RNDO-564-001: A first-in-human, phase 1/1b study of RNDO-564, a bispecific antibody for the treatment of advanced bladder cancer and other tumors associated with Nectin-4 expression.

TPS903 Background: RNDO-564 is a novel CD28 x Nectin-4 bispecific antibody (bsAb) with a high affinity Nectin-4 binding arm and a potency-optimized CD28 arm designed for maximum therapeutic window. RNDO-564-001 (NCT07218003) is an ongoing, open label, multicenter, dose escalation and dose optimization study of RNDO-564 as monotherapy, and in combination with pembrolizumab (anti-programmed death PD-1 monoclonal antibody), in adults with relapsed/refractory (R/R), locally advanced or metastatic urothelial cancer (la/mUC) and other solid tumors associated with Nectin-4 expression. Methods: The objectives of the study are to assess the safety, tolerability, and to determine the recommended phase 2 dose (RP2D) of intravenous RNDO-564 monotherapy given on Days 1, 8, and 15 of a 21-day cycle. Monotherapy dose escalation will include an accelerated titration component using four single participant (pt) cohorts, followed by more gradual dose increments tested using a Bayesian Optimal Interval (BOIN) with backfill design. To determine the RP2D of single agent RNDO-564 in R/R la/mUC, up to two 20 pt dose optimization cohorts at two different dose levels and/or dosing schedules, will be enrolled. Pts with R/R la/mUC, cervical, head and neck, esophageal, gastric, gastroesophageal (GEJ), non-small cell lung, or triple negative breast cancer, who have exhausted, are ineligible for, or declined available standard treatment options, are eligible for the dose escalation phase of the study. Pts must have an ECOG performance status of 0-1. Pts with prior Nectin-4 directed therapies and MMAE exposure and those with ongoing Grade ≤ 2 peripheral neuropathy are eligible. Pts with a history of, or with active, inflammatory skin conditions are ineligible. Safety endpoints include incidence of adverse events per CTCAE v5.0. Secondary endpoints include clinical activity, pharmacokinetics, and incidence of anti-drug antibody development. Retrospective assessment of Nectin-4 expression on tumor tissue by IHC, and measurement of CD28 receptor occupancy, T cell activation, soluble Nectin-4, and serum cytokines in peripheral blood will be performed as exploratory endpoints. Separate dose escalation and optimization stages in combination with pembrolizumab will be conducted to assess the safety, preliminary clinical activity, and recommended doses for further development of the combination treatment. Additional monotherapy and/or combination therapy expansion cohorts may be opened for participants with non-UC tumors, based on emerging clinical data. Conclusions: RNDO-564-001 is an ongoing phase 1/1b study to determine the safety, tolerability, clinical activity, and RP2D of a novel CD28 x Nectin-4 bsAb that has been optimized for safety and efficacy in R/R la/mUC and other solid tumors associated with Nectin-4 expression. Clinical trial information: NCT07218003 .