Poor outcome in pancreatic ductal adenocarcinoma (PDA) is associated partly with stromal hyaluronan (HA) accumulation, which may compromise chemotherapy access to tumors. In animal models, PEGPH20 degrades HA in tumors. Interim data from a phase 2 study showed that PEGPH20 plus chemotherapy improved efficacy over chemotherapy alone in tumors retrospectively identified to accumulate HA (“HA-High”). The objectives of this phase 3 study are to compare efficacy and safety of standard-dose nab-paclitaxel (NAB) and gemcitabine (GEM) combined with either PEGPH20 or placebo in patients with HA-High, previously untreated, Stage IV PDA. Primary endpoints are progression-free survival (PFS) and overall survival (OS). Secondary endpoints are objective response rate, duration of response, and safety.
420 patients ≥18 years with untreated HA-High metastatic PDA, ECOG PS 0-1 will be randomized (stratified by geographic region: North America/Europe/Other) 2:1 to NAB 125 mg/m2 + GEM 1000 mg/m2 + PEGPH20 3.0 µg/kg or to placebo. Patients with HA-High tumors will be prospectively identified by a companion diagnostic test and scoring algorithm (Ventana Medical Systems, Inc.), which defines HA-High staining in the extracellular matrix as ≥50% of the tumor surface. Treatment will be provided in 4-week cycles (Wk 1-3, Wk 4 rest) until disease progression, unacceptable toxicity, death, or consent withdrawal. PEGPH20 or placebo will be given twice weekly (Cycle 1) then weekly (Cycles 2+), NAB + GEM once weekly for all cycles. Dexamethasone will be given before and after PEGPH20 to reduce treatment-related musculoskeletal symptoms and enoxaparin will be given to minimize thromboembolic events. Tumor response will be assessed by an independent central reader by RECIST v1.1. Adverse events will be graded per NCI CTCAE v4.03. An independent Data Monitoring Committee will evaluate safety and interim data for PFS and OS analyzed by an independent statistical analysis center.
Clinical trial identification
EudraCT 2015-004068-13; NCT02715804
Legal entity responsible for the study
E. Van Cutsem: Research funding: Halozyme.
A.E. Hendifar: Advisory boards: Ipsen, Genentech; Research Support: Halozyme.
M. Reni: Grants: Celgene, Baxalta, Merck-Serono, Helsinn. Personal Fees: Celgene, Baxalta, Merck-Serono, Boheringer, Lilly, Pfizer, Astra-Zeneca, Novocure, Genentech. Non-financial support: Celgene.
M. Ducreux: Grants/research supports: Roche, Chugai, Pfizer. Honoraria/consultation fees: Roche, Celgene, Merck Serono, Amgen, Novartis, Sanofi, Pfizer, Lilly, Servier, Halozyme; Spouse. Head of BU, Sandoz.
A. Bullock: Advisory board honoraria: Halozyme.
P. Corrie: Advisory Board honoraria: Roche, Novartis, Bristol Myers Squibb, Merck, Baxalta; Ad hoc honoraria for lectures/meeting presentations: Novartis, Celgene; Research funding: Celgene.
V. Heinemann: Advisory board: Merck, Roche, Sanofi, Amgen, Baxalta, SIRTEX, Halozyme, Lilly. Corporate-sponsored research: Merck, Roche, Amgen; Honorary fees for talks: Merck, Roche, Sanofi, Amgen, Baxalta, SIRTEX.
T. Seery: Advisory board: Bayer.
D. Chondros: Employee: Halozyme Therapeutics.
L. Zheng: Stock: Z&L Medical International; Consulting/Advisory: Halozyme, Percans (personalized medicine), Lifemax (target therapy). Research funding: iTeos (research grant), Halozyme (not the clinical trial). Patents: Gvax (co-inventor, licensed to Aduro). All other authors have declared no conflicts of interest.