Rituximab, Bendamustine and Cytarabine Followed by Venetoclax in High Risk Elderly Patients With MCL

Rituximab, Bendamustine and Cytarabine Followed by Venetoclax (V-RBAC) in High-risk Elderly Patients With Mantle Cell Lymphoma (MCL)

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Lymphoma, Mantle-Cell
• Intervention / Treatment: Drug: Venetoclax

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 .

• Study Type: Interventional
• Enrollment (Actual): 141
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • Alessandria, Italy
    • A.O. SS. Antonio e Biagio e Cesare Arrigo, SC Ematologia
  • Ancona, Italy
    • Università Politecnica delle Marche, Clinica di Ematologia
  • Aviano, Italy
    • Centro Riferimento Oncologico, S.O.C. Oncologia Medica A
  • Bari, Italy
    • IRCCS Istituto Tumori Giovanni Paolo II, UOC Ematologia
  • Bologna, Italy
    • Policlinico S. Orsola-Malpighi, Istituto di Ematologia "Seragnoli"
  • Brescia, Italy
    • ASST Spedali Civili, Ematologia
  • Cagliari, Italy
    • Ospedale Businco, Ematologia
  • Cuneo, Italy
    • Azienda Ospedaliera S. Croce e Carle, SC Ematologia
  • Firenze, Italy
    • Azienda Ospedaliera Universitaria Careggi, Unità funzionale di Ematologia
  • Genova, Italy
    • Ospedale Policlinico San Martino S.S.R.L. - IRCCS per l'Oncologia, Clinica Ematologica
  • Meldola, Italy
    • Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.), Ematologia
  • Milano, Italy
    • ASST Grande Ospedale Metropolitano Niguarda, SC Ematologia
  • Milano, Italy
    • Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Ematologia
  • Milano, Italy
    • Istituto Scientifico San Raffaele, Unità Linfomi - Dipartimento Oncoematologia
  • Milano, Italy
    • Ospedale Maggiore Policlinico - Fondazione IRCCS Ca' Granda, Ematologia
  • Novara, Italy
    • AOU Maggiore della Carità di Novara, SCDU Ematologia
  • Padova, Italy
    • Azienda Ospedaliera Universitaria di Padova, Ematologia
  • Palermo, Italy
    • A.O. Ospedali Riuniti Villa Sofia-Cervello, Divisione di Ematologia
  • Pavia, Italy
    • IRCCS Policlinico S. Matteo, Divisione di Ematologia
  • Piacenza, Italy
    • Ospedale Guglielmo Da Saliceto, UO Ematologia
  • Ravenna, Italy
    • Ospedale delle Croci, Ematologia
  • Reggio Calabria, Italy
    • Grande Ospedale Metropolitano Bianchi Melacrino Morelli, Ematologia
  • Reggio Emilia, Italy
    • Azienda Unità Sanitaria Locale-IRCCS - Arcispedale Santa Maria Nuova, Ematologia
  • Rimini, Italy
    • Ospedale degli Infermi, UO Ematologia
  • Roma, Italy
    • Policlinico Umberto I - Università "La Sapienza", Istituto Ematologia -Dipartimento di Biotecnologie Cellulari ed Ematologia
  • Roma, Italy
    • Università Cattolica S. Cuore, Ematologia
  • Rozzano, Italy
    • Istituto Clinico Humanitas, UO Ematologia
  • Torino, Italy
    • A.O.U. Città della Salute e della Scienza di Torino, SC Ematologia Universitaria
  • Torino, Italy
    • A.O.U. Città della Salute e della Scienza di Torino, SC Ematologia
  • Treviso, Italy
    • Ospedale Ca' Foncello, SC Ematologia
  • Tricase, Italy
    • Azienda Ospedaliera C. Panico, UOC Ematologia e Trapianto
  • Udine, Italy
    • Azienda Sanitaria Universitaria Integrata di Udine, Clinica Ematologica
  • Varese, Italy
    • Ospedale di Circolo, UOC Ematologia
  • Verona, Italy
    • Azienda Ospedaliera Universitaria Integrata di Verona, UO Ematologia
  • Vicenza, Italy
    • Ospedale San Bortolo, Divisione di Ematologia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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)

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: V-RBAC (RBAC followed by 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).

Drug: Venetoclax; Consolidation and maintenance phases with Venetoclax (for a total of 2 years) after an induction phase R-BAC (up to 6 cycles for law risk patients and up to 4 cycles for high risk patients); Other Names: Venclyxto (commercial name)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival of the High Risk patients	2-years progression-free survival (PFS) of the HR patients from date of enrollment	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Molecular response	The proportion of molecular response (analyzed in the labs of the FIL- MRD Network)	10 months and 30 months
Progression-free survival of all patients and different subgroups	The progression-free survival (PFS) of all enrolled patients, and of different subgroups (i.e TP53 mutated patients)	24 months
Overall survival	Overall survival	54 months
Duration of responses	Duration of responses	24 months
Proportion of complete remission in High Risk and Law Risk patients	The proportion of complete remission (CR) before and after venetoclax in the HR group and/or in the LR not responding to R-BAC	6 months and 10 months
Completed expected treatment schedule	The proportion of patients that complete the expected treatment schedule	30 months
Incidence of Treatment-Emergent Adverse Events	The proportion of patients with adverse events as assessed by CTCAE 4.03 during venetoclax administration as consolidation or maintenance after R-BAC	10 months and 30 months

Collaborators and Investigators

• Sponsor: Fondazione Italiana Linfomi - ETS
• Collaborators: AbbVie
• Investigators: Principal Investigator: Carlo Visco, MD, AOU Integrata di Verona - U.O. Ematologia -Verona -Italy

Study record dates

Study Major Dates

• Study Start (Actual): September 3, 2018
• Primary Completion (Actual): July 26, 2021
• Study Completion (Estimated): July 1, 2025

Study Registration Dates

• First Submitted: May 22, 2018
• First Submitted That Met QC Criteria: June 13, 2018
• First Posted (Actual): June 26, 2018

Study Record Updates

• Last Update Posted (Actual): September 13, 2023
• Last Update Submitted That Met QC Criteria: September 12, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Elderly patients; Mantle cell lymphoma; First line
• 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; Antineoplastic Agents; Venetoclax
• Other Study ID Numbers: FIL_V-RBAC

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No