First-in-Human Phase I Trial of a ROR1 Targeting Bispecific T Cell Engager (NVG-111) in Combination with Ibrutinib or As Monotherapy in Subjects with Relapsed Refractory Chronic Lymphocytic Leukaemia (CLL) and Mantle Cell Lymphoma (MCL)

Background: NVG-111 is a first in class, humanized, tandem scFv, ROR1xCD3 bispecific T cell engager that mediates potent killing of ROR1+ tumor by engaging an epitope on the Frizzled domain of ROR1 and redirecting T cell activity via the CD3 binder that has been engineered for lower cytokine release.

Methods: This multi-center, open-label, phase I study is evaluating NVG-111 in relapsed/refractory CLL and MCL subjects who have received ≥2 prior systemic therapies. An adaptive trial design was used for dose escalation, starting with accelerated dose titration (ATD) followed by a Bayesian continual reassessment method with overdose control. Each patient received at least one dose of NVG-111, administered as a continuous intravenous infusion (cIV) over 21 days followed by 7 days off drug (=1 cycle). NVG-111 was administered in combination (cohorts 1-4) with ibrutinib to patients who had achieved a stable or partial response to >1 year of ibrutinib therapy, or as monotherapy in patients who had progressed after BTKi / BCL2 (cohort 4b). Measurable residual disease (MRD) was assessed using a flow cytometric method with sensitivity 1e4 (MRD4). Mesoscale discovery electrochemiluminescence assay (MSD-ECLA) was used for pharmacokinetic analysis of NVG-111. Serum cytokine levels were determined using a human high sensitivity cytokine A premixed magnetic Luminex assay. Primary endpoints consisted of safety, tolerability and determination of maximum tolerated dose (MTD)/Recommended Phase 2 Dose (RP2D). Additional end-points included overall response rates as well as duration of response.

Results: As of July 2022, 10 subjects (8 males and 2 females, median age 60 years) had been enrolled to the study; three into single subject ATD cohorts, 3 into 30 µg/day flat dosing cohort (cohort 4) and 4 into cohort 4b that entailed a step-up dosing of NVG-111 in cycle 1 only; (first week cycle 1: 3 µg/day, second week, cycle 1: 10 µg/day and week 3, cycle 1: 30 µg/day dose). Eight subjects had CLL and 2 MCL. cIV was well tolerated. Adverse events (AEs) were largely limited to week 1 of cycle 1 and all were reversible. The most common AEs were Grade 1 or 2 nausea (70%), headaches (60%), and fatigue (50%) and thrombocytopenia (30%). Grade 1/2 cytokine release syndrome (CRS) was observed in (40%) of subjects. Grade 3 dose limiting toxicities occurred in two subjects consisting of immune effector cell-associated neurotoxicity syndrome-like symptoms (ICANS) in one (cohort 4) and ALT and AST elevation (cohort 4b) in the other. Both subjects recovered upon stopping NVG-111. Average steady-state serum concentration (C_avg.ss) of NVG-111 in serum of patients who received a 10µg/day and 30µg/day dose were 168-288pg/mL and 425-610pg/mL respectively. This was in line with the predicted drug levels from the single species allometric scaling. Evidence of T cell activation was observed in all evaluable subjects (9/10) with cytokine levels at the 30µg/day dose level being: TNFα, 21±6pg/ml; IL6, 206±178pg/ml; IFNɣ, 7±4pg/ml; and IL10, 47±21pg/ml. Objective clinical responses were observed in 66% of subjects and included 2 MRD4 negative clinical remissions (CR). These two subjects remained in MRD4 negative CRs at 6 months after completion of treatment.

Conclusion: Early data shows that NVG-111 is generally well tolerated with a predictable and manageable safety profile. Promising evidence of efficacy was observed which appears to be durable in two subjects with MRD4 negative CR. Dose escalation is ongoing in combination or as monotherapy to determine the MTD/RP2D.

Townsend:Takeda, Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria. Tucker:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Immunovant Corps: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria. Paneesha:AstraZeneca: Honoraria; Janssen: Honoraria; Gilead: Honoraria; AbbVie: Honoraria. El-Sharkawi:AbbVie: Consultancy, Honoraria; Astex: Consultancy; AstraZeneca: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Gilead: Honoraria; Janssen: Consultancy, Honoraria; Kyowa Kirin: Consultancy; Lilly: Consultancy; Novartis: Honoraria; Roche: Consultancy, Honoraria; Takeda: Honoraria. Eyre:AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BeiGene: Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; KITE: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; LOXO Lilly: Membership on an entity's Board of Directors or advisory committees, Other, Speakers Bureau; PeerView: Speakers Bureau; Medscape: Speakers Bureau; Secura Bio: Membership on an entity's Board of Directors or advisory committees. Batten:Veramed: Current Employment. Shah:UCB: Divested equity in a private or publicly-traded company in the past 24 months, Ended employment in the past 24 months. Granger:Haleon: Current equity holder in publicly-traded company; GSK: Current equity holder in publicly-traded company, Patents & Royalties. Nathwani:Biomarin: Research Funding; Genethon: Membership on an entity's Board of Directors or advisory committees.