Immune Checkpoint Therapy With Nivolumab Esophageal Squamous Cell Carcinoma

Inclusion Criteria:

- Histologically or cytologically confirmed, treatment-naive esophageal squamous cell
carcinoma

- Previously obtained archival tumor tissue, or tissue obtained by endoscopically guided
core biopsy at screening

- TanyN1-3 or T3-4 N0as determined by EUS and PET/CT. All palpable or CT/PET visible
lymph nodes outside the usual surgical field must be biopsy-proven negative for
cancer.

- All patients must have locoregional staging determined by endoscopic ultrasound (EUS)
if technically feasible. Endoscopy reports or subsequent GI clinic note should clearly
state both the T and N stage.

- All patients must have initial PET/CT scans to document no evidence of metastatic or
unresectable squamous cell cancer

- All patients with tumors involving the thoracic esophagus must undergo bronchoscopy to
document the absence of a fistula No known contraindication to the use of taxanes or
platinum compounds.

- No history of severe hypersensitivity reaction to Cremophor® EL.

- Patients who are ≥ 18 years old are eligible for this study. Neither specific gender
distribution, nor specific racial or ethnic origins are necessary for enrollment in
this study.

- Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1

- A patient must be capable of giving informed consent or have an acceptable surrogate
capable of giving consent on the subject's behalf

- Deemed a suitable candidate for esophagectomy by the treating surgeon as documented in
a pre-operative assessment visit per standard practice at each participating
institution.

- Deemed a suitable candidate for radiation therapy by the treating radiation oncologist
as documented in a standard pretreatment visit per standard practice at each
participating institution.

- Patient must be non-pregnant and non-nursing. Women of child bearing potential (WOCBP)
must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or
equivalent units of HCG) within 72 hours prior to C1D1.

- Screening Laboratory Values must meet the following criteria and should be obtained
within 14 days prior to C1D1 (see Table 1 below)

- Patients with a positive Hepatitis B core antibody (HBVcAb) must have negative viral
load measurement; Patients with HBV core positive, must have negative viral load
measurements

- Screening Laboratory Values must meet the following criteria and should be obtained
within 14 days prior to randomization/registration (see Table 1 below) Test Acceptable
Result WBC ≥ 2000/µL Neutrophils ≥ 1500/µL Platelets ≥ 100,000 /µL Hemoglobin > 9.0
g/dL Serum Creatinine ≤ 1.5 x ULN OR Creatinine Clearance (CrCl)* ≥ 40 mL/min AST ≤ 3
x ULN ALT ≤ 3 x ULN Total Bilirubin** ≤ 1.5 x ULN

Oxygen Saturation (O2 Sat.) ≥92% on ambient air Hepatitis B status HBV Surface Antigen
Negative HBV Surface Antibody Positive or Negative HBV Core Antibody Negative Hepatitis C
status Anti-HCV Total Antibody Negative HCV RNA analysis Negative HIV status Rapid HIV 1/2
Antibodies Negative *Creatinine Clearance Calculated using the Cockcroft-Gault formula

Female CrCl = (140- age in years) x weight in kg x 0.85 72 x serum creatinine in mg/dL

Male CrCl = (140- age in years) x weight in kg x 1.00 72 x serum creatinine in mg/dL

**Total Bilirubin ≤ 1.5 x ULN, except subjects with Gilbert Syndrome, who can have total
bilirubin < 3.0 mg/dL

Exclusion Criteria:

- T1-2 N0 as determined by EUS and PET/CT.

- Pregnant or lactating women

- Active or prior documented autoimmune or inflammatory disorders including but not
limited to inflammatory bowel disease; systemic lupus erythematosus; type I diabetes
mellitus; Wegener syndrome [granulomatosis with polyangiitis]; myasthenia gravis;
Graves' disease; rheumatoid arthritis, hypophysitis, uveitis) within the past 3 years
prior to the start of treatment. The following are exceptions to this criterion:

- Subjects with vitiligo or alopecia

- Subjects with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone
replacement or psoriasis not requiring systemic treatment

- History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced
pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening
chest Computed Tomography (CT) scan

- The use of immunosuppressive medication within 28 days prior to the first dose of
nivolumab. The following are exceptions to this criterion:

- Intranasal, topical, inhaled corticosteroids or local steroid injections (e.g.
intra-articular injection)

- Systemic corticosteroids at physiologic doses ≤10 mg/day of prednisone or equivalent

- Steroids as premedication for hypersensitivity reactions (e.g. CT scan premedication

- Positive test for Human Immunodeficiency Virus (HIV) or known acquired
immunodeficiency syndrome (AIDS)

- Active Hepatitis B or Hepatitis C (defined as positive-HBV surface antigen or
detectable HCV-antibody) indicating acute or chronic infection. Patients with a
positive Hepatitis B core antibody (HBVcAb) must have negative viral load measurement.

- Prior treatment with any immunotherapy

- Any other factors, including psychiatric or social, that in the opinion of the
treating physician makes the patient an inappropriate candidate for a study.

- Patients are excluded if they have active brain metastases or leptomeningeal
metastases. Subjects with brain metastases are eligible if metastases have been
treated and there is no magnetic resonance imaging (MRI) evidence of progression for
[lowest minimum is 4 weeks or more] after treatment is complete and within 28 days
prior to the first dose of nivolumab administration. There must also be no ESCC
Nivolumab requirement for immunosuppressive doses of systemic corticosteroids (> 10
mg/day prednisone equivalents) for at least 2 weeks prior to study drug
administration.

- Patients should be excluded if they have an active, known or suspected autoimmune
disease. Subjects are permitted to enroll if they have vitiligo, residual
hypothyroidism due to autoimmune condition only requiring hormone replacement,
psoriasis not requiring systemic treatment, or conditions not expected to recur in the
absence of an external trigger

- Patients should be excluded if they have a condition requiring systemic treatment with
either corticosteroids (> 10 mg daily prednisone equivalents) or other
immunosuppressive medications within 14 days of study drug administration. Inhaled or
topical steroids and adrenal replacement doses < 10 mg daily prednisone equivalents
are permitted in the absence of active autoimmune disease.

- As there is potential for hepatic toxicity with nivolumab or nivolumab non-drugs with
a predisposition to hepatoxicity should be used with caution in patients treated with
nivolumab-containing regimen.

- Patients with a history of allergy to the study drug components are excluded.

- No herbal supplements are allowed in this protocol.