Phase 1, first-in-human study of TRAIL receptor agonist fusion protein ABBV-621

3013 Background: ABBV-621 is a potent tumor-necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor agonist fusion protein that induces apoptotic cell death, particularly in DR4/5 expressing tumor models. Methods: Patients (pts) with previously treated solid tumors and ECOG 0–2 were administered ABBV-621 (2.5–15 mg/kg IV) on day (D) 1 (dose level [DL] 1) or D1D8 (DL2 and beyond) of each 21-day cycle. Dose escalation (DE) was guided by a Bayesian continual reassessment method. In addition to PK studies, blood-based PD markers of apoptosis (M30, M65) and drug binding were assessed. Results: As of 14 December 2018, 57 pts were enrolled in the DE portion, of which 30% had pancreatic, 23% colorectal cancer, and 47% other tumor types; 13 were KRAS mutant. Median age was 61 yrs. 60% were male; pts had a median of 4 prior regimens (range 1–10). Pts per DL: 2.5 (5 on D1, 16 on D1D8), 3.75 (12), 5 (6), 6.5 (6), 8.5 (4), 11 (4), and 15 mg/kg (4). Median duration of ABBV-621 exposure was 2 cycles (range 1–11). Seven pts had dose-limiting toxicities: respiratory failure (5 mg/kg; Grade 5, the only treatment-related death), blood bilirubin increased (3.75, 6.5 mg/kg), nausea (3.75 mg/kg), fatigue (3.75 mg/kg), increased ALT (2.5, 3.75, 6.5, 15 mg/kg), and increased AST (6.5 mg/kg). Summary of AEs is shown in Table. Clinical trial information: NCT03082209. A partial response (duration 20 weeks) was observed in a pt with pancreatic cancer (2.5 mg/kg D1D8). 27 pts had stable disease (6 pts for > 12 weeks). ABBV-621 PK was linear (mean ± SD clearance was 1.79 mL/h/kg ± 0.44) with a terminal half-life of 36.7 ± 5.55 h (n = 49). ABBV-621 bound to decoy receptors on neutrophils for up to 168 h; the duration of binding was dose-dependent. M30 and M65 increased at 8, 24, and 48 h following ABBV-621, but effect was independent of dose. Conclusions: ABBV-621 shows evidence of antitumor activity and effect on blood-based markers of apoptosis, with acceptable toxicity (MTD not reached). NCT03082209.[Table: see text]