18

WC

GIC

Poster presented at:

Global Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Compare Efficacy and Safety of PEGylated Recombinant Human Hyaluronidase (PEGPH20) Plus Nab-Paclitaxel

and Gemcitabine vs Placebo Plus Nab-Paclitaxel and Gemcitabine in Patients With Previously Untreated, Hyaluronan (HA)-High, Stage IV Pancreatic Ductal Adenocarcinoma

Margaret A. Tempero,1 Lei Zheng,2 Michele Reni,3 Andrew Hendifar,4 Michel Ducreux,5 Andrea Bullock,6 Pippa G. Corrie,7 William P. Harris,8 Volker Heinemann,9 Tara Seery,10 Wilson Wu,11 Dimitrios Chondros,11 Eric Van Cutsem12

1UCSF Pancreas Center, San Francisco, CA, USA; 2The Johns Hopkins University Hospital, Baltimore, MD, USA; 3Ospedale San Raffaele, Milano, Italy; 4Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA; 5Gustave Roussy, Paris, France; 6Beth Israel Deaconess Medical Center, Boston, MA, USA;

7Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK; 8University of Washington School of Medicine, Seattle, WA, USA; 9Comprehensive Cancer Center, Krebszentrum München, Munich, Germany; 10UC Irvine Medical Center, Orange, CA, USA; 11Halozyme Therapeutics, Inc, San Diego, CA, USA;

12University Hospital Gasthuisberg, Leuven, Belgium

INTRODUCTION

OBJECTIVE

METHODS

ENDPOINTS

COMPANION DIAGNOSTIC BACKGROUND

CURRENT STATUS

• Up to 85% of patients with pancreatic ductal adenocarcinoma (PDA) present with advanced disease1

• Prognosis is dismal for patients with metastatic disease, with 2% surviving for 5 years after diagnosis2

• PDA aggressiveness and resistance to treatment reflect the biophysical nature of the tumor microenvironment (TME) – Desmoplastic stroma is a hallmark of PDA – Extracellular matrix (ECM) of tumor contains abundant hyaluronan (HA), a hydrophilic, viscous polysaccharide that

stabilizes the TME and compromises tumor access by • Elevating tumor interstitial fluid pressure3-5 and • Compressing tumor vasculature, which blocks delivery of systemic therapies and access of immune cells to the

tumor3-7

• HA accumulation has been associated with shorter survival in various tumor types, including PDA8

• PEGPH20 is an engineered enzyme that degrades HA; currently in clinical development• In animal models, PEGPH20 degrades HA and facilitates delivery of coadministered anticancer agents5 (Figure 1)• Final analyses of stage 1 data from a randomized phase 2 study of PEGPH20 combined with gemcitabine and

nab-paclitaxel (PAG) vs gemcitabine and nab-paclitaxel (AG) in patients with metastatic PDA demonstrated promising activity in patients with HA-High tumors9

– Median progression-free survival 9.2 months PAG vs 6.0 months AG (hazard ratio, 0.46; 95% confidence interval, 0.15-1.40)

– Objective response rate 50% PAG vs 33.3% AG

Figure 1. PEGPH20 Targets Hyaluronan in the Tumor Microenvironment.

• To assess the efficacy and safety/tolerability of PEGPH20 in combination with gemcitabine (GEM) and nab-paclitaxel (NAB; referred to as the PAG arm) versus placebo plus gemcitabine and nab-paclitaxel (AG) in patients with HA-High, stage IV previously untreated PDA

Key Inclusion Criteria• Age ≥18 years; Stage IV PDA with histological confirmation via archived or fresh core biopsy of either the primary tumor

or 1 metastatic site – Available tumor tissue (archived or fresh) from primary or metastatic lesion – Formalin-fixed paraffin-embedded [FFPE] block preferred, with enough tumor to make a minimum of 5 to 10 unstained,

consecutive FFPE slides• HA-High status based on tumor biopsy• ≥1 metastatic lesion measurable on computed tomography scan, per RECIST v1.1• Disease recurrence/progression ≥6 months after completing the last dose of prior adjuvant therapy (for patients who

were previously treated for non-metastatic disease)

Key Exclusion Criteria• Clinical evidence of deep vein thrombosis, pulmonary embolism, or other known thromboembolic event during the

screening period• History of cerebrovascular accident or transient ischemic attack, or pre-existing carotid artery disease• Previous radiotherapy, surgery, chemotherapy, or investigational therapy for the treatment of metastatic disease – Palliative radiotherapy for pain control of metastatic bone lesions is allowed• Known central nervous system involvement or brain metastases• New York Heart Association Class III or IV cardiac disease or myocardial infarction within the past 12 months

Poster Number P-288

PEGPH20 + Nab-paclitaxel +gemcitabine (PAG)*

Placebo + Nab-paclitaxel +gemcitabine (AG)*

Stage IV(Metastatic)

PDAHA-Hightumors

N = 420

Primary Endpoints: Progression-Free Survival (PFS) Overall Survival (OS)

• Randomized (2:1, PAG:AG), double-blind, placebo-controlled, global• Patients enrolled based on HA-High tumors• Initiated March 2016• Interim analysis when target number of PFS events reached• Statistical powering to support PFS with a hazard ratio of 0.59

*All patients will receive enoxaparin prophylaxis.

