Safety and Feasibility of Irradiation and Nivolumab in Esophageal Cancer (INEC)

Prior treatment

• Previous treatment with radiotherapy towards volumes within the thoracic cavity
• Previous treatment with any PD-1 or PD-L1/2 inhibitor
• Hypersensitivity to the investigational product or any of the drug formula contents
• History of prior autoimmune disorders requiring systemic therapy (excluding Insulin or Thyroid replacement therapy)
• Participation in any other interventional clinical trial with an investigational product
• Known allergy, hypersensitivity, or contraindication to the investigational product Nivolumab, or the drugs paclitaxel and docetaxel used in the standard chemoradiotherapy protocols (Cohorts B and C) or any components used in their preparation or has a contraindication to taxane therapy.

Other illness

• History of HIV 1 /2, Hepatitis B or C infection
• History of prior malignancy within the last 5 years, excluding curatively treated basal cell or squamous cell carcinoma of the skin.
• Known history of brain metastases
• Need to use immunosuppressive drugs including, but not limited to: Glucocorticoids, everolimus, sirolimus, disease-modifying anti-rheumatic drugs (DMARDS)

Lab values

• History of Immunodeficiency disorders (i.e. immunoglobulin deficiency or white blood cell lineage depletion disorders)

Other

• Patients will be excluded from the study if they meet any of the following criteria:
• Esophageal stenting
• T4b if infiltration into the aorta or the trachea
• Positive pregnancy test (positive hCG blood test)
• Any reason why, in the opinion of the investigator, the patient should not participate.

• Three different cohorts of patients with esophageal cancer are studied.
• All of the following conditions must apply to the prospective patient at screening prior to receiving study treatment or any study related procedures (e.g.):
• Age \> 18 years
• Patients should have previously untreated histologically proven squamous cell carcinoma or adenocarcinoma of the esophagus or the gastroesophageal junction (GEJ), Siewert I, II or III
• Must be ambulatory with a performance status ECOG 0 or 1
• Adequate organ function based on clinical examination and lab values as defined in the below:
  • Absolute neutrophil count: ≥ 1,5 x109/L Platelets: ≥ 100 x109/L Hemoglobin: ≥ 9 x109/L Creatinine ≤ 1,5 upper limit normal (ULN) OR measured/calculated GFR≥60 mL/min Albumin ≥ 30 g/L Total bilirubin ≤ 1,5 ULN ASAT and ALAT ≤ 2,5 ULN, or ≤ 5 ULN for subjects with liver mets. International Normalized Ratio (INR) ≤ 1,5 ULN and Activated Partial Thromboplastin Time (TT) ≤ 1,5 ULN unless subject is receiving anticoagulant therapy. Such therapy (if indicated) should be converted to adequate therapy with low-molecular weight heparin such as Dalteparin before chemotherapy or treatment with IMP.
• Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 28 days prior to the start of study drug (screening phase). Women must not be breastfeeding.
• WOCBP should use highly effective adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for Nivolumab to undergo five half-lives) after the last dose of investigational drug. Adequate methods are described in Appendix I.
• Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception during the study treatment period and until 7 months after last dose of Nivolumab (see Appendix I).
• Signed informed consent and expected cooperation of the patients for the treatment and follow up must be obtained and documented according to ICH GCP, and national/local regulations.
• If Dysphagia score \>2, a nasogastric feeding tube should be inserted during the aid of gastroscopy, and nasogastric tube feeding started before radiotherapy.
• In addition, specific criteria are defined for the three different patient cohorts below:
  • Specific inclusion criteria - Cohort A
• Eligible for palliative fractionated radiotherapy of the esophageal- or gastroesophageal cancer as determined by the multidisciplinary team (MDT) meeting.
• Expected survival \>3 months
• Not bulky disease, i.e. palliative radiotherapy towards the primary tumor is intended to palliate dysphagia and/or pain and systemic treatment could be delayed to AFTER protocol therapy if possible.
  • Specific inclusion criteria - Cohort B
• Eligible for definitive chemoradiation of localized but inoperable esophageal- or gastroesophageal cancer as determined by the multidisciplinary team (MDT) meeting.
• Regional disease, i.e. no metastasis outside the radiation field (PTV).
• Considered candidate/ able to adhere to the intended chemoradiotherapy
  • Specific inclusion criteria - Cohort C
• Eligible for neoadjuvant chemoradiotherapy and surgery of the esophageal- or gastroesophageal cancer as determined by the multidisciplinary team (MDT) meeting.
• Regional disease, i.e. no metastasis outside the radiation field (PTV).
• Considered candidate and able to adhere to the intended neoadjuvant chemoradiotherapy and planned surgery.