Adjuvant immunotherapy in patients with resected gastric cancer following preoperative chemotherapy with high risk for recurrence (N+ and/or R1): an open label randomized controlled phase-2-study (VESTIGE)

Phase 1

Conditions: Gastric, lower esophageal or GE-junction adenocarcinoma
MedDRA version: 20.0 Level: LLT Classification code 10066354 Term: Adenocarcinoma of the gastroesophageal junction System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 20.0 Level: LLT Classification code 10015323 Term: Esophageal adenocarcinoma lower third stage unspecified System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 20.0 Level: PT Classification code 10001150 Term: Adenocarcinoma gastric System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 20.0 Level: PT Classification code 10030137 Term: Oesophageal adenocarcinoma System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 20.0 Level: HLGT Classification code 10017991 Term: Gastrointestinal neoplasms malignant and unspecified System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 20.0 Level: SOC Classification code 10029104 Term: Neoplasms benign, malignant and unspecified (incl cysts and polyps) System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2018-000406-36-ES

Lead Sponsor: European Organisation for Research and Treatment of Cancer (EORTC)

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Authorised-recruitment may be ongoing or finished

Sex: Not specified

Target Recruitment: 240

Inclusion Criteria

- Histologically proven gastric or EGJ and lower esophageal adenocarcinoma
- Subjects must have completed pre-operative chemotherapy with a fluoropyrimidine-platinum containing regimen and macroscopically complete surgery prior to randomization
- Minimal duration of neoadjuvant chemotherapy should be 6 weeks, maximum 12 weeks.
- Total or distal gastrectomy with D2 lymphadenectomy according to ESMO guidelines should have been completed for gastric and junctional Siewert type III cancers. Ivor Lewis or McKeown oesophagectomy with two field lymphadenectomy should have been performed for junctional Siewert type I cancers and lower esophageal adenocarcinomas. For Siewert type II cancers either total gastrectomy with D2-lymphadenectomy or oesophagectomy with two field lymphadenectomy should have been completed. Open, minimal invasive or hybrid surgical approaches are acceptable as long as the requirements above are fulfilled.
- Regardless of the type of surgery a minimum of 15 lymph nodes should have been resected and examined.
- Recovered from surgery and fit for study treatment as assessed by a multidisciplinary team. Ideally, surgery should have been performed within 2 months before randomization.
- ypN1-3 status according to current (8th) version of TNM classification system. In case of an ypN0 status patients must meet the inclusion criterion of R1 resection.
- R0 or R1 resection according to current (8th) version of TNM classification system. In case of R0 resection, patients must meet the inclusion criterion of ypN1-3
- Availability of operative and pathology reports for review
- WHO performance status score of 0 or 1
- Age = 18 years
- Adequate organ function assessed within 7 days before randomization:
- White blood cell count (WBC) > 2 x 10E9/L
- Absolute neutrophil count (ANC) > 1.5 x 10E9/L
- Platelets = 100 x 10E9/L
- Hemoglobin = 9 g/dL
- Measured/calculated creatinine clearance = 60 mL/min (according to Cockroft-Gault formula).
- Total bilirubin within normal limits (if the patient has documented Gilbert’s disease = 1.5 * ULN or direct bilirubin = ULN)
- Aspartate transaminase (AST) and alanine transaminase (ALT) = 1.5ULN
- Normal 12 L ECG, and if clinically indicated, normal cardiac function assessement. In the past 6 months no serious cardiac illness or medical condition including but not confined to:
- History of documented congestive heart failure (CHF)
- High-risk uncontrolled arrhythmias
- Angina pectoris requiring antianginal medication
- Clinically significant valvular heart disease
- Evidence of transmural infarction on ECG
- Poorly controlled hypertension (e.g. systolic >180mm Hg or diastolic greater than 100mm Hg)
- All toxicities (exception alopecia) attributed to prior anti-cancer therapy must have resolved to grade 1 (CTCAE version 5.0) or baseline before administration of study drug.
- Availability of resected tumor tissue for biobanking/translational research (TR).
- Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test

Exclusion Criteria

- R2 resection status
- M1 stage according to current (8th) version of TNM classification system
- Patients who have undergone complete resection of metastases
- Impaired renal, hepatic, cardiac, pulmonary or endocrine status that compromises the eligibility of the patient for postoperative chemotherapy or immunotherapy
- Subjects with previous malignancies are excluded unless a complete remission was achieved at least 5 years prior to study entry. Adequately treated cervical carcinoma in situ, and localized non-melanoma skin cancer are no exclusion criteria, regardless of timepoint of diagnosis.
- Subjects with active, known, or suspected infectious or autoimmune disease
? - Patients who have received antibiotics within the last 14 days before randomization are excluded.
? - Subjects with Type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment are permitted to enroll
? - Subjects with a condition requiring systemic treatment with either corticosteroids (= 10 mg daily prednisone or equivalent) or other immunosuppressive medications within 14 days of study drug administration
- Subjects with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity
- Subjects with > Grade 1 peripheral neuropathy
- Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways
- Prior or concomitant treatment with radiotherapy/radiochemotherapy
- Any positive test result for HBV or HCV indicating acute or chronic infection
- Known history of testing positive for HIV or known AIDS
- Known uncontrollable hypersensitivity to the components of cisplatin/oxaliplatin, fluorouracil (5-FU) or capecitabine, epirubicine or docetaxel
- Known dihydropyrimidine dehydrogenase (DPD) deficiency
- Ongoing or concomitant use of the antiviral drug sorivudine or its chemically related analogs, such as brivudine.

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method

Secondary Outcome Measures

Name	Time	Method