| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| locally advanced resectable adenocarcinoma of the oesophagogastric junction or the stomach |
|
| E.1.1.1 | Medical condition in easily understood language |
| locally advanced resectable gastric cancer and cancer of the oesophagogastric junction |
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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 | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10062878 |
| E.1.2 | Term | Gastrooesophageal cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
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
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|
| E.2.2 | Secondary objectives of the trial |
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
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 for the duration of the pregnancy.
10. Criterion integrated in criterion 9.
11. Adequate hematological, hepatic and renal function as indicated by the following parameters:
o 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.
o 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
o Serum creatinine ≤ 1.5 x upper limit of normal, or glomerular filtration rate > 45 ml/min (calculated using the Cockcroft-Gault formula)
o Serum albumin ≥ 25 g/L (2.5 g/dL)
o For patients not receiving therapeutic anticoagulation: INR or aPTT ≤ 1.5 x ULN; for patients receiving therapeutic anticoagulation: stable anticoagulant regimen |
|
| E.4 | Principal 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 < 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. |
|
| E.5 End points |
| E.5.1 | 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
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| EFS: continuously, tumor assessment every 3 months |
|
| E.5.2 | 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
|
|
| E.5.2.1 | 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
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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) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| 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 | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 60 |
| 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 | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
| Database closure is defined as the end of the trial: Sites need to collect survival data of patients and are involved in the data cleaning process actively (e.g. additional source data may be requested and additonal monitoring visits may be neccessary). Therefore, database closure is considered the end of 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 | 10 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 10 |
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