7055 Figure 2This tagline is for information only;

DO NOT PRINT

Figure 2. Phase 3 Study Design. PDA, pancreatic ductal adenocarcinoma; HA, hyaluronan.

Current Status

• This study is open for enrollment (NCT02715804; EudraCT 2015-004068-13)• The first patient was enrolled in March 2016• This study will enroll patients at approximately 200 sites worldwide (Figure 4

Figure 4. Geographical Distribution of Participating Centers.

Primary Endpoints

• Progression-free survival

• Overall survival

Secondary Endpoints

• Objective response rate

• Duration of response

• Incidence of adverse events (AEs), changes in laboratory values and cardiovascular parameters (ECG and vital signs)

Exploratory Endpoints

• Change in serum CA19-9 level

• Change in plasma and tumor biopsy (when available): HA and other potential biomarkers

• Pharmacokinetics of PEGPH20 in combination with NAB plus GEM

• Pharmacokinetics of NAB and GEM in the PAG group versus the AG group

• Patient-reported outcome measures as determined by the EORTC QLQ-C30, EQ-5D, and NRS

• This study is open for enrollment (NCT02715804; EudraCT 2015-004068-13)

• The first patient was enrolled in March 2016

• This study will enroll patients at approximately 200 sites worldwide (Figure 4)

Figure 4. Geographical Distribution of Participating Centers.

We thank the patients for their participation in this study, as well as the staff at each site. Editorial assistance was provided by ProEd Communications, Inc., and was funded by Halozyme, Inc.

CONTACT INFORMATION

ACKNOWLEDGMENTS

REFERENCES

• Halozyme Study Information

– By phone: (+1) 510-740-2417

– By email: MedInfo@halozyme.com

1. NCI SEER Cancer statistics. Available at: http://seer.cancer.gov/statfacts/html/pancreas.html.2. Siegel R, et al. CA Cancer J Clin. 2016;66:7-30.3. Provenzano PP, Hingorani SR. Br J Cancer. 2013;108(1):1-8.4. Brekken C, et al. Anticancer Res. 2000;20(5B):3503-3512.5. Thompson CB, et al. Mol Cancer Ther. 2010;9(11):3052-3064.6. DuFort CC. Biophys J. 2016;110(9):2106-2119.7. Singha NC, et al. Mol Cancer Ther. 2015;14(2):523-532.8. Whatcott CJ, et al. Clin Cancer Res. 2015;21:15.9. Bullock A, et al. J Clin Oncol. 2016;34(suppl): Abstract 4104.

PEGPH20

Removal of HA by PEGPH20 in HA-High tumor animal models was shown to5

Decreaseintratumoral

pressure

Decompressvasculature

Increase perfusion

Increase access for

therapeutics

Increase access for

immune cells

Fibroblast

MDSC

Adenosine Molecular Receptors

HA

Collagen

Vasculature

Macrophage T cell

Treg

Cancer cell

Figure 1. PEGPH20 Targets Hyaluronan in the Tumor Microenvironment.

Determining HA Status• In collaboration with Ventana Medical Systems, Halozyme has developed a novel companion diagnostic, HA CDx Assay,

to identify patients with HA-High PDA tumors who might benefit from PEGPH20-based treatment• HA CDx Assay is an affinity histochemistry assay with a scoring algorithm based on the HA staining pattern area in the

ECM over the entire tumor surface• PDA tumors are considered to be HA-High when the HA score is ≥50% (Figure 3)

Figure 3. Representative HA-High and HA-Low Tumor Micrographs (PDA Samples). Biopsy samples (from stage 1 of the 109-202 study) are HA stained with Ventana HA CDx assay and scored with corresponding scoring algorithm. HA staining: brown = HA, blue = hematoxylin nuclear counterstain; H&E: purple = eosin, blue = hematoxylin.

Companion Diagnostic Background

Determining HA Status• In collaboration with Ventana Medical Systems, Halozyme has developed a novel companion diagnostic, HA CDx Assay,

to identify patients with HA-High PDA tumors who might benefit from PEGPH20-based treatment• HA CDx Assay is an affinity histochemistry assay with a scoring algorithm based on the HA staining pattern area in the

ECM over the entire tumor surface• PDA tumors are considered to be HA-High when the HA score is ≥50% (Figure 3)

HA-LowHA-High

Figure 3. Representative HA-High and HA-Low Tumor Micrographs (PDA Samples). Biopsy samples (from stage 1 of the 109-202 study) are HA stained with Ventana HA CDx assay and scored with corresponding scoring algorithm. HA staining: brown = HA, blue = hematoxylin nuclear counterstain; H&E: purple = eosin, blue = hematoxylin.

HA H&E HA H&E

2

288--PEric Van DOI: 10.3252/pso.eu.18wgic.2016

Clinical Pancreatic Cancer