Rituximab, Bendamustine and Cytarabine Followed by Venetoclax in High Risk Elderly Patients With MCL
- Registration Number
- NCT03567876
- Lead Sponsor
- Fondazione Italiana Linfomi - ETS
- Brief Summary
Prospective, multicenter, phase II trial designed to evaluate whether the addition of Venetoclax after rituximab, bendamustine and cytarabine (R-BAC) to high risk patients with mantle cell lymphoma improves the results of the standard R-BAC, in terms of Progression Free Survival.
- Detailed Description
The aim of the study is to improve long term results of R-BAC, consolidating patients with high-risk (HR) features (defined as: elevated Ki67 and/or blastoid cytology and/or TP53 mutation after central pathology review) with Venetoclax (ABT-199), which has demonstrated relevant single agent activity in relapsed/refractory MCL in a Phase 1-2 trial.
The updated Progression Free Survival curves of the R-BAC500 trial has shown that the expected 2-years PFS for patients with HR disease is 40% (H0), as compared to low-risk patients (LR) that have a 2-years PFS of 100%. The addition of Venetoclax to HR patients after R-BAC is expected to improve results and efficacy of this regimen in this "difficult -to- treat" population, that represents approximately 40-45 % of newly diagnosed elderly patients with MCL. It appears reasonable to treat with the experimental drug also LR patients that do not respond appropriately (less than CR) at the end of R-BAC. Since the number of such LR patients is hardly predictable based on the present experience with R-BAC500 trial, the analysis of this sub-cohort will be of exploratory nature, and thus assessed separately.
The study objective is to evaluate whether the addition of venetoclax after R-BAC to HR patients improves the results of the standard R-BAC, in terms of Progression Free Survival .
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 141
- Previously untreated patients with MCL aged ≥65 years if they are FIT according to the geriatric CGA assessment.
- age ≤64 years not eliglible to high-dose chemotherapy plus transplantation at physician's judgement (details for non eligibility to be recorded by means of the CIRS, Cumulative Illness rating Scale).
- Measurable nodal or extranodal disease ≥ 1.5 cm in longest diameter, and measurable in 2 perpendicular dimensions.
- ECOG performance status ≤2.
- Positivity for cyclin D1 and/or SOX11 [the latter being mandatory in cases lacking cyclin D1- or t(11;14)-negative].
- Adequate renal function (Creatinine clearance >50 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 <1.5 x ULN, unless directly attributable to the patient's tumor or to congenital causes.
- 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.
- Human immunodeficiency virus (HIV) positive.
- Previous treatment for lymphoma.
- Disease confined to the bone marrow/peripheral blood/spleen, without any other nodal or extranodal involvement.
- In-situ MCL.
- 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 hypoxiemia.
- 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
- Chronic treatment with strong or moderate CYP3A inhibitors (e.g. ketoconazole, ritonavir, clarithromycin, itraconazole, voriconazole)
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description V-RBAC (RBAC followed by Venetoclax) Venetoclax Induction phase: RBAC --\> up to 6 cycles for low risk (LR) patients and up to 4 cycles for high risk (HR) patients. Patients proceeding to Venetoclax treatment will receive consolidation with single agent Venetoclax 800 mg/die x 4 28d cycles (with initial ramp-up dose) of each consolidation cycle. Consolidation will be followed by maintenance with single agent Venetoclax 400 mg/die (V maint ) for a total of 2 years (4 months consolidation+20 months maintenance).
