Results of an ongoing phase 1/2a dose escalation study of HPN424, a tri-specific half-life extended PSMA-targeting T-cell engager, in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Johann S. De Bono, Lawrence Fong, Tomasz M. Beer, Xin Gao, Daniel M. Geynisman, Howard A. Burris III, James Fredric Strauss, Kevin Dale Courtney, David I. Quinn, David James VanderWeele, Yifah Yaron, Che-Leung Law, Mark N. Stein
Journal: Journal of Clinical Oncology (2021)

5013 Background: HPN424 is a prostate-specific membrane antigen (PSMA)-targeting T cell engager designed to redirect T cells to kill PSMA-expressing prostate cancer cells; engineered with three binding domains: anti-PSMA for tumor cell engagement, anti-albumin for half-life extension and anti-CD3 for T cell engagement. HPN424 is optimized for small size and increased stability compared to other bispecific platforms. Methods: This Ph1/2a study is evaluating HPN424 in mCRPC patients (pts) who have received &gt; 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 2/8/21, 80 pts were dosed in 15 cohorts with target doses ranging from 1.3 to 160ng/kg fixed dose, and up to 300ng/kg with step dosing to the target dose after initial priming dose. Pts had received a median of 6 prior systemic regimens, 75% received prior chemotherapy for mCRPC. Median age was 70 (43 – 91). Most common grade &gt; 3 TEAEs were AST increase (18%), anemia (11%) and ALT increase (11%). DLTs include CRS G3 (n = 3), elevated lipase G3 (n = 1) and seizure G3 (n = 1). These events did not limit escalation, MTD has not been reached and escalation continues. All grade CRS occurred in 63% of pts, 4% grade 3 per ASTCT and no Grade 4/5 CRS. CRS G3 events occurred after first administration of target dose (n = 2 fixed dose, n = 1 step dose). Transaminase elevation occurred predominantly during Cycle 1, was transient and had no clinical sequelae. Disease progression was the primary reason for drug discontinuation; 2 pts (3%) discontinued due to TRAE. Reduction in circulating tumor cells (CTC) was seen in 32 of 56 pts (57%) with measurable CTC at baseline. Fifteen of 62 pts (24%) with &gt; 24 weeks follow-up remained on treatment ≥ 24 weeks. Thirteen of 63 pts (21%) with post-baseline levels had PSA declines from baseline, including 3 PSA50, 2 PSA30 responses. In chemo-naïve pts, 5 of 15 (33%) showed PSA declines post-baseline. In the highest fixed dose cohort (160ng/kg) tested to-date, 3 of 7 evaluable pts had PSA declines from baseline and 1 had a confirmed partial response per RECIST. Conclusions: HPN424, a novel half-life extended PSMA-targeting T cell engager, was well tolerated when administered once weekly. AEs were transient, manageable and consistent with class of agent. Grade 3 CRS was observed in 4% of patients, occurring with first administration of target dose. Evidence of antitumor activity included PSA and CTC reductions and treatment duration &gt; 24 weeks in 15/62 pts. Encouraging signals were seen at the highest fixed dose cohort including a confirmed RECIST partial response. NCT03577028 Clinical trial information: NCT03577028.