Tavokinogene Telseplasmid With Electroporation, Pembrolizumab, and Epacadostat in Treating Patients With Unresectable Squamous Cell Carcinoma of the Head and Neck

PRIMARY OBJECTIVES:

I. Determine whether the combination of tavokinogene telseplasmid (tavo)-electroporation
(EP), pembrolizumab, and epacadostat increases the best overall response rate (BORR) in
squamous cell carcinoma of the head and neck (SCCHN) compared with historical data for
pembrolizumab monotherapy.

SECONDARY OBJECTIVES:

I. Assess the safety of tavo-EP and pembrolizumab in combination with epacadostat (Common
Terminology Criteria for Adverse Events [CTCAE] version 4).

II. Determine the durability of clinical benefits in patients treated with tavo-EP,
pembrolizumab, and epacadostat as assessed by time to progression, median progression-free
survival (PFS), median overall survival (OS).

EXPLORATORY OBJECTIVES:

I. Determine whether the combination of tavo-EP, pembrolizumab, and epacadostat increases the
objective response rate in SCCHN compared with emerging data for pembrolizumab in combination
with epacadostat.

II. Determine the effects of combination therapy on treated and untreated lesions by
examining paired biopsy specimens for changes in inflammatory gene expression, relative
proportion of effector versus regulatory T cells, evaluation of inflammatory cytokines,
T-cell activation, clonality, and other hallmarks of immune activation.

III. Explore systemic markers of immune activation by examining circulating T-cell
populations for changes in the frequency and effector function of short-lived effector cells
and memory T cells.

IV. Explore changes in functional immune responses using enzyme-linked immunosorbent spot
(Elispot) and other assays.

V. To explore biomarkers that inform scientific understanding of this therapeutic treatment
through analysis of specimens retained for Future Biomedical Research.

OUTLINE:

Patients receive tavokinogene telseplasmid intratumorally (IT) and undergo electroporation on
days 1, 5 and 8. Patients also receive pembrolizumab intravenously (IV) over 30 minutes on
days 1 and 22, and epacadostat orally (PO) twice daily (BID). Treatment repeats every 42 days
(6 weeks) for up to 9 courses or 12 months in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, then every 3 months
for up to 36 months or 30 days after disease progression.

Inclusion Criteria:

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

- Life expectancy of at least 4 months

- Patients must have histological or cytological diagnosis of carcinoma of the head and
neck that is not amenable to surgical resection or locoregional radiation therapy with
curative intent

- At least one tumor accessible lesion (AL) for intratumoral injection and EP on
investigator?s assessment meeting all criteria. An AL is defined as meeting the
following criteria; (1) at least 0.3 cm x 0.3 cm in longest perpendicular diameters,
(2) in a suitable location for application of electroporation. If the biopsied lesions
were previously irradiated, they must demonstrate either radiographic or pathological
evidence of recurrent or residual disease; Tumors invading the carotid artery or at
other sites that the investigator believes to be at high risk of life-threatening
hemorrhage should not be injected and these lesions may not be used to meet the
inclusion criterion for injectable lesions

- If patient has known brain metastases, they must have stable neurologic status
following local therapy (surgery or radiation) for at least 4 weeks without the use of
steroids or on stable or decreasing dose of =< 10 mg daily prednisone (or equivalent),
and must be without neurologic dysfunction that would confound the evaluation of
neurologic and other adverse events (AEs) (patients with a history of carcinomatous
meningitis are not eligible)

- Patients may have had prior chemotherapy or immunotherapy or radiation therapy. Any
drug related adverse events identified during prior therapy must be well controlled
(typically resolution to =< grade 1, OR resolved upon investigator review prior to
initiation of this therapy

- No systemic antineoplastic therapy may be received by the patient between the time of
the biopsy and the first administration of study treatment

- Patient must agree to any protocol mandated biopsies of tumor (deemed accessible and
safe for biopsy by the investigator?s assessment) and they must allow acquired tissue
to be used for biomarker analysis

- For women of childbearing potential, negative serum or urine pregnancy test within 14
days to the first epacadostat, pembrolizumab, or tavo-EP administration, and use of
birth control from 30 days prior to the first epacadostat, pembrolizumab, or tavo-EP
administration and 120 days following last day of epacadostat, pembrolizumab, or
tavo-EP administration

- Male patients must be surgically sterile, or must agree to use contraception during
the study and at least 120 days following the last day of epacadostat, pembrolizumab,
or tavo-EP administration

Exclusion Criteria:

- Active autoimmune disease that has required systemic treatment in past 2 years.
Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency) is not considered a form
of systemic treatment

- Congestive heart failure (New York Heart Association class III to IV)

