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.
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.
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-naïve (n = 17) and a prior-chemo group (n = 9). Within the chemo-naive group, the MTD was 800 mg LDE225. In the prior-chemo 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 10−3 mm2/s, P < 0.001).
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.
Clinical trial identification
EudraCT number 2013-002370-51 NCT02358161
Legal entity responsible for the study
J.W. Wilmink Academic Medical Center Amsterdam - University of Amsterdam (AMC-UvA).
Academic Medical Center - University of Amsterdam (AMC-UvA) Novartis Pharma BV Cellgene BV.
All authors have declared no conflicts of interest.