Abstract A1-35: RRx-001, a novel first in class epigenetic modulator, “episensitizes” colorectal patients to FOLFIRI: Preliminary resensitization data from the Phase 2 “ROCKET” study
Authors: Reid Tony , Carney Jennifer , Beale Keola , Clayton Chan , Nguyen Huy , Cho-Phan Cheryl , Stirn Meaghan , Ning Shoucheng , Knox Susan , Oronsky Bryan , Scicinski Jan , Caroen Scott , Parker Christopher , Fanger Gary R. , Fisher George 
Published: November 2015

Abstract
Background: RRx-001 is a novel systemically non-toxic pan-epigenetic modulator of DNA methyltransferases, Histone Deacetylases, and lysine demethylases with broad activity both preclinically and clinically. In the first-in-man Phase I trial, five patients who progressed on RRx-001 treatment were resensitized to previously failed therapy, warranting further investigation. Accordingly, a randomized multi-center phase II trial of RRx-001 versus regorafenib (ROCKET) has been initiated to explore the resensitization or ‘episensitization’ potential in irinotecan refractory tumors and its impact on the primary objective of overall survival.
Methods: Eligible patients histological or cytological documentation of adenocarcinoma of the colon or rectum and had previously received at least oxaliplatin-, and irinotecan-based regimens with or without bevacizumab, cetuximab or panitumumab and are refractory to irinotecan. As well as ECOG 0 or 1, adequate bone marrow and hematological functions were required. In this open-label study, patients were randomized to either RRx-001 or regorafenib (2:1). RRx-001 was administered IV weekly at 16.5 mg/m2. At progression on either RRx-001 or regorafenib, patients moved to the second phase of the study and were treated with irinotecan-based therapies to investigate resensitization.
Results: The study is ongoing, and, therefore, the data is preliminary; however of the four patients progressing to the second phase of the study, all have demonstrated marked decreases in CEA when treated with irinotecan post RRx-001, indicative of resensitization. CT scans, where available, confirmed CEA data.
Conclusions: Preliminary results in the ROCKET study suggest resensitization of patients to previously failed therapies. Due to its broad-spectrum inhibition of epigenetic enzymes, exploration of episensitization to conventional first or second-line chemotherapy is also planned in various Phase II cancer indications in addition to CRC such as NSCLC, small cell lung cancer, sarcomas, bladder cancer and multiple myeloma. Since RRx-001 lacks any systemic toxicity, it may offer a promising alternative to currently approved hypomethylating and HDAC agents.
Citation Format: Tony Reid, Jennifer Carney, Keola Beale, Chan Clayton, Huy Nguyen, Cheryl Cho-Phan, Meaghan Stirn, Shoucheng Ning, Susan Knox, Bryan Oronsky, Jan Scicinski, Scott Caroen, Christopher Parker, Gary R. Fanger, George Fisher. RRx-001, a novel first in class epigenetic modulator, “episensitizes” colorectal patients to FOLFIRI: Preliminary resensitization data from the Phase 2 “ROCKET” study. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A1-35.