BT8009-100: A phase I/II study of novel bicyclic peptide and MMAE conjugate BT8009 in patients (pts) with advanced malignancies associated with nectin-4 expression, including urothelial cancer (UC).

498 Background: BT8009 is a Bicycle Toxin Conjugate (BTC), a novel class of chemically synthesized molecules comprising a small (~2 kDa) bicyclic peptide targeting Nectin-4 tumor antigen linked to cytotoxin MMAE via a valine-citrulline cleavable linker. BTCs represent a unique therapeutic class, distinct from ADCs and with pharmacokinetic properties analogous to small molecules. Presented are the monotherapy dose escalation results of the ongoing Phase I/II clinical trial of BT8009 (NCT04561362). Methods: In the Part A 3+3 dose escalation portion of the study, BT8009 monotherapy was administered weekly (2.5, 5, 7.5 mg/m 2 ) or every other week (7.5, 10 mg/m 2 ) of a 28-day cycle, or on days 1 and 8 of a 21-day cycle (7.5 mg/m 2 ). Primary objectives were to assess safety of the monotherapy and define maximum tolerated and recommended Phase II dose(s) (RP2D). Key secondary objectives were antitumor activity per RECIST v1.1 and PK parameters. Results: At time of the 20 Sept 2022 data cut-off, 49 pts had received BT8009 (24 pts with UC): weekly (7 pts at 2.5 mg/m 2 , 20 pts at 5 mg/m 2 , 5 pts at 7.5 mg/m 2 ); biweekly (5 pts at 7.5 mg/m 2 , 7 pts at 10 mg/m 2 ); and days 1+8 of a 21-day cycle (5 pts at 7.5 mg/m 2 ). Two RP2Ds have been determined: 5 mg/m 2 given weekly on a 28-day cycle and 7.5 mg/m 2 given on days 1+8 of a 21-day cycle. Median age was 66 y, 59% pts were male, and median prior lines of therapy was 3 (range 1-15). Most common treatment-related adverse events of any grade experienced by ≥15% of pts were nausea, fatigue, diarrhea, decreased appetite, alopecia, asthenia, pyrexia, and neutrophil count decreased/neutropenia; majority were mild to moderate in severity. One DLT (G3 asthenia) was reported at the 7.5 mg/m 2 weekly dose level and 1 DLT (G4 sepsis) at the 10 mg/m 2 biweekly dose level. Treatment-related SAEs occurred in 5 pts. No pt discontinued treatment due to an AE. No treatment-related deaths occurred. Of 8 efficacy evaluable pts with UC treated with a RP2D of 5 mg/m 2 , there was 1 complete response, 3 partial responses (PR), and 3 stable diseases (SD), for an ORR of 50% and clinical benefit rate of 75% (CR+PR+SD≥16 wks). Median duration of response has not yet been reached, but as of 20 Sept 2022 was at least 11 months. Both plasma BT8009 and MMAE exhibited linear pharmacokinetics, with short half-life for BT8009 (