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New Agents Under Exploration in Pancreatic Cancer

Published Online: May 17,2016
The tolerability of nab-paclitaxel and gemcitabine has opened the door to a host of novel combination strategies that use the two agents as a backbone. In one such study, which generated interest at the 2015 ASCO Annual Meeting, the addition of the enzyme PEGPH20 to standard nab-paclitaxel and gemcitabine improved PFS by 4.9 months compared with the two agents alone in untreated patients with advanced pancreatic cancer with high expression levels of hyaluronan (HA).15

In the ongoing study, patients with metastatic pancreatic cancer were randomized to nab-paclitaxel plus gemcitabine with or without PEGPH20, a pegylated version of recombinant human hyaluronidase. After enrolling 146 patients the study was placed on hold to address concerns regarding thromboembolic events in the investigational arm. At this point, the protocol was amended to exclude those at high risk for a thromboembolic event. Additionally, prophylaxis with enoxaparin was required in the ongoing study. 

In the study, 74 patients in the PEGPH20 arm and 61 in the control arm received treatment prior to the hold placed on the study (Stage 1). Additionally, following the protocol adjustment, the study enrolled an additional 114 patients (Stage 2). Efficacy data presented at ASCO were from Stage 1, while safety data included limited data from Stage 2 and all of Stage 1.

For patients treated in the overall population, the ORR was 41% with PEGPH20 versus 34% in the control arm (P = .48). The median duration of response (DoR) was 7.4 versus 4.2 months, in the investigational and control arms, respectively. The PFS in the full population was 5.7 months with PEGPH20 versus 5.2 months with nab-paclitaxel/gemcitabine (HR, 0.69; P = .11).

The median PFS in the HA-high group was 9.2 months with PEGPH20 versus 4.3 months in the control arm (HR, 0.39; P = .05). In the HA-low arm, the median PFS was 5.3 versus 5.6 months, with PEGPH20 and without, respectively (P = .74).

For those with HA-high tumors, the ORR was 52% with a DOR of 8.1 months compared with 24% and a DoR of 3.7 months, for PEGPH20 and the control, respectively. There was 1 complete response in the PEGPH20 arm, with a median DoR of 7.4 months. In the low group, the ORRs were similar between the two arms (37% vs 38%). 

There was a trend toward improvement in OS with the triplet therapy; however, this was not deemed statistically significant. At the analysis, the median OS was 12 months with PEGPH20 versus 9 months without (HR, 0.62; CI, 0.26-1.46). 

At a median follow-up of 7 months, all but 4 patients had discontinued Stage 1 of the study, primary as a result of progression (44.3% in the PEGPH20 arm versus 52.5% in the comparator). AEs were the cause of discontinuation for 18.6% of patients in the PEGPH20 arm versus 16.4% in the control arm. 

The most significantly increased AEs of all grades with PEGPH20 versus without were peripheral edema (58.1% vs 31.1%), muscle spasms (55.4% vs 1.6%), and neutropenia (32.4% vs 18%). The most frequently observed grade ≥3 adverse event with PEGPH20 was neutropenia (24.3%). 

A phase III study will assess PEGPH20 in combination with nab-paclitaxel and gemcitabine for patients with metastatic pancreatic cancer with high HA levels. The primary endpoint of the study is PFS, with secondary outcomes measures focused on toxicity and OS. Halozyme hopes to use PFS data from the study for a potential new drug application.

Cancer Stem Cell Inhibitors

A group of cancer stem cell inhibitors are currently in development for patients with pancreatic cancer. These agents target different pathways and both are being combined with nab-paclitaxel and gemcitabine.


A phase Ib study explored demcizumab plus gemcitabine with or without nab-paclitaxel in 56 patients with pancreatic cancer.16 Fifty-six patients at a median age of 65 years were treated across doses of demcizumab. Overall, 32 patients received the triplet and 24 received the doublet. 

Of evaluable patients in the triplet arm (n = 28), the ORR was 50% by RECIST criteria. Additionally, 11 patients had stable disease for a clinical benefit rate of 89%. The median PFS was 7.1 months and the median OS was 12.7 months. 

The most common AEs with demcizumab plus gemcitabine were fatigue, vomiting, hypertension, nausea, and decreased appetite. The most common AEs with the triplet were fatigue, nausea, diarrhea, and BNP increase, which appears to be an early indicator of cardiotoxicity that can be prevented with proper management.


The stemness inhibitor napabucasin (BBI-608) has demonstrated promising clinical activity when used in combination with weekly paclitaxel in heavily pretreated patients with metastatic pancreatic cancer, according to phase Ib/II data.17 In the extension phase, 41 patients received oral napabucasin continuously at a starting dose of 480 mg or 500 mg twice daily along with paclitaxel at 80 mg/m2 intravenously on days 3, 10, and 17 of each 28-day cycle. 

Median PFS in the overall population of 41 patients was 2.2 months and median OS was 6.0 months. In 23 patients who were taxane-naïve, median PFS was 3.9 months and median OS was 7.4 months. The durable disease control and the prolonged OS in this pretreated population were notable. 

Treatment-related grade 3 AEs included diarrhea (4.9%), abdominal pain (4.9%), and nausea (2.4%), and were rapidly reversible. Diarrhea was the most common event of any grade. Overall, 65.9% of patients experienced grade 1 diarrhea and 29.3% had a grade 2 event. Grade 1 fatigue occurred in 26.8% of patients and grade 2 events were experienced by 17.1%. 

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New Agents Under Exploration in Pancreatic Cancer
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