title: Phase II and pharmacogenomics study of enzastaurin plus temozolomide during and following radiation therapy in patients with newly diagnosed glioblastoma multiforme and gliosarcoma.
abstract: This open-label, single-arm, phase II study combined enzastaurin with temozolomide plus radiation therapy (RT) to treat glioblastoma multiforme (GBM) and gliosarcoma. Adults with newly diagnosed disease and Karnofsky performance status (KPS) ≥ 60 were enrolled. Treatment was started within 5 weeks after surgical diagnosis. RT consisted of 60 Gy over 6 weeks. Temozolomide was given at 75 mg/m(2) daily during RT and then adjuvantly at 200 mg/m(2) daily for 5 days, followed by a 23-day break. Enzastaurin was given once daily during RT and in the adjuvant period at 250 mg/day. Cycles were 28 days. The primary end point was overall survival (OS). Progression-free survival (PFS), toxicity, and correlations between efficacy and molecular markers analyzed from tumor tissue samples were also evaluated. A prospectively planned analysis compared OS and PFS of the current trial with outcomes from 3 historical phase II trials that combined novel agents with temozolomide plus RT in patients with GBM or gliosarcoma. Sixty-six patients were enrolled. The treatment regimen was well tolerated. OS (median, 74 weeks) and PFS (median, 36 weeks) results from the current trial were comparable to those from a prior phase II study using erlotinib and were significantly better than those from 2 other previous studies that used thalidomide or cis-retinoic acid, all in combination with temozolomide plus RT. A positive correlation between O-6-methylguanine-DNA methyltransferase promoter methylation and OS was observed. Adjusting for age and KPS, no other biomarker was associated with survival outcome. Correlation of relevant biomarkers with OS may be useful in future trials.
authors: Neuro-Oncology Service, Department of Neurological Surgery, University of California, San Francisco, 400 Parnassus Avenue, A808, San Francisco, CA 94143-0350, USA. butowski@neurosurg.ucsf.edu
authors: Nicholas
authors: N
authors: Butowski
authors: Susan M
authors: SM
authors: Chang
authors: Kathleen R
authors: KR
authors: Lamborn
authors: Mei-Yin
authors: MY
authors: Polley
authors: Russell
authors: R
authors: Pieper
authors: Joseph F
authors: JF
authors: Costello
authors: Scott
authors: S
authors: Vandenberg
authors: Rupa
authors: R
authors: Parvataneni
authors: Angelina
authors: A
authors: Nicole
authors: Patricia K
authors: PK
authors: Sneed
authors: Jennifer
authors: J
authors: Clarke
authors: Emily
authors: E
authors: Hsieh
authors: Bruno M
authors: BM
authors: Costa
authors: Rui M
authors: RM
authors: Reis
authors: Maria
authors: M
authors: Hristova-Kazmierski
authors: Steven J
authors: SJ
authors: Nicol
authors: Donald E
authors: DE
authors: Thornton
authors: Michael D
authors: MD
authors: Prados
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000628:therapy*; D016022:Case-Control Studies; D059248:Chemoradiotherapy; D017024:Chemotherapy, Adjuvant; D017326:Clinical Trials, Phase III as Topic; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D005500:Follow-Up Studies; D005909:Glioblastoma / Q000175:diagnosis / Q000235:genetics / Q000628:therapy*; D018316:Gliosarcoma / Q000175:diagnosis / Q000235:genetics / Q000628:therapy*; D006801:Humans; D007124:Immunoenzyme Techniques; D007211:Indoles / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010597:Pharmacogenetics; D016133:Polymerase Chain Reaction; D011446:Prospective Studies; D015996:Survival Rate; D000077204:Temozolomide; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D004273:DNA, Neoplasm; D007211:Indoles; D003606:Dacarbazine; C504878:enzastaurin; D000077204:Temozolomide