
facility: Centro Oncologico Modenese (COM)
state: MO
city: Palermo
country: Italy
facility: "La Maddalena"
state: PA
city: Palermo
country: Italy
facility: Ospedali Riuniti Villa Sofia - Cervello
state: PA
city: Piacenza
country: Italy
facility: Ospedale Civile Guglielmo da Saliceto
state: PC
city: Padova
country: Italy
facility: Università di Padova
state: PD
city: Pescara
country: Italy
facility: Presidio ospedaliero di Pescara
state: PE
city: Aviano
country: Italy
facility: CRO Aviano
state: PN
city: Pavia
country: Italy
facility: Fondazione IRCCS Policlinico San Matteo,
state: PV
city: Ravenna
country: Italy
facility: Osp. S. Maria delle Croci
state: RA
city: Reggio Calabria
country: Italy
facility: Azienda Ospedaliera "Bianchi Melacrino Morelli"
state: RC
city: Reggio Emilia
country: Italy
facility: Azienda Ospedaliera Arcispedale "S.Maria Nuova"
state: RE
city: Roma
country: Italy
facility: A.O. San Camillo Forlanini
state: RM
city: Roma
country: Italy
facility: Nuovo Regina Margherita
state: RM
city: Roma
country: Italy
facility: Università "La Sapienza"
state: RM
city: Roma
country: Italy
facility: A.O. S. Giovanni Addolorata
state: RM
city: Rimini
country: Italy
facility: Ospedale degli Infermi di Rimini
state: RN
city: Rovigo
country: Italy
facility: Azienda ULSS 18
state: RO
city: Nocera Inferiore
country: Italy
facility: Osp. Umberto I
state: SA
city: Salerno
country: Italy
facility: A.O.U. San Giovanni di Dio e Ruggi d'Aragona
state: SA
city: Siena
country: Italy
facility: Az. Ospedaliera Univ. Senese
state: SI
city: Ciriè-Ivrea-Chivasso
country: Italy
facility: ASL TO4
state: TO
city: Orbassano
country: Italy
facility: Ospedale S. Luigi Gonzaga,
state: TO
city: Torino
country: Italy
facility: A.O.U. S. Giovanni Battista -Ematologia 2
state: TO
city: Torino
country: Italy
facility: AOU San Giovanni Battista-Ematologia 1
state: TO
city: Terni
country: Italy
facility: A.O. S. Maria di Terni
state: TR
city: Udine
country: Italy
facility: Azienda Ospedaliero - Universitaria di Udine
state: UD
city: Varese
country: Italy
facility: Ospedale di Circolo e Fondazione Macchi - Ematologia
state: VA
city: Varese
country: Italy
facility: Ospedale di Circolo e Fondazione Macchi - Oncologia
state: VA
city: Vercelli
country: Italy
facility: Osp. S. Andrea Vercelli
state: VC
city: Mirano
country: Italy
facility: Ospedale Civile di Mirano
state: VE
city: Vicenza
country: Italy
facility: Ospedale San Bortolo
state: VI
city: Verona
country: Italy
facility: Ospedale Policlinico G.B. Rossi (Borgo Roma) Di Verona
state: VR
city: Alessandria
country: Italy
facility: A.O. SS. Antonio e Biagio e C. Arrigo
city: Bolzano
country: Italy
facility: Comprensorio sanitario di Bolzano
city: Campobasso
country: Italy
facility: Ospedale Cardarelli
city: Catanzaro
country: Italy
facility: A.O. Pugliese-Ciacci
city: Meldola
country: Italy
facility: IRST
city: Novara
country: Italy
facility: Università del Piemonte Orientale - Novara
Study officials:
affiliation: Ospedale ULSS 6 di Vicenza - Ematologia
name: Carlo Visco, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.