A Trial of CV301 in Combination With Anti-PD-1 Therapy in Subjects With Non-Small Cell Lung Cancer

Inclusion criteria for the Phase 1:

1. Subjects must have a metastatic or unresectable locally advanced malignant solid
tumor, histologically confirmed by the Laboratory of Pathology, NCI. Efforts will be
made, as much as possible, to enroll subjects with tumor types with known increased
expression of CEA or MUC-1 (such as lung, breast, ovarian, prostate, colorectal,
pancreatic, bladder, gastric, cervix, etc.).

2. Subjects may have measurable or nonmeasurable but evaluable disease. Subjects with
surgically resected or ablated metastatic disease at high risk of relapse are also
eligible.

Prior therapy: Subjects must have completed or had disease progression on at least one
prior line of disease-appropriate therapy for locally advanced or metastatic disease,
or not be candidates for therapy of proven efficacy for their disease.

3. Subjects with EGFR or ALK genomic tumor aberrations should have disease progression on
FDA-approved therapy for these aberrations.

4. There should be a minimum of 4 weeks from any prior chemotherapy, immunotherapy and/or
radiation, with the exception of hormonal therapy for prostate and breast cancers,
HER2-directed therapy for HER2+ breast cancer (3+ IHC or FISH+), maintenance therapy
for colorectal or pancreatic cancer, and erlotinib therapy in EGFR-mutated lung cancer
under the condition that subjects are on these therapies for at least two months
before start of trial treatment. There should be a minimum of 6 weeks from any prior
antibody therapies (such as ipilimumab or Anti-PD1/PDL1) due to prolonged half-life.

5. Subjects must have recovered (Grade 1 or baseline) from any clinically significant
toxicity associated with prior therapy. Typically, this is 3-4 weeks for subjects who
most recently received cytotoxic therapy, except for nitrosoureas and mitomycin C, for
which 6 weeks is needed for recovery.

6. Men or women, age ≥ 18 years.

7. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 or Karnofsky ≥ 70%,
(see Section 19.1, Appendix I and Section 19.2, Appendix II).

8. Subjects must have normal organ and marrow function as defined below

a. Serum creatinine ≤ 1.5 x upper limit of normal (ULN) OR creatinine clearance (CrCl)
≥ 40 mL/min (if using the Cockcroft-Gault formula below): i. Female CrCl = [(140 - age
in years) x weight in kg x 0.85] / [72 x serum creatinine in mg/dL] ii. Male CrCl =
[(140 - age in years) x weight in kg x 1.00] / [72 x serum creatinine in mg/dL] b.
Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ≤ 3 x the ULN c.
Total bilirubin ≤ 1.5 x ULN OR in subjects with Gilbert's syndrome, a total bilirubin
≤ 3.0 x ULN d. Hematological eligibility parameters (within 16 days of starting
therapy): i. Platelet count ≥ 100,000/µL ii. Absolute neutrophil count (ANC) ≥ 1/ µL

9. Subjects must have baseline pulse oximetry > 90% on room air.

10. The effects of CV301 on the developing human fetus are unknown. For this reason, women
of child-bearing potential (WOCBP) and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to trial entry and for
the duration of trial participation and for a period of 4 months after the last
vaccination. Should a woman become pregnant or suspect she is pregnant while she or
her partner is participating in this trial, she should inform her treating physician
immediately.

11. Subjects with prostate cancer must continue to receive GnRH agonist therapy (unless
orchiectomy has been done).

12. Subjects must be able to understand and be willing to sign a written informed consent
document.

Inclusion criteria for the Phase 1b:

1. Histologically confirmed non-squamous NSCLC, metastatic or unresectable locally
advanced. Actionable EGFR mutations and ALK/ROS-1 translocations targetable with FDA
approved therapy must be evaluated and found not to be present by standard methods.
Expression of PD-L1 must have been determined with a validated method or tumor sample
must be available for PD-L1 expression determination.

