Organ-Preserving Endoscopic Resection & Adjuvant RADIO-immuno-chemotherapy for Esophageal Cancer

Inclusion Criteria:

• AGE >18

• Able to provide informed consent.

• Pathological stage T1B or T2 esophageal or non-metastatic gastro-esophagealadenocarcinoma, squamous cell cancer or mixed histology.

• Ineligible for or declining esophagectomy.

• Completed endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD).

• Body weight >30kg

• Adequate normal organ and marrow function as defined below:

1. Haemoglobin ≥9.0 g/dL

2. Absolute neutrophil count (ANC) ≥1.0 × 109 /L

3. Platelet count ≥75 × 109/L

4. Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). <<This willnot apply to patients with confirmed Gilbert's syndrome (persistent orrecurrent hyperbilirubinemia that is predominantly unconjugated in the absenceof hemolysis or hepatic pathology), who will be allowed only in consultationwith their physician.>>

5. AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal unless livermetastases are present, in which case it must be ≤5x ULN

6. Measured creatinine clearance (CL) >40 mL/min or Calculated creatinine CL>40mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hoururine collection for determination of creatinine clearance:

Males:

Creatinine CL (mL/min) = Weight (kg) x (140 - Age) 72 x serum creatinine (mg/dL)

Females:

Creatinine CL (mL/min) = Weight (kg) x (140 - Age) x 0.85 72 x serum creatinine (mg/dL)

• Patient is willing and able to comply with the protocol for the duration of thestudy including undergoing treatment and scheduled visits and examinations includingfollow up.

• Must have a life expectancy of at least 12 weeks

Exclusion Criteria:

• • Participation in another clinical study with an investigational product during thelast 4 weeks.

• Concurrent enrolment in another clinical study unless it is an observational (non-interventional) clinical study or during the follow-up period of aninterventional study.

• Receipt of the last dose of anticancer therapy (chemotherapy, immunotherapy,endocrine therapy, targeted therapy, biologic therapy, tumour embolization,monoclonal antibodies) ≤15 days prior to the first dose of study drug. Ifsufficient wash-out time has not occurred due to the schedule or PK propertiesof an agent, a longer wash-out period will be required, as agreed byAstraZeneca and the investigator.

• Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapywith the exception of alopecia and vitiligo.

1. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-casebasis after consultation with the Study Physician.
2. Patients with irreversible toxicity not reasonably expected to beexacerbated by treatment with durvalumab may be included only afterconsultation with the Study Physician.

• Any concurrent chemotherapy, investigative product (IP), biologic, or hormonaltherapy for cancer treatment. Concurrent use of hormonal therapy fornon-cancer-related conditions (e.g., hormone replacement therapy) isacceptable.

• Radiotherapy treatment to more than 30% of the bone marrow within 4 weeks ofthe first dose of study drug.

• Major surgical procedure (as defined by the Investigator) within 28 days priorto the first dose of durvalumab. Note: Local surgery of isolated lesions forpalliative intent is acceptable.

• History of allogenic organ transplantation.

• Active or prior documented autoimmune or inflammatory disorders (includinginflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus,Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis,Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). Thefollowing are exceptions to this criterion:

1. Patients with vitiligo or alopecia.
2. Patients with hypothyroidism (e.g., following Hashimoto syndrome) stableon hormone replacement.
3. Any chronic skin condition that does not require systemic therapy.
4. Patients without active disease in the last 5 years may be included butonly after consultation with the study physician.
5. Patients with celiac disease controlled by diet alone.

• Uncontrolled intercurrent illness, including but not limited to, ongoing oractive infection, symptomatic congestive heart failure, uncontrolledhypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lungdisease, serious chronic gastrointestinal conditions associated with diarrhea,or psychiatric illness/social situations that would limit compliance with studyrequirement, substantially increase risk of incurring AEs or compromise theability of the patient to give written informed consent.

• History of another primary malignancy except for

1. Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of durvalumab and of low potential risk forrecurrence
2. Adequately treated non-melanoma skin cancer or lentigo maligna withoutevidence of disease
3. Adequately treated carcinoma in situ without evidence of disease

• History of leptomeningeal carcinomatosis

• Patients with brain or any other brain metastases

• History of active primary immunodeficiency

• Active infection including tuberculosis (clinical evaluation that includesclinical history, physical examination and radiographic findings, and TBtesting in line with local practice), hepatitis B (known positive HBV surfaceantigen (HBsAg) result), hepatitis C. Patients with a past or resolved HBVinfection (defined as the presence of hepatitis B core antibody [anti-HBc] andabsence of HBsAg) are eligible. Patients positive for hepatitis C (HCV)antibody are eligible only if polymerase chain reaction is negative for HCVRNA.

• Current or prior use of immunosuppressive medication within 14 days before thefirst dose of durvalumab. The following are exceptions to this criterion:

1. Intranasal, inhaled, topical steroids, or local steroid injections (e.g.,intra articular injection)
2. Systemic corticosteroids at physiologic doses not to exceed <<10 mg/day>>of prednisone or its equivalent
3. Steroids as premedication for hypersensitivity reactions (e.g., CT scanpremedication)

• Receipt of live attenuated vaccine within 30 days prior to the first dose ofIP. Note: Patients, if enrolled, should not receive live vaccine whilstreceiving durvalumab and up to 30 days after the last dose of durvalumab.

• Female patients who are pregnant or breastfeeding or male or female patients ofreproductive potential who are not willing to employ effective birth controlfrom screening to 90 days after the last dose of durvalumab monotherapy.

• Known allergy or hypersensitivity to any of the study drugs or any of the studydrug excipients.

• Prior randomisation or treatment in a previous durvalumab clinical studyregardless of treatment arm assignment.

• Patients who have received prior anti-PD-1, anti PD-L1 or anti CTLA-4:

1. Must not have experienced a toxicity that led to permanent discontinuationof prior immunotherapy.
2. All AEs while receiving prior immunotherapy must have completely resolvedor resolved to baseline prior to screening for this study.
3. Must not have experienced a ≥Grade 3 immune related AE or an immunerelated neurologic or ocular AE of any grade while receiving priorimmunotherapy. NOTE: Patients with endocrine AE of ≤Grade 2 are permittedto enroll if they are stably maintained on appropriate replacement therapyand are asymptomatic.
4. Must not have required the use of additional immunosuppression other thancorticosteroids for the management of an AE, not have experiencedrecurrence of an AE if re-challenged, and not currently requiremaintenance doses of > 10 mg prednisone or equivalent per day.

• Judgment by the investigator that the patient is unsuitable to participate inthe study and the patient is unlikely to comply with study procedures,restrictions and requirements.