Randomized phase II study of PEGPH20 plus nab-paclitaxel/gemcitabine (PAG) vs AG in patients (Pts) with untreated, metastatic pancreatic ductal adenocarcinoma (mPDA).

Abstract

4008 Background: Hyaluronan (HA) accumulation in the tumor microenvironment produces elevated tumor pressure, vascular compression, and reduced drug delivery. PEGPH20 degrades HA, increasing the access and therapeutic index of anticancer agents. Methods: In Stage 1 of this phase II study, pts with untreated mPDA were randomized 1:1 to PAG (P; 3 µg/kg IV 2x/wk x 3 wks in C1, then 1x/wk x 3 wks in C2+, plus AG) vs AG every 28 days. An imbalance in thromboembolic (TE) events in the PAG arm led to a clinical hold (~40% of pts discontinued PEGPH20), exclusion of pts at high risk for TE events and enoxaparin prophylaxis in both study arms. In Stage 2, randomization was 2:1 to PAG vs AG. Tumor HA was tested using a novel assay (VENTANA HA RxDx). Primary endpoints were PFS (evaluable pts) and TE event rate (Stage 2). Secondary endpoints were PFS by HA level and ORR. Results: 279 pts were randomized; 231 are evaluable for efficacy. Of 246 pts with HA data, 84 (34%) were HA-High. As of December 16, 2016, the primary PFS endpoint was statistically significant for PAG vs AG (HR 0.73, 95% CI 0.53-1.00; p = 0.048) (Table). PFS in HA-High pts was also statistically significant in the PAG vs AG arm (HR 0.51; 95% CI 0.26-1.00; p = 0.048). ORR in HA-High pts was 46% (PAG) vs 34% (AG). Overall survival in HA-High pts (exploratory) was 11.5 months (mo) (PAG) and 8.5 mo (AG) (HR 0.96, 95% CI 0.57-1.61). TE events were similar (PAG 14% vs AG 10%) following enoxaparin initiation. All grade treatment-related AE included peripheral edema (PAG 63% vs AG 26%), muscle spasms (56% vs 3%), neutropenia (34% vs 19%), and myalgia (26% vs 7%). Conclusions: Randomized Phase II study met both primary endpoints (PFS and TE event rate), with the largest improvement in the secondary endpoint of PFS in HA-High pts. These data support HA as a potential predictive biomarker for patient selection of PEGPH20, currently investigated in the ongoing global Phase III HALO 301 study with PFS and OS as co-primary endpoints. Clinical trial information: NCT01839487. [Table: see text]

ASCO- und ESMO-Update 2017 – Neuigkeiten vom 53. Meeting der American Society of Clinical Oncology/ASCO 2017 und European Society for Medical Oncology/ESMO-Congress 2017

“…Auf dem ASCO und ESMO 2017 wurden nun die Ergebnisse der randomisierten HALO-202-Studie vorgestellt. Diese Phase-I/II-Studie vergleicht die Kombination aus Gemcitabin und nab-Paclitaxel ± PEGPH20 in der palliativen Erstlinientherapie [41,42]. Primärer Endpunkt der Studie war das progressionsfreie Überleben und als zusätzlicher primärer Sicherheits-Endpunkt die Rate an thromboembolischen Ereignissen bei bekannter Risikozunahme unter PEGPH20-Therapie.…”

Understanding Disease Biology and Informing the Management of Pancreas Cancer With Preclinical Model Systems

“…tumorigenesis, survival, metastasis, multiclonality, etc.). The potential for GEMM in advancing PDA therapies is demonstrated by the development of PEGPH20 for enhancing tumoral delivery of cytotoxics, originally tested in the KPC model, which has shown promise in clinical trials for HA-high PDA patients 30,98 .…”

Breaking the Barrier—PEGylated Recombinant Human Hyaluronidase (PEGPH20)—A New Therapeutic Approach to the Treatment of Pancreatic Ductal Adenocarcinoma

“…Multiple preclinical and clinical studies have demonstrated that targeting the biophysical barrier to drug delivery in PDA with PEGPH20 is both feasible and promising. 12,25,34,37 Results from both the phase Ib 34 and phase II (HALO-202) 38 clinical trials have demonstrated that the administration of PEGPH20 with different cytotoxic chemotherapy combinations is feasible and effective.…”

“…38 To date, there have been no studies investigating PEGPH20 as monotherapy in PDA. All studies have investigated PEGPH20 used in combination with chemotherapy.…”

“…Treatmentrelated adverse events of any grade associated with either PAG or AG treatment included peripheral edema (63% for PAG versus 26% for AG), muscle spasms (56% versus 3%), neutropenia (34% versus 19%), and myalgia (26% versus 7%). 38 The HALO 109-202 study therefore met its key endpoints including improvement in the primary outcome of improved PFS in all patients receiving PAG compared with AG, and in the secondary endpoint of improved PFS in HA-High patients receiving PAG versus AG. Stage 2 of the HALO 109-202 study also met its primary safety endpoint of TE reduction.…”