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

Woondong Jeong, Sook Ryun Park, Annamaria Rapisarda, Nicole Fer, Robert J. Kinders, Alice Chen, Giovanni Melillo, Baris Turkbey, Seth M. Steinberg, Peter Choyke, James H. Doroshow, Shivaani Kummar

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

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 languageEnglish (US)
Pages (from-to)340-346
Number of pages7
JournalInvestigational New Drugs
Volume32
Issue number2
DOIs
StatePublished - Apr 2014
Externally publishedYes

Keywords

  • Anti-angiogenic therapy
  • HIF-1α
  • Irinotecan
  • Topoisomerase 1 inhibitor
  • VEGF

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

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