P3.02c-011 A Phase 1b Open-Label Study of PEGPH20 Combined with Pembrolizumab in Patients with Selected Hyaluronan-High Solid Tumors: Topic: Targeted Therapy

Abstract

Hyaluronan (HA) is a megadalton polysaccharide found in the tumor microenvironment (TME). HA accumulation in the TME increases tumor interstitial pressure, which promotes vascular collapse and limits access of chemotherapy and immune cells to tumor sites. In animal models, HA-High tumors exhibit increased growth and metastasis, treatment resistance, and reduced survival. PEGPH20 is a pegylated recombinant human hyaluronidase that enzymatically degrades tumor HA. Pembrolizumab (PEM) is a humanized monoclonal antibody targeting PD-1 and demonstrating tolerability and activity in patients with non-small cell lung cancer (NSCLC). This study evaluates the safety and activity of PEGPH20 plus PEM in patients with HA-High tumors. This is a Phase 1b study comprising a dose escalation portion (up to 30 patients without regard to HA status) followed by a cohort expansion portion in up to 51 patients with HA-High tumors, determined using a companion diagnostic assay developed in collaboration with Ventana Medical Systems. Eligible patients are ≥18 years, ECOG PS 0-1, with either relapsed/refractory stage IIIB/IV NSCLC who failed ≥1 previous platinum-based chemotherapy regimen or relapsed/refractory locally advanced or metastatic gastric adenocarcinoma who failed ≥1 previous chemotherapy regimen. Patients with NSCLC known to be epidermal growth factor receptor (EGFR)- or anaplastic lymphoma kinase (ALK)-positive must have received an EGFR inhibitor or ALK inhibitor, respectively. PEGPH20 (1.6, 2.2, 2.6, 3.0, 4.0 μg/kg) is administered intravenously (IV) over 10 minutes on days 1, 8, and 15 of each 21-day cycle followed by PEM 2 mg/kg IV on day 1, 4 to 6 hours after PEGPH20 is completed. Piroxicam will be given prophylactically for possible musculoskeletal events. Prophylactic proton pump inhibitors will be given to all patients. The primary endpoint for the dose escalation portion is the recommended Phase 2 dose for PEGPH20 in combination with PEM. In the cohort expansion portion, the primary endpoint is objective response rate per RECIST v1.1. Secondary endpoints are duration of response, disease control rate, progression-free survival per RECIST and immune-related response criteria, pharmacokinetics, and adverse events. Exploratory endpoints in patients with HA-High NSCLC include HA levels in plasma and tumor tissue and imaging parameters of tumor blood flow (dynamic contrast-enhanced magnetic resonance imaging [DCE-MRI]) and tumor metabolic activity (positron emission tomography/computed tomography [PET/CT] scans). ClinicalTrials.gov Identifier: NCT02563548. Section not applicable. Section not applicable.