Abstract 2320: Clinical epigenetic resensitization of platinum-resistant, recurrent ovarian cancer patients with SGI-110, a novel, second-generation, subcutaneously administered hypomethylating agent (HMA)

Abstract

Abstract Background: Epigenetic changes have been implicated in acquired resistance to platinum. SGI-110 is a second generation SQ HMA with improved pharmaceutical properties compared to decitabine. Here we report the clinical results and pharmacodynamic analyses of the phase 1 study of SGI-110 in combination with carboplatin in patients with recurrent platinum resistant high-grade serous, epithelial ovarian cancer (EOC), primary peritoneal carcinoma (PPC) or fallopian tube (FT) cancer. Methods: SGI-110 was administered SQ QD x 5 followed by carboplatin IV on Day 8 of a 28-day cycle. Patients were required to have either measurable disease according to RECIST v1.1 or detectable disease (modified Rustin) with clinical response assessed using the applicable criteria. Safety assessments were graded using CTCAE v4. Results: Twenty patients (18 EOC, 1 PPC, 1 FT) were enrolled and treated in the phase 1 portion of the trial. Median age was 55.8 years (38-72); ECOG PS of 0/1/2 was 10/10/0, respectively. Median number of prior regimens was 7 (1-9). The starting doses were SGI-110 45 mg/m2 SQ QD x 5 and carboplatin AUC5 in the first cohort of 6 patients. Four DLTs of myelosuppression (neutropenia and thrombocytopenia) in the first cohort led to dose reduction to SGI-110 30 mg/m2 and carboplatin AUC4 with granulocyte-CSF permitted at the discretion of the physician. No DLTS were observed in 14 patients and this dose was recommended for the subsequent phase 2 study. Grade 3/4 AEs regardless of relationship to the combination ≥ 10% included anemia, leukopenia, neutropenia, thrombocytopenia, nausea, vomiting, constipation, small intestinal obstruction, infusion related reaction and pulmonary embolism. Three PRs and 9 SDs as best response were observed in 20 patients for an overall response rate and clinical benefit rate of 15% and 60%, respectively. All PRs and 3 SDs were accompanied by CA-125 decrease. LINE-1 hypomethylation, a marker of global DNA methylation, was recorded in PBMCs with SGI-110 30 mg/m2 (avg: -19.5%, n=14) and 45 mg/m2 (avg: -17.4%, n=6). Gene specific methylation of RASSF1A and BRCA-1 measured by pyrosequencing was significantly decreased at C2D8 compared to baseline in paired tumor biopsies/ascites (n=9). Gene re-expression measured by quantitative RT-PCR was observed in tumor biopsies. Conclusions: Priming treatment with SGI-110 prior to carboplatin induced clinical responses in a heavily-pretreated platinum resistant ovarian cancer population with expected and manageable safety profile. Potent LINE-1 demethylation and demethylation and re-expression of silenced tumor genes were recorded. The phase 2 portion of the trial is currently ongoing with patients randomized to either the RP2D dose combination or a physician choice of 1 of 4 treatment options (topotecan; liposomal doxorubicin; weekly paclitaxel; or weekly gemcitabine). Citation Format: Gini Fleming, Sharad Ghamande, Yvonne Lin, Angeles Alvarez Secord, John Nemunaitis, Merry-Jennifer Markham, Kenneth Nephew, Fang Fang, Shweta Gupta, Sue Naim, Gavin Choy, Simone Jueliger, Pietro Taverna, Yong Hao, Harold Keer, Mohammad Azab, Daniela Matei. Clinical epigenetic resensitization of platinum-resistant, recurrent ovarian cancer patients with SGI-110, a novel, second-generation, subcutaneously administered hypomethylating agent (HMA). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2320. doi:10.1158/1538-7445.AM2014-2320