期刊
INVESTIGATIONAL NEW DRUGS
卷 32, 期 2, 页码 340-346出版社
SPRINGER
DOI: 10.1007/s10637-013-0048-3
关键词
Topoisomerase 1 inhibitor; HIF-1 alpha; Irinotecan; Anti-angiogenic therapy; VEGF
资金
- National Cancer Institute, National Institutes of Health [HHSN261200800001E]
Background Anti-angiogenic therapies such as bevacizumab upregulate hypoxia-inducible factor-1 alpha (HIF-1 alpha), a possible mechanism of drug resistance. Camptothecin analogues, including SN-38, have been shown to reduce the expression and transcriptional activity of HIF-1 alpha in preclinical models. We hypothesized that co-administration of pegylated SN-38 (EZN-2208) may offset the induction of HIF-1 alpha 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-1 alpha protein and target genes in tumor biopsies following administration of the combination of EZN-2208 administered weekly x 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-1 alpha 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 k(ep). 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-1 alpha 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.
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