Clinical Trials /

Tavo With Electroporation, Pembrolizumab, and Epacadostat in Patients With Unresectable Head and Neck Cancer

NCT03823131

Description:

This phase II trial studies how well tavokinogene telseplasmid with electroporation, 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.

Related Conditions:
  • Head and Neck Squamous Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Tavo With Electroporation, Pembrolizumab, and Epacadostat in Patients With Unresectable Head and Neck Cancer
  • Official Title: The Trifecta Study: Optimizing Antitumor Immunity Using Tavokinogene Telseplasmid With Electroporation, Pembrolizumab, and Epacadostat in Squamous Cell Carcinoma of the Head and Neck

Clinical Trial IDs

  • ORG STUDY ID: 172021
  • SECONDARY ID: NCI-2018-02901
  • NCT ID: NCT03823131

Conditions

  • Metastatic Head and Neck Squamous Cell Carcinoma
  • Recurrent Head and Neck Squamous Cell Carcinoma
  • Unresectable Head and Neck Squamous Cell Carcinoma

Interventions

DrugSynonymsArms
EpacadostatINCB 024360, INCB024360Arm A: Tavo-EP, pembrolizumab, epacadostat
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Arm A: Tavo-EP, pembrolizumab, epacadostat

Purpose

This phase II trial studies how well tavokinogene telseplasmid with electroporation, 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

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A: Tavo-EP, pembrolizumab, epacadostatExperimentaltavo-EP:pUMVC3-hIL-12-NGVL33 (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.
  • Epacadostat
  • Pembrolizumab
Arm B: Tavo-EP, pembrolizumabExperimentaltavo-EP:pUMVC3-hIL-12-NGVL33 (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.
  • Pembrolizumab

Eligibility Criteria

        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 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

          -  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, 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 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 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Best Overall Response Rate
Time Frame:Up to 36 months
Safety Issue:
Description:The best overall response (BORR) is the best response recorded from the start of treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurement recorded since the treatment started). The percentage of patients who attain a confirmed complete response (CR), or partial response (PR) over the trial with the triplet treatment with a 4-week confirmatory scan per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 will be reported and percentage calculated will be relative to all patients who received the study therapy, and 95% confidence interval is calculated by the Clopper-Pearson (exact binomial) method

Secondary Outcome Measures

Measure:Incidence of treatment- related adverse events (AEs)
Time Frame:Up to 36 months
Safety Issue:
Description:Treatment-related AEs will be graded and reported descriptively using by Common Terminology Criteria for Adverse Events version 4
Measure:Progression free survival (PFS)
Time Frame:From enrollment to progression or last assessment, assessed up to 36 months
Safety Issue:
Description:Progression free survival (PFS) is defined as the number of days from the date of enrollment to the date of progression or death regardless of cause. . Patients who do not have a documented progression or death will be censored on the date of last assessment
Measure:Overall survival (OS)
Time Frame:From enrollment to death, or date last known alive, assessed up to 36 months
Safety Issue:
Description:Overall survival (OS) is defined as the number of days from the date of enrollment to the date of death regardless of cause, patients without a death date will be censored on the date last known alive.
Measure:Time to progression
Time Frame:Up to 36 months
Safety Issue:
Description:Will be summarized using the Kaplan-Meier method.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Chase Heaton, MD

Last Updated

August 10, 2020