Optimizing Antitumor Immunity Using Plasmid Electroporation, Pembrolizumab, and Epacadostat

Study Overview
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Brief Summary
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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.

Detailed Description
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PRIMARY OBJECTIVES: I. Dose Escalation Safety Lead-Ins: Assess the safety of tavo-EP and pembrolizumab in combination with epacadostat (CTCAE version 4). II. Dose Expansion: Determine whether the combination therapy in each arm increases the best overall response rate (BORR) compared with historical data for pembrolizumab monotherapy SECONDARY OBJECTIVES: I. Dose Expansion: Determine the durability of clinical benefits in participants treated with combination therapy in each arm, as assessed by time to progression, median progression-free survival (PFS), median overall survival (OS). EXPLORATORY OBJECTIVES: I. 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. II. 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. III. Explore changes in functional immune responses using Elispot and other assays. IV. 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 participants in Stage 1 will receive either tavo-EP with pembrolizumab, and epacadostat (Arm A), tavo-EP and pembrolizumab (Arm B), or CORVax, tavo-EP and pembrolizumab (Arm C). Arms B and C will only open to enrollment if the treatment is determined to be effective in Arm A. Participants will be followed at 3-month intervals for toxicity and radiographic imaging (1) until start of a new anti-cancer treatment, (2) until 30 days after documented disease progression, (3) until death, or (4) until 36 months from the initiation of treatment on study, whichever comes first. Each subject will be followed for overall survival until death, withdrawal of consent, or at the time of study closure, whichever occurs first.

Official Title
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The Trifecta Study: Optimizing Antitumor Immunity Using Plasmid Electroporation, Pembrolizumab, and Epacadostat

Conditions
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Unresectable Head and Neck Squamous Cell Carcinoma, Metastatic Head and Neck Squamous Cell Carcinoma, Recurrent Head and Neck Squamous Cell Carcinoma

Intervention / Treatment
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* Device: ImmunoPulse
* Drug: Epacadostat
* Drug: Pembrolizumab
* Biological: CORVax
* Drug: Tavokinogene telseplasmid


