A phase IB/II randomized study of mFOLFIRINOX (mFFOX) + pegylated recombinant human hyaluronidase (PEGPH20) versus mFFOX alone in patients with good performance status metastatic pancreatic adenocarcinoma (mPC): SWOG S1313 (NCT #01959139).

Abstract

208 Background: PEGPH20 degrades hyaluronan (HA), a major component of the stroma, increases delivery of gemcitabine and prolongs survival in preclinical models. We evaluated the activity of PEGPH20 in combination with mFFOX in mPC , unselected for tumor HA. Methods: Pertinent eligibility: untreated mPC, PS of 0-1 and adequate organ function. Standard FFOX was modified to add prophylactic growth factor support and omit bolus 5FU. Due to increased thromboembolic (TE) events with PEGPH20, an amendment instituted LMWH prophylaxis in the PEGPH20 arm only. Following a dose finding cohort of mFFOX + PEGPH20, the Phase II study randomized patients (1:1) to the combination arm or mFFOX alone (n = 138). The primary endpoint was overall survival (OS), with a null median OS of 10 mo and an alternative of 15 mo (1-sided type 1 error 0.1, 80% power). Results: PEGPH20 at 3 mcg/kg, q2 weeks was more tolerable than twice weekly dosing. The randomized phase II study began May 2015. The planned interim futility analysis when 35 deaths occurred gave a HR of 0.44 favoring the standard arm, thus the study was closed to accrual (March 2017). As of August 22, 2017 (n = 111), the estimated median OS in the mFFOX arm was 15.1 mo (95% CI 10.1-15.7) vs 7.6 mo (95% CI 4.6-9.2) in the PEGPH20 arm. Conclusions: OS in the mFFOX control arm (15.1 mo) is longest yet reported. Addition of PEGPH20 to mFFOX is not recommended for further study and appears to be detrimental (HR = 0.48). The impact of PEGPH20 on OS was unexpected and in contrast to favorable results reported for the combination of gemcitabine/nab-paclitaxel + PEGPH20 especially in the HA high cohort (Hingorani S et al. A 4008, ASCO 2017). PEGPH20 with mFFOX caused increased toxicity (mostly GI and TE events) and decreased treatment duration compared to mFFOX alone. Tumor HA content will be analyzed. Funding: NIH/NCI grants CA180888, CA180819; and in part by Halozyme Inc. Clinical trial information: 01959139. [Table: see text]

Targeting the complexity of Src signalling in the tumour microenvironment of pancreatic cancer: from mechanism to therapy

“…HA regulates interstitial gel fluid pressure within tumours, often impacting on drug delivery. Favourable results are particularly observed when PEGPH20 is combined with Gemcitabine and Abraxane [248,251,252], whereas FOLFIRINOX in contrast may be better utilised in other settings [253]. Of note, PEGPH20 has already shown significant promise in PDAC.…”

“…Clinical studies of PEGPH20 are also promising with phase II data already demonstrating significant efficacy of this agent when combined with chemotherapy, effect particularly prominent in patients with HAhigh tumours [248], highlighting the potential utility of intratumoural HA as a predictive biomarker of response [248][249][250]. Favourable results are particularly observed when PEGPH20 is combined with Gemcitabine and Abraxane [248,251,252], whereas FOLFIRINOX in contrast may be better utilised in other settings [253]. Development of a liquid biopsy-based companion diagnostic for selecting potential PEGPH20 responders is also underway [254].…”

Shattering the castle walls: Anti-stromal therapy for pancreatic cancer

“…In contrast, a recently presented randomized phase I/II study evaluating the efficacy of PEGPH20 and modified FOLFIRINOX in patients with metastatic PC who have a good performance status suggested that PEGPH20 can have a detrimental effect on OS (HR = 0.48). Therefore, further studies are needed to clarify whether the benefit from the use of PEGPH20 is restricted to patients treated with gemcitabine and nab-paclitaxel[ 74 ] .…”

Emerging Therapies and Future Directions in Targeting the Tumor Stroma and Immune System in the Treatment of Pancreatic Adenocarcinoma

“…These results led to HALO 301, an ongoing international randomized phase 3 trial, where patients with treatment naïve metastatic pancreatic adenocarcinoma with HA high tumors are randomized in a 2:1 fashion to receive gemcitabine/nab-paclitaxel alone or in combination with PEGPH20 [ 23 ]. In contrast, S1313, a randomized phase 1b/2 trial that investigated FOLFIRINOX cytotoxic chemotherapy in combination with PEGPH20, was halted for futility based off the planned interim analysis [ 24 ]. The median overall survival in the FOLFIRINOX arm was 14.4 months vs. 7.7 months in the PEGPH20 arm, favoring the standard arm (HR 0.48; p < 0.01) [ 24 ].…”

“…In contrast, S1313, a randomized phase 1b/2 trial that investigated FOLFIRINOX cytotoxic chemotherapy in combination with PEGPH20, was halted for futility based off the planned interim analysis [ 24 ]. The median overall survival in the FOLFIRINOX arm was 14.4 months vs. 7.7 months in the PEGPH20 arm, favoring the standard arm (HR 0.48; p < 0.01) [ 24 ]. These findings suggest a potential detrimental effect with the addition of PEGPH20 to FOLFIRINOX in patients with metastatic pancreas cancer.…”