Efficacy and Safety of Atezolizumab with FLOT Versus FLOT Alone in Locally Advanced Resectable Esophagogastric Adenocarcinoma
- Trial ID
- 2024-514945-12-00
- Protocol
- DANTE/FLOT8
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare **event-free survival** (EFS) in patients with locally advanced, operable esophagogastric adenocarcinoma receiving perioperative FLOT with atezolizumab versus FLOT alone. This is clinically relevant as it aims to determine the efficacy of adding atezolizumab to the standard FLOT regimen, potentially improving patient outcomes in terms of disease progression and recurrence.
Secondary objectives include:
- Comparing pathological complete and subtotal regression (TRG1a/b by Becker) between treatment arms.
- Comparing R0 resection rates between treatment arms.
- Comparing overall survival (OS) between treatment arms, specifically in Phase III.
- Comparing OS and event-free survival (EFS) in subgroups of patients with PD-L1 CPS scores ≥ 5 and ≥ 10, and patients with MSI, between treatment arms in Phase III.
- Comparing the incidence, frequency, severity, and timing of adverse events (AEs) between treatment arms.
- Comparing changes in vital signs, physical findings, and clinical laboratory results between treatment arms.
- Comparing perioperative morbidity and mortality between treatment arms.
Participants
The clinical trial involves a total of **50 participants** diagnosed with **locally advanced resectable adenocarcinoma of the oesophagogastric junction or the stomach**. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on their diagnosis of histologically confirmed adenocarcinoma, with specific criteria ensuring the absence of distant metastases and the medical and technical resectability of the tumor. The trial includes individuals with adequate hematological, hepatic, and renal function, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Both genders are required to adhere to strict contraceptive measures during and after the study period. The trial population is not limited to any specific lifestyle considerations such as diet or physical activity, but participants must not have received prior cytotoxic or targeted therapy, nor have undergone partial or complete esophagogastric tumor resection. The study also involves a vulnerable population, indicating additional ethical considerations in the trial design and execution.
Plans and Procedures
The clinical trial is designed as a **randomized**, open-label Phase II/III study to evaluate the efficacy and safety of **atezolizumab** in combination with FLOT chemotherapy compared to FLOT alone in patients with locally advanced resectable adenocarcinoma of the oesophagogastric junction or the stomach. The primary objective of the Phase III portion is to compare event-free survival (EFS) between the two treatment groups. The trial is expected to run from September 2018 to June 2028, with participant involvement lasting up to 12 months, depending on individual treatment response and progression.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as adequate hematological, hepatic, and renal function, and the absence of prior cytotoxic or targeted therapy. Following randomization, participants will receive treatment according to their assigned group, with regular follow-up visits to monitor safety, tolerability, and treatment efficacy. These visits will include assessments of pathological complete responses, overall survival, and perioperative morbidity and mortality rates. The end-of-study visit will occur after the completion of the treatment period or upon early termination due to disease progression, adverse events, or withdrawal of consent.
Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they are unable to comply with the study protocol. The trial will adhere to rigorous scientific standards to ensure the reliability and validity of the results, contributing valuable data to the understanding of treatment options for gastroesophageal cancer.
Treatment
The clinical trial involves the administration of several **experimental medications**. The first medication is **Tecentriq**, which contains the active substance **atezolizumab**. It is provided as a concentrate for solution for infusion, with a dosage of 1,200 mg. The route of administration is **intravenous**, and it is administered every three weeks. The maximum treatment period is 12 months, with a maximum total dose of 16,320 mg. Atezolizumab is a protein-based substance, specifically classified as "Protein - Other".
Another medication used in the trial is **Leucovorin**, which contains **calcium folinate pentahydrate**. This medication is available as a solution for injection or infusion, with a concentration of 10 mg/ml. It is administered intravenously, with a maximum daily dose of 200 mg/m² and a total maximum dose of 1,600 mg/m² over a 12-month period. Calcium folinate pentahydrate is a chemically derived substance.
**Docetaxel Accord** is also part of the treatment regimen, containing the active substance **docetaxel**. It is provided as a concentrate for solution for infusion, with a dosage of 20 mg/1 ml. The administration is intravenous, with a maximum daily dose of 50 mg/m² and a total maximum dose of 400 mg/m² over the course of 12 months. Docetaxel is a chemical substance.
The trial includes **5-FU medac**, which contains **fluorouracil** as the active ingredient. This medication is available as a solution for injection, with a concentration of 50 mg/ml. It is administered intravenously, with a maximum daily dose of 2,600 mg/m² and a total maximum dose of 20,800 mg/m² over a 12-month period. Fluorouracil is classified as a chemical substance.
Lastly, **Oxaliplatin medac** is used, containing the active substance **oxaliplatin**. It is provided as a concentrate for solution for infusion, with a concentration of 5 mg/ml. The administration is intravenous, with a maximum daily dose of 85 mg/m² and a total maximum dose of 680 mg/m² over 12 months. Oxaliplatin is a chemically derived substance.
All medications are administered intravenously, and participant compliance is monitored throughout the trial to ensure adherence to the dosing schedules. The trial aims to evaluate the efficacy and safety of these treatments in patients with gastric cancer and adenocarcinoma of the oesophago-gastric junction.
Efficacy
Efficacy in this clinical trial will be assessed primarily through the measurement of **event-free survival (EFS)** in patients with locally advanced, operable esophagogastric adenocarcinoma. EFS is defined as the time from randomization to disease progression, relapse after surgery, or death from any cause. This primary endpoint will be evaluated in Phase III of the study. Additionally, in Phase II, the primary exploratory endpoint will be the rate of pathological complete response (pCR) or TRG 1a, which is defined as the absence of residual tumor based on the evaluation of the resected esophagogastric specimen and postoperative TNM stage according to the 8th version of the UICC classification.
Secondary endpoints include the rate of pathological complete responses (pCR, TRG1a) and the rate of pathological complete and subtotal remission (pCR+pSR, TRG1a/b) as assessed according to the Becker criteria. Other secondary endpoints are the R0 resection rate, overall survival (OS) in Phase III, and OS and EFS in subgroups of patients with PD-L1 CPS scores ≥ 5 and ≥ 10, and patients with MSI. Safety and tolerability will be assessed according to NCI-CTCAE V 4.03, along with perioperative morbidity and mortality rates. Exploratory endpoints include circulating tumor DNA (ctDNA) analysis.
The efficacy parameters will be collected and analyzed at various timepoints throughout the trial, with specific methodologies for each endpoint. The trial is designed to compare the efficacy of atezolizumab in combination with FLOT versus FLOT alone in patients with gastric cancer and adenocarcinoma of the oesophago-gastric junction, focusing on high immune responsiveness. The study is expected to conclude by June 2028.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Have provided written informed consent
- In the investigator's judgement, is willing and able to comply with the study protocol including the planned surgical treatment
- Female and male patients* ≥ 18 years of age
- 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.
- No prior cytotoxic or targeted therapy
- No prior partial or complete esophagogastric tumor resection
- ECOG ≤ 1
- 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).
- 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.
- Criterion integrated in criterion 9.
- 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
Exclusion Criteria
- 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
- Any known contraindication (including hypersensitivity) to docetaxel, 5-FU, leucovorin, or oxaliplatin.
- 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: o Rash must cover < 10% of body surface area o Disease is well controlled at baseline and requires only low- potency topical corticosteroids o 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
- Prior allogeneic bone marrow transplantation or prior solid organ transplantation
- 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.
- Positive test for human immunodeficiency virus (HIV)
- 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).
- Active tuberculosis
- 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 lead investigator and sponsor.
- Uncontrolled tumor-related pain; Patients requiring pain medication must be on a stable regimen at study entry
- 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
- Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA4, anti-PD-1, or anti-PD-L1 therapeutic antibodies
- 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
- 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.
- 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.
- Clinically significant valvular defect
- 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
- Known central nervous system metastases
- Peripheral polyneuropathy ≥ NCI CTCAE grade 2
- Serum albumin < 2.5 g/dL
- Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12 mg/dL or corrected serum calcium > ULN)
- Serious infection requiring oral or IV antibiotics within 14 days prior to study enrollment
- Chronic inflammatory bowel disease
- Clinically significant active gastrointestinal bleeding
- Major surgical procedure other than for diagnosis within 4 weeks prior to initiation of study treatment
- 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
- 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
- Receipt of an investigational drug within 28 days prior to initiation of study drug
- 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 enrollment.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Not Recruiting | 01 Sept 2018 | 624 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Docetaxel Accord 20 mg/1 ml concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 50 | 12 | PRD3445550 |
5-FU medac 50 mg/ml, Injektionslösung | Test | INJEKTIONSLÖSUNG | INTRAVENOUS | 2600 | 12 | PRD536079 |
Tecentriq 1 200 mg concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 1200 | 12 | PRD5434939 |
Oxaliplatin medac 5 mg/ml concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 85 | 12 | PRD1598593 |
Leucovorin 10 mg/ml Lösung zur Injektion/ Infusion | Test | LÖSUNG ZUR INJEKTION/ INFUSION | INTRAVENOUS | 200 | 12 | PRD4259228 |