| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| GE junction cancer, gastric cancer |
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| E.1.1.1 | Medical condition in easily understood language |
| resectable gastric cancer |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10017768 |
| E.1.2 | Term | Gastric cancer stage IV without metastases |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10066350 |
| E.1.2 | Term | Adenocarcinoma of the gastrooesophageal junction |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To explore the safety and feasibility of neoadjuvant capecitabine, oxaliplatin, docetaxel, and atezolizumab in GE-junction and gastric adenocarcinoma |
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| E.2.2 | Secondary objectives of the trial |
• To assess pathological tumor regression and rates of complete response
• To explore the immune activating capacity of atezolizumab in combination with chemotherapy using changes in CD8 T-cell infiltration and immune checkpoints upregulation
• To assess disease-free survival
• To assess overall survival
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Signed informed consent
- Primary resectable, histologically confirmed gastric or GEJ adenocarcinoma
- ECOG performance status of 0 or 1
- Patients age 18 and older
- No signs of distant metastases
- Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained within 14 days prior to initiation of study treatment:
o ANC 1.5 109/L (1500/L) without granulocyte colony-stimulating factor support
o Lymphocyte count 0.5 109/L (500/L)
o Platelet count 100 109/L (100,000/L) without transfusion
o Hemoglobin 5,6mmol/L (patients may be transfused to meet this criterion)
o AST, ALT, and alkaline phosphatase (ALP) 2.5 upper limit of normal (ULN)
o Serum bilirubin 1.5 ULN except for patients with known Gilbert disease: serum bilirubin level 3 ULN
o Serum creatinine 1.5 ULN or Creatinine clearance 40 mL/min (calculated using the Cockcroft-Gault formula)
o Serum albumin 25 g/L
o For patients not receiving therapeutic anticoagulation: INR or aPTT 1.5 ULN
- For patients receiving therapeutic anticoagulation: stable anticoagulant regimen
- CT-scan of thorax and abdomen < 4 weeks to registration. PET-scan and EUS are required for GEJ tumors and are optional for gastric cancers
- For diffuse type gastric cancers, diagnostic laparoscopy should be performed and show no signs of peritoneal metastases
- Patients must be willing to undergo esophagogastroduodenoscopy and biopsies prior to start of treatment and during treatment at defined timepoints
- Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 147 days prior to the start of treatment;
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| E.4 | Principal exclusion criteria |
- Clinical symptoms or radiological suspicion of perforation
- Signs or suspicion of metastatic disease
- Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis:
Patients with a history of autoimmune-related hypothyroidism who are on thyroid replacement hormone are eligible for the study.
- Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications
- Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during atezolizumab treatment or within 5 months after the last dose of atezolizumab
- Current treatment with anti-viral therapy for HBV
- Treatment with investigational therapy within 28 days prior to initiation of study treatment
- Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including antiCTLA-4, antiPD-1, and antiPD-L1 therapeutic antibodies
- Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin 2 [IL-2]) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to initiation of study treatment
- Conditions requiring systemic treatment with either corticosteroids (>10mg daily prednisone equivalents or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease;
- History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
- Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab formulation
- Intercurrent illnesses, including but not limited to infections, that are determined incompatible with the study treatment and protocol by the study team
- Underlying medical conditions that will make the administration of the study drug hazardous or obscure the interpretation of toxicity determination of adverse events
- Positive test for hepatitis B surface antigen (HBsAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection;
- History of testing positive human immunodeficiency virus or known acquired immunodeficiency syndrome (AIDS);
- History of uncontrolled medical or psychiatric illness. Psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule;
- Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or within months after the last dose of study treatment
- History of malignancy within 3 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate 90%), such as adequately treated carcinoma in situ of the cervix, non melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer
Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study.
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
- History of idiopathic pulmonary fibrosis, organizing pneumonia , drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan. - Known active tuberculosis
- Significant cardiovascular disease within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina
- Major surgical procedure other than diagnostic laparoscopy, within 4 weeks prior to initiation of study treatment,
- Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia
- Prior allogeneic stem cell or solid organ transplantation
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety will be measured by SAEs and treatment related complications leading to delays in systemic treatment and/or surgery. Pre-operative treatmend-related complications include all immune-related adverse events, attributable to the study medication, that lead to delays in systemic treatment or surgery. Logistical reasons or non-study-medication related complications leading to delays will not be considered treatment-related.
Post-operative complications, including, but not limited to anastomotic dehiscence/leakage, wound dehiscence, abcess, perforation, bleeding and infection will be recorded.
The rate of clinical and/or radiological anastomotic leakage in our institute is 35,5% for cervical anastomoses (no national rates since many centers use intrathoracic anastomoses) after esophagectomy and around 5% (national 8%) for (sub)total gastrectomy with Roux-Y or BII reconstruction. Therefore, depending on the type of operation, different leakage rates will be reason to consider the study treatment as unsafe.
Since we expect inclusion of mainly patients with GEJ carcinomas who will undergo esophagectomy, the study will be re-evaluated if four or more of the first 10 patients experience anastomotic leakage.
With 4 leakages out of 10 patients, the 95% confidence interval runs from 12% - 74%. The type of operation will be considered herein. If it is deemed feasible, the study will continue to include 10 more patients. Feasibility will be measured by adherence to the timelines of the study protocol.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| safety measured by SAEs or delays in treatment or delay in surgery, within 1 year after randomisation |
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| E.5.2 | Secondary end point(s) |
| Pathological tumor regression grade, effect of therapy on intratumoral T-cell infiltration, radiological tumor regression, immunogenic mutational load, |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| measured within 1 year after randomisation |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 21 |
| E.8.9.1 | In the Member State concerned days | |
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