The purpose of this Phase I study is to determine the recommended phase 2 dose (RP2D) and safety profile of NBTXR3 activated by radiation therapy with concurrent chemotherapy for the treatment of patients with esophageal adenocarcinoma. NBTXR3 is a drug that when activated by radiation therapy, may cause targeted destruction of cancer cells. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Chemotherapy drugs, such as oxaliplatin, fluorouracil, capecitabine, docetaxel, paclitaxel, and carboplatin, 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. Giving NBTXR3 activated by radiation therapy with concurrent chemotherapy may help control the disease.

PRIMARY OBJECTIVE:

I. To determine the recommended phase II dose (RP2D) of hafnium oxide-containing nanoparticles NBTXR3 (NBTXR3) activated by radiotherapy with concurrent chemotherapy, per standard of care, for treatment naive patients with adenocarcinoma of the esophagus.

SECONDARY OBJECTIVES:

I. To evaluate the safety and feasibility of radiation with NBTXR3 in patients with adenocarcinoma of the esophagus.

II. To evaluate the anti-tumor response of chemoradiation with NBTXR3 in patients with adenocarcinoma of the esophagus.

III. To evaluate time-to-event outcomes after chemoradiation with NBTXR3 in patients with adenocarcinoma of the esophagus.

EXPLORATORY OBJECTIVES:

I. To evaluate the body kinetic profile of intratumorally/intranodally injected NBTXR3.

II. To evaluate time to event outcomes for patients with clinical staging of locally advanced, unresectable disease.

III. To evaluate surgical outcomes in patients who undergo surgery after study treatment.

IV. To evaluate radiomic measurements with outcomes. V. To assess immune-related biomarkers of response.

OUTLINE: This is a dose-escalation study of NBTXR3.

Patients receive NBTXR3 intratumorally (IT) or intranodally (IN) on day 1. Beginning day 15, patients undergo intensity-modulated radiation therapy (IMRT) 5 days per week for 6 weeks for a total of 28 fractions in the absence of disease progression or unacceptable toxicity. Beginning on day 15, concurrent with IMRT, patients receive a chemotherapy regimen consisting of either fluorouracil and oxaliplatin with or without leucovorin, oxaliplatin and capecitabine, docetaxel and fluorouracil with or without leucovorin, docetaxel and paclitaxel, or carboplatin and paclitaxel per physician discretion.

After completion of study treatment, patients are followed up every 3 months for 1 year.

Inclusion Criteria:

• Biopsy proven adenocarcinoma of the cervical or thoracic esophagus or gastroesophageal junction

• Adenocarcinoma of the esophagus stages II-III allowed

• Medically able to receive chemoradiation. Following chemotherapy regimens are allowed:

  • Oxaliplatin and fluorouracil (5-FU) or capecitabine
  • Docetaxel and/or 5-FU or paclitaxel
  • Carboplatin and paclitaxel

• Amenable to undergo the endoscopic ultrasound (EUS) guided injection of NBTXR3 as determined by the investigator or treating physician

  • Patients with lesions for which the EUS scope is not able to traverse the tumor are allowed on this trial as long as an injection can be performed as per treating physician's discretion

• Has at least 1 and up to 4 target lesion(s) in the esophagus that are measurable on cross sectional imaging and repeated measurements (via Response Evaluation Criteria in Solid Tumors [RECIST] version [v] 1.1) at the same anatomical location should be achievable

  • Local nodal disease around the esophagus allowed
  • Nodal target lesions must be >= 15 mm (short axis) based on computed tomography (CT) (slice thickness of 5 mm or less) or magnetic resonance imaging (MRI)

• Eastern Cooperative Oncology Group (ECOG) performance status 0-2

• Hemoglobin >= 8.0 g/dL

• Absolute neutrophil count (ANC) >= 1,500/mm^3

• Platelet count >= 100,000/mm^3

• Creatinine =< 1.5 x upper limit of normal (ULN)

• Calculated (Calc.) creatinine clearance > 30 mL/min

• Glomerular filtration ratio > 40 mL/min per 1.73 m^2

• Total bilirubin =< 2.0 mg/dL

• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN)

• Negative urine or serum pregnancy test =< 7 days of NBTXR3 injection in all female participants of child-bearing potential

• Signed informed consent form (ICF) indicating that participant understands the purpose of, and procedures required for, the study and is willing to participate in the study

Exclusion Criteria:

• Prior radiation or any therapy for the treatment of esophageal cancer

• Prior surgical resection of esophageal tumor

• Esophageal cancer with radiographic evidence of metastases at screening

• At screening, past medical history of:

  • Esophageal fistula
  • Tracheoesophageal fistula
  • Siewert type III tumors

• Evidence of bulky disease and/or abutment of tumor above the carina that may result in tracheoesophageal fistulas as determined by the investigator or treating physician

  • Tumors above the carina without defacement of the fat plane between tumor and the airway are allowed

• Known uncontrolled (grade >= 2) or active esophageal or gastric ulcer disease within 28 days of enrollment

• Known contraindication to iodine-based or gadolinium-based intravenous (IV) contrast

• Active malignancy, in addition to esophageal cancer except for basal cell carcinoma of the skin or non-metastatic low risk prostate cancer definitively treated and relapse free within at least 3 months from time of screening

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, renal failure, cardiac arrhythmia, or psychiatric illness that would limit compliance with treatment

• Known active, uncontrolled (high viral load) human immunodeficiency virus (HIV) or hepatitis B or hepatitis C infection

• Female patients who are pregnant or breastfeeding

• Women of child-bearing potential and their male partners who are unwilling or unable to use an acceptable method of birth control to avoid pregnancy for the entire study period. Acceptable methods of contraception are those that, alone or in combination, result in a failure rate of < 1% per year when used consistently and correctly

• Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (e.g., compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments