Study of Atezolizumab + FLOT vs. FLOT Alone in Patients With GC/GEJ and High Immune Responsiveness

NCT03421288 | Active Not Recruiting Phase 2 DMC

• 5 other identifiers: DANTE/FLOT82017-001979-23MO30039/MO43340AIO-STO-0317IKF-s633
• Study Type: interventional
• Target: 677
• Locations: 2 countries
• Sites: 2

Brief Summary

This is a multicenter, randomized, controlled, open-label study comparing perioperative atezolizumab with FLOT chemotherapy versus FLOT alone in patients with locally advanced, operable adenocarcinoma of the stomach or GEJ with high immune responsiveness.

Conditions

Gastric Cancer; Gastroesophageal Junction Adenocarcinoma

Outcome Measures

Primary Outcomes (1)

• Comparison of Event free survival (EFS) between arms

  to compare Event free survival (EFS) in patients with locally advanced, operable esophagogastric adenocarcinoma receiving perioperative FLOT with atezolizumab versus FLOT alone in the intent to treat population (ITT) and where EFS is defined as the time from randomization to disease progression or relapse after surgery or death from any cause

  10 years

Secondary Outcomes (5)

• Pathological complete regression (pCR, TRG 1a by Becker) rate

  after 4 cycles (each cycle is 14 days) + surgery; i.e. after 12 weeks in total

• Pathological complete and subtotal regression (TRG1a/b by Becker)

  after 4 cycles (each cycle is 14 days) + surgery; i.e. after 12 weeks in total

• R0 resection rate

  after 4 cycles (each cycle is 14 days) + surgery; i.e. after 12 weeks in total

• Overall survival (OS)

  10 years

• Overall survival (OS) and EFS in the subgroup of patients with PD-L1 CPS score ≥ 5 and ≥ 10 and patients with MSI

  10 years

Other Outcomes (2)

• Detectable ctDNA after curative surgery

  after surgery (approx. 12 weeks after first dose)

• ctDNA clearance on treatment

  at baseline, before and after surgery (approx. 10 and 12 weeks after first dose), during study treatment (for up to 1 year), in case of relaps/progression

Study Arms (2)

Arm A: FLOT with Atezolizumab

EXPERIMENTAL

Patients randomized to treatment Arm A will receive atezolizumab (840 mg IV over 1 hour) + FLOT in four 2-week treatment cycles prior to undergoing surgery. Following surgery, patients will receive another four 2-week cycles of atezolizumab + FLOT followed by 8 additional 3-week treatment cycles with atezolizumab alone (maintenance setting: 1,200 mg q3w). FLOT can be deescalated to FLO, FLT or FL in case of chemorelated toxicity at any time and at the discretion of investigator.

Drug: Atezolizumab; Drug: 5-Fluorouracil; Drug: Calciumfolinat; Drug: Oxaliplatin; Drug: Docetaxel

Arm B: FLOT alone

ACTIVE COMPARATOR

Patients randomized to Arm B will receive FLOT alone for four 2-week treatment cycles prior to surgery. Following surgery, patients will receive another four 2-week cycles of chemotherapy alone. FLOT can be deescalated to FLO, FLT or FL in case of chemo-related toxicity at any time and at the discretion of investigator. Docetaxel 50 mg/m², d1 Oxaliplatin 85 mg/m², d1 Calciumfolinat 200 mg/m², d1 5-Fluorouracil 2600 mg/m², d1

Drug: 5-Fluorouracil; Drug: Calciumfolinat; Drug: Oxaliplatin; Drug: Docetaxel

Interventions

Atezolizumab DRUG

Day 1 q2w: 840 mg IV over 1 hour (4 cycles perioperative with FLOT) + Day 1 q3w: 1200 mg IV over 1 hour (8 additional cycles monotherapy)

Also known as: TECENTRIQ

Arm A: FLOT with Atezolizumab

5-Fluorouracil DRUG

Day 1 q2w: 2600 mg/m² IV over 24 hours

Also known as: 5-FU

Arm A: FLOT with Atezolizumab; Arm B: FLOT alone

Calciumfolinat DRUG

Day 1 q2w: 200 mg/m² IV over 1 hour

Also known as: Leucovorin

Arm A: FLOT with Atezolizumab; Arm B: FLOT alone

Oxaliplatin DRUG

Day 1 q2w: 85 mg/m² IV over 2 hours

Also known as: ELOXATIN

Arm A: FLOT with Atezolizumab; Arm B: FLOT alone

Docetaxel DRUG

Day 1 q2w: 50 mg/m² IV over 1 hour

Also known as: TAXOTERE

Arm A: FLOT with Atezolizumab; Arm B: FLOT alone

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• is not infiltrating any adjacent organs or structures by CT or MRI evaluation
• does not involve peritoneal carcinomatosis
• 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 9.1). 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 9.2).
• 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.

You may not qualify if:

• 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:
• 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
• 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

Sponsors & Collaborators

• Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest: lead
• Roche Pharma AG: collaborator

Study Sites (2)

Krankenhaus Nordwest

Frankfurt, 60488, Germany

Location

SAKK Coordinating Center

Bern, 3008, Switzerland

Location

Related Publications (2)

• Lorenzen S, Gotze TO, Thuss-Patience P, Biebl M, Homann N, Schenk M, Lindig U, Heuer V, Kretzschmar A, Goekkurt E, Haag GM, Riera-Knorrenschild J, Bolling C, Hofheinz RD, Zhan T, Angermeier S, Ettrich TJ, Siebenhuener AR, Elshafei M, Bechstein WO, Gaiser T, Loose M, Sookthai D, Kopp C, Pauligk C, Al-Batran SE; AIO and SAKK Study Working Groups. Perioperative Atezolizumab Plus Fluorouracil, Leucovorin, Oxaliplatin, and Docetaxel for Resectable Esophagogastric Cancer: Interim Results From the Randomized, Multicenter, Phase II/III DANTE/IKF-s633 Trial. J Clin Oncol. 2024 Feb 1;42(4):410-420. doi: 10.1200/JCO.23.00975. Epub 2023 Nov 14.

  PMID: 37963317 DERIVED

• Chang X, Ge X, Zhang Y, Xue X. The current management and biomarkers of immunotherapy in advanced gastric cancer. Medicine (Baltimore). 2022 May 27;101(21):e29304. doi: 10.1097/MD.0000000000029304.

  PMID: 35623069 DERIVED

MeSH Terms

Conditions

Stomach Neoplasms

Interventions

atezolizumab; Fluorouracil; Leucovorin; Oxaliplatin; Docetaxel

Condition Hierarchy (Ancestors)

Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Stomach Diseases

Intervention Hierarchy (Ancestors)

Uracil; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Coenzymes; Enzymes and Coenzymes; Coordination Complexes; Organic Chemicals; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Diterpenes; Terpenes

Study Officials

• Salah-Eddin Al-Batran, Prof.

  Institute of Clinical Cancer Research IKF at Krankenhaus Nordwest

  STUDY DIRECTOR

• Thorsten Goetze, Prof.

  University Cancer Center Frankfurt, Krankenhaus Nordwest

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 11, 2018
• First Posted: February 5, 2018
• Study Start: September 14, 2018
• Primary Completion (Estimated): May 31, 2027
• Study Completion (Estimated): December 31, 2027
• Last Updated: July 25, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will not share

Locations

DE (1); CH (1)