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

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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 Ktrans 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.

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Acknowledgments

We thank Drs. Yvonne A. Evrard and Yiping Zhang for assistance with pharmacodynamic analysis in the preparation of this manuscript. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

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Authors and Affiliations

  1. Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, 20892, USA

    Woondong Jeong, Sook Ryun Park, Alice Chen, James H. Doroshow & Shivaani Kummar

  2. Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA

    Annamaria Rapisarda, Nicole Fer, Robert J. Kinders & Giovanni Melillo

  3. Center for Cancer Research, National Cancer Institute, Bethesda, MD, 20892, USA

    Baris Turkbey, Seth M. Steinberg, Peter Choyke, James H. Doroshow & Shivaani Kummar

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  1. Woondong Jeong
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  2. Sook Ryun Park
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  4. Nicole Fer
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Correspondence to Shivaani Kummar.

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Jeong, W., Park, S.R., Rapisarda, A. et al. Weekly EZN-2208 (PEGylated SN-38) in combination with bevacizumab in patients with refractory solid tumors. Invest New Drugs 32, 340–346 (2014). https://doi.org/10.1007/s10637-013-0048-3

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