Personalized Targeted IMMUNOtherapy-based Regimens in Recurrent GASTric Adenocarcinoma (IMMUNOGAST)

Inclusion Criteria:

• Histologically and/or cytologically documented recurrent advanced/metastatic gastricor gastroesophageal junction adenocarcinomas* previously treated with a platinum andfluoropyrimidine-based regimen.

• The gastric or gastroesophageal junction adenocarcinomas that overexpress HER2should have previously been treated with trastuzumab, except in the case ofcontraindication.

• Patients older than 18 years
• Patients with Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
• Patients must have documented disease progression
• Patients who have measurable disease according to Response Evaluation Criteria inSolid Tumors (RECIST) v1.1
• Accessible tumor lesion (primitive lesion or metastasis) for trial dedicated tumorbiopsy.
• Left ventricular ejection fraction (LVEF) ≥ 50% by echocardiogram (echo) or multigatedacquisition (MUGA) scan within 28 days before day 1 of treatment.
• Child-Pugh class A
• Patients must have normal organ and marrow function:
• Absolute neutrophil count ≥ 1,500/μL, platelets ≥ 100,000/μL, hemoglobin ≥ 9 g/dL
• Total bilirubin ≤ 1.5 ULN except subject with documented Gilbert's syndrome,AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional ULN, Serum alkaline phosphatase ≤ 2.5 xULN. Patients with bone metastases: alkaline phosphatase ≤ 5 x ULN.
• Albumin > 2.5 mg/dL.
• Glomerular filtration rate ≥ 60 mL/min as determined by the CKD-EPI equation (orreference methodology such as Iohexol or isotopic technic).
• Urine dipstick for proteinuria < 2+. If urine dipstick is ≥ 2+, 24-hour urinemust demonstrate < 1 g of protein in 24 hours.
• Normal blood pressure or adequately treated and controlled hypertension (systolicBP ≤ 140 mmHg and/or diastolic BP ≤ 90 mmHg).
• Female patients of childbearing potential must have a negative serum pregnancy testwithin 8 days of initiating protocol therapy.
• Female patients of childbearing potential must agree to use contraceptive methods witha low failure rate (< 1% per year) during the treatment period and for 6 months afterthe last dose of study drugs.
• Male patients of childbearing potential must agree to use contraceptive methods with alow failure rate during the treatment period and for 6 months after the last dose ofstudy drugs.
• Patient is capable of understanding and complying with the protocol and has signed theinformed consent document.
• Patients affiliated to a social insurance regime.

Exclusion Criteria:

• Residual toxicity from previous treatment grade ≥1, except for alopecia or peripheralneuropathy grade ≤ 2
• Radiotherapy within 28 days before inclusion, except for palliative radiotherapy ifpatients recovered from all side effects
• Congenital risk of bleeding, or acquired coagulopathy, or curative anti-coagulanttherapies (except for low molecular weight heparin).
• Active digestive bleeding within 3 months before inclusion
• Patients pretreated with one of the experimental drugs, other immune checkpointinhibitor anti-cancer drugs (anti-PD1, anti-PDL1, anti-CTLA4, …), or with ramucirumab.
• Uncontrolled high cholesterol or triglyceride grade ≥ 2
• Uncontrolled intercurrent illness, including, but not limited to, ongoing or activeinfection, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiacarrhythmia, congestive heart failure-New York Heart Association Class III or IV,active ischemic heart disease, myocardial infarction within the previous six months,uncontrolled diabetes mellitus, gastric or duodenal ulceration diagnosed within theprevious 6 months, chronic liver or renal disease, or severe malnutrition.
• Current peripheral neuropathy of Grade ≥ 3 according to National Cancer InstituteCommon Terminology Criteria for Adverse Events (NCI-CTCAE) v.5.0
• Active, second potentially life-threatening cancer
• Other malignancy within the last 5 years except: adequately treated non-melanoma skincancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS). Patient with a history of localized malignancy diagnosed over 5 years ago maybe eligible provided he completed her adjuvant systemic therapy and remains free ofrecurrent or metastatic disease.
• Active or prior documented autoimmune or inflammatory disorders (includinginflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [withthe exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome,or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoidarthritis, hypophysitis, uveitis, etc]). The following are exceptions to thiscriterion:
• Patients with vitiligo or alopecia
• Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable onhormone replacement
• Any chronic skin condition that does not require systemic therapy
• Patients without active disease in the last 5 years may be included but onlyafter consultation with the study physician
• Major surgery within 28 days before cycle 1, day 1
• Active infection requiring iv antibiotics at day 1 of cycle 1
• Medical condition that requires chronic systemic steroid therapy or on any other formof immunosuppressive medication. For example, patients with autoimmune disease thatrequires systemic steroids or immunosuppression agents should be excluded. Replacementtherapy (eg., thyroxine, or physiologic corticosteroid replacement therapy for adrenalor pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• Symptomatic intrinsic lung disease or extensive tumor involvement of the lungs,resulting in dyspnea at rest
• Patient is positive for the human immunodeficiency virus (HIV), HepBsAg, or HCV RNA.
• Live vaccine within 28 days of planned start of study therapy
• History of abdominal fistula, gastrointestinal perforation and/or intra-abdominalabscess within the previous 6 months
• History of Type I or Type II diabetes mellitus requiring insulin
• History of severe allergic, anaphylactic, or other hypersensitivity reactions tochimeric or humanized antibodies or fusion proteins or Chinese Hamster Ovary (CHO)cell proteins or loperamide drug or excipient
• Known hypersensitivity to any of the components of atezolizumab, bevacizumab oripatasertib
• Participation in other interventional clinical research that may interfere with theexperimental drugs efficacy
• History of severe or life-threatening skin adverse reaction on prior treatment withother immune-stimulatory anticancer agents