A Phase I Study of FOLFIRINOX Plus IPI-926, a Hedgehog Pathway Inhibitor, for Advanced Pancreatic Adenocarcinoma

Abstract

Objectives In mouse models of pancreatic cancer, IPI-926, an oral Hedgehog inhibitor, increases chemotherapy delivery by depleting tumor-associated stroma. This multicenter phase Ib study evaluated IPI-926 in combination with FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, oxaliplatin) in patients with advanced pancreatic cancer. Methods Patients were treated with once-daily IPI-926 plus FOLFIRINOX. A 3 + 3 dose escalation design was used, with cohort expansion at the maximum tolerated dose. A subset of patients underwent perfusion computed tomography to assess changes in tumor perfusion. Results The maximum tolerated dose was identified 1 dose level below standard FOLFIRINOX. Common treatment-related adverse events included liver function test abnormalities, neuropathy, nausea/vomiting, and diarrhea. Objective response rate was high (67%), and patients receiving IPI-926 maintenance showed further declines in CA19-9 levels even after FOLFIRINOX discontinuation. Treatment did not result in consistent increases in tumor perfusion. The study closed early when a separate phase II trial of IPI-926 plus gemcitabine indicated detrimental effects of this combination. Conclusions This is the first study to demonstrate the feasibility of using FOLFIRINOX as the chemotherapeutic backbone in a clinical trial design. Although robust antitumor activity and acceptable safety were observed with the addition of IPI-926 to this regimen, future development of Hedgehog inhibitors in pancreatic cancer seems unlikely.

Expression of Hedgehog Pathway Mediator GLI Represents a Negative Prognostic Marker in Human Acute Myeloid Leukemia and Its Inhibition Exerts Antileukemic Effects

“…Because of the importance of dysregulated HH signaling in basal cell carcinomas, first clinical trials using HH inhibitors were conducted with basal cell carcinoma patients (40,41). Furthermore, first signs of clinical efficacy have been observed in solid tumors such as medulloblastoma, pancreatic cancer, or sarcomas (42)(43)(44).…”

The hedgehog pathway in nonalcoholic fatty liver disease

“…A synthetic cyclopamine analogue, saridegib or IPI-926, achieved improved stability, kinetic profile and potency as compared to cyclopamine (Peluso et al, 2014). Phase I and II clinical trials of saridegib in basal cell carcinoma showed potent anti-tumoral effect, but saridegib showed no effect or deleterious effects in patients with myelofibrosis, chondrosarcoma or pancreatic cancer (Jimeno et al, 2013; Ko et al, 2016; Sasaki et al, 2015). …”

Phase I trial of the oral smoothened inhibitor sonidegib in combination with paclitaxel in patients with advanced solid tumors

“…The limited single-agent activity observed in other solid tumors prompted combination studies with chemotherapy. However, results of these studies failed to demonstrate any benefit of adding an Hh inhibitor to standard chemotherapy regimens in advanced small cell-lung cancer (SCLC), pancreatic and colon cancer [21][22][23][24]. In a recently reported phase I trial sonidegib was combined with etoposide and cisplatin in 15 patients with newly diagnosed extensive SCLC.…”