- PEGPH20 may be associated with venous thromboembolic events [VTE].
- VTE are common in pancreatic cancer.
- Prohylaxis for VTE is possible with low molecular weight heparin.
On April 4, 2014, Halozyme Therapeutics announced that it was halting the Phase 2 clinical trial of PEGPH20 and suffered a 27% decline in stock price. The trial was initiated in September 2011 and included an open enrollment Phase 1b component, the results of which were presented in 2013. In the Phase 2 clinical trial, patients with metastatic pancreatic cancer received the standard of care with PEGPH20 or with placebo. As is common, in double blind clinical trials, the safety of the trial was monitored by a Data Monitoring Committee [DMC]. The DMC reported a possible difference in the thromboembolic event rate between the group of patients treated with PEGPH20, nab-paclitaxel and gemcitabine versus the group of patients treated with nab-paclitaxel and gemcitabine without PEGPH20.
Venous thromboembolism [VTE] is a relatively common risk associated with malignant disease. In a retrospective study of the IMPACT healthcare claims database of patients with a range of solid tumors who started chemotherapy from January 2005 through December 2008, the overall incidence of VTE 3.5 months after starting chemotherapy was 7.3% (range 4.6%-11.6%) rising to 13.5% at 12 months (range 9.8%-21.3%). The highest VTE risk was identified in patients with pancreatic, stomach, and lung cancer. Another smaller study has reported an incidence of thromboembolism of up to 28.9% in pancreatic cancers patients. The pathogenesis of hypercoagulability in cancer is multifactorial: increased expression of pro-thrombotic factors, decreased inhibitors of anticoagulation and an increase in platelet aggregation. In addition, chemotherapy is associated with about a five-fold increased risk of thromboembolism.
Thus, the question facing the DMC is whether in the presence of a fairly common complication associated with pancreatic cancer treatment, there is an imbalance in VTE between the two treatment arms that is significantly higher in the PEGPH20 treated patients. The DMC probably evaluated a data set from a pre-specified cut-off and presumably now will totally review the available data. Such a review may or may not confirm the original suspicion. In the event VTEs are confirmed to be more common with PEGPH20 does this mean that PEGPH20 has no future as a therapeutic? Not necessarily.
While venous VTE is a leading cause of death among outpatient chemotherapy patients, prophylaxis for VTE is not currently widely used, perhaps because of fear of bleeding complications. However, the results of a number of recent clinical trials show that the routine use of prophylactic low molecular weight heparin (LMWH) is feasible in patients with advanced pancreatic cancer and is associated with a low risk of hemorrhage. For example, the Charité Onkologie (CONKO)-004 trial, randomized patients with advanced pancreatic cancer to chemotherapy alone versus simultaneous LMWH and chemotherapy. There was a significant decrease in the incidence of symptomatic VTE in the treatment versus the no treatment arm after 3 months (1.25% vs. 9.87%, respectively) as well as after 12 months (5.00% vs. 15.13%, respectively), with no significant difference in major bleeding episodes between the two arms.
Despite all the advances in treatment modalities for pancreatic cancer, the prognosis remains poor, with reported 5-year survival of only 2-4%. In this context, the preliminary results of the Phase 1b clinical trial of PEGPH20 were encouraging, though far from definitive, particularly the overall survival (OS) of the subset patients with high tumor associated hyaluronan that is associated with a poor prognosis. Should the Phase 2 suggest similar improvements in OS, mitigated by a higher incidence of VTE, it is likely that a way forward can be found for the development of PEGPH20, perhaps involving patient prophylaxis with LMWH.