PII-080 - PHARMACOKINETICS OF A FULLY HUMAN BISPECIFIC PROSTATE-SPECIFIC MEMBRANE ANTIGEN (PSMA) AND CLUSTER OF DIFFERENTIATION (CD3) BINDING MONOCLONAL ANTIBODY (AMG 340) IN SUBJECTS WITH METASTATIC CASTRATE-RESISTANT PROSTATE CANCER

I. Vuu¹, B. Houk¹; ¹Amgen Inc., Thousand Oaks, CA, USA.

Background: AMG 340, a fully human bispecific monoclonal IgG4 antibody targeting PSMA-CD3, was investigated in a phase 1, open-label, first-in-human dose-escalation study. One objective of this study was to characterize AMG 340 pharmacokinetics (PK) in subjects with metastatic castrate-resistant prostate cancer (mCRPC).

Methods: Subjects with mCRPC (who had received ≥2 prior lines of prior therapy) were enrolled across 11 cohorts and received AMG 340 (1.5-800 mg IV Q3W). Cohorts 1-5 were dosed with 1.5-100 mg Q3W. Cohorts 6-9 had one step dose of 20-40 mg on C1D1 and a target dose on C1D8 ranging from 100-400 mg Q3W. Cohort 10 had step doses of 40 mg on C1D1, 400 mg on C1D5, and a target dose of 800 mg on C1D8. Intensive PK samples were collected in Cycles 1, 3 and 6. AMG 340 serum concentrations were measured by an electrochemiluminescence assay. PK parameters were estimated using noncompartmental analysis (NCA). Relationships between clearance and volume estimates against baseline weight and age were evaluated.

Results: 41 subjects were enrolled and PK evaluable. With increasing doses of AMG 340, mean exposures (maximum concentration and area under the curve from time 0 to tau) increased in a dose-proportional manner. Mean accumulation ratio (calculated after the third and sixth target doses) were 1.7 and 1.6, respectively, corresponding to an effective half-life of 16.4 and 14.8 days. At doses of 1.5-400 mg Q3W, after the third target dose on Day 42, geometric mean clearance (CL) and volume of distribution (Vd) were 0.25 L/day and 3.3 L, respectively, consistent with those of other monoclonal antibodies (mAbs). Bodyweight trended positively with Vd.

Conclusion: AMG 340, a fully human bispecific monoclonal IgG4 antibody targeting PSMA with a novel low-affinity CD3 binding domain, displayed dose-proportional, time-independent PK within the 1.5-800 mg Q3W dose range. CL and Vd were consistent with those of other mAbs, and distribution was predominantly limited to the vascular space. Bodyweight trended positively with Vd. The mean effective half-life was 16.4 days, and steady-state exposures were achieved after the fourth Q3W target dose.