- History or presence of an abnormal electrocardiogram (ECG) that, in the investigator's
opinion, is clinically meaningful. Screening corrected QT (QTc) interval > 480
milliseconds is excluded. In the event that a single QTc is > 480 milliseconds, the
subject may enroll if the average QTc for the 3 ECGs is < 480 milliseconds. For
subjects with an intraventricular conduction delay (QRS interval > 120 milliseconds),
the corrected JT (JTc) interval may be used in place of the QTc with sponsor approval.
The JTc must be < 340 milliseconds if JTc is used in place of the QTc. Subjects with
left bundle branch block are excluded

- Uncontrolled or clinically significant conduction abnormalities (e.g., ventricular
tachycardia on anti-arrhythmics are excluded), 1st degree atrioventricular (AV) block
or asymptomatic left anterior fascicular block (LAFB)/right bundle branch block (RBBB)
are eligible

- Uncontrolled, symptomatic ischemia within 6 months of first dose of study treatment or
known myocardial infarction in the previous six months

- Patients with electronic pacemakers or defibrillators

- Evidence of interstitial lung disease or active, noninfectious pneumonitis including
symptomatic and/or pneumonitis requiring treatment

- Any other current or previous malignancy within the past 2 years that, in the opinion
of the principal investigator will interfere with study-specific endpoints

- Evidence of significant active infection (e.g., pneumonia, cellulitis, wound abscess,
etc.) requiring systemic therapy at time of study enrollment

- Hepatitis B ? Most nasopharyngeal cancer (NPC) patients have been infected with
hepatitis B (Cancer Epidemol Biomarkers Prev. 2015. 24:1766-73, N = 711) and,
therefore, the inclusion of healthy patients with a history of hepatitis B is a
central part of this study. In addition, PD-1 antibodies have been proven to be safe
in patients with active hepatitis and hepatocellular carcinoma (e.g. KEYNOTE 224).
However, patients with hepatitis B virus (HBV) surface antigen positive (HBSAg) must
have aspartate aminotransferase (AST) and total bilirubin < 1.5 x upper limit of
normal (ULN) AND

- Negative HBV ribonucleic acid (RNA) polymerase chain reaction (PCR) OR

- On antivirals for HBV AND at least 8 weeks of prior anti-PD1 antibody therapy AND no
history of AST or total bilirubin levels > 1.5 x ULN due to PD-1 antibody therapy

- Hepatitis C (hepatitis C virus [HCV] RNA [qualitative] is detected)

- Presence of a gastrointestinal condition that may affect drug absorption.
Administration of epacadostat through a feeding tube is permitted

- Patients receiving systemic steroid therapy for a chronic inflammatory condition.
Topical steroids, nasal and inhaled steroids are permitted. Prednisone or equivalent
=< 10 mg/day is permitted as hormone replacement; higher dosage prednisone should be
stopped at least 14 days prior to course 1 day 1 (C1D1)

- Receipt of live attenuated vaccine within 30 days before the first dose of study
treatment. Examples of live vaccines include, but are not limited to, the following:
measles, mumps, rubella, chicken pox, yellow fever, rabies, Bacillus Calmette-Guerin
(BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally
killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g.,
FluMist) are live attenuated vaccines and are not allowed

- Subjects receiving monoamine oxidase inhibitors (MAOIs) or drug which has significant
MAOI activity (meperidine, linezolid, methylene blue) within the 21 days before
screening

- Any history of serotonin syndrome (SS) after receiving serotonergic drugs

- Use of any UGT1A9 inhibitor from screening through follow-up period, including the
following: diclofenac, imipramine, ketoconazole, mefenamic acid, and probenecid

- Known allergy or reaction to any component of epacadostat, pembrolizumab, or tavo-EP
formulation

- Absolute neutrophil count (ANC) < 1.0 x 10^9/L

- Platelets < 75 x 10^9/L

- Hemoglobin < 9 g/dL or < 5.6 mmol/L (transfusion is acceptable to meet this criterion)

- Serum creatinine >= 1.5 x institutional upper limit of normal (ULN) OR measured or
calculated creatinine clearance (glomerular filtration rate can also be used in place
of creatinine or creatinine clearance [CrCl]) < 50 mL/min for subjects with creatinine
levels > 1.5 x institutional ULN

- AST or alanine aminotransferase (ALT) > 2.5 x institutional ULN

- Alkaline phosphatase > 2.5 x ULN. Note: Subjects with 1) bone metastases and
gamma-glutamyl transpeptidase (GGT) < 2.5 x ULN may enroll if the alkaline phosphatase
is < 5 x ULN

- Total bilirubin above 1.5 x the institutional ULN AND conjugated bilirubin >= 2.0 x
ULN

- International normalized ratio (INR) or prothrombin time (PT) > 1.5 x ULN

- Activated partial thromboplastin time (aPTT) > 1.5 x ULN