Weekly EZN-2208 (PEGylated SN-38) in combination with bevacizumab in patients with refractory solid tumors.

ABSTRACT: BACKGROUND:Anti-angiogenic therapies such as bevacizumab upregulate hypoxia-inducible factor-1? (HIF-1?), a possible mechanism of drug resistance. Camptothecin analogues, including SN-38, have been shown to reduce the expression and transcriptional activity of HIF-1? in preclinical models. We hypothesized that co-administration of pegylated SN-38 (EZN-2208) may offset the induction of HIF-1? 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? 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-1? 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? 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.

SUBMITTER: Jeong W 

PROVIDER: S-EPMC7670584 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature