Combination Therapy With Intravenous VSV-IFNβ-NIS and Pembrolizumab in Refractory NSCLC and HCC

The safety run-in portion of this study is designed to identify the optimal dose of
VSV-IFNβ-NIS in combination with pembrolizumab in patients with solid tumors, and follows the
3+3 design. The expansion portion will use one-sample binomial designs to assess the efficacy
of the combination in pateints with refractory NSCLC or HCC. The optimal dose determined in
the dose escalation portion of the trial will be used as the starting dose for the expansion
portion. The primary endpoint of the dose escalation portion of this trial is to find the
optimal dose of VSV-IFNβ-NIS+pembrolizumab. For the expansion portion of the trial, the
primary endpoint is RECIST 1.1 confirmed response.

Inclusion Criteria:

- Histologically confirmed diagnosis of:

Arm 1: dose level 1 and below: Advanced and/or metastatic solid tumors for which no
existing options are felt to provide clinical benefit

Arm 2: dose level 2: Advanced and/or metastatic NSCLC OR HCC in which radiological
progression has been demonstrated during therapy with a PD-1/PD-L1 immune checkpoint
inhibitor, and for which no existing options are felt to provide clinical benefit.

Arm 3: Advanced and/or metastatic HCC in which radiological progression has been
demonstrated during therapy with a PD-1/PD-L1 immune checkpoint inhibitor, and for which no
existing options are felt to provide clinical benefit.

Arm4: Advanced and/or metastatic NSCLC in which radiological progression has been
demonstrated during therapy with a PD-1/PD-L1 immune checkpoint inhibitor, and for which no
existing options are felt to provide clinical benefit.

- Measurable disease based on RECIST 1.1. The first 3 patients in the safety run-in
phase do not need measurable disease. HCC lesions that have been previously embolized
(bland embolization, chemo- or radio-embolization) or have undergone percutaneous
thermoablation are not eligible as target lesions.

- Performance status of 0 or 1 on the ECOG Performance Scale.

- Life expectancy of >3 months if not on active anti-cancer therapy

- Willingness to provide biological samples required for the duration of the study
including a fresh tumor biopsy sample (See Section 14.0).

- Adequate organ function using predefined laboratory values obtained ≤14 days prior to
registration.

- Negative pregnancy test for female patients of childbearing potential

- Absence of active CNS involvement. NOTE: Pre-enrollment imaging of asymptomatic
patients not mandatory

- Ability to provide written informed consent.

Exclusion Criteria:

- Availability of and patient acceptance of curative therapy.

- Recent or ongoing serious infection, including:

1. Any active Grade 3 or higher (per the NCI CTCAE, version 4.03) viral, bacterial,
or fungal infection within 2 weeks of registration.

2. Known seropositivity for or active infection by the human immunodeficiency virus
(HIV).

3. Acute hepatitis B or acute hepatitis C. Patients with chronic hepatitis B or
hepatitis C may be enrolled provided their liver function is adequate as per
section 3.17

4. Known history of active TB (Bacillus tuberculosis).

- Any serious health condition, which, in the opinion of the investigator, would place
the patient at undue risk from the study, including uncontrolled hypertension and/or
diabetes, clinically significant pulmonary disease (e.g., chronic obstructive
pulmonary disease requiring hospitalization within 3 months) or neurological disorder
(e.g., seizure disorder active within 3 months)

- Prior therapy within the following timeframe before the planned start of study
treatment as follows:

- Chemotherapy, small molecule inhibitors, radiation, interventional radiology
procedure, and/or other investigational agent: ≤3 weeks or 5 half-lives,
whichever is shorter

- Other monoclonal antibodies, antibody-drug conjugates, radioimmunoconjugates, or
experimental therapies: ≤4 weeks (≤3 weeks with documented disease progression)

- New York Heart Association classification III or IV, known symptomatic coronary artery
disease, or symptoms of coronary artery disease on systems review, or known cardiac
arrhythmias (atrial fibrillation or SVT) (Appendix II).

- Any known or suspected active organ-threatening autoimmune disease, such as
inflammatory bowel disease, autoimmune hepatitis, lupus, or pneumonitis, with the
exception of hypothyroidism and type 1 diabetes that are controlled with treatment.

- Immunodeficiency or immunosuppression, including systemic corticosteroids at >10mg/day
prednisone or equivalent within 1 week prior to planned start of study treatment

- History of severe immune-mediated adverse reaction to immune checkpoint inhibitors.

- Toxicities from previous therapies that have not resolved to a grade 1 or less.

- History of non-infectious pneumonitis that required steroids, or current pneumonitis.

- High volume disease, as assessed clinically via parameters such as radiologic
impression and tumor markers or LDH.

- Portal vein thrombosis involving more than intrahepatic portal vein branches:
thrombosis of the right or left portal vein branch or the bifurcation, partial or
complete obstruction of the portal vein trunk.

- Known concurrent malignancy that is progressing or requires active treatment.
EXCEPTIONS: basal cell carcinoma of the skin, squamous cell carcinoma of the skin,
in-situ cervical cancer that has been treated with curative intent, prostate cancer
confined to the prostate gland with Gleason score <6 or PSA <1, as well as any stage I
cancer treated with curative intent or any prior cancer with a disease-free interval
of ≥3 years.

- Other concurrent anti-cancer therapy (chemotherapy, immunotherapy, radiotherapy, or
any ancillary therapy considered investigational (used for a non-FDA approved
indication and in the context of a research investigation)).

- Has received a live vaccine within 30 days of planned start of study treatment.
Seasonal influenza vaccines for injection are generally inactivated flu vaccines and
are allowed; intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated
vaccines and are NOT allowed.

- Any of the following because this study involves an investigational agent whose
genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are
unknown:

- Pregnant women or women of reproductive ability who are unwilling to use highly
effective contraception

- Nursing women

- Men who are unwilling to use a condom (even if they have undergone a prior
vasectomy) while having intercourse with any woman, while taking the drug and for
4 weeks after stopping treatment.