Phase Ib Study of PEGylated Recombinant Human Hyaluronidase and Gemcitabine in Patients with Advanced Pancreatic Cancer

Abstract

Purpose: This phase Ib study evaluated the safety and tolerability of PEGylated human recombinant hyaluronidase (PEGPH20) in combination with gemcitabine (Gem), and established a phase II dose for patients with untreated stage IV metastatic pancreatic ductal adenocarcinoma (PDA). Objective response rate and treatment efficacy using biomarker and imaging measurements were also evaluated.

Experimental design: Patients received escalating intravenous doses of PEGPH20 in combination with Gem using a standard 3+3 dose-escalation design. In cycle 1 (8 weeks), PEGPH20 was administrated twice weekly for 4 weeks, then once weekly for 3 weeks; Gem was administrated once weekly for 7 weeks, followed by 1 week off treatment. In each subsequent 4-week cycle, PEGPH20 and Gem were administered once weekly for 3 weeks, followed by 1 week off. Dexamethasone (8 mg) was given pre- and post-PEGPH20 administration. Several safety parameters were evaluated.

Results: Twenty-eight patients were enrolled and received PEGPH20 at 1.0 (n = 4), 1.6 (n = 4), or 3.0 μg/kg (n = 20), respectively. The most common PEGPH20-related adverse events were musculoskeletal and extremity pain, peripheral edema, and fatigue. The incidence of thromboembolic events was 29%. Median progression-free survival (PFS) and overall survival (OS) rates were 5.0 and 6.6 months, respectively. In 17 patients evaluated for pretreatment tissue hyaluronan (HA) levels, median PFS and OS rates were 7.2 and 13.0 months for "high"-HA patients (n = 6), and 3.5 and 5.7 months for "low"-HA patients (n = 11), respectively.

Conclusions: PEGPH20 in combination with Gem was well tolerated and may have therapeutic benefit in patients with advanced PDA, especially in those with high HA tumors. Clin Cancer Res; 22(12); 2848-54. ©2016 AACR.

Conflict of interest statement

Disclosure of Potential Conflicts of Interest

S.R. Hingorani is a consultant/advisory board member for Halozyme Therapeutics. W.P. Harris reports receiving a commercial research grant from Halozyme. S. Tjulandin reports receiving speakers bureau honoraria from AstraZeneca and Pfizer. R. Korn has ownership interest (including patents) in Imaging Endpoints. H.M. Shepard reports receiving a commercial research grant from Halozyme and has ownership interest (including patents) in Halozyme. No potential conflicts of interest were disclosed by the other authors.

©2016 American Association for Cancer Research.

Figures

Figure 1.

Representative micrographs of tumor biopsies with high HA (A) and low HA (B) content. HA is detected with HA binding protein, and nuclei are counterstained with hematoxylin. Corresponding hematoxylin and eosin (H&E) stains are also shown. PFS (C) and OS (D) of patients who received either 1.6 or 3.0 μg/kg of PEGPH20+Gem. Gray line, all patients in the efficacy-evaluable population (n = 24); dark blue line, high HA (n = 6, 1 patient withdrew consent and was censored for PFS and OS, 1 patient withdrew consent and was censored for PFS); light blue line, low HA (n = 11, 1 patient who was censored for PFS and OS was withdrawn from study by investigator decision). Magnification, ×200.