A phase II study of the gamma secretase inhibitor RO4929097 in patients with previously treated metastatic pancreatic adenocarcinoma

Abstract

Purpose The notch pathway is overexpressed in pancreatic adenocarcinoma. RO4929097, an oral inhibitor of the γ-secretase enzyme has been safely given as a single agent in patients with advanced solid tumors. We aimed to evaluate the efficacy of RO4929097 in patients with pancreatic adenocarcinoma (PDA). Methods A two-stage, single-arm Phase II trial was conducted in patients with previously treated metastatic PDA. RO4929097 was administered at a dose of 20 mg daily on days 1-3, 8-10 and 15-17 of 21-day cycles. The primary endpoint was survival at 6 months. Secondary endpoints included overall survival (OS), response rate, toxicities, pharmacokinetic and pharmacodynamic analyses. Results Eighteen patients were recruited, 17 in the first stage and one in the 2nd stage. It was decided to stop further enrollment after RO4929097 was discontinued by the sponsor and was no longer a development candidate. Three (25%) of 12 evaluable patients achieved stable disease. The six-month survival rate was 27.8% (95 % CI 9.7–53.5). The median OS was 4.1 months (95 % CI 2.7–5.8 months) and median progression-free survival was 1.5 months (95 % CI 1.3–1.6 months). Pharmacokinetic properties of RO4929097 in patients (n=5) with PDA was similar to that previously reported in other patient populations. There was a trend towards a decrease in HeyL (p = 0.08) gene expression in three patients following study drug administration. Conclusions RO4929097 was well-tolerated in patients with previously treated PDA. Development of RO4929097 has been discontinued, but development of other notch-targeting agents in pancreatic cancer is continuing.

Nuclear orphan receptor NR2F6 confers cisplatin resistance in epithelial ovarian cancer cells by activating the Notch3 signaling pathway

“…GSI with drugs including RO4929097, a small and potent inhibitor of γ‐secretase, lead to the blockade of Notch signaling in tumor cells, and the significant antitumor effects of GSIs have been verified in preclinical studies . Nevertheless, in a current phase II study performed in patients with pancreatic adenocarcinoma, colorectal cancer and EOC, RO4929097 showed minimal clinical activity and the median progression‐free survival time was not superior relative to historical treatment data . Based on our data, we propose two reasons that may partly explain the underwhelming clinical response to RO4929097, and we suggest strategies to improve the objective responses to this GSI.…”

EpCAM-regulated intramembrane proteolysis induces a cancer stem cell-like gene signature in hepatitis B virus-infected hepatocytes

“…Indeed, γ-secretase inhibitors are in clinical trials for other human cancers [49,50]. Likewise, Wnt signaling inhibitors may also be considered for treatment of HBV-associated HCCs [51].…”

Notch-1 Confers Chemoresistance in Lung Adenocarcinoma to Taxanes through AP-1/microRNA-451 Mediated Regulation of MDR-1

“…29 GSIs possess potent antitumour activity to inhibit cell growth and induce cell apoptosis in many human cancers, such as breast cancer, hepatoma, myeloma, and pancreatic cancer, and some of them have already been tested in clinical trials. 30,31,32,33,34 Thus, to investigate the effect of Notch-1 inhibition on DTX-resistant LAD, we introduced a widely used GSI DAPT. Our data revealed that inhibition of Notch-1 by DAPT sensitizes resistant LAD cells to DTX treatment in vitro and in vivo .…”