Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Investigational new drugs, 2014-04, Vol.32 (2), p.340-346

Ort / Verlag

New York: Springer US

Erscheinungsjahr

2014

Link zum Volltext

Quelle

SpringerLink (Online service)

Beschreibungen/Notizen

• Summary 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 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-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.