O3.8 - Early Results: “ROCKET” a phase II Study of RRx-001, a novel triple epigenetic inhibitor, Resensitization to Irinotecan in Colorectal Cancer

Abstract

ABSTRACT Background: RRx-001 is a novel broad-spectrum anticancer agent that triply inhibits DNA methyltransferases (DNA MTases), Histone Deacetylases (HDAC), and Lysine Demethylases. In the first-in-human, Phase I trial, 5/5 patients who progressed on RRx-001 treatment were resensitized to previously refractory irinotecan therapy, hinting at a generalized resensitization effect. A randomized open-label multi-part, multi-center phase II trial of RRx-001 versus regorafenib (ROCKET) is underway to explore the resensitization and/or ‘episensitization’ potential in irinotecan refractory tumors and its impact on overall survival. Methods: Patients with irinotecan-refractory metastatic colorectal cancer with an ECOG PS 0–1 who progressed on oxaliplatin-, and irinotecan-based regimens with or without bevacizumab, cetuximab or panitumumab are randomized 2:1 to receive RRx-001 16.5 mg/m2 IV 1x/week or regorafenib 160 mg orally 21 of 28 days until progression or unacceptable toxicity followed by treatment with refractory irinotecan-based therapies. Results: To date, 23 patients have been randomized with 10 patients evaluable for resensitization. Post RRx-001 patients demonstrated marked decreases in CEA in all 6 patients as compared to 4 patients receiving regorafenib who were too systemically unwell to proceed to subsequent treatment. Progression free survival (ongoing) for RRx-001 + irinotecan is 5.9 months compared 0.92 months on Regorafenib + irinotecan. Combined Disease Control Rate (SD + PR) for the combination of RRx-001 and reintroduction of Irinotecan based therapy is currently 100%, whereas no patients to date randomized to the regorafenib arm have been able to start irinotecan based therapy secondary to decreasing performance status. Conclusions: Early results in the ROCKET study suggest that RRx-001-mediated resensitization to previously refractory therapies may have a generalized effect, independent of KRAS or p53 status. These early results are intriguing and may be a major advancement in epigenetic therapy. RRx-001 is a novel pan-epigenetic inhibitor that may potentially offer improved QOL and overall survival over currently approved therapy in the chemotherapy refractory colorectal cancer.