First-in-human phase I study of HPN424, a tri-specific half-life extended PSMA-targeting T-cell engager in patients with metastatic castration-resistant prostate cancer (mCRPC).

Abstract

5552 Background: HPN424 is a first-in-class, prostate-specific membrane antigen (PSMA)-targeting T-cell engager designed as a small, globular protein to enable efficient solid-tumor penetration with prolonged half-life. HPN424 is derived from the TriTAC platform (Tri-specific T-Cell-Activating Construct) and engineered with three binding domains: anti-PSMA for tumor cell engagement, anti-albumin for half-life extension and anti-CD3 for T-cell engagement. Methods: This Ph I study is evaluating HPN424 in progressing mCRPC patients (pts) who have received >2 prior systemic therapies. Primary endpoints are safety, tolerability and determination of MTD/RP2D. Secondary objectives are pharmacokinetics (PK), pharmacodynamics, immunogenicity, and preliminary anti-tumor activity. HPN424 is administered IV once weekly. Tumor assessments include PSA, CT, and bone scans every 9 weeks. Results: As of 1/17/20, 27 pts were dosed in 8 cohorts ranging from 1.3 to 72ng/kg. Pts received a median of 6 prior systemic regimens, including >1 novel AR therapy, and 59% received prior chemotherapy for mCRPC. Median PSA at baseline was 251 ng/mL (range: 0.05 – 5000). No DLTs have been observed. The most common grade >3 TRAEs were cytokine release syndrome (CRS) (3 pts) and transient elevated liver transaminases (2 pts) that occurred concurrently with CRS. All CRS events resolved and pts were successfully re-treated. Short-term steroid premedication was effective in limiting CRS and allowing long-term weekly treatment. HPN424 demonstrated dose proportional increase in Cmax and AUC with a geometric mean T1/2 of 30.5 hours. Dose-dependent, transient increases in peripheral cytokine and chemokine levels were observed. Reduction in circulating tumor cells (CTCs) was seen in 11 of 19 pts with measurable CTC at baseline. Six pts had PSA decreases from baseline ranging from -3.8% to -76%, including 2 pts with PSA decline ≥50%. Ten of 20 pts (50%) with > 18 weeks follow-up remained on study beyond week 18 and includes 8 pts on study > 24 weeks. Conclusions: HPN424 represents a novel half-life extended PSMA-targeting T-cell engager that can be safely administered once weekly. AEs have been transient and manageable. Cytokine increases indicate T-cell activation. CTC reductions in subset of pts suggest target engagement. Early signs of clinical activity include PSA reductions and time on study, including 8 pts on study > 24 weeks. Dose escalation is ongoing, including exploration of step dosing. Clinical trial information: NCT03577028 .