2. Patient population:

• Phase 1b, Cohort 1 (Nivolumab + CV301): Patients with progression on or after prior
platinum, with or without switch maintenance chemotherapy are eligible

• Phase 1b, Cohort 2 (Pembrolizumab + CV301): Patients must have been on Pembrolizumab
as first-line therapy for NSCLC as per FDA approved indications in first line for at
least 11 weeks and assessed by RECIST to have CR, PR, or SD at week 12 (+/- 1 week).

As of June 2017, FDA-approved indications for front-line treatment include 2
indications for Pembrolizumab:

- As a single agent for the first-line treatment of patients with metastatic NSCLC
whose tumors have high PD-L1 expression (Tumor Proportion Score (TPS) ≥50%) as
determined by an FDA-approved test, with no EGFR or ALK genomic tumor
aberrations.

- In combination with pemetrexed and carboplatin, as first-line treatment of
patients with metastatic nonsquamous NSCLC. This indication is approved under
accelerated approval based on tumor response rate and progression-free survival.
Continued approval for this indication may be contingent upon verification and
description of clinical benefit in the confirmatory trials.

Pemetrexed single agent maintenance after the initial 4 cycles of pemetrexed in
combination with carboplatinum and Pembrolizumab is allowed and optional as per
investigator or institutional standard practice.

3. In case of metastatic recurrence of a previous early stage NSCLC, any chemotherapy or
radiation therapy must have finalized more than 12 months before the start of the
first-line treatment, either Pembrolizumab alone or in combination with pemetrexed and
carboplatinum.

4. ECOG performance status 0 and 1.

5. Men or women, age ≥ 18 years

6. Have normal organ and marrow function as defined below:

- Serum creatinine ≤ 1.5 x upper limit of normal (ULN) OR creatinine clearance
(CrCl) ≥ 40 mL/min (if using the Cockcroft-Gault formula below):

i. Female CrCl = [(140 - age in years) x weight in kg x 0.85] / [72 x serum
creatinine in mg/dL] ii. Male CrCl = [(140 - age in years) x weight in kg x 1.00]
/ [72 x serum creatinine in mg/dL]

- ANC > 1/µL

- Platelets ≥ 100 000/µL

- Hemoglobin > 9 g/dL

- Total bilirubin ≤ 1.5 x institutional ULN or direct bilirubin < ULN if total
bilirubin > 1.5-3.0 x ULN

- AST/ALT < 2.5 × institutional ULN, or < 5 x ULN, if liver metastases are present

7. Have measurable disease by computed tomography (CT)/Magnetic resonance imaging (MRI)
per RECIST 1.1.

8. Willingness and ability to comply with scheduled visits, treatment plan, laboratory
tests, and other trial procedures.

9. Able to understand and be willing to sign a written informed consent document.

10. WOCBP must use appropriate method(s) of contraception. WOCBP should use an adequate
method to avoid pregnancy for 23 weeks (30 days plus the time required for Nivolumab
to undergo five half-lives) after the last dose of investigational drug (Phase 1b,
Cohort 1). WOCBP should use an adequate method to avoid pregnancy for at least 4
months (as per approved Pembrolizumab prescribing information) after the last dose of
investigational drug (Phase 1b, Cohort 2).

11. Women of childbearing potential must have a negative serum or urine pregnancy test
(minimum sensitivity 25 IU/L or equivalent units of β-human choriogonadotropin (HCG))
at screening. They must have confirmation by a negative urine pregnancy test within 24
hours prior to the first dose of Nivolumab (Phase 1b, Cohort 1), or within 24 hours
prior to the first dose of Pembrolizumab (Phase 1b, Cohort 2) in the setting of this
trial.

12. Men who are sexually active with WOCBP must use any contraceptive method with a
failure rate of less than 1% per year. Men receiving Nivolumab and who are sexually
active with WOCBP will be instructed to adhere to contraception for a period of 31
weeks after the last dose of investigational product. Women who are not of
childbearing potential (ie, who are postmenopausal or surgically sterile) as well as
azoospermic men, do not require contraception.

13. Subjects must have, prior to trial treatment, at least 10 unstained tissue slides (or
a tissue block from which 10 slides can be cut) from a prior biopsy or surgical
resection for submission for research purposes.

Optional for Phase 1b.

Exclusion Criteria for all Phases:

1. Subjects with EGFR mutations, ALK or ROS-1 translocations candidates to targeted
therapy.

2. Squamous histology of NSCLC.

3. Other concurrent investigational agents (subjects are eligible to enroll 4 weeks after
completion of prior investigational agent).

4. More than 1 prior chemotherapy regimen for locally advanced or metastatic NSCLC with
the exception of the Phase 1 portion, in which multiple therapies are allowed in all
tumor types. Any prior chemotherapy regimen different from pemetrexed-carboplatinum in
combination with Pembrolizumab as first-line chemotherapy for candidates to
Pembrolizumab maintenance of first line (Phase 1b).

5. Concurrent chemotherapy or radiotherapy or other immunotherapy not explicitly allowed
by inclusion criteria for that phase of trial.

6. Subjects treated with PD-1/L1 or any other experimental immunotherapeutic agents
outside the parameters established in the inclusion criteria, are excluded from
enrollment into Phase 1b, but can be enrolled into Phase 1.

7. Other malignancy within last 5 years with an estimated risk of recurrence higher than
50%. Examples of low risk of recurrence malignancies are non-melanoma skin cancer, in
situ cervical, superficial bladder cancer, colorectal cancer stage I and II, breast
cancer stages I and II, prostate cancer stages I and II, etc.

8. Patients with metastatic lesions in the brain.

9. History of allergy or untoward reaction to prior vaccination with vaccinia virus,
aminoglycoside antibiotics or egg products; history of allergy to smallpox
vaccination.

10. Active infection within 72 hours prior to vaccination.

11. Subjects should have no known evidence of being immunocompromised as listed below:

1. Human immunodeficiency virus (HIV) positivity, chronic hepatitis infection,
including hepatitis B and C virus

2. Active, known or suspected autoimmune disease. Subjects are permitted to enroll
if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to
autoimmune condition only requiring hormone replacement, psoriasis not requiring
systemic treatment, or conditions not expected to recur in the absence of an
external trigger

3. Immunosuppressive therapy post-organ transplant

4. Asplenia is an exclusion for Phase 1b, but is not an exclusion for Phase 1.

12. Altered immune function, including, but not limited to: inflammatory bowel disease;
active infectious enteritis; eosinophilic enteritis; lupus erythematosus; ankylosing
spondylitis; scleroderma; multiple sclerosis. These criteria do not include all
diseases with an immune-related component, but are not auto-immune in nature or have a
primary alteration in the general immune function that may interfere with the vaccine
mechanism of action, for example celiac disease.

13. Concurrent chronic use of systemic steroids, except for physiologic doses of systemic
steroids for replacement, defined as 5 mg of prednisone per day or equivalent, or
local (topical, nasal, ophthalmic or inhaled) steroid use or prior concomitant use
with chemotherapy. Systemic steroids must have been discontinued ≥ 2 weeks prior to
first treatment. Prior use of corticoids in short-term schemes (duration shorter than
3 days) for indications such as prophylaxis of reactions to intravenous contrast for
imaging studies or chemotherapy-related AEs are not considered part of this exclusion.
Prior use of corticoids for brain metastasis ending before day -14 is not considered
part of this exclusion criteria.

14. Subjects with interstitial lung disease that is symptomatic or may interfere with the
detection or management of suspected drug-related pulmonary toxicity.

15. Pregnant or breastfeeding women.

16. Clinically significant cardiomyopathy, coronary disease, heart failure New York Heart
Association class III or IV, or cerebrovascular accident within 1 year.

17. Uncontrolled intercurrent illness, which would interfere with the ability of the
subject to carry out the treatment program.

18. Any other condition, which would, in the opinion of the Principal Investigator or
Medical Monitor, indicate the subject is a poor candidate for treatment with CV301 or
would jeopardize the subject or the integrity of the data obtained.

19. Medical or psychological impediment to compliance with protocol.