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:
This is a multi-center, open label, 2-stage, double-arm, clinical trial in which patients in
Stage 1 will receive either tavo-EP with pembrolizumab, and epacadostat (Arm A) or tavo-EP
and pembrolizumab (Arm B) after a dose escalation safety lead-in phase. Stage 2 will open
pending additional clinical and translational data emerging from Stage 1.
Inclusion Criteria:
- Age >= 18 years old
- 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 accessible lesion (AL) for intratumoral injection. 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. 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
- Measureable disease as defined by Response Evaluation Criteria in Solid Tumors
(RECIST) v1.1; at least one lesion where the longest perpendicular diameter is at
least 1.0 cm by clinical measurement; or at least 1.0 cm by radiographic imaging for
non-nodal lesions; at least 1.5 cm in short axis by radiographic imaging for malignant
lymph nodes; If the biopsied lesions were previously irradiated, they must demonstrate
either radiographic or pathological evidence of recurrent or residual disease. It is
not necessary that this lesion is also an AL.
- 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
- Has history of (non-infectious) pneumonitis/interstitial lung disease that required
steroids or has current pneumonitis/interstitial lung disease
- 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, programmed cell death protein 1 (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-PD-1 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 a live vaccine or live attenuated vaccine within 30 days before the first
dose of study treatment. Administration of killed vaccines is 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 uridine 5'-diphospho-glucuronosyltransferase 1-9 (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
