A phase 1 trial of ABT-510 concurrent with standard chemoradiation for patients with newly diagnosed glioblastoma

Academic Article

Abstract

  • Objective: To determine the maximum tolerated dose of ABT-510, a thrombospondin-1 mimetic drug with antiangiogenic properties, when used concurrently with temozolomide and radiotherapy in patients with newly diagnosed glioblastoma. Design: Phase 1 dose-escalation clinical trial. Setting: Comprehensive Cancer Center, University of Alabama at Birmingham. Patients: A total of 23 patients with newly diagnosed, histologically verified glioblastoma enrolled between April 2005 and January 2007. Interventions: Four cohorts of 3 patients each received subcutaneous ABT-510 injection at doses of 20, 50, 100, or 200 mg/d. The maximum cohort was expanded to 14 patients to obtain additional safety and gene expression data. The treatment plan included 10 weeks of induction phase (temozolomide and radio therapy with ABT-510for6weeks plus ABT-510 monotherapy for 4 weeks) followed by a maintenance phase of ABT-510 and monthly temozolomide. Main Outcome Measures: Patients were monitored with brain magnetic resonance imaging and laboratory testing for dose-limiting toxicities, defined as grades 3 or 4 nonhematological toxicities and grade 4 hematological toxicities. Therapy was discontinue dif14 maintenance cycles were completed, disease progression occurred, or if the patient requested withdrawal. Diseaseprogression, survival statistics,andgene expression arrays were analyzed. Results: There were no grade 3 or 4 dose-limiting toxicity events that appeared related to ABT-510 for the dose range of 20 to 200 mg/d. A maximum tolerated dose was not defined. Most adverse events were mild, and injectionsite reactions. The median time to tumor progression was 45.9 weeks, and the median overall survival time was 64.4 weeks. Gene expression analysis using TaqMan low density arrays identified angiogenic genes that were differentially expressed in the brains of controls compared with patients with newly diagnosed glioblastoma, and identified FGF-1 and TIE-1 as being downregulated in patients who had better clinical outcomes. Conclusions: ABT-510, at subcutaneous doses up to 200 mg/d, is tolerated well with concurrent temozolomide and radiotherapy in patients with newly diagnosed glioblastoma, and low-density arrays provide a useful method of exploring gene expression profiles. ©2010 American Medical Association. All rights reserved.
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    Author List

  • Nabors LB; Fiveash JB; Markert JM; Kekan MS; Gillespie GY; Huang Z; Johnson MJ; Meleth S; Kuo H; Gladson CL
  • Start Page

  • 313
  • End Page

  • 319
  • Volume

  • 67
  • Issue

  • 3