A Phase 2 Randomized, Open-Label Study of RRx-001 vs Regorafenib in Subjects With Metastatic Colorectal Cancer

This two-stage study is designed to compare the safety and activity between RRx-001 against regorafenib followed by irinotecan-based therapies in a parallel comparative study. Patients who are suffering from advanced or metastatic (meaning the disease has spread) colorectal cancer are invited to participate in this study. There will be two groups of patients (Randomized, open label study), one of these will receive RRx-001 and the other one will receive regorafenib. If patients qualify to participate in this study, they will be randomly assigned to the 'interventional arm' where patients will receive the experimental drug, RRx-001, or the 'control arm' where they will receive the current standard-of-care, Regorafenib. Patients have a 66% chance (2 out of 3) of receiving RRx-001 and a 33 % chance (1 out of 3) of receiving regorafenib. On progression in the first part of the study, provided ECOG performance status is adequate, and if clinically appropriate i.e. there are no absolute or relative contraindications in the opinion of the Investigator, all subjects will enter the second part of the study and receive irinotecan plus bevacizumab. Whether patients are given RRx-001 or regorafenib, they will also receive best supportive care, which includes treatments to help manage side effects and symptoms of cancer. This is an open label study, which means patients will know to which of these treatments, RRx-001 or regorafenib, they are assigned.

Sex

All

Minimum age

18 Years

Inclusion Criteria:

* Histological or cytological documentation of adenocarcinoma of the colon or rectum;
* Subject must have received at least oxaliplatin-, and irinotecan-based regimens with bevacizumab and with, cetuximab or panitumumab if KRAS wildtype and are refractory to irinotecan;
* Subject has measurable disease by radiographic techniques (computerized tomography \[CT\] or magnetic resonance imaging \[MRI\]);
* Subjects with a history of brain metastasis are eligible for the study as long as they meet all the following criteria: their brain metastases have been treated, they have no evidence of progression or hemorrhage after treatment, have been off dexamethasone for 4 weeks prior to first study drug administration, and have no ongoing requirement for dexamethasone or anti-epileptic drugs;
* Life expectancy of at least 12 weeks
* Subject's Eastern Cooperative Group (ECOG) performance status is 0 or 1;
* Adequate organ function
* Fertile subjects must use effective contraception during the course of the study and for 30 days following withdrawal from the study;

Exclusion Criteria:

* Clinically significant cardiovascular disease;
* Unresolved toxicity higher attributed to any prior therapy/procedure excluding alopecia, hypothyroidism and oxaliplatin- induced neurotoxicity ≤ Grade 2 for at least 14 days;
* Evidence or history of tendency or predisposition to active bleeding. Any hemorrhage or bleeding event of Grade 3 or higher within 4 weeks of start of study medication;
* Symptoms or signs of active brain metastases;
* History of an allergic reaction or intolerance to irinotecan
* Hepatic encephalopathy
* Cholangitis that required treatment or intervention within 4 weeks of study enrollment
* Concurrent anticancer therapy or any cytotoxic therapy within 1 month prior to Day 1. Corticosteroid therapy is not allowed except on dosing days;
* Subject has previously received regorafenib;
* Clear contraindication for systemic corticosteroids (diabetes mellitus is not per se a clear contraindication);
* Severe hypoalbuminemia (albumin \< 3.0 g/dL);
* Subjects who are pregnant or lactating or who are planning to become pregnant during the course of the study are excluded.

• BACKGROUNDOronsky B, Scribner C, Aggarwal R, Cabrales P. RRx-001 protects normal tissues but not tumors via Nrf2 induction and Bcl-2 inhibition. J Cancer Res Clin Oncol. 2019 Aug;145(8):2045-2050. doi: 10.1007/s00432-019-02958-4. Epub 2019 Jun 27. PMID 31250159
• BACKGROUNDScicinski J, Fisher G, Carter C, Cho-Phan C, Kunz P, Ning S, Knox S, Oronsky B, Caroen S, Parker C, Fanger G, Reid T. The Development Of RRx-001, A Novel Nitric-Oxide-Mediated Epigenetically Active Anticancer Agent. Redox Biol. 2015 Aug;5:422. doi: 10.1016/j.redox.2015.09.035. Epub 2015 Dec 30. PMID 28162292
• RESULTReid TR, Abrouk N, Caroen S, Oronsky B, Stirn M, Larson C, Beale K, Knox SJ, Fisher G. ROCKET: Phase II Randomized, Active-controlled, Multicenter Trial to Assess the Safety and Efficacy of RRx-001 + Irinotecan vs. Single-agent Regorafenib in Third/Fourth Line Colorectal Cancer. Clin Colorectal Cancer. 2023 Mar;22(1):92-99. doi: 10.1016/j.clcc.2022.11.003. Epub 2022 Dec 2. PMID 36529613
• RESULTReid T, Dad S, Korn R, Oronsky B, Knox S, Scicinski J. Two Case Reports of Resensitization to Previous Chemotherapy with the Novel Hypoxia-Activated Hypomethylating Anticancer Agent RRx-001 in Metastatic Colorectal Cancer Patients. Case Rep Oncol. 2014 Jan 24;7(1):79-85. doi: 10.1159/000358382. eCollection 2014 Jan. PMID 24575021