The main objective of the trial is to assess the feasibility and the safety of the addition
of immunotherapy with PD-1 antibody nivolumab +/- CTLA-4 antibody ipilimumab to concomitant
chemoradiation therapy (CRT) in inoperable patients with early or locally advanced
oesophageal cancer and to select the more promising experimental arm among the two possible
combinations in terms of activity (based on progression free survival (PFS) at 12 months
according to RECIST 1.1) for further evaluation in a phase III trial.
The secondary objectives will aim to evaluate progression-free survival, failure-free
survival and overall survival and pattern of progression (including incidence of distance
metastasis).
Inclusion Criteria:
- Histologically proven oesophageal squamous cell carcinoma or adenocarcinoma
- Both early stage and locally advanced tumor patients (according to TNM staging version
8):
- T1, N1-3, M0 after complete work-up
- T2, N0-3, M0 after complete work-up
- T3, N0-3, M0
- Patient eligible for definitive chemoradiation and not considered for primary surgery
after multidisciplinary meeting decision or patient refuses to undergo surgery
- Subject must be previously untreated with systemic treatment given as primary therapy
for advanced or metastatic disease
- At least one measurable lesion by CT scan or MRI based on RECIST version 1.1 with
radiographic tumor assessment performed within 28 days prior to randomization
- Availability of adequate tissue in terms of quality and quantity for
immunohistochemical staining for PDL-1
- WHO performance status 0 or 1
- Adequate organ function within 14 days prior to randomization
Exclusion Criteria:
- Cancer of cervical oesophagus (15 to 19 cm from dental ridge)
- Known Her2 positive adenocarcinoma
- Weight loss > 15 % over the last 3 months without improvement after nutritional
support
- Patient with cardiac dysfunction e.g. symptomatic congestive heart failure,
uncontrolled hypertension
- Known history of positive test for human immunodeficiency virus (HIV) or known
acquired immunodeficiency syndrome (AIDS), hepatitis B or hepatitis C.
- Any prior treatment for advanced disease including treatment with an anti-Programmed
Death receptor-1 (PD-1), anti-Programmed Death-1 ligand-1 (PD-L1), anti-PD-L2,
anti-cytotoxic T lymphocyte associated antigen-4 (anti-CTLA-4) antibody or any other
antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.
- Live vaccines within 30 days prior to the first dose of study therapy. Examples of
live vaccines include, but are not limited to the following: measles, mumps, rubella,
chicken pox, yellow fever, H1N1 flu, rabies, BCG, and typhoid vaccine
- History of hypersensitivity to study drugs or any excipient (refer to SmPCs for
ipilimumab, nivolumab, 5-FU and oxaliplatin)
- Current participation or treatment with an investigational agent or use of an
investigational agent within 4 weeks of the first dose of study treatment
- Serious comorbidity or life expectancy less than one year
- Contraindication to chemoradiation therapy
- Treatment history of radiotherapy
- Child-Pugh B/C and patients with history of acute or chronic pancreatitis
- Patient with Type I diabetes mellitus, or skin disorders
- Known severe systemic autoimmune disease affecting the lungs or the bowel
- Known contraindication to CT scans with IV contrast
- Chronic use of immunosuppressive agents and/or systemic corticosteroids or any use in
the last 15 days prior to enrollment
- Active autoimmune disease that has required systemic treatment in past 2 years
- Autoimmune paraneoplastic syndrome requiring immunosuppressive or dedicated treatment
- History of any other hematologic or primary solid tumor malignancy, unless in
remission for at least 5 years.
