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.

Purpose 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. Qualifying patients will be randomly assigned (like the flip of a coin) to the 'interventional arm' and receive the experimental drug, RRx-001, or the 'control arm' where they will receive the current standard-of-care, Regorafenib. Patients will 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 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.

Background Oxygen is vital to life, we need it to breathe, for example, but at the same time it gives rise to byproducts that are toxic called free radicals. Free radicals are defined as "oxidants". Similarly, substances that interact with and neutralize free radicals, thus preventing them from causing damage, are called "antioxidants". Examples of recognizable antioxidants are Vitamin E, Vitamin C and beta-carotene. Antioxidants are also known as "free radical scavengers." When free radicals are present in excess of antioxidants damage may occur.

A free radical is an unstable molecule with an unpaired electron, an electrically charged particle, which seeks out another electron to return to a state of balance. An example of a free radical is hydrogen peroxide, recognizable as the household product that "bubbles" when it's poured on wounds. These bubbles come from oxygen free radicals, which are toxic to bacteria and all living cells, including cancer. The fact that these free radicals are toxic has to do with how reactive they are-imagine free radicals as high-speed ball bearings that smash into other molecules in order to "steal" back an electron and end their radical state, which sets off a chain reaction that transforms once stable compounds into a string of reactive radicals.

As new free radicals are created in this chain reaction, they randomly slam into whatever molecules they are closest to and steal their electrons, corroding them, like a biological form of rust. This process is repeated over and over, picking up speed, until an antioxidant can "neutralize" the free radicals and put a stop to the snowball effect. In the same way that this free radical bombardment can damage not only bacteria but also healthy tissues in the body, it is also capable of destroying cancer cells.

The current consensus is that compared to normal tissue tumor cells may accumulate elevated levels of free radicals, which contribute to the development of cancer. This is potentially a fatal weakness, a form of biological "Kryptonite", which can be used to advantage since the addition of even a small amount of free radicals may push the tumor over the edge, past the tipping point, above tolerable thresholds, breaking the camel's back. Similar to the expression "live by the sword, die by the sword", free radicals may lead to the development of cancer but they also are capable of harming it when present in excess.

RRx-001 is a completely new type of drug that comes from the U.S. aerospace or rocket science industry. It is activated to deliver free radicals to tissues that have low levels of oxygen. Compared to normal tissues, which have higher levels of oxygen, most, if not all, tumors exist in a low-oxygen environment, perhaps to prevent oxidation. In this way the free radicals delivered by RRx-001 to cancer cells under low oxygen conditions are able, in theory, to cause their targeted destruction without harming normal cells.

In general, colorectal tumors have low levels of antioxidants and, without this antioxidant protection, these tumors are more likely to be harmed by free radicals, so a treatment like RRx-001, which is able to increase the free radicals in the tumor, may benefit patients with colorectal cancer; this is a reason for studying RRx-001 in colorectal cancer. So far, in a Phase 1 study, 25 men and women with advanced, incurable cancer have received RRx-001 for different lengths of time and at doses that ranged from 10 mg/m2 to 83 mg/m2 once a week.

Regorafenib is a drug approved by the FDA to treat colon cancer after previous chemotherapy is no longer effective. It belongs to a class of targeted drugs known as tyrosine kinase inhibitors. Tyrosine kinases, which play a key role in many cell functions including cell growth and division, are commonly mutated or changed in cancer cells, becoming super-active and producing cells that have uncontrolled growth, and, therefore, blocking them with drugs like regorafenib may keep the cancer cells from growing.

Eligibility Criteria:
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.