- Primary Outcome Measures
Name Time Method Progression-free survival of the High Risk patients 24 months 2-years progression-free survival (PFS) of the HR patients from date of enrollment
- Secondary Outcome Measures
Name Time Method Incidence of Treatment-Emergent Adverse Events 10 months and 30 months The proportion of patients with adverse events as assessed by CTCAE 4.03 during venetoclax administration as consolidation or maintenance after R-BAC
Duration of responses 24 months Duration of responses
Completed expected treatment schedule 30 months The proportion of patients that complete the expected treatment schedule
Progression-free survival of all patients and different subgroups 24 months The progression-free survival (PFS) of all enrolled patients, and of different subgroups (i.e TP53 mutated patients)
Overall survival 54 months Overall survival
Molecular response 10 months and 30 months The proportion of molecular response (analyzed in the labs of the FIL- MRD Network)
Proportion of complete remission in High Risk and Law Risk patients 6 months and 10 months The proportion of complete remission (CR) before and after venetoclax in the HR group and/or in the LR not responding to R-BAC
Trial Locations
- Locations (35)
Grande Ospedale Metropolitano Bianchi Melacrino Morelli, Ematologia
🇮🇹Reggio Calabria, Italy
IRCCS Istituto Tumori Giovanni Paolo II, UOC Ematologia
🇮🇹Bari, Italy
ASST Spedali Civili, Ematologia
🇮🇹Brescia, Italy
Azienda Ospedaliera S. Croce e Carle, SC Ematologia
🇮🇹Cuneo, Italy
Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Ematologia
🇮🇹Milano, Italy
AOU Maggiore della Carità di Novara, SCDU Ematologia
🇮🇹Novara, Italy
Ospedale degli Infermi, UO Ematologia
🇮🇹Rimini, Italy
Ospedale Businco, Ematologia
🇮🇹Cagliari, Italy
A.O. SS. Antonio e Biagio e Cesare Arrigo, SC Ematologia
🇮🇹Alessandria, Italy
Università Politecnica delle Marche, Clinica di Ematologia
🇮🇹Ancona, Italy
Centro Riferimento Oncologico, S.O.C. Oncologia Medica A
🇮🇹Aviano, Italy
Policlinico S. Orsola-Malpighi, Istituto di Ematologia "Seragnoli"
🇮🇹Bologna, Italy
Azienda Ospedaliera Universitaria Careggi, Unità funzionale di Ematologia
🇮🇹Firenze, Italy
Ospedale Policlinico San Martino S.S.R.L. - IRCCS per l'Oncologia, Clinica Ematologica
🇮🇹Genova, Italy
ASST Grande Ospedale Metropolitano Niguarda, SC Ematologia
🇮🇹Milano, Italy
Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.), Ematologia
🇮🇹Meldola, Italy
Istituto Scientifico San Raffaele, Unità Linfomi - Dipartimento Oncoematologia
🇮🇹Milano, Italy
Ospedale Maggiore Policlinico - Fondazione IRCCS Ca' Granda, Ematologia
🇮🇹Milano, Italy
Azienda Ospedaliera Universitaria di Padova, Ematologia
🇮🇹Padova, Italy
A.O. Ospedali Riuniti Villa Sofia-Cervello, Divisione di Ematologia
🇮🇹Palermo, Italy
Ospedale delle Croci, Ematologia
🇮🇹Ravenna, Italy
Ospedale Guglielmo Da Saliceto, UO Ematologia
🇮🇹Piacenza, Italy
IRCCS Policlinico S. Matteo, Divisione di Ematologia
🇮🇹Pavia, Italy
Azienda Unità Sanitaria Locale-IRCCS - Arcispedale Santa Maria Nuova, Ematologia
🇮🇹Reggio Emilia, Italy
Università Cattolica S. Cuore, Ematologia
🇮🇹Roma, Italy
Policlinico Umberto I - Università "La Sapienza", Istituto Ematologia -Dipartimento di Biotecnologie Cellulari ed Ematologia
🇮🇹Roma, Italy
Istituto Clinico Humanitas, UO Ematologia
🇮🇹Rozzano, Italy
A.O.U. Città della Salute e della Scienza di Torino, SC Ematologia Universitaria
🇮🇹Torino, Italy
Ospedale Ca' Foncello, SC Ematologia
🇮🇹Treviso, Italy
Azienda Sanitaria Universitaria Integrata di Udine, Clinica Ematologica
🇮🇹Udine, Italy
A.O.U. Città della Salute e della Scienza di Torino, SC Ematologia
🇮🇹Torino, Italy
Azienda Ospedaliera C. Panico, UOC Ematologia e Trapianto
🇮🇹Tricase, Italy
Ospedale San Bortolo, Divisione di Ematologia
🇮🇹Vicenza, Italy
Ospedale di Circolo, UOC Ematologia
🇮🇹Varese, Italy
Azienda Ospedaliera Universitaria Integrata di Verona, UO Ematologia
🇮🇹Verona, Italy