CT-012 - PHARMACOKINETICS OF BT8009, A BICYCLE TOXIN CONJUGATE (BTC), IN PATIENTS WITH SOLID TUMOR MALIGNANCIES AND VARIOUS DEGREES OF RENAL FUNCTIONS

J. Bader, Z. Wang, A. Dickson, S. Hazard, P. Jeffrey, H. Xu; Bicycle Therapeutics.

Background: BT8009 is a BTC, a chemically synthesized molecule comprised of a small (~3.5 kDa) bicyclic peptide targeting tumor antigen (Nectin-4) linked to cytotoxin (MMAE). BTCs represent a unique therapeutic class, distinct from antibody drug conjugates (ADCs) and with pharmacokinetic (PK) properties analogous to small molecules. It is important to assess the impact of renal function on the PK of BT8009 and MMAE to determine appropriate dosing for patients with various degrees of renal function. To assess the impact of renal impairment on the PK of BT8009 and MMAE, we evaluated preliminary results from BT8009-100, an ongoing Phase I/II clinical trial (NCT04561362).

Methods: Patients with various advanced solid tumor malignancies receiving BT8009 monotherapy were evaluated (n=97). Intravenous doses were administered ranging from 2.5–10 mg/m2 (weekly, bi-weekly, or on Days 1 and 8 of a 21-day cycle) . Intensive PK sampling was collected following C1D1 dosing. Patients were grouped by renal functions based on creatinine clearance at C1D1 and exposures (AUC0-inf [ng*h/mL] and Cmax [ng/mL]) from C1D1 for BT8009 and MMAE were generated using non-compartmental analyses and dose-normalized.

Results: As of 18 June 2023, patients evaluated included 27, 40, and 30 with normal renal function (≥90 mL/min), mild impairment (60-89 mL/min), and moderate renal impairment (30-59 mL/min), respectively. BT8009 and MMAE exposures were similar for patients with mild or moderate renal impairment relative to those with normal renal function. Geometric mean ratios of the dose-normalized exposures for patients with mild and moderate renal impairment versus normal renal function were similar based on BT8009 AUC0-inf (1.17 and 1.15, respectively), BT8009 Cmax (1.10 and 1.18, respectively), MMAE AUC0-inf (1.35 and 1.08, respectively), and MMAE Cmax (1.20 and 1.05, respectively). Moreover, the 90% CI for almost all scenarios evaluated crossed 1 (unity), indicating no statistically significant difference.

Conclusion: BT8009 and MMAE AUC0-inf and Cmax across participants with normal renal function, mild renal impairment, and moderate renal impairment were similar. Therefore, no dose adjustments are recommended for participants with mild or moderate renal impairment.