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

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)