Randomized phase 2 study of PEGPH20 Plus nab-paclitaxel/gemcitabine (PAG) vs AG in patients (Pts) with untreated, metastatic pancreatic ductal adenocarcinoma (mPDA)

Abstract

Background: Hyaluronan (HA) accumulation in the tumor microenvironment produces elevated tumor pressure, vascular compression, and reduced drug delivery. PEGPH20 degrades HA, increasing the access and therapeutic index of anticancer agents. Methods: In Stage 1 of this phase 2 study, pts with untreated mPDA were randomized 1:1 to PAG (P; 3 μg/kg IV 2x/wk x 3 wks in C1, then 1x/wk x 3 wks in C2+, plus AG) vs AG every 28 days. An imbalance in thromboembolic (TE) events in the PAG arm led to a clinical hold (∼40% of pts discontinued PEGPH20), exclusion of pts at high risk for TE events and enoxaparin prophylaxis for all pts. In Stage 2, randomization was 2:1 to PAG vs AG. Tumor HA was tested using a novel assay (VENTANA HA RxDx). Primary endpoints were PFS (evaluable pts) and TE event rate (Stage 2). Secondary endpoints were PFS by HA level and ORR. Results: 279 pts were randomized; 231 are efficacy evaluable. Of 246 pts with HA data, 84 (34%) were HA‐High. As of December 16, 2016, the primary PFS endpoint was statistically significant for PAG vs AG (HR 0.73, 95% CI 0.53‐1.00; p=0.048) (Table). PFS in HA‐High pts was also statistically significant for PAG vs AG (HR 0.51; 95% CI 0.26‐ 1.00; p=0.048). ORR in HA‐High pts was 46% (PAG) vs 34% (AG). Overall survival in HA‐High pts (exploratory) was 11.5 months (mo) (PAG) and 8.5 mo (AG) (HR 0.96, 95% CI 0.57‐1.61). TE events were similar (PAG 14% vs AG 10%) with enoxaparin initiation. Conclusions: Randomized Phase 2 study met both primary endpoints (PFS and TE event rate), with the largest improvement in the secondary endpoint of PFS in HAHigh pts. These data support HA as a potential predictive biomarker for pt selection of PEGPH20, currently investigated in the global Phase 3 HALO 301 study with PFS and OS as co‐primary endpoints. (Table presented).