260TiP - Phase 3, randomized, double-blind, placebo-controlled study of PEGylated recombinant human hyaluronidase PH20 (PEGPH20)+nab-paclitaxel/gemcitabine in patients with previously untreated, hyaluronan-high, stage IV pancreatic ductal adenocarcinoma (PDA)

Abstract

Background: Poor outcome in PDA is associated with stromal hyaluronan (HA) accumulation, which may compromise treatment access. In animal models, PEGPH20 degrades tumor HA. Key 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 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. Trial design: 420 patients ≥18 years with untreated HA-High metastatic PDA, ECOG PS 0-1 are randomized (stratified by North America/Europe/other) 2:1 to NAB 125 mg/m2 + GEM 1000 mg/m2 + PEGPH20 3.0 μg/kg or to NAB + GEM + placebo, respectively. Patients with HA-High tumors are prospectively identified by the co-developed VENTANA HA RxDx Assay, which identifies HA in the extracellular matrix. HA-High status (indicating patients who may achieve clinical benefit) was determined by Halozyme to be ≥ 50% HA staining based on clinical outcome data from a Phase 2 study. Treatment is provided in 4-week cycles (Wk 1-3, Wk 4 rest) until disease progression, unacceptable toxicity, death, or consent withdrawal. PEGPH20 or placebo is given twice weekly (Cycle 1) then weekly (Cycles 2+), NAB + GEM once weekly for all cycles. Dexamethasone is given before and after PEGPH20 to reduce treatment-related musculoskeletal symptoms and enoxaparin is given to minimize thromboembolic events. Tumor response will be assessed by an independent central imaging vendor using RECIST v1.1. Adverse events will be graded per NCI CTCAE v4.03. An independent Data Monitoring Committee will evaluate safety and efficacy (PFS and OS) data. Trial initiated Q12016. Clinical trial indentification: EudraCT 2015-004068-13; NCT02715804. Legal entity responsible for the study: Halozyme Therapeutics Funding: Halozyme Therapeutics Disclosure: D-Y. Oh: Research funding from AstraZeneca, Array BioPharma. Y-J. Bang: Research funding: AstraZeneca, Novartis, Roche, MSD, Merck Serano, Bayer, GSK, BMS, Pfizer, Eli Lilly, Boeringer-Ingelheim, MacroGenics, Boston Biomedical, FivePrime, CKD, Ono, Otsuka, Taiho, Takeda, BeiGene, Hanmi, Green Cross, Curis Ad board member: AstraZeneca, Novartis, Roche, Genentech, MSD, Pfizer, Bayer, BMS, Eli Lilly, Merck Serano, FivePrime, Merrimack, Taiho, Ono, ADC Therapeutics, GreenCross, Samyang Biopharm. E. Van Cutsem: Research funding: Halozyme. A. Hendifar: Consulting or Advisory Role: Xbiotech, Novartis (self) Research Funding: Ipsen, Halozyme (institution). L. Zheng: Employment: Roche, Stock or Other Ownership: Roche, Honoraria: Roche, Travel, Accommodations, Expenses: Roche. M. Ducreux: Honoraria/Consultation Fees: Roche, Celgene, Merck Serono, Amgen, Novartis, Sanofi, Pfizer, Lilly, Servier, Halozyme; Grants/Research funding: Roche, Chugai, Pfizer Spouse: Head of BU, Sandoz. W. Harris: Consulting or Advisory Role: Neotherma Oncology, Bayer (self); Research Funding: Halozyme, BMS, Exelixis, Arqule, Polaris, Medimmune, BTG (institution). P. Corrie: Honoraria: Roche, Novartis, Bristol Myers Squibb, Merck Sharpe & Dohme, Pierre Fabre Research funding: Celgene; Ad hoc honoraria for lectures/meeting presentations: Novartis, Celgene, Merck Sharpe & Dohme. T. Seery: Consulting or Advisory Role: Bayer (self) Speakers' Bureau: Ipsen, Bayer (self). D. Chondros: Employment: Halozyme (self) Leadership: Halozyme (self) Stock or Other Ownership: Halozyme, Roche (self) Travel Accommodations, Expenses: Halozyme, Roche/Genentech (self). A. Bullock: Consulting or advisory board participation support: Halozyme, Celgene, and EMD Serono (self). All other authors have declared no conflicts of interest.