Background: The development of resistance to chemotherapies in cancer leads to disease progression resulting in impaired survival. RRx-001, a ROS-mediated DNMT and HDAC inhibitor, may resensitize patients to previously effective, now refractory therapies, improving survival. A randomized two-stage Phase 2 trial of RRx-001 vs regorafenib (ROCKET) is underway to assess the impact of resensitization to irinotecan on overall survival in irinotecan refractory tumors. Transition Probability Functions(TPF) using Markov Chains have previously been used in clinical trials and provide a powerful tool for resensitization analysis. Methods: Patients with metastatic colorectal cancer who previously responded, then progressed on irinotecan-based therapies, with or without bevacizumab, cetuximab or panitumumab and an ECOG PS 0-1 are randomized to receive RRx-001 1x/week or regorafenib until progression or unacceptable toxicity in Stage 1. Patients then advance to Stage 2 to receive irinotecan-based therapies. This trial is designed to detect an increase in median OS of 3 mo., corresponding to a 33% reduction in risk of death. The primary endpoint, overall survival (OS), employs a two-sided log-rank test to compare treatment groups. The hazard ratio and its 95% CI are derived from the Cox proportional hazards model. Kaplan-Meier survival curve estimates are graphically depicted by treatment group. Secondary endpoints include PFS, PFS2 and Transition Probability Functions to address the resensitization hypothesis, KRAS or p53 status dependence. The analysis of PFS2, defined as time to progression (or death) from randomization to progression in Stage 2 (post Irinotecan therapy) is a key secondary endpoint and its analysis uses the standard two-sided log-rank test. TPF estimates will be derived from the Markov Chain transition probability matrix. The study should provide compelling evidence in support of the ability to return to previously beneficial chemotherapy treatment. Recruitment is ongoing. Clinical trial information: NCT02096354