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.

Define cancer-associated fibroblasts (CAFs) in the tumor microenvironment: new opportunities in cancer immunotherapy and advances in clinical trials

“…The median OS was 6 months. Moreover, six treatment-related grade 4 adverse events (AEs) and three grade 5 AEs were observed in phase 2 [ 332 ]. Moreover, CXCR2 signaling was found to be involved in iCAF formation and CAF to myCAF conversion.…”

Functional biomarkers derived from computed tomography and magnetic resonance imaging differentiate PDAC subgroups and reveal gemcitabine-induced hypo-vascularization

“…Consequently, it has led to the introduction of therapies intended to normalize intra-tumoral pressure, vascularization, and drug delivery [43]. Indeed, therapy trials with stroma targeting agents have shown improved perfusion, monitored non-invasively by contrast enhanced ultrasound [4,42] and DCE-MRI [18] in mPDAC as well as in hPDAC [30]. Subsequent reduced vascular collapse and increased drug delivery lead to prolonged survival of the treated animals [4,5,18,42].…”

“…For DCE-MRI, commonly used parameters are the volume transfer constant (K trans ) and the extravascular extracellular volume fraction (v e ) determined using Tofts pharmacokinetic modeling [28]. Differences in tumor perfusion and permeability, measured by K trans , were also correlated with biological variations in tissue composition, response to therapy and clinical outcome in PDAC [29][30][31][32]. However, such modeling introduces a high level of complexity and uncertainty.…”

Sonidegib Suppresses Production of Inflammatory Mediators and Cell Migration in BV2 Microglial Cells and Mice Treated with Lipopolysaccharide via JNK and NF-κB Inhibition

“…As the second SMO antagonist, sonidegib was approved in 2015 for the treatment of advanced basal cell carcinoma. Subsequent studies including clinical trials are in progress to expand its application to other types of cancer [18,19,33]. Apart from its role in cancer therapies, sonidegib was shown to exhibit protective effects in several animal models of CNS disorders, such as AD and ischemic stroke, by inhibiting Aβ-induced memory deficits, neuroinflammation, and glutamate toxicity [22,34].…”