Abstract
Background Anti-angiogenic therapies such as bevacizumab upregulate hypoxia-inducible factor-1α (HIF-1α), a possible mechanism of drug resistance. Camptothecin analogues, including SN-38, have been shown to reduce the expression and transcriptional activity of HIF-1α in preclinical models. We hypothesized that co-administration of pegylated SN-38 (EZN-2208) may offset the induction of HIF-1α following bevacizumab treatment, resulting in synergistic antitumor effects. Patients and Methods Patients with refractory solid tumors were enrolled. Objectives were to evaluate the modulation of HIF-1α protein and target genes in tumor biopsies following administration of the combination of EZN-2208 administered weekly × 3 (days 1, 8, 15) and bevacizumab administered every 2 weeks, in 28-day cycles, and to establish the safety and tolerability of the combination. Tumor biopsies and dynamic contrast enhanced MRI (DCE-MRI) were obtained following bevacizumab alone (before EZN-2208) and after administration of both study drugs. Results Twelve patients were enrolled; ten were evaluable for response. Prolonged stable disease was observed in 2 patients, one with HCC (16 cycles) and another with desmoplastic round cell tumor (7 cycles). Reduction in HIF-1α protein levels in tumor biopsies compared to baseline was observed in 5 of 7 patients. Quantitative analysis of DCE-MRI from 2 patients revealed changes in K trans and kep. The study closed prematurely as further clinical development of EZN-2208 was suspended by the pharmaceutical sponsor. Conclusion Preliminary proof-of-concept for modulation of HIF-1α protein in tumor biopsies following administration of EZN-2208 was observed. Two of 10 patients had prolonged disease stabilization following treatment with the EZN-2208 and bevacizumab combination.
Original language | English (US) |
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Pages (from-to) | 340-346 |
Number of pages | 7 |
Journal | Investigational New Drugs |
Volume | 32 |
Issue number | 2 |
DOIs | |
State | Published - Apr 2014 |
Externally published | Yes |
Keywords
- Anti-angiogenic therapy
- HIF-1α
- Irinotecan
- Topoisomerase 1 inhibitor
- VEGF
ASJC Scopus subject areas
- Oncology
- Pharmacology
- Pharmacology (medical)