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.
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.
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.Table:
|Population||Events/Total, n Median PFS, months||HR (95% CI)||P value|
|Efficacy Evaluable (n = 231)||100/139; 6.0||65/92; 5.3||0.73 (0.53, 1.00)||0.048|
|HA-High (n = 84)||24/49; 9.2||19/35; 5.2||0.51 (0.26-1.00)||0.048|
All grade treatment-related AE included peripheral edema (PAG 63% vs AG 26%), muscle spasms (56% vs 3%), neutropenia (34% vs 19%), and myalgia (26% vs 7%).
Randomized Phase 2 study met both primary endpoints (PFS and TE event rate), with the largest improvement in the secondary endpoint of PFS in HA-High 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. NCT01839487
Clinical trial identification
Legal entity responsible for the study
Halozyme Therapeutics, Inc.
Halozyme Therapeutics, Inc.
S.R. Hingorani: Consulting or Advisory Role: Halozyme, Aduro Biotech Research Funding: Halozyme (institution). A. Bullock: Consulting or advisory board participation support: Halozyme, Celgene, and EMD Serono. T. Seery: Consulting or Advisory Role: Bayer Speakers\' Bureau: Ipsen, Bayer. L. Zheng: Consult/Advisor: Merrimack; Patents, royalties, Other Intellectual Property: GVAX, Licensed to Aduro Biotech; Stock/Other: Z&L Medical Intl; Res Fund: BM Squibb, Amgen, Iteos Therap, Gradalis, Merck, Halozyme. D. Sigal: Stock or Other Ownership: Novartis, BMS, Ignyta, Halozyme; Honoraria: Novartis, Serond, Halozyme; Speakers\' Bureau: Novartis, Celgene, Bayer; Research Funding: Halozyme. F.S. Braiteh: Honoraria, consulting or advisory role, Speaker\'s Bureau, travels, accommodation, expenses. M. Zalupski: Research Funding: Halozyme, OncoMed, Newlink Genetics. N. Bahary: Consulting or Advisory Role: Bayer/Onyx, EMD Serono Research Funding: New Links Genetics. W. Harris: Consulting or Advisory Role: Neotherma Oncology, Bayer Research Funding: Halozyme, BMS, Exelixis, Argule, Polaris, Medimmune, BTG. J. Pu: Employment: Roche; Research Funding: Roche;Patents, Royalties, Other Intellectual Property: Roche (for author and institution). C. Aldrich: Employment: Roche Tissue Diagnostics. S. Khelifa: Employment: Ventana Medical System Inc.- member of the Roche group; Stock or Other Ownership: Ventana Medical System Inc.- member of the Roche group. W. Wu: Employment: Halozyme Stock or Other Ownership: Halozyme. D. Chondros: Employee of Halozyme Therapeutics, Inc. P. Jiang: Employment: Halozyme; Stock or Other Ownership: Halozyme Therapeutics Inc.; Patents, Royalties, Other Intellectual Property: Halozyme Therapeutics Inc. A. Hendifar: Consulting or Advisory Role: Genentech, Novartis, Ipsen, Perthera Travel, Accommodations, Expenses: Halozyme. All other authors have declared no conflicts of interest.