Enzastaurin plus temozolomide with radiation therapy in glioblastoma multiforme: A phase I study

Nicholas Butowski, Susan M. Chang, Kathleen R. Lamborn, Mei Yin Polley, R. Parvataneni, Maria Hristova-Kazmierski, Luna Musib, Steven J. Nicol, Donald E. Thornton, Michael D. Prados

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

We conducted a phase I study to determine the safety and recommended phase II dose of enzastaurin (oral inhibitor of the protein kinase C-beta [PKCb] and the PI3K/AKT pathways) when given in combination with radiation therapy (RT) plus temozolomide to patients with newly diagnosed glioblastoma multiforme or gliosarcoma. Patients with Karnofsky performance status ≥60 and no enzyme-inducing anti-epileptic drugs received RT (60 Gy) over 6 weeks, concurrently with temozolomide (75 mg/m2 daily) followed by adjuvant temozolomide (200 mg/m2) for 5 days/28-d cycle. Enzastaurin was given once daily during RT and adjuvantly with temozolomide; the starting dose of 250 mg/d was escalated to 500 mg/d if ≤1/6 patients had dose-limiting toxicity (DLT) during RT and the first adjuvant cycle. Patients continued treatment for 12 adjuvant cycles unless disease progression or unacceptable toxicity occurred. Twelve patients enrolled. There was no DLT in the first 6 patients treated with 250 mg enzastaurin. At 500 mg, 2 of 6 patients experienced a DLT (1 Grade 4 and 1 Grade 3 thrombocytopenia). The patient with Grade 3 DLT recovered to Grade <1 within 28 days and adjuvant temozolomide and enzastaurin was reinitiated with dose reductions. The other patient recovered to Grade <1 toxicity after 28 days and did not restart treatment. Enzastaurin 250 mg/d given concomitantly with RT and temozolomide and adjuvantly with temozolomide was well tolerated and is the recommended phase II dose. The proceeding phase II trial has finished accrual and results will be reported in 2009.

Original languageEnglish (US)
Pages (from-to)608-613
Number of pages6
JournalNeuro-oncology
Volume12
Issue number6
DOIs
StatePublished - Jun 2010

Keywords

  • Adjuvant therapy
  • Enzastaurin
  • Glioblastoma multiforme
  • Radiation therapy
  • Temozolomide

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

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    Butowski, N., Chang, S. M., Lamborn, K. R., Polley, M. Y., Parvataneni, R., Hristova-Kazmierski, M., Musib, L., Nicol, S. J., Thornton, D. E., & Prados, M. D. (2010). Enzastaurin plus temozolomide with radiation therapy in glioblastoma multiforme: A phase I study. Neuro-oncology, 12(6), 608-613. https://doi.org/10.1093/neuonc/nop070