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-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.

• Authors: 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
• Journal: Investigational new drugs (Invest New Drugs) Vol. 32 Issue 2 Pg. 340-6 (Apr 2014) ISSN: 1573-0646 [Electronic] United States
• PMID: 24242862 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Angiogenesis Inhibitors
• Antibodies, Monoclonal, Humanized
• EZN-2208
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• RNA, Messenger
• Bevacizumab
• Polyethylene Glycols
• Camptothecin

Topics

• Adult
• Aged
• Angiogenesis Inhibitors (administration & dosage, adverse effects)
• Antibodies, Monoclonal, Humanized (administration & dosage, adverse effects)
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects)
• Bevacizumab
• Camptothecin (administration & dosage, adverse effects, analogs & derivatives)
• Female
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• Male
• Middle Aged
• Neoplasms (drug therapy, metabolism)
• Polyethylene Glycols (administration & dosage, adverse effects)
• RNA, Messenger (metabolism)
• Young Adult