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

TPS4640 Background: RNDO-564 is a novel CD28 x Nectin-4 bispecific antibody (bsAb) with high affinity Nectin-4 binding and optimized CD28 costimulatory arms designed to maximize the therapeutic window. RNDO-564-001 (NCT07218003) is an ongoing, open label, multicenter, phase 1/1b 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 Nectin-4 positive solid tumors. 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 using a Bayesian Optimal Interval (BOIN) with backfill design. Pts with R/R la/mUC, cervical, head and neck, esophageal, gastric, gastroesophageal, 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 Monomethyl Auristatin E (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. Enrollment into Cohorts 1 and 2 have been completed without dose limiting toxicity (DLT). Enrollment to cohort 3 opened in January 2026. Safety endpoints include incidence of adverse events per CTCAE v6.0. Secondary endpoints include clinical activity, pharmacokinetics, and incidence of anti-drug antibody development. Retrospective assessment of Nectin-4 expression on tumor tissue by immunohistochemistry (IHC), and measurement of CD28 receptor occupancy, T cell activation, and serum cytokines in peripheral blood will be performed as exploratory endpoints. To determine the optimal RP2D in R/R la/mUC, up to two 20 pt dose optimization cohorts at two different dose levels will be enrolled. Separate dose escalation and optimization stages in combination with pembrolizumab will be conducted to assess safety, clinical activity, and RP2D for further development of combination treatment. Based on emerging clinical data, additional monotherapy and/or combination therapy expansion cohorts may be opened for pts with non-UC Nectin-4 positive solid tumors. Conclusions: RNDO-564-001 is an ongoing phase 1/1b study to determine the safety, tolerability, clinical activity, and RP2D of RNDO-564 in R/R la/mUC and other Nectin-4 positive solid tumors. Clinical trial information: NCT#07218003 .