Clinical trial NCT03567876: Rituximab, Bendamustine and Cytarabine Followed by Venetoclax in High Risk Elderly Patients With MCL
Official title: Rituximab, Bendamustine and Cytarabine Followed by Venetoclax (V-RBAC) in High-risk Elderly Patients With Mantle Cell Lymphoma (MCL)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Lymphoma, Mantle-Cell
Keywords: Mantle cell lymphoma
Elderly patients
First line
Lead sponsor: Fondazione Italiana Linfomi - ETS
Sponsor class: OTHER
Collaborators: name: AbbVie
First posted: 2018-06-26
Enrollment: 141
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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 .

Eligibility criteria: Inclusion Criteria:

1. Previously untreated patients with MCL aged ≥65 years if they are FIT according to the geriatric CGA assessment.
2. 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).
3. Measurable nodal or extranodal disease ≥ 1.5 cm in longest diameter, and measurable in 2 perpendicular dimensions.
4. ECOG performance status ≤2.
5. Positivity for cyclin D1 and/or SOX11 \[the latter being mandatory in cases lacking cyclin D1- or t(11;14)-negative\].
6. Adequate renal function (Creatinine clearance \>50 mL/min), with preserved diuresis.
7. 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.
8. 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.
9. Written informed consent.

Exclusion Criteria:

1. Human immunodeficiency virus (HIV) positive.
2. Previous treatment for lymphoma.
3. Disease confined to the bone marrow/peripheral blood/spleen, without any other nodal or extranodal involvement.
4. In-situ MCL.
5. Medical conditions or organ injuries that could interfere with administration of therapy.
6. Active bacterial, viral, or fungal infection requiring systemic therapy.
7. Seizure disorders requiring anticonvulsant therapy.
8. Severe chronic obstructive pulmonary disease with hypoxiemia.
9. 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.
10. Uncontrolled diabetes mellitus.
11. Active secondary malignancy.
12. Known hypersensitivity or anaphylactic reactions to murine antibodies and proteins, to Bendamustine or mannitol.
13. Major surgery within 4 weeks of study Day 1.
14. HBsAg+
15. HCVAb+ patients with active viral replication (HCV-RNA+ with AST\>2 x normal limit)
16. 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.
17. CNS involvement
18. Chronic treatment with strong or moderate CYP3A inhibitors (e.g. ketoconazole, ritonavir, clarithromycin, itraconazole, voriconazole)

Primary outcomes:
measure: Progression-free survival of the High Risk patients
timeFrame: 24 months
Secondary outcomes:
measure: Molecular response
timeFrame: 10 months and 30 months
measure: Progression-free survival of all patients and different subgroups
timeFrame: 24 months
measure: Overall survival
timeFrame: 54 months
measure: Duration of responses
timeFrame: 24 months
measure: Proportion of complete remission in High Risk and Law Risk patients
timeFrame: 6 months and 10 months
measure: Completed expected treatment schedule
timeFrame: 30 months
measure: Incidence of Treatment-Emergent Adverse Events
timeFrame: 10 months and 30 months
Other outcomes:
Locations:
city: Alessandria
country: Italy
facility: A.O. SS. Antonio e Biagio e Cesare Arrigo, SC Ematologia
city: Ancona
country: Italy
facility: Università Politecnica delle Marche, Clinica di Ematologia
city: Aviano
country: Italy
facility: Centro Riferimento Oncologico, S.O.C. Oncologia Medica A
city: Bari
country: Italy
facility: IRCCS Istituto Tumori Giovanni Paolo II, UOC Ematologia
city: Bologna
country: Italy
facility: Policlinico S. Orsola-Malpighi, Istituto di Ematologia "Seragnoli"
city: Brescia
country: Italy
facility: ASST Spedali Civili, Ematologia
city: Cagliari
country: Italy
facility: Ospedale Businco, Ematologia
city: Cuneo
country: Italy
facility: Azienda Ospedaliera S. Croce e Carle, SC Ematologia
city: Firenze
country: Italy
facility: Azienda Ospedaliera Universitaria Careggi, Unità funzionale di Ematologia
city: Genova
country: Italy
facility: Ospedale Policlinico San Martino S.S.R.L. - IRCCS per l'Oncologia, Clinica Ematologica
city: Meldola
country: Italy
facility: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.), Ematologia
city: Milano
country: Italy
facility: ASST Grande Ospedale Metropolitano Niguarda, SC Ematologia
city: Milano
country: Italy
facility: Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Ematologia
city: Milano
country: Italy
facility: Istituto Scientifico San Raffaele, Unità Linfomi - Dipartimento Oncoematologia
city: Milano
country: Italy
facility: Ospedale Maggiore Policlinico - Fondazione IRCCS Ca' Granda, Ematologia
city: Novara
country: Italy
facility: AOU Maggiore della Carità di Novara, SCDU Ematologia
city: Padova
country: Italy
facility: Azienda Ospedaliera Universitaria di Padova, Ematologia
city: Palermo
country: Italy
facility: A.O. Ospedali Riuniti Villa Sofia-Cervello, Divisione di Ematologia
city: Pavia
country: Italy
facility: IRCCS Policlinico S. Matteo, Divisione di Ematologia
city: Piacenza
country: Italy
facility: Ospedale Guglielmo Da Saliceto, UO Ematologia
city: Ravenna
country: Italy
facility: Ospedale delle Croci, Ematologia
city: Reggio Calabria
country: Italy
facility: Grande Ospedale Metropolitano Bianchi Melacrino Morelli, Ematologia
city: Reggio Emilia
country: Italy
facility: Azienda Unità Sanitaria Locale-IRCCS - Arcispedale Santa Maria Nuova, Ematologia
city: Rimini
country: Italy
facility: Ospedale degli Infermi, UO Ematologia
city: Roma
country: Italy
facility: Policlinico Umberto I - Università "La Sapienza", Istituto Ematologia -Dipartimento di Biotecnologie Cellulari ed Ematologia
city: Roma
country: Italy
facility: Università Cattolica S. Cuore, Ematologia
city: Rozzano
country: Italy
facility: Istituto Clinico Humanitas, UO Ematologia
city: Torino
country: Italy
facility: A.O.U. Città della Salute e della Scienza di Torino, SC Ematologia Universitaria
city: Torino
country: Italy
facility: A.O.U. Città della Salute e della Scienza di Torino, SC Ematologia
city: Treviso
country: Italy
facility: Ospedale Ca' Foncello, SC Ematologia
city: Tricase
country: Italy
facility: Azienda Ospedaliera C. Panico, UOC Ematologia e Trapianto
city: Udine
country: Italy
facility: Azienda Sanitaria Universitaria Integrata di Udine, Clinica Ematologica
city: Varese
country: Italy
facility: Ospedale di Circolo, UOC Ematologia
city: Verona
country: Italy
facility: Azienda Ospedaliera Universitaria Integrata di Verona, UO Ematologia
city: Vicenza
country: Italy
facility: Ospedale San Bortolo, Divisione di Ematologia
Study officials:
affiliation: AOU Integrata di Verona - U.O. Ematologia -Verona -Italy
name: Carlo Visco, MD
role: PRINCIPAL_INVESTIGATOR
References: