Clinical trial: Phase II Study of Atezolizumab + FLOT vs. FLOT Alone in Patients With Gastric Cancer and GEJ (NCT03421288)

Eligibility criteria:
Inclusion Criteria:

          1. Have provided written informed consent

          2. In the investigator's judgement, is willing and able to comply with the study protocol
             including the planned surgical treatment

          3. Female and male patients* ≥ 18 years of age

          4. Diagnosed with histologically confirmed adenocarcinoma of the GEJ (Type I-III) or the
             stomach (cT2, cT3, cT4, any N category,

             M0), or (any T, N+, M0) that:

               1. is not infiltrating any adjacent organs or structures by CT or MRI evaluation

               2. does not involve peritoneal carcinomatosis

               3. is considered medically and technically resectable

             Note: the absence of distant metastases must be confirmed by CT or MRI of the thorax
             and abdomen, and, if there is clinical suspicion of osseous lesions, a bone scan. If
             peritoneal carcinomatosis is suspected clinically, its absence must be confirmed by
             laparoscopy. Diagnostic laparoscopy is mandatory in patients with T3 or T4 tumors of
             the diffuse type histology in the stomach or upon request of the central review.

          5. No prior cytotoxic or targeted therapy

          6. No prior partial or complete esophagogastric tumor resection

          7. ECOG ≤ 1

          8. Availability of a representative tumor specimen that is suitable for determination of
             PD-L1 and MSI status; MSI assessment will be performed locally or centrally and result
             must be available prior to randomization (for details, see chapter 9). PD-L1 will be
             assessed centrally but is not used for enrolment of the patients. The analysis
             requires paraffin embedded biopsy samples of the tumor.

          9. Females of childbearing potential must agree to remain abstinent (refrain from
             heterosexual intercourse) or use contraceptive methods that result in a failure rate
             of <1% per year during the treatment period and for at least 5 months after the last
             study treatment. A woman is considered to be of childbearing potential if she is
             postmenarcheal, has not reached a postmenopausal state (has not had ≥12 continuous
             months of amenorrhea with no identified cause other than menopause), and has not
             undergone surgical sterilization (removal of ovaries and/or uterus). Examples of
             contraceptive methods with a failure rate of < 1% per year include tubal ligation,
             male sterilization, hormonal implants, established, proper use of combined oral or
             injected hormonal contraceptives, and certain intrauterine devices. Alternatively, two
             methods (e.g., two barrier methods such as a condom and a cervical cap) may be
             combined to achieve a failure rate of < 1% per year. Barrier methods must always be
             supplemented with the use of a spermicide. The reliability of sexual abstinence should
             be evaluated in relation to the duration of the clinical trial and the preferred and
             usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation,
             symptothermal, or postovulation methods) and withdrawal are not acceptable methods of
             contraception.

         10. Males must agree to remain abstinent (refrain from heterosexual intercourse) or use
             contraceptive measures, and agree to refrain from donating sperm, as defined below:

             a. With female partners of childbearing potential or pregnant female partners, men
             must remain abstinent or use a condom plus an additional contraceptive method that
             together result in a failure rate of 1% per year during the treatment period and for
             at least 3 months after the last dose of study treatment to avoid exposing the embryo.
             Men must refrain from donating sperm during this same period. Men with a pregnant
             partner must agree to remain abstinent or to use a condom for the duration of the
             pregnancy.

         11. Adequate hematological, hepatic and renal function as indicated by the following
             parameters:

               -  Leukocytes ≥ 3.000/mm³, platelets ≥ 100.000/mm3 without transfusion, absolute
                  neutrophil count (ANC) ≥ 1500/mm3 without granulocyte colony-stimulating factor
                  support, Hemoglobin ≥ 90 g/L (9 g/dL) - Patients may be transfused to meet this
                  criterion.

               -  Bilirubin ≤ 1.5 x upper limit of normal, aspartate transaminase and alanine
                  transaminase ≤ 2.5 x upper limit of normal, alkaline phosphatase ≤ 2.5 x upper
                  limit of normal

               -  Serum creatinine ≤ 1.5 x upper limit of normal, or glomerular filtration rate >
                  45 ml/min (calculated using the Cockcroft-Gault formula)

               -  Serum albumin ≥ 25 g/L (2.5 g/dL)

               -  For patients not receiving therapeutic anticoagulation: INR or aPTT ≤ 1.5 x ULN;
                  for patients receiving therapeutic anticoagulation: stable anticoagulant regimen
                  *There are no data that indicate special gender distribution. Therefore patients
                  will be enrolled in the study gender-independently.

