First-in-human phase I study of a ROR1-targeting bispecific T-cell engager (NVG-111) shows evidence of efficacy in patients with relapsed/refractory CLL and MCL.

7535 Background: NVG-111 is a first in class, humanized, tandem scFv ROR1xCD3 bispecific T cell engager that mediates potent killing of ROR1+ tumours by engaging an epitope on the Frizzled domain of ROR1 and redirecting T cell activity via the CD3 binder. Methods: This phase I/II study is evaluating NVG-111 in patients with relapsed/refractory (R/R) CLL and MCL who have received ≥2 prior systemic therapies and have achieved a stable, or partial response to the last line of therapy. NVG-111 was delivered as continuous intravenous (cIV) infusion over 21 days per cycle, with each patient typically receiving 3 cycles of treatment. The first 3 single patient cohorts were subjected to accelerated dose titration (ADT) over a range of 0.3-30µg/day. Dose-escalation steps in the subsequent, multi-patient, cohorts were determined using a continuous reassessment method with overdose control. The primary endpoints are safety and determination of MTD/RP2D. Secondary objectives are pharmacokinetics, pharmacodynamics, immunogenicity and anti-tumor activity, assessed by multicolor flow cytometry to quantitate minimal residual disease (MRD4). Results: As of January 2022, six patients (all males, median age 60 years) had been enrolled to the study; three into each of the ADT cohorts and the remaining into a 30 µg/day flat dosing cohort. Five patients had CLL, and one had MCL, with all subjects remaining on ibrutinib whilst receiving NVG-111. The most common adverse events were Grade 1 lethargy, headaches, nausea, vomiting and thrombocytopenia. All 3 patients exposed to a flat dose of NVG-111 at 30µg/day suffered Grade 1 cytokine release syndrome (CRS) during week 1 of cycle 1. This did not require tocilizumab or dose interruption except in one patient who developed transient, grade 3 immune effector cell–associated neurotoxicity syndrome-like symptoms (ICANS). CRS or ICANS was not observed in subsequent cycles of treatment at this dose level. Response was observed in all 5 evaluable patients who had completed efficacy assessment after 3 cycles of NVG-111. Amongst these, 2 patients had undetectable MRD in the blood with one being MRD negative in the bone marrow. Dose escalation is ongoing, including exploration of step-up dosing. Conclusions: Early data with NVG-111 shows promising efficacy with a predictable and manageable safety profile. Clinical trial information: NCT04763083.