Phase 1b Study of PEGylated Recombinant Human Hyaluronidase and Gemcitabine in Patients with Advanced Pancreatic Cancer
Mené sur 28 patients atteints d'un adénocarcinome canalaire du pancréas de stade IV, cet essai de phase Ib évalue la toxicité et l'acitivité antitumorale d'un traitement à l'aide d'injections d'une forme pégylée de la hyaluronidase recombinante humaine, en combinaison avec la gemcitabine
Purpose: This Phase 1b study evaluated the safety and tolerability of PEGylated human recombinant hyaluronidase (PEGPH20) in combination with gemcitabine (Gem), and established a Phase 2 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) were 5.0 and 6.6 months, respectively. In 17 patients evaluated for pre-treatment tissue hyaluronan (HA) levels, median PFS and OS 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. Conclusion: 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.