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

Ana De Jesus-Acosta, Daniel Laheru, Anirban Maitra, John Arcaroli, Michelle A. Rudek, Arvind Dasari, Patrick J. Blatchford, Kevin Quackenbush, Wells Messersmith

Research output: Contribution to journalArticlepeer-review

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 6-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.

Original languageEnglish (US)
Pages (from-to)739-745
Number of pages7
JournalInvestigational New Drugs
Volume32
Issue number4
DOIs
StatePublished - Aug 2014

Keywords

  • Gamma secretase inhibitor
  • Notch signaling
  • Pancreatic cancer
  • Pharmacokinetics

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

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