A Phase 1b clinical trial of LDE225 (Sonidegib) in combination with fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFIRINOX) in previously untreated locally advanced or metastatic pancreatic adenocarcinoma

Background: Fluorouracil (5-FU), leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) chemotherapy improves survival for metastatic pancreatic cancer patients. However, significant room for improvement exists. Preclinical experiments suggest that inhibiting Sonic Hedgehog (SHH) could improve chemotherapy delivery with potential improved response. This study evaluated whether targeting pancreatic tumor stroma with SHH inhibitor LDE225 was feasible and would enhance effectiveness of FOLFIRINOX.Methods: This multicenter, single-arm phase 1b trial enrolled patients with histologically confirmed pancreatic adenocarcinoma who had not received prior chemotherapy for locally advanced or metastatic disease. Prior adjuvant chemotherapy was allowed. Patients received FOLFIRINOX on days 1–3 of a 14-day cycle. LDE225 was given orally every day. Primary objectives were to determine the: maximum tolerated doses (MTDs) of LDE225 in combination with FOLFIRINOX in patients with locally advanced or metastatic pancreatic adenocarcinoma; and, toxicity and safety profile of LDE225 in combination with FOLFIRINOX. Other objectives included determining the: response rate of pancreatic cancers treated with LDE225 and FOLFIRINOX, overall survival (OS), progression-free survival (PFS), and whether any patients with locally advanced disease were converted to resectable.Results: Among 39 patients enrolled, 35 received at least 1 dose of combined FOLFIRINOX and LDE225. Patient characteristics included: 51% female; median age 64 years; 90% metastatic and 10% locally advanced disease. The most frequent drug-related adverse events (AEs) were: fatigue (88%), nausea (86%), diarrhea (71%), and peripheral sensory neuropathy (66%). Elevated liver transaminases occurred in 49%. The most common grade 3 toxicities were nausea (17%), diarrhea (14%), fatigue (11%), dehydration (9%), and liver transaminase elevation (9%). Four patients (11%) had grade 4 AEs (three elevated liver transaminases, one hypoglycemia). There were no grade 5 events. For the entire cohort, median PFS was 6.1 (95% CI: 3.8–9.9) months and median OS was 11.2 (95% CI: 8.8–15.0) months.Conclusions: LDE225 could be combined with FOLFIRINOX with acceptable toxicity, although significant modifications of FOLFIRINOX dosing were required. The combination did not enhance PFS or OS beyond that expected with FOLFIRINOX alone. Doses of FOLFIRINOX had to be reduced when used in combination, demonstrating the difficulty of building on the FOLFIRINOX chemotherapy backbone.