ME-401-003 (TIDAL): A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Two-Arm, Phase 2 Study of ME-401 Investigating Continuous and Intermittent Dosing Schedules in Patients with Relapsed/Refractory Follicular Lymphoma
Authors: Zelenetz Andrew D. , Zinzani Pier Luigi Luigi , Chan Henry , Buske Christian , Ribrag Vincent , Cunningham David , Jurczak Wojciech , Abrisqueta Pau , Li Joanne , Gorbatchevsky Igor , Brown Jennifer R. 
Published: November 2019

Background: PI3Kδ signaling is at the crossroads of B-cell receptor signaling pathways that are major drivers of survival and proliferation of B-cell malignancies, making it an attractive target for drug development. PI3Kδ inhibitors have proven clinical efficacy in relapsed or refractory non-Hodgkin's lymphoma (NHL); however, the high incidence of immune-related adverse events (irAEs) of early generation PI3Kδ inhibitors has limited their use. Management of toxicities by daily dose reduction may reduce the incidence of toxicities but also can lead to potential loss of efficacy, therefore novel approaches are needed to maximize clinical utility. ME-401 is an oral once-daily selective PI3Kδ with a molecular structure and pharmacodynamic characteristics that are distinct from other PI3Kδ inhibitors, either approved or under development. ME-401's high volume of distribution, long half-life (~30 hours), and intracellular penetration/ retention kinetics predict a significantly higher tumor exposure to drug relative to plasma which has been borne out in pre-clinical mouse lymphoma studies. These properties allow use of an intermittent dosing schedule to minimize immune-related toxicities common to other PI3kδ agents. ME-401 has demonstrated high and objective response rates (ORR) in both FL and CLL/SLL; 80% in 50 patients with relapsed/refractory (R/R) FL and 100% in 14 patients with R/R CLL/SLL (Zelenetz et al 2019). During the Phase 1b dose escalation study of ME-401 administered on a continuous daily dosing schedule (CS, 28-day cycle), no dose limiting toxicities were identified, and the first dose level of 60 mg was selected for further development due to its high response rate. Delayed (≥ cycle 3) grade 3 AEs such as diarrhea and rash occurred in approximately one third of patients (Zelenetz, 2018). These AEs are likely related to on-target effects on T-regulatory cells (T-regs) resulting in immune-mediated toxicity. With the goal of improving tolerability we developed a novel dosing approach for ME-401, reducing dose intensity via intermittent dosing (IS) 7 days on/21 days off, with the goal of allowing Treg repopulation. The IS is introduced after an initial period (2 cycles) of daily dosing for tumor debulking. Preliminary evaluation of this novel schedule resulted in a marked decrease in delayed Grade 3 irAEs compared to the CS. The ME-401-003 (TIDAL) study was designed to further evaluate risk-benefit profiles of these two treatment schedules of this potent PI3Kδ inhibitor in patients with relapsed or refractory FL.
Study Design and Methods:ME-401-003 (TIDAL) is a global study of ME-401 in patients with FL after failure of ≥2 prior systemic therapies and will enroll approximately 166 subjects. Subjects must have received prior therapy with an anti-CD20 antibody and chemotherapy with an alkylating agent or purine analogue with adequate organ and bone marrow function; no prior therapy with a PI3Kδ is allowed. Upon meeting eligibility criteria, patients are randomized to the CS or IS dosing group with a 1:1 allocation ratio at baseline and receive open-label ME-401 at 60 mg daily for the first two cycles. The stratification factors for randomization are disease status (relapsed or refractory) and tumor bulk. Patients with stable disease or an objective response after 2 cycles will then continue onto the blinded, placebo-controlled portion of the study and will receive ME-401 either on a CS or an IS. Patients who experience disease progression on IS will be able to receive open-label ME-401 on CS to explore the recapture of response. Subjects who develop grade ≥ 2 adverse of special interest (AESI) will have study drug halted and upon resolution of AE will continue on open label IS to mitigate toxicity. The primary objectives are ORR using Lugano Response Criteria, as determined by an Independent Response Review Committee, and tolerability defined as the rate of AEs requiring dose modification or study drug discontinuation utilizing a sample size of 75 subjects per treatment schedule. A correlative study will evaluate the effects of ME-401 on T-cell subsets, cytokines and chemokines. The study opened to enrollment in December 2018 with sites planned in North America, Europe, Asia, New Zealand and Australia. (NCT03768505)

Disclosures
Zelenetz: Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Zinzani:VERASTEM: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CELLTRION: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GILEAD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; JANSSEN-CILAG: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SERVIER: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SANDOZ: Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; IMMUNE DESIGN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CELGENE: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PORTOLA: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ROCHE: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSAPHARMA: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; KYOWA KIRIN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SANOFI: Consultancy. Buske:Janssen: Honoraria, Research Funding, Speakers Bureau; Amgen: Research Funding; Roche: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria; Bayer: Research Funding; Celltrion: Honoraria, Speakers Bureau; Hexal: Honoraria, Speakers Bureau. Ribrag:AZ: Membership on an entity's Board of Directors or advisory committees; argenX: Research Funding; Infinity: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Epizyme: Honoraria, Research Funding; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees. Cunningham:Bayer: Research Funding; Amgen: Research Funding; MedImmune: Research Funding; Clovis: Research Funding; Merck: Research Funding; 4SC: Research Funding; Eli Lilly: Research Funding; Merrimack: Research Funding; AstraZeneca: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Janssen: Research Funding. Jurczak:Gilead: Research Funding; Takeda: Research Funding; Celtrion: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Research Funding; Incyte: Research Funding; Celgene Corporation: Research Funding; TG Therapeutics: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Morphosys: Research Funding; Novo Nordisk: Research Funding; Roche: Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding. Abrisqueta:Celgene: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau; Roche: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau. Brown:Kite, a Gilead Company: Consultancy, Research Funding; Pharmacyclics: Consultancy; Pfizer: Consultancy; Juno/Celgene: Consultancy; BeiGene: Consultancy; Loxo: Consultancy, Research Funding; Genentech/Roche: Consultancy; Gilead: Consultancy, Research Funding; Catapult Therapeutics: Consultancy; Dynamo Therapeutics: Consultancy; AstraZeneca: Consultancy; Novartis: Consultancy; Octapharma: Consultancy; Invectys: Other: Data safety monitoring board; Morphosys: Other: Data safety monitoring board; Teva: Honoraria; Janssen: Honoraria; Sun Pharmaceuticals: Research Funding; Verastem: Consultancy, Research Funding; TG Therapeutics: Consultancy; Sunesis: Consultancy; Acerta Pharma: Consultancy; AbbVie: Consultancy.