Dose-Escalation Study of RRx-001 in Combination With Whole Brain Radiation in Subjects With Brain Metastases

The purpose of this research study is to test the safety and activity of whole brain
radiation therapy with RRx-001, an experimental radiation sensitizer, in participants with
brain metastases. As a radiation sensitizer, RRx-001 may increase the effect of whole brain
radiation, the standard of care for brain metastases, on cancer cells in a specific target
area while reducing damage to normal healthy cells. The ability to sensitize the cancer cells
to radiation sets off a 'domino effect' of free radical damage in the tumor from a given
amount or dose of radiation.

This study, which is called BRAINSTORM, since RRx-001 is associated with the development of a
"free radical storm" in the brain tumors, is divided into two stages. In the first stage,
approximately 3 participants at a time will be entered at a particular dose level of RRx-001
and then observed in order to see whether that dose results in side effects with radiation.
If no bad side effects are observed, a second group of approximately 3 subjects will be given
a slightly higher dose of RRx-001 and also monitored for side effects with radiation. This
process will be repeated until a dose is reached, which has the most activity against the
cancer cells without unacceptable side effects. At this point, more participants will be
entered at this dose level until a maximum enrollment of approximately 30 participants has
been reached.

RRx-001 releases a gas called nitric oxide, which widens the diameter of blood vessels, and
allows the delivery of more oxygen to tumors. The presence of oxygen in tumors is critical
for the effectiveness of radiation therapy, since cancer cells are about two to three times
more vulnerable to radiation when oxygen is present. The reason that cancer cells are so much
more vulnerable to the effects of radiation when oxygen is present is that radiation relies
on the formation of harmful molecules known as free radicals that damage proteins and genetic
material (DNA); without oxygen lower levels of free radicals are produced. Changes in the
diameter go blood vessels will be studied by magnetic resonance imaging.

Unlike chemotherapies or other radiation sensitizers, RRx-001 does not have to enter the
tumor to be effective because nitric oxide, as a gas, is able to spread or diffuse from the
bloodstream into cancer cells.

Inclusion Criteria:

- Written informed consent

- Age ≥18 years

- Eastern Cooperative Oncology Group (ECOG) performance status 0-2

- One or more brain metastases

- Prior radiation therapy to the brain is allowed with the exception of whole brain
irradiation

- Subjects must be neurologically stable for at least 14 days prior to first dose of
study drug;

- Male and female subjects who are not surgically sterile or post-menopausal must agree
to use reliable methods of birth control for the duration of the study and for 90 days
after the last dose of study drug administration; male partners of female subjects
should use condoms for the duration of the study, and for 90 days after the last dose
of study drug administration

Exclusion Criteria:

- Pregnant or lactating females

- Any evidence of severe or uncontrolled diseases

- Inadequate bone marrow reserve

- Previous whole brain radiotherapy

- Prior RRx-001 therapy

- Insufficient recovery from all side effects of previous anticancer therapies

- Evidence of blood clotting or bleeding abnormalities