title: Phase I study of arsenic trioxide and temozolomide in combination with radiation therapy in patients with malignant gliomas.
abstract: To evaluate the toxicity and maximum tolerated dose (MTD) of arsenic trioxide (ATO) in combination with temozolomide (TMZ) and radiation therapy (RT) in malignant gliomas. A 3 + 3 dose escalation study was performed in patients with newly diagnosed glioblastoma, anaplastic astrocytoma (AA), and anaplastic oligoastrocytoma (AOA). All patients received RT 59-61 Gy in 28-33 fractions, TMZ for 42 days, and ATO 1-2 h prior to RT for 5 days during the first week, then twice weekly until completing RT. Dose levels (DL) were: (1) TMZ 60 mg/m(2)/ATO 0.2 mg/kg; (2) TMZ 75 mg/m(2)/ATO 0.2 mg/kg; (3) TMZ 75 mg/m(2)/ATO 0.25 mg/kg. Dose-limiting toxicity (DLT) was defined as grade 3 non-hematologic toxicity or grade 4 toxicity of any type from enrollment until 3 weeks after finishing RT. 17 patients (13 glioblastoma, 4 AA/AOA) were accrued. Median age was 52 (range 25-80). Median KPS was 90 %. DLT's occurred at DL 2 (grade 4 transaminase elevation) and DL 3 (grade 4 neutropenia and grade 3 QTc prolongation). The MTD of TMZ 75 mg/m(2)/ATO 0.2 mg/kg was safe and well tolerated. A phase II study evaluating the efficacy of this combination is underway.
authors.affiliation: Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. SGrimm@nmff.org
authors.forename: Sean A
authors.initials: SA
authors.lastname: Grimm
authors.forename: Maryanne
authors.initials: M
authors.lastname: Marymont
authors.forename: James P
authors.initials: JP
authors.lastname: Chandler
authors.forename: Kenji
authors.initials: K
authors.lastname: Muro
authors.forename: Steven B
authors.initials: SB
authors.lastname: Newman
authors.forename: Robert M
authors.initials: RM
authors.lastname: Levy
authors.forename: Borko
authors.initials: B
authors.lastname: Jovanovic
authors.forename: Katie
authors.initials: K
authors.lastname: McCarthy
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Raizer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000008:administration & dosage; D001932:Brain Neoplasms / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D059248:Chemoradiotherapy; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D019583:Dose Fractionation, Radiation; D005260:Female; D005910:Glioma / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D010087:Oxides / Q000008:administration & dosage; D011379:Prognosis; D011879:Radiotherapy Dosage; D015996:Survival Rate; D000077204:Temozolomide
chemical_list: D001152:Arsenicals; D010087:Oxides; D003606:Dacarbazine; D000077237:Arsenic Trioxide; D000077204:Temozolomide