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: Tavo-EP, pembrolizumab, epacadostat<br>Tavo-EP will be injected intratumorally on Days 1, 5 and 8 every 6 weeks to up to 7 accessible lesions without exceeding 20 mL per day. Injected lesions will then be electroporated using the ImmunoPulse electroporation device. Pembrolizumab will be administered by a 30 minute IV infusion at a dose of 200 mg every 3 weeks. Epacadostat will be administered at the dose level determined in the dose escalation safety lead-in. | Device: ImmunoPulse<br>* Intratumoral<br>* Other names: electroporation therapy (EPT);Drug: Epacadostat<br>* Given PO<br>* Other names: INCB024360;Drug: Pembrolizumab<br>* Given IV<br>* Other names: SCH 900475;Drug: Tavokinogene telseplasmid<br>* Intratumoral<br>* Other names: plasmid IL-12 pUMVC3-hIL-12-NGVL3;|
| Experimental: Arm B: Tavo-EP, pembrolizumab<br>Tavo-EP will be injected intratumorally on Days 1, 5 and 8 every 6 weeks to up to 7 accessible lesions without exceeding 20 mL per day. Injected lesions will then be electroporated using the ImmunoPulse electroporation device. Pembrolizumab will be administered by a 30 minute IV infusion at a dose of 200 mg every 3 weeks. | Device: ImmunoPulse<br>* Intratumoral<br>* Other names: electroporation therapy (EPT);Drug: Pembrolizumab<br>* Given IV<br>* Other names: SCH 900475;Drug: Tavokinogene telseplasmid<br>* Intratumoral<br>* Other names: plasmid IL-12 pUMVC3-hIL-12-NGVL3;|
| Experimental: Arm C: Tavo-EP, pembrolizumab, CORVax<br>Tavo-EP will be injected intratumorally on Days 1, 5 and 8 every 6 weeks to up to 7 accessible lesions without exceeding 20 mL per day. Injected lesions will then be electroporated using the ImmunoPulse electroporation device. Pembrolizumab will be administered by a 30-minute IV infusion at a dose of 200 mg every 3 weeks. CORVax will be administered at a total dose of 0.2 mg of (S) protein plasmid in 120 microliter (uL) per lesion intratumorally into a maximum of 4 lesions of at least 0.3 mm in diameter for a total plasmid dose of 0.8 mg on treatment days 1 and 29 of cycle 1 followed by electroporation of the plasmid solution in infiltrated regions. On days when both tavo and CORVax is administered to the same lesions, tavo and CORVax will each be injected into the lesion followed by electroporation. | Device: ImmunoPulse<br>* Intratumoral<br>* Other names: electroporation therapy (EPT);Drug: Pembrolizumab<br>* Given IV<br>* Other names: SCH 900475;Biological: CORVax<br>* Intratumoral<br>* Other names: DNA-encodable coronaviral vaccine;Drug: Tavokinogene telseplasmid<br>* Intratumoral<br>* Other names: plasmid IL-12 pUMVC3-hIL-12-NGVL3;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall Response Rate | The best overall response (BORR) is defined as the best response recorded from the start of treatment until disease progression/recurrence. Per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, Complete Response (CR) is defined as the disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR) is defined as having at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. The combined percentage of participants relative to the total size of the All Treated Subjects population having a demonstrated best response of CR or PR, with a confirmatory scan will be reported. | Up to 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Months of Progression-Free Survival (PFS) | Progression-free survival will be calculated as number of months from the first dosing date until the date of disease progression (i.e the date of the tumor imaging following baseline per central imaging assessment by a radiologist) or death from any cause. Per RECIST version 1.1, Progressive Disease (PD) is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). Participants who do not have documented disease progression will have their months of PFS censored on the last date of tumor assessment, or death, whichever comes first. Censoring data on date of last tumor imaging to calculate the median PFS will not occur until the overall survival data collection for all participants has been completed. | Up to 36 months | 
| Median Overall Survival (OS) | Overall survival (OS) is defined as the number of months from the date of enrollment until the date of death regardless of cause, last date of follow-up, or date of study closure (if still alive), whichever comes first. Median months of overall participant survival will be reported using descriptive statistics. | Up to 36 months | 
| Median Time to Response | Time to response is defined as the number of days from the date of enrollment to the date of the first documented response of CR or PR. The median time to response will be summarized by descriptive statistics. | Up to 36 months | 
| Disease Control Rate (DCR) | The disease control rate is defined as the best response recorded from the start of treatment including stable disease, until disease progression/recurrence (PD). Per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, Complete Response (CR) is defined as the disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR) is defined as having at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease (SD) is defined as having neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. The proportion of participants relative to the total size of the All Treated Subjects population having a demonstrated response of CR, PR, or SD, with a confirmatory scan will be reported. | Up to 36 months | 
| Clinical Benefit Rate (CBR) | Clinical benefit rate (CBR) is defined as the percentage of participants who achieved a best overall response of CR, PR and SD with a duration of response lasting at least 6 months or longer. | Up to 36 months | 
| Median Duration of Response | The duration of response (DOR) will be calculated for participants who achieved a best overall response of CR or PR and calculated as the number of days from the date when CR or PR is first confirmed to the date of progression or death. Participants who do not have a documented progression or death will be censored on the last date of tumor assessment. The median DOR and 95% confidence intervals will be reported. | Up to 36 months | 
| Proportion of Participants With Reported Treatment-related Adverse Events (AEs) | The proportion of participants with reported treatment-related adverse events, which are adverse events defined as having an attribution of possible, probable, or definite according to NCI Common Terminology Criteria for Adverse Events (CTCAE) v. 4 will be reported. | Up to 36 months |