Phase I/II Study of LDE225 With Gemcitabine and Nab-paclitaxel in Patients With Pancreatic Cancer

The 5 year survival of patients with locally advanced or metastatic pancreatic cancer is less than 5 %. Since the introduction of gemcitabine, further advances in therapy in the advanced/metastatic setting have been extremely slow. Numerous phase III studies have evaluated different gemcitabine-based regimens as first-line therapy, but in most cases, any observed benefits have been small and restricted to patients with a good performance status (PS). Recently two new chemotherapy combination schedules, FOLFIRINOX and Gemcitabine + nab-paclitaxel demonstrated a significant survival improvement compared to gemcitabine alone. Nab-paclitaxel is especially interesting because it is able to break-down the tumor matrix and increases the concentration of cytotoxic drugs in the tumor. Our study will explore the modification of the desmoplastic reaction seen in pancreatic cancer using two approaches, targeting tumor stroma by nab-paclitaxel and the hedgehog inhibitor LDE225 and targeting the tumor cells with gemcitabine and nab-paclitaxel.

Growing body of evidence suggests that the stroma is not only a mechanical barrier that may prevent efficient delivery of various anticancer therapies to the tumor, but also constitutes a dynamic compartment of pancreatic tumors that is critically involved in tumor formation, progression and metastasis. Thus, targeting both tumor stroma and cancer cells could be a lucrative strategy to increase the efficacy of our therapeutic approach. In the present study we want to explore the safety and activity of the chemotherapy combination: Gemcitabine + nab-paclitaxel + LDE225. LDE225 is a hedgehog inhibitor with promising antitumor activity in several cancer models, including pancreatic cancer. One of the main activities is also the degradation of the tumor matrix. Patients with locally advanced or metastatic pancreatic cancer will be treated with fixed doses of gemcitabine + nab-paclitaxel, the same doses used in the recently presented phase III study (von Hoff American Society of Clinical Oncology ASCO 2013). In the phase I part of the study LDE225 will be added according to standard dose escalation strategy for phase I studies, and at the maximum tolerated dose (MTD) patients will be treated in the phase II part of the study.