P-183 - A pilot trial of PEGPH20 (Pegvorhyaluronidase alfa) in combination with avelumab (anti-PD-L1 MSB0010718C) in chemotherapy resistant pancreatic cancer (PDAC) - Trial in progress

Abstract

Introduction: PDAC is characterized by excessive hyaluronan (HA) accumulation in the tumor microenvironment, elevating interstitial pressure, resulting in tumor vascular collapse, hypoxia, blocking chemotherapeutic agent perfusion and immune cells. Consequently, checkpoint inhibitors and immunotherapy strategies have failed in PDAC. PEGPH20 targets tumors that accumulate HA. Enzymatically depleting HA from the extracellular matrix (ECM), resulting in decompression of intratumoral blood vessels and increased penetration of antitumor agents. In preclinical models, depletion of HA in the tumor microenvironment has been shown to inhibit the growth of tumors characterized by accumulation of HA. PEGPH20 has been evaluated in a phase II trial in combination with gemcitabine and nab–paclitaxel (PAG) versus gemcitabine plus nab–paclitaxel (AG). For patients with high HA expression on baseline biopsies, the combination arm with PEGPH20 increased progression-free survival (PFS) by 4 months (9.2 vs. 5.2 months; HR 0.51; p = 0.048). Our study tests the hypothesis that elimination of HA in tumor microenvironment by PEGPH20 will result in stromal remodeling and may facilitate the activity of checkpoint inhibitors like avelumab, by at least two mechanisms including increase in drug delivery and increasing immune infiltrate. Methods: A pilot, open label, multicenter, pharmacodynamics, safety, and efficacy study of PEGPH20 in combination with avelumab in chemotherapy resistant advanced or locally advanced PDAC. PEGPH20 3 microg/Kg dose will be administered on days 1, 4, 8, 11, 15, 18 during the first cycle (28 days) and days 1 and 15 thereafter. Avelumab at dose of 10 mg/Kg will start on day 15 after 4 doses of PEGPH20 and continued to be administered every 2 weeks during the study. Enoxaparin will be administered to all subjects to minimize the risk of thromboembolic events (TE) associated to PEGPH20 administration. Pharmacokinetics (Pk) samples for PEGPH20 will be collected. Other assessments: serum CA 19-9 and tissue biomarkers (including collagen content, cancer associated fibroblasts [CAF], and immune infiltrate). Objectives: Primary: To determine the objective response rate (ORR) as per RECIST v1.1 criteria. Secondary: To determine the overall survival (OS), progression free survival (PFS) and CA19-9 tumor marker response. Exploratory: To determine the effect of PEGPH20 in HA content in plasma and paired tumor biopsies. Key inclusion criteria: progression to first line treatment for locally advanced or advanced disease, life expectancy ≥ 3 months and no clinical evidence of prior TE within 12 months or other known TE during the screening.