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: Tavokinogene Telseplasmid With Electroporation, Pembrolizumab, and Epacadostat in Treating Patients With Unresectable Squamous Cell Carcinoma of the Head and Neck
  • Official Title: The Trifecta Study: Optimizinging 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
  • SECONDARY ID: 17-24044
  • SECONDARY ID: 172021
  • SECONDARY ID: P30CA082103
  • 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, INCB024360Treatment (tavo-EP, pembrolizumab, epacadostat)
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Treatment (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:

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (tavo-EP, pembrolizumab, epacadostat)ExperimentalPatients receive tavokinogene telseplasmid IT and undergo electroporation on days 1, 5 and 8. Patients also receive pembrolizumab IV over 30 minutes on days 1 and 22, and epacadostat PO 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.
  • Epacadostat
  • 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 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Best overall response rate by Response Evaluation Criteria in Solid Tumors version 1.1
Time Frame:Up to 36 months
Safety Issue:
Description:The best overall response(BOR) 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).

Secondary Outcome Measures

Measure:Incidence of adverse events (AEs) by Common Terminology Criteria for Adverse Events version 4
Time Frame:Up to 36 months
Safety Issue:
Description:AEs will be graded and reported descriptively.
Measure:Progression free survival (PFS)
Time Frame:From enrollment to progression or last assessment, assessed up to 36 months
Safety Issue:
Description:PFS is defined as the number of days from enrollment to progression (for subjects who have progression) and the number of days from enrollment to last assessment (for subjects who do not have progression).
Measure:Overall survival (OS)
Time Frame:From enrollment to death, or date last known alive, assessed up to 36 months
Safety Issue:
Description:OS is defined as the number of days from enrollment to death, or from enrollment to 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:Not yet recruiting
Lead Sponsor:University of California, San Francisco

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