Optimizing Antitumor Immunity Using Plasmid Electroporation, Pembrolizumab, and Epacadostat
Condition: Metastatic Head and Neck Squamous Cell Carcinoma; Recurrent Head and Neck Squamous Cell Carcinoma; Unresectable Head and Neck Squamous Cell Carcinoma
MeSH terms: Carcinoma; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck
Intervention: ImmunoPulse; Epacadostat; Pembrolizumab; CORVax; Tavokinogene telseplasmid
Intervention description: Intratumoral; Given PO; Given IV; Intratumoral; Intratumoral
Intervention MeSH terms: Pembrolizumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Enrollment: 14.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This phase II trial studies how well tavokinogene telseplasmid with electroporation
      (tavo-EP), pembrolizumab, and epacadostat work in treating patients with squamous cell
      carcinoma of the head and neck that cannot be removed by surgery. Tavokinogene telseplasmid
      with electroporation is a gene therapy that may delay of tumor growth and which may have less
      toxicity than other methods of gene delivery. Immunotherapy with monoclonal antibodies, such
      as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with
      the ability of tumor cells to grow and spread. Epacadostat may stop the growth of tumor cells
      by blocking some of the enzymes needed for cell growth. Giving tavokinogene telseplasmid with
      electroporation, pembrolizumab, and epacadostat may work better in treating squamous cell
      carcinoma of the head and neck.
    

Eligibility criteria:

        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 cancer originating in 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.

          -  Measurable 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 of first dose of study drug(s) and use of birth control from 30 days prior to the
             first study drug administration and 120 days following last administration of study
             drug, or for participants in Arm C, 180 days after last dose of CORVax, whichever is
             longer.

          -  Male patients must be surgically sterile or must agree to use contraception during the
             study and at least 120 days following the last administration of study drug, or for
             participants in Arm C, 180 days after last dose of CORVax, whichever is longer.

        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 study drug 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.

          -  Aspartate aminotransferase (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.