locally advanced resectable adenocarcinoma of the oesophagogastric junction or the stomach MedDRA version: 20.1 Level: PT Classification code 10062878 Term: Gastrooesophageal cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Sponsors
Frankfurter Institut für Klinische Krebsforschung IKF GmbH am Krankenhaus Nordwest
Eligibility
Sex/Gender
All
Inclusion 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: a. is not infiltrating any adjacent organs or structures by CT or MRI evaluation b. does not involve peritoneal carcinomatosis c. 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. 5. No prior cytotoxic or targeted therapy 6. No prior partial or complete esophagogastric tumor resection 7. ECOG = 1 8. Phase II only: 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. Phase III only: Assessment of MSI and PD-L1 [and optional TMB/EBV] must be performed locally and results for either of the following MSI-high, PD-L1 CPS=1, TMB =10/MB or EBV+ must be available prior to randomization (for details, see chapter 9). 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 bilateral tubal ligation, male sterilization, hormonal implants, established, proper use of combined oral or injected hormonal contraceptives, and certain intrauterine devices. 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. 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 f
Exclusion criteria
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. 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. 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 8. Active tuberculosis 9. Known Dihydropyrimidine dehydrogenase (DPD) deficiency. Patients with a reduced DPD activity (CPIC activity score of 1.0-1.5) might participate in the study and receive a reduced dosage of 5-FU after discussion with the coordinating investigator and sponsor. 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-PD-L1 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 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 18. Known central nervous system metastases 19. Peripheral polyneuropathy = NCI CTCAE grade 2 20. Serum albumin 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 t
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Primary Efficacy Objective Phase III: to compare event-free survival (EFS) in patients with locally advanced, operable esophagogastric adenocarcinoma receiving perioperative FLOT with atezolizumab versus FLOT alone Primary Efficacy Objective Phase II (exploratory): to compare pathological complete regression and postoperative TNM (pTNM) stage in patients with locally advanced, operable esophagogastric adenocarcinoma receiving perioperative FLOT with atezolizumab versus FLOT alone ;Secondary Objective: To compare pathological complete and subtotal regression (TRG1a/b by Becker) between arms, to compare R0 resection rate between arms, to compare overall survival (OS) between arms (Phase III only), to compare OS and EFS in the subgroups of patients with PD-L1 CPS score = 5 and = 10 patients and patients with MSI between arms (Phase III only), to compare incidence, frequency, severity, and timing of adverse events (AEs) between arms, to compare changes in vital signs, physical findings, and clinical laboratory results between arms, to compare perioperative morbidity and mortality between arms ;Primary end point(s): Primary Endpoint Phase III: Event-free survival EFS, defined as the time from randomization to disease progression or relapse after surgery or death from any cause Primary Endpoint Phase II (exploratory): pCR or TRG 1a rate where pCR is defined as the absence of residual tumor based on evaluation of the resected esophagogastric specimen in the primary (as assessed by local pathology) and postoperative TNM (pTNM) stage according to the 8th version of the UICC classification (as assessed by local pathology) – both as exploratory endpoints ;Timepoint(s) of evaluation of this end point: EFS: continuously, tumor assessment every 3 months | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • Rate of pathological complete responses (pCR, TRG1a) as assessed according to the Becker criteria • Rate of pathological complete and subtotal remission (pCR+pSR, TRG1a/b) as assessed according to the Becker criteria • R0 resection rate • Overall survival (OS) (Phase III only) • OS and EFS in the subgroups of patients with PD-L1 CPS score = 5 and = 10 and patients with MSI (Phase III only) • Safety (according to NCI-CTCAE V 4.03) and tolerability • Perioperative morbidity and mortality rates • ctDNA exploratory endpoints ;Timepoint(s) of evaluation of this end point: - Rates of pathological remission: after surgery - R0 resection rate: after surgery - EFS: continuously, tumor assessment every 3 months - OS: continuously - safety and tolerability: continuously - Perioperative morbidity and mortality: after surgery - ctDNA: baseline, during treatment, before and after surgery, during follow-up | — |
Countries
Germany, Switzerland
Contacts
Public ContactDr. Claudia Pauligk
Frankfurter Institut für Klinische Krebsforschung IKF GmbH am Krankenhaus Nordwest
Outcome results
None listed