J. Xu,1 R. Zhang,1 O. Saad,1 J. F. Liu,2 K. N. Moore,3 H. A. Burris, III,4 E. Humke,1 K. Achilles Poon,1 S. Girish1; 1Genentech, A member of the Roche Group, South San Francisco, CA, 2Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 3University of Oklahoma Health Sciences Center, Oklahoma City, OK, 4Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN

BACKGROUND: DMUC5754A is an ADC comprising a humanized anti-MUC16 IgG1 and a potent anti-mitotic agent, monomethyl auristatin E (MMAE) through a protease-labile linker. A Phase I study in PROC and PANC patients is ongoing to assess the safety, efficacy and PK of DMUC5754A given weekly (Q1W) or every 3 weeks (Q3W). The pharmacokinetics (PK) of DMUC5754A is presented here.
METHODS: Serum/plasma samples at multiple time points were quantified for three analytes (unconjugated MMAE, DMUC5754A total antibody (tAb), and DMUC5754A conjugate (antibody-conjugated MMAE, acMMAE)). PK was assessed by standard non-compartmental analysis, and evaluated by dose regimen and cancer type. The impact of serum CA125 (a soluble form of MUC16) on PK was investigated.
RESULTS: Within the test dose range (0.3-3.2 mg/kg), acMMAE and tAb showed nonlinear PK, and a clear correlation of acMMAE with tAb exposure was observed. For unconjugated MMAE, exposure increased with dose and half-life was 2-4 days. Accumulation of either analyte was minimal after repeated dosing. At a dose of 2.4 mg/kg (Q3W MTD) and 1.6 mg/kg (Q1W MAD): acMMAE clearance were ~27 and ~32 mL/day/kg; half-life of acMMAE were ~5 and ~1.6 days. At the MTD: exposure of acMMAE and tAb were comparable in patients with PROC and PANC; the baseline CA125 levels did not show a clear impact on cycle 1 exposure; Cmax of acMMAE was comparable across cycles. High dose intensity would be needed in Q1W to achieve similar acMMAE exposure to Q3W at steady state in one cycle.
CONCLUSION: In this ongoing study, nonlinear PK of acMMAE and tAb were observed, and exposures of acMMAE and tAb were highly correlated. The Q1W regimen did not offer a higher exposure benefit than Q3W in one cycle. Similar exposure was observed in PROC and PANC patients. Finally, serum CA125 did not impact PK at MTD.