A multicenter phase 1 study of γ -secretase inhibitor RO4929097 in combination with capecitabine in refractory solid tumors

Noelle K. Loconte, Albiruni R.A. Razak, Percy Ivy, Amye Tevaarwerk, Rachael Leverence, Jill Kolesar, Lillian Siu, Sam J. Lubner, Daniel L. Mulkerin, William R. Schelman, Dustin A. Deming, Kyle D. Holen, Lakeesha Carmichael, Jens Eickhoff, Glenn Liu

Research output: Contribution to journalArticlepeer-review

29 Scopus citations


Background RO4929097 is an oral inhibitor of γ -secretase that results in Notch signaling inhibition. Prior work has demonstrated that Notch signaling inhibition enhances chemotherapy sensitivity of cancer cells. This phase I study was conducted to determine maximum tolerated dose (MTD), toxicities and efficacy of RO4929097 and capecitabine in advanced solid tumors. Methods Patients with refractory solid tumors received capecitabine at a fixed dose of 1,000 mg/m2 twice daily with escalating doses of RO4929097 on a 21-day cycle in a 3+3 design. Capecitabine was administered for 14 days and the RO49029097 once daily, 3 days per week, both for a 21 day cycle. Results Thirty patients were treated on six dose levels (20 to 150 mg). The maximally tolerated dose was not reached. One dose limiting toxicity was observed at each level 3 through 6 (hypophosphatemia, fatigue, and nausea/vomiting). Three confirmed partial responses were observed: two patients with fluoropyrimide-refractory colon cancer and one patient with cervical cancer. Autoinduction of RO4929097 was demonstrated with increasing dose levels and duration. Conclusions The recommended phase 2 dose is capecitabine 1,000 mg/m2 orally twice daily on days 1 through 14 with RO4929097 20 mg orally once daily on days 1-3, 8-10 and 15-17 with a 21 day cycle. Clinical benefit was observed in cervical and colon cancer. Autoinduction of RO4929097 was seen both with increasing cycle number and increasing dose. Plasma concentrations of RO4929097 were above those needed for Notch inhibition.

Original languageEnglish
Pages (from-to)169-176
Number of pages8
JournalInvestigational New Drugs
Issue number1
StatePublished - Feb 2015

Bibliographical note

Funding Information:
The investigators gratefully acknowledge the patients and families who participated in this study. Funding was provided by the National Cancer Institute Grant U01 CA062491 (University of Wisconsin) and U01-CA132123 (Princess Margaret Hospital). Further support is provided by the University of Wisconsin Carbone Cancer Center Core Grant P30 CA014520 and the Princess Margaret Hospital Phase I Consortium. Amye Tevaarwerk is supported by the National Institutes of Health Clinical and Translational Science Awards program 9U54TR000021.

Publisher Copyright:
© 2014 Springer Science+Business Media New York.


  • Capecitabine
  • Colorectal cancer
  • Phase 1
  • RO4929097

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)


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