title: A phase 1 trial of ABT-510 concurrent with standard chemoradiation for patients with newly diagnosed glioblastoma.
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.
  
  
  METHODS
  Phase 1 dose-escalation clinical trial.
  
  
  METHODS
  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.
  
  
  METHODS
  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 radiotherapy with ABT-510 for 6 weeks plus ABT-510 monotherapy for 4 weeks) followed by a maintenance phase of ABT-510 and monthly temozolomide.
  
  
  METHODS
  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 discontinued if 14 maintenance cycles were completed, disease progression occurred, or if the patient requested withdrawal. Disease progression, survival statistics, and gene 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 injection-site 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.
authors.affiliation: Neuro-oncology Program, University of Alabama at Birmingham, 510 20th St S, FOT 1020, Birmingham, AL 35294, USA. bnabors@uab.edu
authors.forename: Louis B
authors.initials: LB
authors.lastname: Nabors
authors.forename: John B
authors.initials: JB
authors.lastname: Fiveash
authors.forename: James M
authors.initials: JM
authors.lastname: Markert
authors.forename: Manasi S
authors.initials: MS
authors.lastname: Kekan
authors.forename: George Y
authors.initials: GY
authors.lastname: Gillespie
authors.forename: Zhi
authors.initials: Z
authors.lastname: Huang
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Johnson
authors.forename: Sreelatha
authors.initials: S
authors.lastname: Meleth
authors.forename: Huichien
authors.initials: H
authors.lastname: Kuo
authors.forename: Candece L
authors.initials: CL
authors.lastname: Gladson
authors.forename: Hassan M
authors.initials: HM
authors.lastname: Fathallah-Shaykh
mesh_terms: D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000532:radiotherapy; D003131:Combined Modality Therapy; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000627:therapeutic use; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D016220:Fibroblast Growth Factor 1 / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000532:radiotherapy; D006801:Humans; D053208:Kaplan-Meier Estimate; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000009:adverse effects*; D042810:Receptor, TIE-1 / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077204:Temozolomide; D016896:Treatment Outcome
chemical_list: D018906:Antineoplastic Agents, Alkylating; C500617:NAc-Sar-Gly-Val-(d-allo-Ile)-Thr-Nva-Ile-Arg-ProNEt; D009842:Oligopeptides; D016220:Fibroblast Growth Factor 1; D003606:Dacarbazine; D042810:Receptor, TIE-1; D000077204:Temozolomide