title: Phase 1/2 trials of Temozolomide, Motexafin Gadolinium, and 60-Gy fractionated radiation for newly diagnosed supratentorial glioblastoma multiforme: final results of RTOG 0513.
abstract: OBJECTIVE
  The purpose of phase 1 was to determine the maximum tolerated dose (MTD) of motexafin gadolinium (MGd) given concurrently with temozolomide (TMZ) and radiation therapy (RT) in patients with newly diagnosed supratentorial glioblastoma multiforme (GBM). Phase 2 determined whether this combination improved overall survival (OS) and progression-free survival (PFS) in GBM recursive partitioning analysis class III to V patients compared to therapies for recently published historical controls.
  
  
  METHODS
  Dose escalation in phase 1 progressed through 3 cohorts until 2 of 6 patients experienced dose-limiting toxicity or a dose of 5 mg/kg was reached. Once MTD was established, a 1-sided 1-sample log-rank test at significance level of .1 had 85% power to detect a median survival difference (13.69 vs 18.48 months) with 60 deaths over a 12-month accrual period and an additional 18 months of follow-up. OS and PFS were estimated using the Kaplan-Meier method.
  
  
  RESULTS
  In phase 1, 24 patients were enrolled. The MTD established was 5 mg/kg, given intravenously 5 days a week for the first 10 RT fractions, then 3 times a week for the duration of RT. The 7 patients enrolled in the third dose level and the 94 enrolled in phase 2 received this dose. Of these 101 patients, 87 were eligible and evaluable. Median survival time was 15.6 months (95% confidence interval [CI]: 12.9-17.6 months), not significantly different from that of the historical control (P=.36). Median PFS was 7.6 months (95% CI: 5.7-9.6 months). One patient (1%) experienced a grade 5 adverse event possibly related to therapy during the concurrent phase, and none experience toxicity during adjuvant TMZ therapy.
  
  
  CONCLUSIONS
  Treatment was well tolerated, but median OS did not reach improvement specified by protocol compared to historical control, indicating that the combination of standard RT with TMZ and MGd did not achieve a significant survival advantage.
authors.affiliation: Arizona Oncology Services Foundation, Scottsdale, Arizona; Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona. Electronic address: david.brachman@dignityhealth.org.
authors.forename: David G
authors.initials: DG
authors.lastname: Brachman
authors.affiliation: Radiation Therapy Oncology Group Statistical Center, Philadelphia, Pennsylvania.
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Pugh
authors.affiliation: Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona.
authors.forename: Lynn S
authors.initials: LS
authors.lastname: Ashby
authors.affiliation: Arizona Oncology Services Foundation, Scottsdale, Arizona.
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Thomas
authors.affiliation: University of Florida College of Medicine, Gainesville, Florida.
authors.forename: Erin M
authors.initials: EM
authors.lastname: Dunbar
authors.affiliation: St. Joseph Mercy Hospital, Ann Arbor, Michigan.
authors.forename: Samir
authors.initials: S
authors.lastname: Narayan
authors.affiliation: University of Wisconsin Hospital, Madison, Wisconsin.
authors.forename: H Ian
authors.initials: HI
authors.lastname: Robins
authors.affiliation: Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Bovi
authors.affiliation: University of Washington Medical Center, Seattle, Washington.
authors.forename: Jason K
authors.initials: JK
authors.lastname: Rockhill
authors.affiliation: Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona.
authors.forename: Minhee
authors.initials: M
authors.lastname: Won
authors.affiliation: Emory University, Atlanta, Georgia.
authors.forename: Walter P
authors.initials: WP
authors.lastname: Curran
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000037:antagonists & inhibitors; D001932:Brain Neoplasms / Q000401:mortality* / Q000628:therapy*; D059248:Chemoradiotherapy / Q000009:adverse effects* / Q000379:methods; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D019583:Dose Fractionation, Radiation; D005260:Female; D005909:Glioblastoma / Q000401:mortality* / Q000628:therapy*; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008665:Metalloporphyrins / Q000008:administration & dosage / Q000009:adverse effects; D015999:Multivariate Analysis; D015173:Supratentorial Neoplasms / Q000401:mortality* / Q000628:therapy*; D000077204:Temozolomide
chemical_list: D018906:Antineoplastic Agents, Alkylating; D008665:Metalloporphyrins; C437683:motexafin gadolinium; D003606:Dacarbazine; D000077204:Temozolomide
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