Phase 1b Study Of Everolimus (RAD001), a mTORC1 Inhibitor In Combination With Rituximab (R), In Patients With Relapsed Or Refractory Indolent CD20+ Lymphomas Or Transformed Aggressive CD20+ Lymphomas
Authors: Ribrag Vincent , Karlin Lionel , Terriou Louis , Gastinne Thomas , Camara-Clayette Valérie , Le Gouill Steven , Morschhauser Franck , Tilly Herve , Coiffier Bertrand 
Published: October 2019

Abstract

Background
Everolimus is an orally bioavailable mTORC inhibitor that has cytostatic activity in lymphoma in vitroand has shown single agent activity in aggressive B-cell lymphomas and Hodgkin’s lymphomas. The combination of everolimus and rituximab has also been recently explored in aggressive CD20+ DLBCL lymphomas with an ORR of bout 40%. The current study investigates the combination of everolimus and rituximab as a treatment for relapsed or refractory indolent lymphoma or transformed indolent CD20+lymphomas.

Methods
Lymphoma patients were assigned to sequential cohorts of oral dose of RAD001 (5 mg per day, 5 mg every other day), and R, 375 mg/m2 every week (4W) followed by one infusion of R every 2 months. The primary objective was the determination of the maximum tolerated dose (MTD) and the recommended dose (RD) for RAD001/R. Secondary objectives included characterization of safety profile, pharmacokinetics (PK) and anti-tumor activity of RAD001/R.

Results
21 patients were included and 20 patients treated (men: 11; women: 10 and median age of 72 (r: 51- 86). Histologies: FL: 8, MCL: 5, MZL: 4, transformed indolent lymphoma: 3, SLL: 1. The MTD was 5 mg/day of RAD001 and R 375mg/m2, as 2/6 patients experienced dose limiting toxicities (DLTs) [grade (G) 4 febrile neutropenia, one G 3 atrial fibrillation]. The RD was RAD001 5 mg every other day with R 375 mg/m2, with no patients experiencing DLTs. 6 pts were treated at the 5 mg every other day without DLT and 7 pts were treated at the same dose in an expansion cohort. Out of the 21 pts included, 2 pts planned at 5 mg every other day were not evaluable due to rapid progression before therapy in one case and at C1 day16 for one case. One pt is not evaluable (ongoing treatment before cycle 3 day1) and 2 pts had a DLT. 16 pts received 2 cycles and were evaluable for response. 6 achieved a response (5 PR and 1Cru), 6 had stable disease and 4 were progressive.
As per 06-13, 5 patients are still ongoing in study with 2 pts showing a partial response and a CRu and 3 patients showing stable disease. 9 pts discontinued the treatment due to progression of disease, and 2 patients due to treatment-emergent adverse events: anorexia and pulmonary toxicity at C3 day 8 and C2day 28 respectively. One pt stopped therapy due to a pulmonary infection not related to treatment during cycle 6. Preliminary PK analysis showed a large variability of RAD001 exposure between pts. Preliminary PD analysis confirmed target engagement (S6K) in 5/7 evaluable pts and showed s6K inhibition of phosphorylation at 4 hours post dosing in peripheral blood mononuclear cells stimulated with GM-CSF.

Conclusion
Preliminary results indicate that the combination of RAD001/R may be effective for the treatment of relapsed or refractory indolent lymphomas or transformed indolent lymphomas and has an acceptable safety profile.

Disclosures:
Ribrag: Servier: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity’s Board of Directors or advisory committees; Bayer: Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Johnson & Johnson: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Off Label Use: The abstract shows scientific information on SAR3419 which is an investigational product developed by Sanofi. This investigational product is not approved by any health authority for any indication. Karlin:Celgene: Expert board Other, Honoraria; Janssen: Honoraria. Morschhauser:novartis: Honoraria, Research Funding. Tilly:Roche: Honoraria; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity’s Board of Directors or advisory committees; Pfizer: Honoraria; Janssen: Honoraria; Amgen: Research Funding. Coiffier:Pfizer: Membership on an entity’s Board of Directors or advisory committees; Roche: Membership on an entity’s Board of Directors or advisory committees.