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

Lymphoma, Mantle-Cell Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03567876
• Other study ID #: FIL_V-RBAC
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: September 3, 2018
• Est. completion date: July 2025

Study information

• Verified date: September 2023
• Source: Fondazione Italiana Linfomi - ETS
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Active, not recruiting
• Enrollment: 141
• Est. completion date: July 2025
• Est. primary completion date: July 26, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Lymphoma
• Lymphoma, Mantle-Cell

Intervention

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)

Locations

Country	Name	City	State
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	IRCCS Istituto Tumori Giovanni Paolo II, UOC Ematologia	Bari
Italy	Policlinico S. Orsola-Malpighi, Istituto di Ematologia "Seragnoli"	Bologna
Italy	ASST Spedali Civili, Ematologia	Brescia
Italy	Ospedale Businco, Ematologia	Cagliari
Italy	Azienda Ospedaliera S. Croce e Carle, SC Ematologia	Cuneo
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	Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.), Ematologia	Meldola
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	Milano
Italy	AOU Maggiore della Carità di Novara, SCDU Ematologia	Novara
Italy	Azienda Ospedaliera Universitaria di Padova, Ematologia	Padova
Italy	A.O. Ospedali Riuniti Villa Sofia-Cervello, Divisione di Ematologia	Palermo
Italy	IRCCS Policlinico S. Matteo, Divisione di Ematologia	Pavia
Italy	Ospedale Guglielmo Da Saliceto, UO Ematologia	Piacenza
Italy	Ospedale delle Croci, Ematologia	Ravenna
Italy	Grande Ospedale Metropolitano Bianchi Melacrino Morelli, Ematologia	Reggio Calabria
Italy	Azienda Unità Sanitaria Locale-IRCCS - Arcispedale Santa Maria Nuova, Ematologia	Reggio Emilia
Italy	Ospedale degli Infermi, UO Ematologia	Rimini
Italy	Policlinico Umberto I - Università "La Sapienza", Istituto Ematologia -Dipartimento di Biotecnologie Cellulari ed Ematologia	Roma
Italy	Università Cattolica S. Cuore, Ematologia	Roma
Italy	Istituto Clinico Humanitas, UO Ematologia	Rozzano
Italy	A.O.U. Città della Salute e della Scienza di Torino, SC Ematologia	Torino
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 Ospedaliera C. Panico, UOC Ematologia e Trapianto	Tricase
Italy	Azienda Sanitaria Universitaria Integrata di Udine, Clinica Ematologica	Udine
Italy	Ospedale di Circolo, UOC Ematologia	Varese
Italy	Azienda Ospedaliera Universitaria Integrata di Verona, UO Ematologia	Verona
Italy	Ospedale San Bortolo, Divisione di Ematologia	Vicenza

Sponsors (2)

Lead Sponsor	Collaborator
Fondazione Italiana Linfomi - ETS	AbbVie

Country where clinical trial is conducted

Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Molecular response	The proportion of molecular response (analyzed in the labs of the FIL- MRD Network)	10 months and 30 months
Secondary	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
Secondary	Overall survival	Overall survival	54 months
Secondary	Duration of responses	Duration of responses	24 months
Secondary	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
Secondary	Completed expected treatment schedule	The proportion of patients that complete the expected treatment schedule	30 months
Secondary	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