RRx-001 Prior to a Platinum Doublet or a Platinum Doublet Alone in Patients With Small Cell Carcinoma

Small cell cancer (SCC), which mostly arises in the lungs but also in other parts of the body
as well such as the prostate and the intestines, is one of the most aggressive forms of
cancer; in fact, SCC is so aggressive that in 2012 Congress designated it a recalcitrant or
difficult-to-treat cancer, along with pancreatic cancer and glioblastoma or GBM, a primary
tumor of the brain, which share the terrible "distinction" of having a 5 year survival rate
less than 50%.

One of the main reasons that SCC is so recalcitrant or difficult-to-treat has to do with the
development of resistance. Almost all cancers (and SCC is no exception) are treated according
to lines of therapy. A line of therapy is a particular course of treatment or treatment
regimen. So, in SCC, the first line of treatment is a platinum doublet, with the word doublet
meaning two, and consists of the double chemotherapy regimen of cisplatin or carboplatin +
etoposide. Most patients initially respond well to the platinum doublet but unavoidably, as a
matter of course, resistance to treatment develops and, with that development, a new
treatment in second line is started. The same pattern is followed in later lines of therapy:
resistance in second line leads to the start of another treatment in 3rd line, and with
resistance in 3rd line, which is, unfortunately, just as inevitable, and usually happens even
sooner, since the later the line of therapy the more aggressive the tumor, a 4th line
treatment is started and so on and so forth until, eventually, no lines of treatment are
left. The implicit or unwritten rule in cancer therapy is that once resistance occurs on a
particular treatment that same treatment is never reintroduced or restarted.

RRx-001 is a form of immunotherapy that has the potential to overturn this unwritten rule by
sensitizing tumors, in other words, by making them more sensitive to the platinum doublet
that they received in first line. This is very important because, as previously stated, the
platinum doublet is usually the most effective therapy, so it is a benefit to patients if
sensitivity to the platinum doublet is restored or increased (even in cases where no response
ever occurred) and now they respond as if they were in 1st line rather than in 3rd line or
beyond.

In this study, which is called REPLATINUM, because patients will be reintroduced to or
restarted on a platinum doublet, there is a 50% chance of receiving either RRx-001 + platinum
doublet in Arm 1 or a platinum doublet without RRx-001 in Arm 2. However, patients in arm 2
whose cancer progresses or gets worse (as determined by imaging scans), have the opportunity
to "cross-over" to Arm 1 and receive RRx-001 + platinum doublet until such time as their
cancer progresses. In this way, all patients, even those on Arm 2, are potentially eligible
to be treated with RRx-001.

Inclusion Criteria:

1. Age ≥ 18 and < 80 years

2. Prior platinum treatment is required

3. Biopsy confirmation of small cell carcinoma from any primary

4. Capable of providing informed consent and complying with trial procedures

5. Measurable disease by RECIST 1.1. Measurable lesions will be confirmed by imaging (CT
scan)

6. PS 0-1

Exclusion Criteria:

1. Symptomatic central nervous system metastases or neurologically unstable patients that
are on increasing steroid dose.

2. Patients with clinically significant illnesses which would compromise participation in
the study, including, but not limited to active or uncontrolled infection, immune
deficiencies, Hepatitis B, Hepatitis C, uncontrolled diabetes, uncontrolled
hypertension, certain heart conditions, or mental illness/social situations that would
limit compliance with study requirements.

3. History of an allergic reaction to previously received platinum-based regimen, or
history of having to discontinue previously received platinum-based regimen secondary
to toxicity

4. Any clinical laboratory findings, which give reasonable suspicion of a disease or
condition that contraindicates the use of any study medication or renders the patient
at high risk from treatment

5. Uncontrolled or symptomatic pleural or pericardial effusion

6. Pregnant or nursing. There is a potential for congenital abnormalities and for this
regimen to harm nursing infants