The Trifecta Study: Optimizing Antitumor Immunity Using Plasmid Electroporation, Pembrolizumab, and Epacadostat
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 发起方
- 入组人数
- 14
- 试验地点
- 1
- 主要终点
- Best Overall Response Rate
研究概览
简要总结
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.
详细描述
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age >= 18 years old.
- •Eastern Cooperative Oncology Group (ECOG) performance status 0-
- •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.
排除标准
- •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.
- •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.
研究组 & 干预措施
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.
干预措施: ImmunoPulse (Device)
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.
干预措施: Epacadostat (Drug)
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.
干预措施: Pembrolizumab (Drug)
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.
干预措施: Tavokinogene telseplasmid (Drug)
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.
干预措施: ImmunoPulse (Device)
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.
干预措施: Pembrolizumab (Drug)
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.
干预措施: Tavokinogene telseplasmid (Drug)
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.
干预措施: ImmunoPulse (Device)
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.
干预措施: Pembrolizumab (Drug)
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.
干预措施: CORVax (Biological)
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.
干预措施: Tavokinogene telseplasmid (Drug)
结局指标
主要结局
Best Overall Response Rate
时间窗: Up to 36 months
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.
次要结局
- Median Duration of Response(Up to 36 months)
- Proportion of Participants With Reported Treatment-related Adverse Events (AEs)(Up to 36 months)
- Median Months of Progression-Free Survival (PFS)(Up to 36 months)
- Median Overall Survival (OS)(Up to 36 months)
- Median Time to Response(Up to 36 months)
- Disease Control Rate (DCR)(Up to 36 months)
- Clinical Benefit Rate (CBR)(Up to 36 months)
研究者
Chase Heaton, MD
Asst Clinical Professor
University of California, San Francisco