Investigational New Drugs

, Volume 32, Issue 4, pp 739–745 | Cite as

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

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


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.


Pancreatic cancer Notch signaling Gamma secretase inhibitor Pharmacokinetics 



The authors would like to thank Ping He, Teresia Wanjiku, and Ming Zhao for technical support for the pharmacokinetic data; and Linping Xu for her quality assurance of the pharmacokinetic data. The authors would also like to thank the patients and their families for participating in the study.


This research was supported by the Lustgarten Foundation Correlative Study Grant Application (WAM, AM, MAR); NIH/NCI grant U01 CA070095 (MAR); Analytical Pharmacology Core of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (NIH grants P30 CA006973 and UL1 RR025005; Shared Instrument Grant (1S10RR026824-01); and the Genomics Core at the University of Colorado Cancer Center (P30-CA046934). This publication was made possible in part by Grant Number UL1RR025005 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.

Disclosure of Potential Conflicts of Interest

WM: clinical research support, Roche

JA: laboratory research support, Roche

Supplementary material

10637_2014_83_MOESM1_ESM.doc (205 kb)
Supplemental Figure 1 (DOC 205 kb)


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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Ana De Jesus-Acosta
    • 1
    Email author
  • Daniel Laheru
    • 1
  • Anirban Maitra
    • 2
    • 4
    • 5
  • John Arcaroli
    • 3
  • Michelle A. Rudek
    • 1
  • Arvind Dasari
    • 4
    • 5
  • Patrick J. Blatchford
    • 3
  • Kevin Quackenbush
    • 3
  • Wells Messersmith
    • 3
  1. 1.Department of OncologyThe Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of MedicineBaltimoreUSA
  2. 2.Department of PathologyThe Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of MedicineBaltimoreUSA
  3. 3.University of Colorado Cancer CenterAuroraUSA
  4. 4.Department of PathologyUT MD Anderson Cancer CenterHoustonUSA
  5. 5.Department of Translational Molecular PathologyUT MD Anderson Cancer CenterHoustonUSA

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