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Optimizing Antitumor Immunity Using Plasmid Electroporation, Pembrolizumab, and Epacadostat

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ClinicalTrials.gov Identifier: NCT03823131
Recruitment Status : Active, not recruiting
First Posted : January 30, 2019
Last Update Posted : December 2, 2021
Sponsor:
Collaborators:
Incyte Corporation
OncoSec Medical Incorporated
Information provided by (Responsible Party):
Chase Heaton, MD, University of California, San Francisco

Brief 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.

Condition or disease Intervention/treatment Phase
Metastatic Head and Neck Squamous Cell Carcinoma Recurrent Head and Neck Squamous Cell Carcinoma Unresectable Head and Neck Squamous Cell Carcinoma Device: ImmunoPulse Drug: Epacadostat Drug: Pembrolizumab Biological: CORVax Drug: Tavokinogene telseplasmid Phase 2

Detailed Description:

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 patients 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 patients 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). Depending on the response from Stage 1, Stage 2 will continue to investigate the study treatments.

Patients 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 the end of the study, whichever occurs first.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 14 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: The Trifecta Study: Optimizing Antitumor Immunity Using Plasmid Electroporation, Pembrolizumab, and Epacadostat
Actual Study Start Date : May 2, 2019
Estimated Primary Completion Date : May 31, 2024
Estimated Study Completion Date : May 31, 2024

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Arm A: Tavo-EP, pembrolizumab, epacadostat
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
Intratumoral
Other Names:
  • Electroporation
  • electroporation therapy (EPT)

Drug: Epacadostat
Given PO
Other Names:
  • INCB 024360
  • INCB024360

Drug: Pembrolizumab
Given IV
Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475

Drug: Tavokinogene telseplasmid
Intratumoral
Other Names:
  • Tavo-EP
  • DNA plasmid
  • plasmid IL-12 pUMVC3-hIL-12-NGVL3

Experimental: Arm B: Tavo-EP, pembrolizumab
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
Intratumoral
Other Names:
  • Electroporation
  • electroporation therapy (EPT)

Drug: Pembrolizumab
Given IV
Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475

Drug: Tavokinogene telseplasmid
Intratumoral
Other Names:
  • Tavo-EP
  • DNA plasmid
  • plasmid IL-12 pUMVC3-hIL-12-NGVL3

Experimental: Arm C: Tavo-EP, pembrolizumab, CORVax
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
Intratumoral
Other Names:
  • Electroporation
  • electroporation therapy (EPT)

Drug: Pembrolizumab
Given IV
Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475

Biological: CORVax
Intratumoral
Other Name: DNA-encodable coronaviral vaccine

Drug: Tavokinogene telseplasmid
Intratumoral
Other Names:
  • Tavo-EP
  • DNA plasmid
  • plasmid IL-12 pUMVC3-hIL-12-NGVL3




Primary Outcome Measures :
  1. Best Overall Response Rate [ Time Frame: Up to 36 months ]
    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 :
  1. Median Progression free survival (PFS) [ Time Frame: From enrollment to progression or last assessment, assessed up to 36 months ]
    PFS is defined as the time, in months, from the first dosing date until the date of disease progression (i.e., the date of the tumor imaging) or death from any cause. RECIST v1.1 will be used to determine the dates of progression as this methodology is accepted by regulatory authorities.

  2. Median Overall survival (OS) [ Time Frame: From enrollment to death, or date last known alive, assessed up to 36 months ]
    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.

  3. Median Time to progression (TTP) [ Time Frame: Up to 36 months ]
    TTP is defined as the time, in months, from the first dosing date until the date of disease progression (i.e., the date of the tumor imaging). RECIST v1.1 will be used to determine the dates of progression as this methodology is accepted by regulatory authorities.

  4. Disease control rate (DCR) [ Time Frame: Up to 36 months ]
    Disease control rate (DCR) is defined as the percentage of patients who achieved a best overall response of CR, PR or stable disease (SD) using RECIST v1.1

  5. Clinical benefit rate (CBR) [ Time Frame: Up to 36 months ]
    Clinical benefit rate (CBR) is defined as the percentage of patients who achieved a best overall response of CR, PR and SD with a duration of at least 6 months or longer

  6. Median Duration of Response [ Time Frame: Up to 36 months ]
    Duration of response (DOR) will be calculated for patients 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 met to the date of progression or death. Patients who do not have a documented progression or death will be censored on the last date of tumor assessment. The number and percentage of patients whose DOR is longer than certain milestone times (such as 6 months, 9 months and 12 months) will be quantified. The median DOR and 95% confidence intervals calculated similar to PFS and OS analysis will be reported

  7. Porportion of participants with reported treatment-related adverse events (AEs) [ Time Frame: Up to 36 months ]
    Treatment-related AEs will be graded and reported descriptively using by Common Terminology Criteria for Adverse Events version 4



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03823131


Locations
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United States, California
University of California, San Francisco
San Francisco, California, United States, 94143
Sponsors and Collaborators
Chase Heaton, MD
Incyte Corporation
OncoSec Medical Incorporated
Investigators
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Principal Investigator: Chase Heaton, MD University of California, San Francisco
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Responsible Party: Chase Heaton, MD, Asst Clinical Professor, University of California, San Francisco
ClinicalTrials.gov Identifier: NCT03823131    
Other Study ID Numbers: 172021
NCI-2018-02901 ( Registry Identifier: NCI Clinical Trials Reporting Program (CTRP) )
First Posted: January 30, 2019    Key Record Dates
Last Update Posted: December 2, 2021
Last Verified: November 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: Yes
Device Product Not Approved or Cleared by U.S. FDA: Yes
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Squamous Cell
Squamous Cell Carcinoma of Head and Neck
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Squamous Cell
Head and Neck Neoplasms
Neoplasms by Site
Pembrolizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents