A Feasibility Trial of Nivolumab With Neoadjuvant CF or DCF Therapy for Locally Advanced Esophageal Carcinoma

Study Overview
=================
Brief Summary
-----------------
The main purpose of this study is to evaluate the safety of the neoadjuvant therapy, nivolumab with CF (5-FU, CDDP) or nivolumab with DCF (5-FU, CDDP, DTX), for locally advanced esophageal carcinoma.

Official Title
-----------------
A Feasibility Trial of Nivolumab With Neoadjuvant CF or DCF Therapy for Locally Advanced Esophageal Carcinoma FRONTiER Trial

Conditions
-----------------
Locally Advanced Esophageal Squamous Cell Carcinoma

Intervention / Treatment
-----------------
* Biological: Nivolumab
* Drug: 5-FU
* Drug: CDDP
* Drug: DTX


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: Endoscopic biopsy of esophageal primary lesion histologically diagnosed as squamous cell carcinoma, adenosquamous carcinoma, or basal cell carcinoma All esophageal cancer lesions are localized in the thoracic esophagus Patients are classified as clinical stage T1N1-3M0 or T2-3N0-3M0 in the UICC-TNM classification 8th edition The age is over 20 years old and under 75 on the enrollment date PS 0-1 With or without measurable lesions Patients who have no medical history of treatment for esophageal cancer Patients who have no medical history of chemotherapy, radiotherapy, and endocrine therapy, including treatment for other types of cancer The results of laboratory tests within 14 days before enrollment meet the inclusion criteria Esophageal cancer radical surgery (R0) by open-chest surgery (or thoracoscopic surgery) and laparotomy (or laparoscopic surgery) is judged possible Patients who have no complication or history of thyroid dysfunction Patients who have no complication or history of autoimmune disease Patients who don't have treatment with systemic corticosteroids (dose of 10mg/day over in prednisolone equivalent) or immunosuppressants within 14 days before enrollment Patients who have no complication or history of pneumonitis or pulmonary fibrosis which had been diagnosed by imaging tests or physical examination For females, who have agreed with contraception from start of investigational drug administration to 5 months after last dose of an investigational drug. For males who have agreed with contraception from start of investigational drug administration to 7 months after last dose of an investigational drug. Obtained written informed consent from patients Exclusion criteria: Patients who have active multiple cancers Patients who have an infectious disease that is active and need the systemic treatment Positive with HBs antigen, HCV-RNA or anti-HIV antibody, or anti-HTLV-1 antibody tests Negative with HBs antigen test and positive with anti HBs antibody or anti HBc antibody tests, and positive with HBV-DNA quantitative test Pregnant, suspected pregnant, or lactating Patients who have Psycosis or psychiatric symptoms are judged inappropriate for participation in the trial Patients who need the treatment with continued use of flucytosine, phenytoin, or warfarin potassium Patients who have a medical history of allergy to iodine Patients who have hypersensitivity to docetaxel, cisplatin, and drug-containing polysorbate 80 Patients who have a complication or a history of highly sensitive reactions to antibody formulations Even if insulin or oral hypoglycemic agent is continued use, the result of HbA1c test is 6.5% or more in JDS or 6.9% or more in NGSP Patients who have advanced pulmonary emphysema, which is observed by pulmonary function test or CT test Patients who have uncontrollable hypertension Patients who have unstable angina or a medical history of myocardial infarction within 6 months before enrollment Patients who have diverticulitis or symptomatic peptic ulcer disease Patients who have a history of transplantation therapy, such as hematopoietic stem cell transplantation Patients who have a medical history of treatment with an anti-PD-1 antibody, anti-PD-L1 antibody, anti-PD-L2 antibody, anti-CD137 antibody, anti-CTLA-4 antibody, or any other antibody for inhibition or modulation of T cell costimulatory pathway or cancer vaccine.

