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

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

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.

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.

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 0-2 within 14 days prior to registration

• Adequate hematologic function within 14 days prior to registration defined as follows 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)

• Adequate renal function within 14 days prior to registration defined as follows 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)

• AST/ALT ≤ 2.5 x ULN

• Patients for whom non-operative management is a viable option in the opinion of a thoracic surgeon and/or multidisciplinary team and are candidates for chemoradiation; this does not preclude patients from receiving surgery after chemoradiation if felt to me medically indicated;

• 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 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