Ibrutinib, Venetoclax Plus Obinutuzumab in Newly Diagnosed Mantle Cell Lymphoma Patients
Authors: Le Gouill Steven , Morschhauser Franck , Bouabdallah Kamal , Cartron Guillaume , Casasnovas Olivier , Gastinne Thomas , Chevallier Patrice , Rossi Cédric , Tchernonog Emmanuelle , McCulloch Rory , Herbaux Charles , Chiron David , Callanan Mary , Rule Simon 
Published: November 2019

Background. Novel targeted therapies have demonstrated high efficacy in relapse and/or refractory (R/R) MCL. Ibrutinib, a first in class BTK inhibitor, is approved for R/R MCL. Venetoclax, a first in class bcl-2 inhibitor, is currently under investigation in prospective trials in R/R MCL. Obinutuzumab is a type II glycol-engineered, humanized anti-CD20 antibody approved in frontline and R/R follicular lymphoma which has shown efficacy in MCL (Chiron Blood 2016, Le Gouill ICML/EHA 2019). Pre-clinical investigations have demonstrated the utility of combining these three molecules in MCL (Chiron et al, Blood 2016) The OAsIs trial (NCT02558816) is a multicenter, non-randomised, phase I study that was designed to assess the safety, tolerability and efficacy of Ibrutinib/ Venetoclax/Obinutuzumab in both R/R MCL and in newly diagnosed MCL. The study is divided into three steps (A, B,C, respectively) : step A enrolled nine R/R MCL who were treated with Ibrutinib plus Obinutuzumab and step B enrolled 24 R/R MCL patients who were treated with Ibrutinib/Venetoclax/Obinutuzumab (Venetoclax dose from 200 to 800mg ). The Ibrutinib/Venetoclax/Obinutuzumab combination demonstrated a good safety profile and high response rates in R/R MCL (step B). No DLT was reported in either step (Le Gouill et al, ASH 2018). Herein, we present the safety (primary objective), clinical and MRD results for Oasis step C where Ibrutinib/Venetoclax/Obinutuzumab was given to newly-diagnosed, untreated MCL patients.
Methods: Obinutuzumab was given at 1000mg IV C1D1, 8, 15, C2-6 D1 and every 2 months until C23. Ibrutinib was given as a standard dose (560mg/d) from C1D2 and until progression. The dose of Venetoclax was 400mg (according to step B analysis and DSMC recommendations) and administered from C1-bis (to prevent TLS: C1-bis W1-20mg, C1-bis W2-50, C1-bis W3-100, C1-bis W4-200) and at 400mg from C2 to C23. Response was assessed by cheson 99 criteria at C2, C4 and C6 and by Lugano criteria at Cycle 6. MRD by ASO-qPCR (assay sensitivity 10-5) was measured at the end of C3 and 6 in blood and / or bone marrow. DLTs were assessed during the first 3 months (C1, C1-bis and C2) of treatment.
Results. Fifteen untreated MCL patients were enrolled from August 2018 to April 2019, in 6 participating centers (France and UK). Median age at inclusion was 65y (range 51-77). All patients presented with stage III/IV disease and nodal disease (four patients had tumor mass &gt;5cm). The MIPI score was high in 9 cases, intermediate in 5 and low in one case. One patient presented with pleomorphic variant. TP53 status at diagnosis was assessed in 13 patients (one was not informative and two are ongoing) of these one presented TP53 mutation. IGHV status (assessed in 13 patients, ongoing in 2) was mutated in two cases including the p53mutcase and not mutated in 8 (not informative in 3 cases). During the first three months of treatment (C1, C1-bis and C2), the relative dose intensity (ratio of delivered to the planned dose intensity) was 87% for Ibrutinib, 93% for Obinutuzumab and 100% for Venetoclax. During this period, non-hematological grade 3-4 AEs were hepatobiliary disorders (n=4; 3 patients with raised GGT-grade 3-, alanine -grade 3- and aspartate -grade 4- aminotransferase and one with biological cytolysis - grade 4) and rash (n=1; grade 3). Hematological grade 3-4 AEs were lymphocytosis (n=1; grade 3) and neutropenia (n=1; grade 4). All (n=15) patients are in response (including CR/uCR in 7 cases) at end of cycle 2 according to Cheson 99 criteria. In terms of MRD status, 8 patients (others are ongoing) were assessed at end of cycle 3 and all were MRD negative in BM (n=6) and/or in blood (n=8), including the p53mutpatient. Seven patients completed 6 cycles, all reached CR according to Lugano criteria (6 in CR/Cru according to Cheson criteria) and were MRD neg (in blood in all cases and in BM in 6 cases -one not done), including the P53mut patient. At date of last monitoring (Jul 2019), no disease progression is reported and all patients remain under the planned treatment.
Conclusion. Ibrutinib/Venetoclax/Obinutuzumab combination therapy has a very good safety profile and shows high efficacity rates at the molecular level in untreated patients. Oasis step C is the first trial that report the use of Ibrutinib/Venetoclax/Obinutuzumab as frontline therapy in MCL.

Disclosures
Le Gouill: Janssen-cilag: Consultancy, Honoraria; Novartis: Consultancy; Abbvie: Consultancy, Honoraria; Roche Genentech: Consultancy, Honoraria; Gilead-Kite: Consultancy, Honoraria; Servier: Consultancy; loxo: Consultancy, Honoraria; Takeda: Consultancy. Morschhauser:Bayer: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; BMS: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees. Bouabdallah:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Cartron:Roche, Celgene: Consultancy; Sanofi, Gilead, Janssen, Roche, Celgene: Honoraria. Chevallier:Jazz Pharmaceuticals: Honoraria; Daiichi Sankyo: Honoraria; Incyte: Consultancy, Honoraria. Rule:Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Honoraria; Napp: Consultancy; TG Therapeutics: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Kite: Consultancy.

OffLabel Disclosure:
Venetoclax, obinutuzumab in mantle cell lymphoma