Phase I trial of vorinostat combined with bevacizumab and CPT-11 in recurrent glioblastoma

Prakash Chinnaiyan, Sajeel Chowdhary, Lisa Potthast, Antony Prabhu, Ya Yu Tsai, Bhaswati Sarcar, Soumen Kahali, Steven Brem, H. Michael Yu, Amyn Rojiani, Ryan Murtagh, Edward Pan

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

A phase I study was conducted to determine the doselimiting toxicities (DLT) and maximum tolerated dose (MTD) for the combination of vorinostat with bevacizumab and CPT-11 in recurrent glioblastoma. Vorinostat was combined with bevacizumab and CPT-11 and was escalated using a standard 3 1 3 design. Vorinostat was escalated up to 2 actively investigated doses of this compound or until the MTD was identified on the basis of DLTs. Correlative science involving proteomic profiling of serial patient plasma samples was performed. Nineteen patients were treated. The MTD of vorinostat was established at 400 mg on days 1-7 and 15-21 every 28 days when combined with bevacizumab and CPT-11. Common toxicities were fatigue and diarrhea. DLTs included fatigue, hypertension/hypotension, and central nervous system ischemia. Although the MTD was established, CPT-11 dose reductions were common early in therapy. High-dose vorinostat had an improved progression-free survival and overall survival when compared with low-dose vorinostat. Serum proteomic profiling identified IGFBP-5 and PDGF-AA as markers for improved PFS and recurrence, respectively. A MTD for the combination of vorinostat with bevacizumab and CPT-11 has been established, although it has poor long-term tolerability. With the increased toxicities associated with CPT-11 coupled with its unclear clinical significance, investigating the efficacy of vorinostat combined with bevacizumab alone may represent a more promising strategy to evaluate in the context of a phase II clinical trial.

Original languageEnglish (US)
Pages (from-to)93-100
Number of pages8
JournalNeuro-Oncology
Volume14
Issue number1
DOIs
StatePublished - Jan 2012

Keywords

  • Bevacizumab
  • CPT-11
  • Recurrent glioblastoma
  • Vorinostat

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

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    Chinnaiyan, P., Chowdhary, S., Potthast, L., Prabhu, A., Tsai, Y. Y., Sarcar, B., Kahali, S., Brem, S., Yu, H. M., Rojiani, A., Murtagh, R., & Pan, E. (2012). Phase I trial of vorinostat combined with bevacizumab and CPT-11 in recurrent glioblastoma. Neuro-Oncology, 14(1), 93-100. https://doi.org/10.1093/neuonc/nor187