J. Xu,1 H. Burris III,2 M. Gordon,3 D. Gerber,4 Y. Choi,1 K. Lin,1 D. Maslyar,1 S. Girish1; 1Genentech, A member of the Roche Group, South San Francisco, CA, 2Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN, 3Pinnacle Oncology Hematology, Scottsdale, AZ, 4Harold C. Simmons Cancer Center, UT Southwestern Medical Center, Dallas, TX

BACKGROUND: NaPi2b is a transmembrane transporter overexpressed on ovarian cancer and non-small cell lung cancer. DNIB0600A is an antibody-drug conjugate containing the potent anti-mitotic agent monomethyl auristatin E (MMAE) conjugated to a humanized anti-NaPi2b IgG1 via a protease labile linker. A Phase I study is ongoing in platinum-resistant OC and NSCLC patients to assess the safety, efficacy and PK of DNIB0600A (0.2-2.8 mg/kg) given every 3 weeks. We discuss DNIB0600A cycle 1 pharmacokinetics (PK) here.
METHODS: Serum/plasma samples were obtained from patients (N=68) at pre-specified time points. Three major analytes, including total antibody (unconjugated and conjugated antibody, Tab), unconjugated MMAE and DNIB0600A conjugate (antibody conjugated MMAE, acMMAE), were quantified and assessed with non-compartmental analysis.
RESULTS: Within the tested dose range, the systemic exposure of acMMAE and Tab increased linearly. The Tab and acMMAE clearance ranged from 10.6 to 17.0 mL/day/kg, and 15.4 to 26.8 mL/day/kg. The half-life for Tab, acMMAE and unconjugated MMAE ranged from 4.7 to 9.3 days, 4.0 to 6.1 days, and 3.5 to 4.8 days. No significant accumulation of either analyte was observed after repeated dosing. At 2.4 mg/kg (recommended Phase II dose (RP2D) (N=44)): clearance was ~19 mL/day/kg (acMMAE) and ~13 mL/day/kg (Tab); the steady state volume of distribution for acMMAE and Tab was ~92 mL/kg and ~67 mL/kg; exposure of unconjugated MMAE was ~46 ng/ml*day (AUCinf) and ~5 ng/mL (Cmax); and there were no differences in exposure and PK parameters between patients with OC and NSCLC.
CONCLUSION: In this ongoing study, linear PK of acMMAE and Tab was observed. At RP2D, no impact of cancer type on the PK was observed. Systemic unconjugated MMAE concentrations were low and consistent with other MMAE ADCs (approved or in clinical development).