Ages Eligible for Study
-----------------
Minimum Age: 20 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A<br>Nivolumab: 360 mg, every 3 week 5-FU: 800 mg/m^2, every 3 week CDDP: 80 mg/m^2, every 3 week  | Biological: Nivolumab<br>* 240 mg or 360 mg<br>* Other names: ONO-4538;Drug: 5-FU<br>* 750 or 800 mg^2<br>* Other names: 5-Fluorouracil;Drug: CDDP<br>* 70 or 80 mg/m^2<br>* Other names: Cisplatin;|
| Experimental: Cohort B<br>Nivolumab: 240 mg lead-in followed by 360 mg, every 3 week 5-FU: 800 mg/m^2, every 3 week CDDP: 80 mg/m^2, every 3 week  | Biological: Nivolumab<br>* 240 mg or 360 mg<br>* Other names: ONO-4538;Drug: 5-FU<br>* 750 or 800 mg^2<br>* Other names: 5-Fluorouracil;Drug: CDDP<br>* 70 or 80 mg/m^2<br>* Other names: Cisplatin;|
| Experimental: Cohort C<br>Nivolumab: 360 mg, every 3 week 5-FU: 750 mg/m^2, every 3 week CDDP: 70 mg/m^2, every 3 week DTX: 70mg/m^2, every 3 weeks | Biological: Nivolumab<br>* 240 mg or 360 mg<br>* Other names: ONO-4538;Drug: 5-FU<br>* 750 or 800 mg^2<br>* Other names: 5-Fluorouracil;Drug: CDDP<br>* 70 or 80 mg/m^2<br>* Other names: Cisplatin;Drug: DTX<br>* 70 mg/m^2<br>* Other names: Docetaxel;|
| Experimental: Cohort D<br>Nivolumab: 240 mg lead-in followed by 360 mg, every 3 week 5-FU: 750 mg/m^2, every 3 week CDDP: 70 mg/m^2, every 3 week DTX: 70mg/m^2, every 3 weeks | Biological: Nivolumab<br>* 240 mg or 360 mg<br>* Other names: ONO-4538;Drug: 5-FU<br>* 750 or 800 mg^2<br>* Other names: 5-Fluorouracil;Drug: CDDP<br>* 70 or 80 mg/m^2<br>* Other names: Cisplatin;Drug: DTX<br>* 70 mg/m^2<br>* Other names: Docetaxel;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of participants with dose limiting toxicities (DLTs) | To evaluate the safety of combination chemotherapy with nivolumab as neoadjuvant Tx | from initial dose to 30 post-operative days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate (RR): percentage of participants with with a best response of CR or PR | To evaluate the efficacy of combination chemotherapy with nivolumab as neoadjuvant Tx | from baseline to date of disease progression, approximately 24 months | 
| Pathological complete response rate | To evaluate the efficacy of combination chemotherapy with nivolumab as neoadjuvant Tx | from baseline to operation, average of 10 weeks after initial dose | 
| Radical resection rate | To evaluate the efficacy of combination chemotherapy with nivolumab as neoadjuvant Tx | at operation, average of 10 weeks after initial dose | 
| Treatment completion rate | To evaluate the efficacy of combination chemotherapy with nivolumab as neoadjuvant Tx | from baseline to operation, average of 10 weeks after initial dose | 
| Adverse event (AE) expression rate | To evaluate the safety of combination chemotherapy with nivolumab as neoadjuvant Tx | up to 30 postoperative days | 
| Progression-free survival (PFS) | To evaluate the efficacy of combination chemotherapy with nivolumab as neoadjuvant Tx | from baseline to date of disease progression or death, approximately 24 month | 
| Overall survival (OS) | To evaluate the efficacy of combination chemotherapy with nivolumab as neoadjuvant Tx | from baseline to date of death, approximately 24 month | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Esophageal squamous cell carcinoma, Neoadjuvant chemotherapy, Nivolumab, JCOG