Investigational New Drugs

, Volume 32, Issue 4, pp 739–745

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

Authors

    • Department of OncologyThe Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine
  • Daniel Laheru
    • Department of OncologyThe Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine
  • Anirban Maitra
    • Department of PathologyThe Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine
    • Department of PathologyUT MD Anderson Cancer Center
    • Department of Translational Molecular PathologyUT MD Anderson Cancer Center
  • John Arcaroli
    • University of Colorado Cancer Center
  • Michelle A. Rudek
    • Department of OncologyThe Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine
  • Arvind Dasari
    • Department of PathologyUT MD Anderson Cancer Center
    • Department of Translational Molecular PathologyUT MD Anderson Cancer Center
  • Patrick J. Blatchford
    • University of Colorado Cancer Center
  • Kevin Quackenbush
    • University of Colorado Cancer Center
  • Wells Messersmith
    • University of Colorado Cancer Center
PHASE II STUDIES

DOI: 10.1007/s10637-014-0083-8

Cite this article as:
De Jesus-Acosta, A., Laheru, D., Maitra, A. et al. Invest New Drugs (2014) 32: 739. doi:10.1007/s10637-014-0083-8
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Summary

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.

Keywords

Pancreatic cancerNotch signalingGamma secretase inhibitorPharmacokinetics

Supplementary material

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

Copyright information

© Springer Science+Business Media New York 2014