A Phase I study of LDE225 in combination with gemcitabine and nab-paclitaxel in patients with metastasized pancreatic cancer

Abstract

Background: Metastasized pancreatic cancer has a dismal survival due to poor responses to chemotherapy. Preclinical research suggests that targeting pancreatic tumor stroma with the Sonic Hedgehog inhibitor LDE225 may improve chemotherapy delivery to the tumor. Method(s): We performed a phase IB dose-escalation clinical trial. The primary objectives were to determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and the anti-tumor efficacy of LDE225 in combination with 1000 mg/m2 gemcitabine and 125 mg/m2 nab-paclitaxel in patients with metastasized pancreatic cancer. The LDE225 dose was to be escalated, gemcitabine and nab-paclitaxel doses were fixed. Treatment evaluation was performed by CT after 2 cycles of therapy according to RECIST 1.1 criteria. Additional diffusion-weighted MRI scans were performed before and after 2 cycles of treatment. Result(s): 26 patients received study treatment for a median duration of 109 days (IQR 54-245) during a median of 4 (IQR 2-8.5) chemotherapeutic cycles. 6 patients discontinued due to toxicity and 20 patients because of progressive disease. At the starting dose level (400 mg LDE225), 1 out of 6 patients experienced a DLT. Because the DLT and most adverse events occurred in patients who received prior chemotherapeutic treatment we divided the cohort in a chemo-naive (n=17) and a prior-chemo group (n=9). Within the chemo-naive group, the MTD was 800 mg LDE225. In the priorchemo group, the MTD was 200 mg LDE225. No therapy-related grade 4 adverse events were reported. The most frequent grade 3 reported adverse events were: fatigue (27%), neutropenia (15%) and diarrhea (12%). Of 23 evaluable patients, 6 patients had progressive disease (26%), 8 had stable disease (35%), 8 had a partial response (35%) and 1 patient had a complete response (4%). 12 patients with SD/PR underwent both MRI scans. These patients showed a significant increase in diffusion coefficient after treatment (1.39+/-0.24 x 10-3vs. 1.62+/-0.25 x 10-3mm2/s, P< 0.001). Conclusion(s): The addition of LDE225 to gemcitabine and nab-paclitaxel was well tolerated and showed promising anti-tumor activity, regardless of whether or not patients had received prior chemotherapy for metastatic pancreatic cancer.