Combination of Chemoradiation With Immunotherapy in Inoperable œsophageal Cancer

Study Overview
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Brief Summary
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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).

Official Title
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Phase II Trial in Inoperable œsophageal Cancer Evaluating the Feasibility of the Combination of Definitive Chemoradiation With the Immune Checkpoint Blockers Nivolumab +/- Ipilimumab

Conditions
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Inoperable œsophageal Cancer

Intervention / Treatment
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* Drug: Nivolumab
* Drug: Ipilimumab
* Other: Chemoradiation


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: Chemoradiation + Nivolumab<br>All patients will receive standard fractionation radiation therapy (RT) scheme: 50Gy in 25 fractions over 5 weeks (i.e. 2Gy per fraction), concurrently with 3 cycles of 2 weeks of FOLFOX followed by 3 cycles of 2 weeks of FOLFOX without RT. Induction phase: Nivolumab IV 240 mg on days 1, 15 and 29 followed by a maintenance phase (to start on day 43) of Nivolumab IV 240 mg q2 weekly for up to 1 year. | Drug: Nivolumab<br>* Induction phase: Nivolumab IV 240 mg on days 1, 15 and 29 followed by a maintenance phase (to start on day 43) of Nivolumab IV 240 mg q2 weekly for up to 1 year.<br>Other: Chemoradiation<br>* All patients will receive standard fractionation radiation therapy (RT) scheme: 50Gy in 25 fractions over 5 weeks (i.e. 2Gy per fraction), concurrently with 3 cycles of 2 weeks of FOLFOX (oxaliplatin 85 mg/m2, leucovorin 200 mg/m2, bolus fluorouracil 400 mg/m2, and infusional fluorouracil 1600 mg/m2 over 48 h), followed by 3 cycles of 2 weeks of FOLFOX without RT.<br>|
| Experimental: Arm B: Chemoradiation + Nivolumab + Ipilimumab<br>Same as arm A + induction phase: Ipilimumab IV 1 mg/kg on day 1 followed by a maintenance phase (to start on day 43) of Ipilimumab IV 1 mg/kg q6 weekly for up to 1 year | Drug: Nivolumab<br>* Induction phase: Nivolumab IV 240 mg on days 1, 15 and 29 followed by a maintenance phase (to start on day 43) of Nivolumab IV 240 mg q2 weekly for up to 1 year.<br>Drug: Ipilimumab<br>* Induction phase: Ipilimumab IV 1 mg/kg on day 1 followed by a maintenance phase (to start on day 43) of Ipilimumab IV 1 mg/kg q6 weekly for up to 1 year.<br>Other: Chemoradiation<br>* All patients will receive standard fractionation radiation therapy (RT) scheme: 50Gy in 25 fractions over 5 weeks (i.e. 2Gy per fraction), concurrently with 3 cycles of 2 weeks of FOLFOX (oxaliplatin 85 mg/m2, leucovorin 200 mg/m2, bolus fluorouracil 400 mg/m2, and infusional fluorouracil 1600 mg/m2 over 48 h), followed by 3 cycles of 2 weeks of FOLFOX without RT.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 12-Month Progression-free survival using RECIST 1.1 | The analysis of the 12-Month Progression-free survival rate (PFS-12) will be done when all patients achieved at least 15 months follow-up (12 months for the primary endpoint plus 100 days after the end of the protocol treatment). | 3.8 years from first patient in | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best overall response according to RECIST 1.1 |  | 3.8 years from first patient in | 
| Pattern of first cause of progression (either local relapse/progression,either regional relapse/progression, either distant metastasis) |  | 3.8 years from first patient in | 
| Progression-free survival using RECIST 1.1 |  | 3.8 years from first patient in | 
| Failure-free survival |  | 3.8 years from first patient in | 
| Overall survival |  | 3.8 years from first patient in | 
| Percentage of patients receiving the planned chemoradiation |  | 3.8 years from first patient in | 
| Relative dose intensity of oxaliplatinum | The dose intensity and relative dose intensity of treatments will be presented by drug and by treatment arm using median, range and interquartile range. | 3.8 years from first patient in | 
| Relative dose intensity of 5FU | The dose intensity and relative dose intensity of treatments will be presented by drug and by treatment arm using median, range and interquartile range. | 3.8 years from first patient in | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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œsophageal cancer nivolumab ipilimumab