Phase I/II Study of LDE225 in Combination with Gemcitabine and Nab-Paclitaxel in Patients with Metastatic Pancreatic Cancer

Abstract

Background: Desmoplasia is a central feature of the tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC). LDE225 is a pharmacological Hedgehog signaling pathway inhibitor and is thought to specifically target tumor stroma. We investigated the combined use of LDE225 and chemotherapy to treat PDAC patients.

Methods: This was a multi-center, phase I/II study for patients with metastatic PDAC establishing the maximum tolerated dose of LDE225 co-administered with gemcitabine and nab-paclitaxel (phase I) and evaluating the efficacy and safety of the treatment combination after prior FOLFIRINOX treatment (phase II). Tumor microenvironment assessment was performed with quantitative MRI using intra-voxel incoherent motion diffusion weighted MRI (IVIM-DWI) and dynamic contrast-enhanced (DCE) MRI.

Results: The MTD of LDE225 was 200 mg once daily co-administered with gemcitabine 1000 mg/m² and nab-paclitaxel 125 mg/m². In phase II, six therapy-related grade 4 adverse events (AE) and three grade 5 were observed. In 24 patients, the target lesion response was evaluable. Three patients had partial response (13%), 14 patients showed stable disease (58%), and 7 patients had progressive disease (29%). Median overall survival (OS) was 6 months (IQR 3.9-8.1). Blood plasma fraction (DCE) and diffusion coefficient (IVIM-DWI) significantly increased during treatment. Baseline perfusion fraction could predict OS (>222 days) with 80% sensitivity and 85% specificity.

Conclusion: LDE225 in combination with gemcitabine and nab-paclitaxel was well-tolerated in patients with metastatic PDAC and has promising efficacy after prior treatment with FOLFIRINOX. Quantitative MRI suggested that LDE225 causes increased tumor diffusion and works particularly well in patients with poor baseline tumor perfusion.

Keywords: Hedgehog signaling pathway inhibitor; LDE225; metastatic pancreatic ductal adenocarcinoma; pancreatic neoplasms; quantitative MRI.

Figure 1

Waterfall plot of tumor response depicted as percentage of tumor volume change phase I and II combined for the patients of phase I that received prior treatment with FOLFIRINOX and treatment with LDE225 200 mg.

Figure 2

Swimmers plot for evaluation of progression and responses in days, responses as indicated phase I and II combined for the patients of phase I that received prior treatment with FOLFIRINOX and treatment with LDE225 200 mg. PD = progressive disease, PR = partial response, SD = stable disease.

Figure 3

Example of an anatomical image (Dixon), T1 map, parameter maps of DCE MRI (ktrans, kep, ve, and vp), and parameter maps of IVIM-DWI MRI (D, f and D*) for one patient at baseline. The primary tumor is manually delineated in red. The delineation is performed separately for IVIM-DWI and DCE MRI scans.

Figure 4

Plot of v_p and D at baseline and post-treatment. Both parameters significantly increased after treatment.

Figure 5

ROC curve of baseline f and Δf values for the prediction of OS > 222 days. The black dots indicate the cut-off values on which the sensitivity and specificity are determined. The AUC of f and Δf are 0.846 and 0.786, respectively.