Application of Model Informed Drug Development (MIDD) to BT8009, a Bicycle Toxin Conjugate (BTC®), in Patients with Advanced Urothelial Cancer
Authors: Lu Yasong , Wang Zixu , Wada Russ , Ko Paul , Bader Justin , Li Mengyao , Arroyo Santiago , Xu Hongmei 
Published: February 2025

Objectives: BT8009 is a chemically synthesized BTC® (~4.2 kDa) comprising a small Nectin-4-targeting bicyclic peptide linked to a cytotoxin MMAE. BT8009 has been studied in a dose-escalation (2.5 to 10 mg/m2 QW, Q2W, or on Days 1 and 8 of a 21-day cycle) and expansion Ph1/2 study (Duravelo-1, NCT04561362) in patients with solid advanced malignancies, and has demonstrated preliminary antitumor activities with an acceptable safety profile. We employed population PK (PopPK) and exposure-safety (E-S) analyses of Duravelo-1 to inform selection of dosing regimens for investigation in patients with urothelial cancer. Methods: Patients with measurable PK were included in the PopPK analysis; those with PK and safety data were included in the E-S analysis. PopPK development used a sequential approach: the model for BT8009 was developed first, then with all BT8009 parameters fixed, the model for MMAE was developed. For both models, the development advanced from base model to covariate evaluation (of a prespecified list of factors, using the full covariate approach) and to final model. Individual post hoc exposure metrics [Cycle 1 Cmax, Cycle 1 weekly average AUC, average concentration to event (Cavg) of BT8009 and MMAE] were derived. Safety endpoints Grade 3+ (Gr3+) treatment-related adverse events (TRAE), Gr3+ neutropenia, any grade gastrointestinal (GI) disorder, and dose modification due to TRAE were analyzed using logistic regression with the exposure metrics as predictors. Final models were selected using a likelihood ratio test. Exposure metrics and AE probabilities simulated from a virtual population using the final PopPK and E-S models were used to inform dosing regimen selection. Results: The PopPK dataset included 1140 and 2378 observations for BT8009 and MMAE, respectively, from 136 patients. The BT8009 model was a 2-compartment model with linear clearance from the central compartment. No covariates were retained in the model per predefined criteria. The MMAE model was a 3-compartment model with linear clearance from the central compartment; the input of MMAE was governed by BT8009 clearance through a transit compartment. The final model retained tumor size to account for the variability in MMAE input. The PopPK model performance was confirmed by diagnostics. The AEs analyzed were positively correlated with the exposure metrics, with the strongest correlations with BT8009 Cmax (Gr3+ neutropenia) or Cavg (the others). At the two regimens of developmental interest, 5 mg/m2 QW and 6 mg/m2 on Days 1 and 8 of a 21-day cycle, generally comparable probabilities of AEs (e.g., Gr3+ TRAE 33.8% vs 27.1%; GI disorder 43.5% vs 35.9%) were expected from model simulations, supporting both doses for further development. Conclusions: The analyses informed selection of 2 distinct regimens (5 mg/m2 QW and 6 mg/m2 on Days 1 and 8 of a 21-day cycle) to be investigated in patients with urothelial cancer in a pivotal Ph2/3 study (Duravelo-2, NCT06225596).Citations: NA