Testing the Addition of the Anti-cancer Viral Therapy Telomelysin™ to Chemoradiation for Patients With Advanced Esophageal Cancer and Are Not Candidates for Surgery

Study Overview
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Brief Summary
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This phase I trial studies the side effects of OBP-301 when given together with carboplatin, paclitaxel, and radiation therapy in treating patients with esophageal or gastroesophageal cancer that invades local or regional structures. OBP-301 is a virus that has been designed to infect and destroy tumor cells (although there is a small risk that it can also infect normal cells). Chemotherapy drugs, such as carboplatin and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving OBP-301 with chemotherapy and radiation therapy may work better than standard chemotherapy and radiation therapy in treating patients with esophageal or gastroesophageal cancer.

Detailed Description
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PRIMARY OBJECTIVE: I. To determine if the addition of OBP-301 to chemoradiation with carboplatin/paclitaxel is safe. SECONDARY OBJECTIVES: I. To assess toxicities associated with the addition of OBP-301 to chemoradiation. II. To assess the number of clinical complete responses (cCR). III. To assess the number of patients alive/without progression (progression-free survival [PFS]) and the number of patients alive (overall survival [OS]) at 1 and 2 years. EXPLORATORY OBJECTIVE: I. To report correlate outcomes - cCR, PFS and OS - with immune and virus-based correlative assays. OUTLINE: This study will evaluate an initial dose of OBP-301 and a de-escalated dose, if needed. Patients receive OBP-301 by intratumoral injection via endoscopy on days -3, 12, and 26. Patients also receive carboplatin intravenously (IV) over 30 minutes and paclitaxel IV over 60 minutes on days 1, 8, 15, 22, and 29, and undergo radiation therapy on Monday through Friday beginning day 1 for 28 fractions over 5.5 weeks. All treatment continues in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 1 and 6-8 weeks, then every 3 months for 2 years.

Official Title
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Phase I Trial With Expansion Cohort of OBP-301 (Telomelysin™) and Definitive Chemoradiation for Patients With Locally Advanced Esophageal and Gastroesophageal Cancer Who Are Not Candidates for Surgery

Conditions
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Advanced Esophageal Adenocarcinoma, Advanced Gastroesophageal Junction Adenocarcinoma, Clinical Stage II Esophageal Adenocarcinoma AJCC v8, Clinical Stage II Gastroesophageal Junction Adenocarcinoma AJCC v8, Clinical Stage IIA Esophageal Adenocarcinoma AJCC v8, Clinical Stage IIA Gastroesophageal Junction Adenocarcinoma AJCC v8, Clinical Stage IIB Esophageal Adenocarcinoma AJCC v8, Clinical Stage IIB Gastroesophageal Junction Adenocarcinoma AJCC v8, Clinical Stage III Esophageal Adenocarcinoma AJCC v8, Clinical Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8, Pathologic Stage II Esophageal Adenocarcinoma AJCC v8, Pathologic Stage II Gastroesophageal Junction Adenocarcinoma AJCC v8, Pathologic Stage IIA Esophageal Adenocarcinoma AJCC v8, Pathologic Stage IIA Gastroesophageal Junction Adenocarcinoma AJCC v8, Pathologic Stage IIB Esophageal Adenocarcinoma AJCC v8, Pathologic Stage IIB Gastroesophageal Junction Adenocarcinoma AJCC v8, Pathologic Stage III Esophageal Adenocarcinoma AJCC v8, Pathologic Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8, Pathologic Stage IIIA Esophageal Adenocarcinoma AJCC v8, Pathologic Stage IIIA Gastroesophageal Junction Adenocarcinoma AJCC v8, Pathologic Stage IIIB Esophageal Adenocarcinoma AJCC v8, Pathologic Stage IIIB Gastroesophageal Junction Adenocarcinoma AJCC v8, Postneoadjuvant Therapy Stage II Esophageal Adenocarcinoma AJCC v8, Postneoadjuvant Therapy Stage II Gastroesophageal Junction Adenocarcinoma AJCC v8, Postneoadjuvant Therapy Stage III Esophageal Adenocarcinoma AJCC v8, Postneoadjuvant Therapy Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8, Postneoadjuvant Therapy Stage IIIA Esophageal Adenocarcinoma AJCC v8, Postneoadjuvant Therapy Stage IIIA Gastroesophageal Junction Adenocarcinoma AJCC v8, Postneoadjuvant Therapy Stage IIIB Esophageal Adenocarcinoma AJCC v8, Postneoadjuvant Therapy Stage IIIB Gastroesophageal Junction Adenocarcinoma AJCC v8, Unresectable Gastroesophageal Junction Adenocarcinoma, Squamous Cell Carcinoma, Squamous Cell Cancer

Intervention / Treatment
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* Drug: Carboplatin
* Drug: Paclitaxel
* Radiation: Radiation Therapy
* Biological: Telomerase-specific Type 5 Adenovirus OBP-301


