Background: RRx-001 is a novel cysteine-targeted alkylating agent that, upon binding, under severe hypoxia, which is primarily present in tumors, releases nitric oxide (NO) and other cytotoxic metabolites. The primary biological activities of this hybrid molecule include macrophage repolarization, CD47 downregulation, and vascular normalization. The purpose of this clinical trial (ROCKET) (NCT02096354) was to compare the safety and efficacy of the combination therapy RRx-001 + irinotecan vs. regorafenib + irinotecan in 3^rd/4^th line colorectal cancer that previously received treatment with irinotecan. Methods: A total of 34 patients were randomized (24 to RRx-001 + irinotecan (RxI) and 10 to regorafenib + irinotecan (RegI)) and were the basis for the intention-to-treat analysis (ITT, comprising all 34 patients). RRx-001 treatment was administered as an up-to-2-month induction therapy or “primer” followed by irinotecan for patients randomized to the RRx-001 arm (24). The efficacy and safety data are presented for the 34 patients in the ITT efficacy analysis. Therapy consisted of intravenous administration of RRx-001 at 4 mg once weekly for up to 2 months followed by intravenous infusion of irinotecan at 180 mg/m² on day 1 in a 21-day cycle vs. 160 mg oral regorafenib daily for 3/4 weeks followed at progression, if applicable, by irinotecan 180 mg/m² on day 1 in a 21-day cycle. Results: Median patient follow-up was approximately 14.5 months (SD 4.5 months). Median overall survival was 8.6 months for RxI and 4.7 months for RegI. Median progression free survival was 6.1 months for RxI vs. 1.7 months for RegI (a statistically significant result, two-sided log-rank test, p = 0.0030). Overall response rate was 20.8% for RxI vs. 0% for RegI. Moreover, the toxicity profile of RxI was substantially improved compared with RegI. Conclusions: The results of this trial demonstrate improved efficacy of RxI compared with RegI in patients with metastatic colorectal cancer after previous treatment with irinotecan, and late-stage clinical development in this indication is planned on the strength of the observed “signal” accompanied by a sufficient safety profile. Clinical trial information: NCT02096354.