Ultimately succumbing to pancreatic cancer, Steve Jobs certainly emphasized its striking fatality toll. But having lived with the daunting malignancy for far longer than expected, Jobs has also heightened the hope of surpassing the associated dismal survival rates often cited in today’s literature. Long regarded as the most lethal form of cancer and a leading cause of death from cancer worldwide, pancreatic cancer remains largely elusive to early detection and warning symptoms, ultimately causing 34,000 deaths annually.1
Worldwide, approximately 230,000 cases are diagnosed every year (≥43,000 of which occur in the United States),1 and those treated for locally advanced or metastatic pancreatic cancer typically have a median survival time of approximately 5 to 6 months. While these statistics have not budged significantly over the years, advancements in use of current multimodal treatment (surgery, chemotherapy, targeted therapy), as well as emerging research developments may fulfill Jobs’ legacy of cancer survival beyond odds and expectations.
First-line therapy, and the standard of care for locally advanced or metastatic pancreatic cancer, is gemcitabine (Gemzar, Eli Lilly and Company), which is approved by the FDA as monotherapy. Combination therapy with erlotinib (Tarceva, Genentech) has also been approved for the treatment of patients with advanced pancreatic cancer. Pancreatic cancer commonly becomes resistant to treatment, thus prompting the necessity for continued drug development.
Phase 1/2 Development
Many cancer cell types are, phenotypically, high expressers of tissue factor (TF). In one study, approximately 89% of patients with pancreatic cancer express TF. In this patient population, 26.3% of high TF expressers had venous thromboembolism compared to 4.5% in patients with low TF expression.2 Furthermore, this study demonstrated that TF expression is an important early event in malignant transformation of the pancreas.
Binding of TF to Factor VIIa leads to the activation of Factor VIIa. This event, in turn, induces intracellular signaling pathways that ultimately lead to increased expression of interleukin-8 and vascular endothelial growth factor, 2 proteins that promote tumor growth, metastases, and angiogenesis. Factor VIIa activity in cancers is also implicated in the high incidence of thromboembolic events, a major cause of death in patients with cancer. Treatment with anticoagulants improves survival.
Currently in clinical trials is Pharmacyclics’ Factor VIIa inhibitor, PCI-27483.3 This small-molecule inhibitor selectively targets Factor VIIa, consequently inhibiting tumor growth and metastasis, as well as formation of emboli. In Phase 1 testing of PCI-27483, which assessed the pharmacodynamic and pharmacokinetic profiles of PCI-27483 at ascending doses following a single, subcutaneous injection in healthy volunteers, it was well tolerated with no adverse events.
A separate Phase 1/2 study of the effects of PCI-27483 in metastatic or locally advanced pancreatic cancer patients that had previously received a standard regimen of gemcitabine was composed of 2 parts.4 In Part A, patients received escalating doses of PCI-27483, administered subcutaneously, twice daily, in combination with gemcitabine. In Phase 1, twice-daily subcutaneous administration of PCI-27483 at 0.8mg/kg or 1.2mg/kg has been shown to be associated with dose- and plasma concentration-dependent increases in INR values. In Part B, which is still ongoing, patients are being randomized to receive gemcitabine with or without PCI-27483.