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathologically (histologically or cytologically) proven diagnosis of adenocarcinoma or squamous cell carcinoma (SCC) of the esophagus or gastroesophageal junction (GEJ) within 90 days prior to registration Gastroesophageal junction tumors must be Siewert type I/II Required diagnostic workup for study entry: History/physical examination prior to registration Computed tomography (CT) of the chest/abdomen with intravenous contrast within 28 days prior to registration; If CT contrast is contraindicated magnetic resonance imaging (MRI) of the chest/abdomen without contrast is permitted Bronchoscopy for squamous cell carcinoma (SCC) tumors that are adjacent to the airway to exclude a tracheoesophageal fistula within 42 days prior to registration Endoscopic ultrasound (if technically feasible) within 90 days prior to registration Whole body positron emission tomography (PET)/CT scan within 42 days prior to registration: Note: scan will be used for radiation treatment planning, in addition to ruling out metastatic disease Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 within 14 days prior to registration White blood cell (WBC) ≥ 3,000/mcL (within 14 days prior to registration) Absolute neutrophil count ≥ 1,500/mcL (within 14 days prior to registration) Hemoglobin ≥ 9 gm/dL (within 14 days prior to registration) Platelets ≥ 100,000/mcL (within 14 days prior to registration) Creatinine clearance of ≥ 50 ml/min (as calculated by Cockcroft-Gault equation) (within 14 days prior to registration) Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (within 14 days prior to registration) Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 2.5 x ULN (within 14 days prior to registration) Patients must, in the opinion of a thoracic surgeon and/or multidisciplinary team, not be a candidate for surgery but are candidates for chemoradiation Patients must, in the opinion of a treating gastroenterologist, have a tumor that is amenable to intratumoral injection with at least 1 mL (1 x 10^12 vp/mL) of OBP-301 and be a candidate for 3 endoscopy procedures Female patients of child bearing potential must have a negative serum/urine pregnancy test within 14 days prior to study entry. A female not of childbearing potential is one who has undergone a hysterectomy, bilateral oophorectomy, tubal ligation, or who has had no menses for 12 consecutive months Patients of reproductive potential must agree to use effective contraception for the duration of study treatment as well as 6 months (for women) or 12 months (for men) after the last administered injection of OBP-301. Effective contraception includes oral contraceptives, implantable hormonal contraception, double-barrier method or intrauterine device The patient or a legally authorized representative must provide study-specific informed consent prior to study entry Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial Known acute or chronic hepatitis B or C infection (testing not required prior to study entry in patients with no known history of hepatitis B or C) For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated For patients with a history of hepatitis C virus (HCV) infection, they must (i) have been treated and cured, (ii) for patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months prior to study entry are eligible for this trial Exclusion Criteria: Definitive clinical or radiologic evidence of metastatic disease including: Positive malignant cytology of the pleura, pericardium or peritoneum Radiographic evidence of involvement of any adjacent mediastinal structure, e.g. aorta, trachea, which would increase the risk of repeated endoscopic interventions Tracheoesophageal fistula Radiographic evidence of distant organ involvement Non-regional lymph nodes that cannot be contained within a radiation field More than 1 esophageal lesion Prior systemic chemotherapy for the study cancer Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields Biopsy-proven tumor invasion of the tracheobronchial tree or presence of tracheoesophageal fistula or recurrent laryngeal or phrenic nerve paralysis For patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, a New York Heart Association functional classification 2C or worse Uncontrolled diabetes Infection requiring IV antibiotics at the time of registration Patients requiring immunosuppressive medications including chronic suppressive steroid therapy (greater than the equivalent of 20 mg/day of prednisone), methotrexate, azathioprine and TNF-alpha blockers within 7 days prior to study entry Received live vaccine within 30 days prior to registration Received a blood transfusion, hematopoietic agent; granulocyte-colony stimulating factor (G-CSF), and/or oxygen supplementation within 7 days before the screening lab Breast feeding females

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (OBP-301, carboplatin, paclitaxel, radiation)<br>Patients receive OBP-301 by intratumoral injection on days -3, 12, and 26. Patients also receive carboplatin IV over 30 minutes and paclitaxel IV over 60 minutes on days 1, 8, 15, 22, and 29, and undergo radiation therapy on Monday through Friday beginning day 1 for 28 fractions over 5.5 weeks. All treatment continues in the absence of disease progression or unacceptable toxicity. | Drug: Carboplatin<br>* Given IV<br>* Other names: Ribocarbo;Drug: Paclitaxel<br>* Given IV<br>* Other names: Taxol Konzentrat;Radiation: Radiation Therapy<br>* Undergo radiation therapy<br>* Other names: Therapy, Radiation;Biological: Telomerase-specific Type 5 Adenovirus OBP-301<br>* Given by intratumoral injection<br>* Other names: Telomelysin ™;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Limiting Toxicity | All adverse events will be graded according to Common Terminology Criteria for Adverse Events version 5.0 | From start of protocol treatment until 30 days after the completion of chemoradiation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse Events | Assessed using Common Terminology Criteria for Adverse Events version 5.0. Counts of all adverse events (AEs) by grade will be provided by treatment arm. Counts and frequencies will be provided for the worst grade AE experienced by the patient by treatment arm and within the subset of AEs related to treatment. No formal statistical testing will be performed on these summary data. | Up to 2 years | 
| Clinical Complete Response (cCR) | If one of the OBP-301 regimens is declared to be safe, the number of cCRs will be reported. No formal statistical testing will be performed on these summary data. | 6-8 weeks after completion of chemoradiation | 
| Progression-free Survival | If one of the OBP-301 regimens is declared to be safe, number of patients alive without progression will be reported. No formal statistical testing will be performed on these summary data. | Time from registration to progressive disease or death, whichever occurs first, assessed up to 2 years | 
| Overall Survival | If one of the OBP-301 regimens is declared to be safe, number of patients alive will be reported. No formal statistical testing will be performed on these summary data. | Time from registration to death, assessed up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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OBP-301, viral therapy