Study of Anti-PD-L1 in Combination With Chemo(Radio)Therapy for Oesophageal Cancer

Study Overview
=================
Brief Summary
-----------------
This is an open-label, Phase 1/2 study to evaluate the safety of durvalumab (MEDI4736) in combination with oxaliplatin/capecitabine chemotherapy in metastatic/locally advanced oesophageal cancer (OC) and with neoadjuvant chemo(radio)therapy before surgery in operable OC. The immunotherapy will be given for a 4-week period before starting the standard chemo(radio)therapy, continuing durvalumab treatment once the chemotherapy starts. The study will include 2 phases, a safety run-in Phase 1 (Cohorts A1 and A2) and an expansion Phase 2 (Cohorts B, C, C-FLOT, D).

Official Title
-----------------
Phase 1/2 Study of Anti-PD-L1 in Combination With Chemo(Radio)Therapy for Oesophageal Cancer

Conditions
-----------------
Esophageal Cancer

Intervention / Treatment
-----------------
* Drug: Durvalumab
* Drug: Tremelimumab
* Drug: Oxaliplatin
* Drug: Capecitabine
* Radiation: Radiotherapy
* Drug: Paclitaxel
* Drug: Carboplatin
* Drug: 5-fluorouracil (5-FU)
* Drug: Leucovorin
* Drug: docetaxel


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histological diagnosis of oesophageal or gastrooesophageal cancer and have not received prior chemotherapy Cohorts A and B - metastatic/locally advanced cancer Cohorts C/C-FLOT and D/D2 - deemed suitable for surgery with curative intent Anticipated lifespan greater than 4 months Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. At the time of day 1 of the study, subjects with brain metastases must be asymptomatic for at least 4 weeks and: at least 8 weeks without tumour progression after any whole brain radiotherapy at least 4 weeks since craniotomy and resection or stereotactic radiosurgery at least 3 weeks without new brain metastases as evidenced by MRI/CT Adequate normal organ and marrow function. Laboratory parameters for vital functions should be in the normal range. Laboratory abnormalities that are not clinically significant are generally permitted. Written informed consent obtained from the subject; subject been informed of other treatment options, and able to comply with study requirements Age 18 years or older. Exclusion Criteria Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site). Previous enrollment in the present study. Participation in another clinical study with an investigational product during the last 4 weeks Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 electrocardiograms (ECGs) using Fredericia's Correction Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis) History of allogeneic organ transplant Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses including any subject known to have evidence of acute or chronic hepatitis B, hepatitis C, known immunodeficiency or human immunodeficiency virus (HIV), or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent Known history of previous clinical diagnosis of tuberculosis History of pneumonitis or interstitial lung disease.

Ages Eligible for Study
-----------------
Minimum Age: 18 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: Durvalumab and standard of care chemotherapy<br>Phase 1 will evaluate the safety of durvalumab alone (Cohort A1) administered before chemotherapy (oxaliplatin + capecitabine) in subjects with metastatic or locally advanced Oesophageal Cancer + Chemotherapy | Drug: Durvalumab<br> <br> * Other names: Imfinzi;Drug: Oxaliplatin<br>* IV administered Chemotherapy<br>* Other names: Eloxatin;Drug: Capecitabine<br>* orally-administered chemotherapy<br>* Other names: Xeloda;|
| Experimental: Durvalumab + tremelimumab and standard of care chemotherapy<br>Dose-escalation for Tremelimumab 37.5mg - 75mg + Durvalumab 750mg + Chemotherapy (Cohort A2). | Drug: Durvalumab<br> <br> * Other names: Imfinzi;Drug: Tremelimumab<br> <br> Drug: Oxaliplatin<br>* IV administered Chemotherapy<br>* Other names: Eloxatin;Drug: Capecitabine<br>* orally-administered chemotherapy<br>* Other names: Xeloda;|
| Experimental: Recommended combination of doses from Cohort A1 or A2<br>Subjects in Cohort B are subjects with metastatic/locally advanced Oesophageal Cancer. Subjects in Cohort B will receive the recommended combination dose from Cohort A1 (durvalumab alone administered before chemotherapy (oxaliplatin + capecitabine)) or A2 (Dose-escalation for Tremelimumab 37.5mg - 75mg + Durvalumab 750mg + Chemotherapy) and Chemotherapy. | Drug: Durvalumab<br> <br> * Other names: Imfinzi;Drug: Tremelimumab<br> <br> Drug: Oxaliplatin<br>* IV administered Chemotherapy<br>* Other names: Eloxatin;Drug: Capecitabine<br>* orally-administered chemotherapy<br>* Other names: Xeloda;|
| Experimental: Durvalumab, surgery and standard of care chemotherapy<br>Durvalumab 750mg + Chemotherapy (Cohort C) | Drug: Durvalumab<br> <br> * Other names: Imfinzi;Drug: Oxaliplatin<br>* IV administered Chemotherapy<br>* Other names: Eloxatin;Drug: Capecitabine<br>* orally-administered chemotherapy<br>* Other names: Xeloda;|
| Experimental: Durvalumab, surgery, standard of care chemo and radiotherapy<br>Durvalumab 750mg + Chemotherapy Radiotherapy (Cohort D) | Drug: Durvalumab<br> <br> * Other names: Imfinzi;Radiation: Radiotherapy<br> <br> * Other names: Radiation;Drug: Paclitaxel<br>* IV administered Chemotherapy<br>* Other names: Taxol;Drug: Carboplatin<br>* IV administered Chemotherapy<br>* Other names: Paraplatin;|
| Experimental: Durvalumab, surgery, new standard of care chemotherapy C-FLOT<br>Durvalumab 750mg + Chemotherapy (Cohort C-FLOT) | Drug: Durvalumab<br> <br> * Other names: Imfinzi;Drug: Oxaliplatin<br>* IV administered Chemotherapy<br>* Other names: Eloxatin;Drug: 5-fluorouracil (5-FU)<br>* IV administered Chemotherapy<br>Drug: Leucovorin<br>* orally-administered chemo-protective agent<br>Drug: docetaxel<br>* IV administered Chemotherapy<br>* Other names: Taxotere;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects reporting Adverse Events |  | up to 1 year | 
| Number of subjects experiencing a dose-limiting toxicity |  | up to 10 weeks after the first dose of study medication | 
| Change from Baseline in laboratory evaluations |  | Screening through 3 months after the last dose of study medication | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor response by irRECIST |  | up to 12 months | 
| Progression Free Survival |  | up to 36 months | 
| Overall Survival |  | up to 36 months | 
| 1 year Survival Rate in subjects with operable oesophageal cancer |  | up to 12 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Oesophageal Cancer, Oesophageal adenocarcinoma, Oesophageal squamous cell carcinoma, Immunotherapy, Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), Programmed cell death protein 1 (PD-1), Programmed death ligand 1 (PD-L1)