Abstract 2416: Weekly EZN-2208 (pegylated SN-38) in combination with bevacizumab in patients with refractory solid tumors.
Authors: Jeong Woondong , Park Sook Ryun , Rapisarda Annamaria , Eugeni Michelle , Kinders Robert , Chen Alice , Melillo Giovanni , Turkbey Baris , Doroshow James H. , Kummar Shivaani 
Published: August 2014

Background: Anti-angiogenic therapies such as bevacizumab (Bev) have been shown to up-regulate hypoxia-inducible factor-1α (HIF-1α), a possible mechanism of resistance. Camptothecin analogues, including SN-38, have been shown to reduce the expression and transcriptional activity of HIF-1α in preclinical models. Thus, co-administration of pegylated SN 38 (EZN 2208) could offset the induction of HIF-1α following administration of Bev, resulting in synergistic anti-tumor effects. We are conducting a trial of the combination of EZN 2208 (E) with Bev in patients with refractory solid tumors to determine the safety and tolerability of the combination, and to evaluate modulation of HIF-1α protein in tumor biopsies following administration of study drugs. Methods: Eligible pts have refractory advanced solid tumors that have progressed following standard therapy; ≥ 18 yrs of age; ECOG PS 0-2; adequate organ function. Bev at 5mg/kg is administered on D-7 and D15 for cycle 1 only and on D1, 15 for each subsequent cycle; q28d cycles. E(9mg/kg) is administered on D1, 8, and 15. Tumor biopsies and dynamic contrast enhanced MRI (DCE-MRI) are obtained on D1 prior to EZN administration (7 days post Bev) and on C2D15 post Bev and E. An additional DCE-MRI is also performed at baseline prior to Bev on D-7. Tumor biopsies are analyzed for HIF-1α protein levels using a validated immunoassay, and HIF-1α response genes, Hexokinase 2(HK), vascular endothelial growth factor A(VEGF), pyruvate dehydrogenase kinase, isozyme 1(PDK1), carbonic anhydrase IX(CA9), solute carrier family 2 (GLUT1), are assessed using RTPCR.

Results: Twelve pts have been enrolled to date; median age 50 (range 27-76 yrs); median # prior therapies 3 (1-6); Dx: Soft tissue sarcoma (4), colorectal cancer (2), parotid gland cancer (1), malignant hurthle cell tumor (1), HCC (1), melanoma (1), gastrointestinal stromal tumor (1), Head and neck cancer (1). Grade 3/4 toxicities (#pts): neutropenia (8), leucopenia (3), lymphopenia (2), hypertension (1). Eight pts are evaluable for response; prolonged stable disease was observed in 2 pts: HCC 16 cycles, desmoplastic round cell tumor 7 cycles. HIF-1α protein and mRNA levels of HIF-1α dependent genes were assessed in 5 pts who had paired biopsies. Reduction in HIF-1α protein levels compared to baseline (post Bev alone) was seen in 4 of 5 pts (range 24% - 64%), with evidence of modulation of mRNA in 3 of 5 pt tumors evaluated. Quantitative analysis of DCE MRI from 3 pts revealed changes in Ktrans and kep maps following drug administration. Correlation of observed changes with tumor response is ongoing.

Conclusions: This clinical trial provides preliminary proof of mechanism demonstrating modulation of HIF-1α levels in tumors following administration of a camptothecin analog, EZN 2208. Accrual is ongoing to establish safety, efficacy, and further proof of target modulation.

Citation Format: Woondong Jeong, Sook Ryun Park, Annamaria Rapisarda, Michelle Eugeni, Robert Kinders, Alice Chen, Giovanni Melillo, Baris Turkbey, James H. Doroshow, Shivaani Kummar. Weekly EZN-2208 (pegylated SN-38) in combination with bevacizumab in patients with refractory solid tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2416. doi:10.1158/1538-7445.AM2013-2416