        Exclusion Criteria:

          1. History of severe allergic, anaphylactic, or other hypersensitivity reactions to
             chimeric or humanized antibodies or fusion protein; Known hypersensitivity to Chinese
             hamster ovary cell products or to any component of the atezolizumab formulation

          2. Any known contraindication (including hypersensitivity) to docetaxel, 5-FU,
             leucovorin, or oxaliplatin.

          3. Active or History of autoimmune disease including, but not limited to, myasthenia
             gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid
             arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener's
             granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis,
             vasculitis, or glomerulonephritis. Note: History of autoimmune-related hypothyroidism
             on a stable dose of thyroid replacement hormone, or controlled Type 1 diabetes
             mellitus on a stable insulin regimen may be eligible based on consultation with the
             sponsor's medical monitor. Patients with eczema, psoriasis, lichen simplex chronicus,
             or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic
             arthritis are excluded) are eligible for the study provided all of following
             conditions are met:

               -  Rash must cover < 10% of body surface area

               -  Disease is well controlled at baseline and requires only low-potency topical
                  corticosteroids

               -  No occurrence of acute exacerbations of the underlying condition requiring
                  psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents,
                  oral calcineurin inhibitors, or high potency or oral corticosteroids within the
                  previous 12 months

          4. Prior allogeneic bone marrow transplantation or prior solid organ transplantation

          5. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced
             pneumonitis, idiopathic pneumonitis, organizing pneumonia (i.e., bronchiolitis
             obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on
             screening chest computed tomography (CT) scan. Note: History of radiation pneumonitis
             within the radiation field (fibrosis) is permitted.

          6. Positive test for human immunodeficiency virus (HIV)

          7. Active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg]
             test prior to randomization) or hepatitis C Note: Patients with past hepatitis B virus
             (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and
             a positive antibody to hepatitis B core antigen antibody test) are eligible. Patients
             positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain
             reaction testing is negative for HCV ribonucleic acid (RNA).

          8. Active tuberculosis

          9. Known Dihydropyrimidine dehydrogenase (DPD) deficiency

         10. Uncontrolled tumor-related pain; Patients requiring pain medication must be on a
             stable regimen at study entry

         11. Administration of a live, attenuated vaccine within four weeks prior to start of
             enrollment, or anticipation that such a live attenuated vaccine will be required
             during the study or within 5 months after the last dose of atezolizumab

         12. Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including
             anti-CTLA4, anti-PD-1, or anti-PDL1 therapeutic antibodies

         13. Treatment with systemic immunostimulatory agents (including but not limited to
             interferons or interleukin-2) within four weeks or five half-lives of the drug,
             whichever is longer, prior to study enrollment

         14. Treatment with systemic corticosteroids or other systemic immunosuppressive
             medications within 2 weeks prior to study enrollment. The use of inhaled
             corticosteroids and mineralocorticoids (e.g., fludrocortisone) is allowed.

         15. Significant cardiovascular disease, such as cardiac disease (New York Heart
             Association Class II or greater), myocardial infarction or cerebrovascular accident
             within 3 months prior to initiation of study treatment, unstable arrhythmias, or
             unstable angina.

         16. Clinically significant valvular defect

         17. History of other malignancy within 5 years prior to screening, except for
             appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or
             Stage I uterine cancer

         18. Known central nervous system metastases

         19. Peripheral polyneuropathy ≥ NCI CTCAE grade 2

         20. Serum albumin < 2.5 g/dL.

         21. Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12
             mg/dL or corrected serum calcium > ULN)

         22. Serious infection requiring oral or IV antibiotics within 14 days prior to study
             enrollment

         23. Chronic inflammatory bowel disease

         24. Clinically significant active gastrointestinal bleeding

         25. Major surgical procedure other than for diagnosis within 4 weeks prior to initiation
             of study treatment

         26. Evidence of any other disease, neurologic or metabolic dysfunction, physical
             examination finding or laboratory finding giving reasonable suspicion of a disease or
             condition that contraindicates the use of any of the study medications, puts the
             patient at higher risk for treatment-related complications or may affect the
             interpretation of study results

         27. Participation in another interventional clinical study ≤ 30 days prior to study
             enrollment or planned participation in such a study at the same time as this study

         28. Receipt of an investigational drug within 28 days prior to initiation of study drug

         29. Pregnancy or breast feeding, or planning to become pregnant within 5 months after the
             end of treatment. Women of childbearing potential must have a negative serum pregnancy
             test result within 7 days prior to initiation of study treatment.
No condition on gender to be admitted to the trial.
No healthy subjects accepted to join the trial.
Subject must be at least 18 Years old.


Patient description (medical language): A 63-year-old man comes to the clinic for recent unintentional weight loss. The patient also has epigastric discomfort after meals. He has no known medical problems and takes no medications. His blood pressure is 130/75 and pulse rate is 88/min. He is not febrile. Upper endoscopy shows a lesion in the stomach that shows typical features of diffuse-type adenocarcinoma presenting with signet ring cells that do not form glands.

Patient description (patient's own words): I went to the clinic because I had been losing so much weight that it was concerning. I'm a 63-year-old guy, and it is something rather unusual. I'm always suffering from stomachache after every meal. I've never been sick, and I don't take any medicine. The doctor took my blood pressure and told me it was 130/75, and my pulse rate was 88/min. I'm not febrile! I also had to do an endoscopy, and they found a lesion in my stomach that shows typical features of stomach cancer. I'm totally devastated...

Does the patient match the trial criteria? 1