Study of Anti-PD-L1 in Combination With Chemo(Radio)Therapy for Resectable Esophageal Squamous Cell Carcinoma

Study Overview
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Brief Summary
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This is a study to evaluate the efficacy and safety of preoperative treatment with durvalumab combined with neoajuvant therapy (carboplatin, paclitaxel with/without radiation) in locally advanced resectable oesophageal squamous carcinoma.

Detailed Description
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The primary objective of the study is to assess the tumor response (by irRECIST) and pathological response of preoperative treatment with durvalumab combined with neoadjuvant therapy (carboplatin, paclitaxel with/without radiation). Secondary objectives are: To assess completion of treatment with durvalumab combined with chemotherapy with/without radiation treatment. To assess toxicities of durvalumab in combination with chemoradiation. [Time Frame: up to 1 year] To assess completion of chemotherapy with/without radiation treatment. To assess withdrawal rate from surgery. To assess delay rate from surgery. To assess R0 resection rate. To assess post-operative complications. Progression Free Survival. [ Time Frame: up to 24 months ] Overall Survival. [ Time Frame: up to 24 months ]

Official Title
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A Prospective, Randomized Controlled Study to Evaluate the Efficacy and Safety of Durvalumab Combined With Neoadjuvant Therapy in Patients With Local Advanced Esophageal Squamous Cell Carcinoma

Conditions
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Esophageal Squamous Cell Carcinoma

Intervention / Treatment
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* Drug: Durvalumab
* Drug: Carboplatin
* Drug: Paclitaxel
* Radiation: Radiotherapy 23 x 1.8 Gy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically proven squamous cell carcinoma of the esophagus. Surgical resectable (T3 or T4b, N0 or N+, M0), as determined by Endoscopic Ultra Sound (EUS),PET/CT, Esophageal MRI and enhanced CT scan of neck, thorax and abdomen. Tumor length longitudinal ≤ 10 cm; if larger than 10 cm, inclusion should be discussed with the principal investigator. 18≤Age≤75. Tumor does not involve gastro-esophageal junction. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Adequate hematological, renal and hepatic functions defined as: neutrophiles ≥ 1.5 x 109/L platelets ≥ 100 x 109/L alanine transaminase≤2 x upper normal limit hemoglobin ≥ 5.6 mmol total bilirubin ≤ 1.5 x upper normal limit creatinine clearance (Cockroft) ≥60 ml/min Written, voluntary informed consent. Exclusion Criteria: Past or current history of malignancy other than entry diagnosis interfering with prognosis of esophageal cancer. T1, T2 tumors or in situ carcinoma. metastatic oesophageal cancer. Pregnancy (positive serum pregnancy test), planning to become pregnant, and lactation. Previous chemotherapy, radiotherapy, and/or treatment with checkpoint inhibitors. Clinically significant cardiovascular disease (including myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) precluding major surgery. Pulmonary fibrosis and/or severely impaired lung function precluding major surgery. Pre-existing motor or sensory neurotoxicity greater than WHO grade 1. Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (>10 mg/day prednisone or equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. Dementia or altered mental status that would prohibit the understanding and giving of informed consent Serious underlying medical condition which would impair the ability of the patient to receive the planned treatment, including prior allergic reactions to drugs containing Cremophor, such as teniposide or cyclosporine. Has an active infection requiring systemic therapy which has not resolved 3 days (simple infection such as cystitis) to 7 days (severe infection such as pyelonephritis) prior to the first dose of trial treatment. Has a diagnosis of acute or chronic hepatitis B, hepatitis C, known immunodeficiency or human immunodeficiency virus (HIV). Patients with prior allogeneic stem cell or solid organ transplantation.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: durvalumab and neoadjuvant therapy<br>durvalumab 1500mg i.v. day 1-22-43-64 Carboplatin AUC = 4-5 i.v day 1-22-43-64 Paclitaxel 75 mg/m2 i.v day 1-22-43-64 with/without Radiotherapy 23 x 1.8 Gy | Drug: Durvalumab<br>* Durvalumab 1500mg i.v. day 1-22-43-64<br>Drug: Carboplatin<br>* Chemotherapy<br>* Other names: Chemotherapy;Drug: Paclitaxel<br>* Chemotherapy<br>* Other names: Chemotherapy;Radiation: Radiotherapy 23 x 1.8 Gy<br>* Radiotherapy 23 x 1.8 Gy<br>* Other names: Radiotherapy;|
| Placebo Comparator: normal saline and neoadjuvant therapy<br>normal saline 500ml i.v. day 1-22-43-64 Carboplatin AUC = 4-5 i.v day 1-22-43-64 Paclitaxel 75 mg/m2 i.v day 1-22-43-64 with/without Radiotherapy 23 x 1.8 Gy | Drug: Carboplatin<br>* Chemotherapy<br>* Other names: Chemotherapy;Drug: Paclitaxel<br>* Chemotherapy<br>* Other names: Chemotherapy;Radiation: Radiotherapy 23 x 1.8 Gy<br>* Radiotherapy 23 x 1.8 Gy<br>* Other names: Radiotherapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| tumor response | assess the tumor response (by irRECIST) of preoperative treatment with durvalumab combined with neoadjuvant therapy | up to 12 months | 
| pathological response | assess the pathological response (by CAP classification) of preoperative treatment with durvalumab combined with neoadjuvant therapy | up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage completion of treatment with durvalumab combined with chemotherapy with/without radiation treatment | Percentage completion of treatment with durvalumab combined with chemotherapy with/without radiation treatment | up to 3 months | 
| Incidence and severity of toxicity | Incidence and severity of toxicity defined to CTCAE v4.03 and Radiation Oncology Group (RTOG) criteria | up to 12 months | 
| Percentage completion of chemotherapy with/without radiation treatment | Percentage completion of chemotherapy with/without radiation treatment | up to 3 months | 
| Percentage withdrawal rate from surgery due to durvalumab related complications | Percentage withdrawal rate from surgery due to durvalumab related complications | up to 3 months | 
| Percentage delay of surgery due to durvalumab related complications | Percentage delay of surgery due to durvalumab related complications | up to 3 months | 
| R0 resection rate | R0 resection rate | up to 3 months | 
| Incidence and severity of post-operative complications to the Dindo classification | Incidence and severity of post-operative complications to the Dindo classification | up to 3 months | 
| Progression free survival | Progression free survival | up to 24 months | 
| Overall survival | Overall survival | up to 24 months |