Abstract 2947: Pharmacodynamic (PD) and pharmacokinetic (PK) results of the second-generation hypomethylating agent, SGI-110, in patients with hepatocellular carcinoma (HCC) after progression on sorafenib
Authors: El-Khoueiry Anthony , Mulcahy Mary F. , Bekaii-Saab Tanios , Kim Richard , Denlinger Crystal , Goel Rakesh , Gupta Shweta , Jueliger Simone , Oganesian Aram , Keer Harold , Nemunaitis John 
Published: August 2015

Abstract
Background:
HCC is the sixth most common cancer and the third most common cause of cancer death worldwide. Sorafenib treatment improves survival in advanced disease, but no therapy has demonstrated significant activity after progression on sorafenib. Increased methylation of genes implicated in tumorigenesis has been described in HCC and has been associated with outcome and etiology. We evaluated the therapeutic and biologic effects of SGI-110, a hypomethylating agent in patients with HCC. SGI-110, a dinucleotide of decitabine and deoxyguanosine, increases decitabine exposure by protecting it from deamination due to slow release on subcutaneous (SC) injection. PK and PD results of an open-label, phase 2 study in patients with HCC are presented here.
Methods:
Adults with histologically confirmed, advanced-stage HCC who had received sorafenib, had evidence of disease progression, and ECOG PS 0-1 were enrolled. SGI-110 (SC) was given on D1-5 of a 28-day cycle. Blood samples were taken for PK/PD analysis and, when possible, paired tumor biopsies were taken for analysis of global DNA (LINE-1) and gene-specific methylation and gene expression. Patients were imaged every 8 weeks and allowed to continue treatment after radiologic but not clinical progression. End points include disease control rate (DCR) at 16 weeks, overall response rate, progression-free survival, and overall survival.
Results:
50 HCC patients (43M/7F; median age 60 years [range 32-82]; ECOG PS 0/1: 21/29) were enrolled. The initial dose of SGI-110 was 60 mg/m2 (4 patients treated), but due to grade 4 neutropenia, the dose was decreased to 45 mg/m2 for subsequent patients. SGI 110 was well tolerated at 45 mg/m2; myelosuppression was the major adverse event. Full PK was available from 16 patients (3F/13M). The PK profile for SGI-110 after 45 mg/m2 showed protracted conversion to deliver active metabolite decitabine with exposure window lasting beyond 8-hr and mean(SD) decitabine AUC exposures of 94(22) ng*hr/mL that were comparable to those achieved in AML/MDS after 60 mg/m2. Potent LINE-1 demethylation was observed in blood (-35.6%, n = 27) and in tumor (-12.9%, n = 10) DNA; significant demethylation (-27.4%, n = 6) was also observed on promoter of tumor suppressor gene MZB1 which is frequently hypermethylated and silenced in HCC.
Conclusions:
SGI-110 was well tolerated at a dose of 45 mg/m2 administered SC on D1-5 of a 28-day cycle. PK was consistent with that seen in another solid tumor study and provided more persistent decitabine exposures compared with PK in hematologic malignancies. The PD changes in blood and tumor LINE-1 and MZB-1 methylation are promising and consistent with the desired biologic effect of SGI-110. Analysis for clinical efficacy is ongoing.
Citation Format: Anthony El-Khoueiry, Mary F. Mulcahy, Tanios Bekaii-Saab, Richard Kim, Crystal Denlinger, Rakesh Goel, Shweta Gupta, Simone Jueliger, Aram Oganesian, Harold Keer, John Nemunaitis. Pharmacodynamic (PD) and pharmacokinetic (PK) results of the second-generation hypomethylating agent, SGI-110, in patients with hepatocellular carcinoma (HCC) after progression on sorafenib. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2947. doi:10.1158/1538-7445.AM2015-2947