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.

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 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.

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 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.

Figure 1.

ABT-510 phase 1 trial treatment schema. The initial induction therapy phase of the clinical trial involved the Stupp regimen of temozolomide chemoradiation followed by chemotherapy maintenance. qd indicates every day; RT, radiation therapy; and SC, subcutaneous.

Figure 2.

Kaplan-Meier curves for time to progression (A) and overall survival time (B).

Figure 3.

Genes differentially expressed in 100% of tumors. Shown are the log₂-transformed expression ratios of the genes whose expression levels in 15 of 15 tumors fall outside the reference range determined from 5 control brains. ANGPT2indicates the gene encoding angiopoietin 2; COL4A1, collagen type IV α1; COL4A2, collagen type IV α2; EDIL3, epithelial growth factor–like repeats and discoidin I–like domains containing protein 3; FN1, fibronectin 1; IL8, interleukin 8; ITGA4, integrin α4; ITGB3, integrin β3; NRP2, neuropilin 2; and PECAM1, platelet-endothelial cell adhesion molecule 1.

Figure 4.

Genes differentially expressed in 73% to 99% of the tumors. Shown are the log₂-transformed expression ratios of the genes whose expression levels in 11 to 14 of 15 tumors fall outside the reference range determined from 5 control brains. ANGPTL2 indicates the gene encoding angiopoietin-like 2; CD44, CD44 antigen; CTGF, connective tissue growth factor; ECGF-1, endothelial cell growth factor 1, thymidine phosphorylase, ectonucleotide pyrophosphatase/ phosphodiesterase 2; HSPG2, heparan sulfate proteoglycan of basement membrane; INFG, suppressor of cytokine signaling 1; ITGAV, integrin α5; MMP2, matrix metalloproteinase 2; SEMA3F, semaphorin 3F; TIMP3, tissue inhibitor of metalloproteinase 3; TINN1, troponin 1; VEGFB, vascular endothelial growth factor B.

Figure 5.

Molecules that correlate with longer survival times. Shown are the genes discovered in a 2-sample t test at the 1% significance level comparing the expression levels of patients who were still alive with the expression levels of those who did not survive. TIE1 indicates the gene encoding tyrosine kinase with immunoglobulin and endothelial growth factor homology domains 1; FGF1, fibroblast growth factor 1.