Phase 2 Study of REOLYSIN® in Combination With Paclitaxel and Carboplatin for Non-Small Cell Lung Cancer With KRAS or EGFR Activation

Reovirus Serotype 3 - Dearing Strain (REOLYSIN®) is a naturally occurring, ubiquitous,
non-enveloped human reovirus. Reovirus has been shown to replicate selectively in
Ras-transformed cells causing cell lysis. Activating mutations in ras or mutation in
oncogenes signaling through the ras pathway may occur in as many as 80% of human tumors. The
specificity of the reovirus for Ras-transformed cells, coupled with its relatively
nonpathogenic nature in humans, makes it an attractive anti-cancer therapy candidate.

Given the ability of reovirus to replicate and cause oncolysis in Ras-activated cells, the
high incidence of K-ras mutations in lung cancers, and the Ras-mediated activation often
encountered in EGFR-addicted tumors, the administration of REOLYSIN® in combination with
chemotherapy is expected to result in enhanced clinical benefit in non-small cell lung
cancer (NSCLC) patients with K-ras mutations and/or EGFR aberrant activation in their
tumors. Patients with de novo or acquired EGFR mutations in their tumors that confer
resistance to EGFR TKIs (e.g. T790) are expected to benefit as well. This is a single arm,
open-label, Phase 2 study of REOLYSIN® given intravenously with paclitaxel and carboplatin
every 3 weeks (21 days is defined as a cycle) in NSCLC patients with tumors driven by these
pathways.

Paclitaxel at a dose of 175 mg/m2 will be given i.v. as a 3 hour infusion on Day 1 followed
by carboplatin given i.v. AUC 5 mg/mL•minute. REOLYSIN® will be given over 60 min on Day 1
(starting after completion of the carboplatin infusion), and on Days 2 - 5. The treatment
cycle will be repeated every 21 days.

Patients will receive 4 to 6 cycles of paclitaxel and carboplatin, at the treating
physician's discretion according to standard of practice, in conjunction with REOLYSIN®.
After completion of the 4 to 6 cycles of paclitaxel and carboplatin, REOLYSIN® may be
continued as monotherapy Days 1-5 of each 21 day cycle until there is evidence of disease
progression or unacceptable toxicity. Patients may continue to receive therapy under this
protocol, provided they have not experienced either progressive disease or unacceptable
drug-related toxicity that does not respond to either supportive care or dose reduction.

Inclusion Criteria:

- have histologically or cytologically confirmed stage IIIB (pleural effusion; IVA on
revised IASLC staging) or stage IV, or recurrent, non-small cell lung cancer with
evidence of RAS- or EGFR- activation in their tumors, as defined by EGFR activating
mutations in exons 18 to 21, EGFR FISH amplification, or K-ras mutations in exon 2
(codons 12,13,61).

- have evidence of measurable disease. For patients previously irradiated, the
measurable lesion(s) must be outside of the treated field.

- be chemotherapy naïve for their metastatic or recurrent NSCLC. Prior adjuvant
chemotherapy or chemo-XRT for treatment of localized disease is allowed, provided it
has been ≥ 6 months since the last chemotherapy infusion. Previous radiation for
palliative purposes is also allowed, as long as it has been ≥4 weeks from the last
dose.

- Patients who have been previously treated with EGFR tyrosine kinase inhibitors as
their only systemic treatment are eligible, provided this treatment has been
discontinued for ≥4 weeks. Patients who have received erlotinib as first line
treatment without chemotherapy and experience tumor progression will be eligible.

- have NO continuing acute toxic effects (except alopecia) of any prior radiotherapy,
chemotherapy, or surgical procedures, i.e., all such effects must have resolved to
Common Terminology Criteria for Adverse Events (CTCAE, version 3.0) Grade ≤ 1.
Surgery (except biopsies) must have occurred at least 28 days prior to study
enrollment.

- have an ECOG Performance Score of ≤ 2.

- have a life expectancy of at least 3 months.

- have baseline laboratory results as follows:

- Absolute neutrophil count (ANC) ≥ 1.5 x 10E9 [SI units 10^9/L]

- Platelets ≥ 100 x10E9 [SI units 10E9/L] (without platelet transfusion)

- Hemoglobin ≥ 9.0 g/dL [SI units gm/L] (with or without RBC transfusion)

- Serum creatinine ≤ 1.5 x upper limit of normal (ULN)

- Bilirubin ≤ 1.5 x ULN

- AST/ALT ≤ 2.5 x ULN

- Negative pregnancy test for females of childbearing potential.

- be willing and able to comply with scheduled visits, the treatment plan, and
laboratory tests.

Exclusion Criteria:

- Receive concurrent therapy with any other anticancer agent while on study.

- Received chemotherapy within 6 months, or radiotherapy or EGFR therapy within 4
weeks, prior to entering the study or have not recovered from adverse events due to
agents administered more than 4 weeks earlier.

- Have brain metastases. Patients with resected oligometastasis are eligible if post
resection MRI demonstrates resolution. Gamma knife treated patients are also
eligible, if there are no more than two treated metastases confined to the same area
of the brain and a post treatment MRI shows a decrease in the metastases.

- Have ≥ grade 2 peripheral neuropathy at baseline.

- Have uncontrolled cardiac dysfunction, including a myocardial infarction in the
preceding 6 months, or known cardiac ejection fraction < 40%.

- Be on immunosuppressive therapy or have known HIV infection or active hepatitis B or
C.

- Be a pregnant or breast-feeding woman. Female patients of childbearing potential must
agree to use effective contraception, must be surgically sterile, or must be
postmenopausal. Male patients must agree to use effective contraception or be
surgically sterile. Barrier methods are a recommended form of contraception.

- Have uncontrolled intercurrent illness including, but not limited to, ongoing or
active infection, symptomatic congestive heart failure, unstable angina pectoris,
cardiac arrhythmia, or psychiatric illness/ social situations that would limit
compliance with study requirements.

- Have dementia or altered mental status that would prohibit informed consent.

- Have any other severe, acute or chronic medical or psychiatric condition or
laboratory abnormality that may increase the risk associated with study participation
or study drug administration or may interfere with the interpretation of study
results and, in the judgment of the Principal Investigator, would make the patient
inappropriate for this study.