Phase II Study of Total Neoadjuvant Durvalumab Plus FLOT Combination Therapy Followed by Postoperative Durvalumab in Resectable Gastroesophageal Adenocarcinoma
- Trial ID
- 2026-525185-21-00
- Protocol
- IKF-099/D-FLOT-TNT
Trial statistics
Diseases & Conditions
Objectives
The primary objective is to evaluate the efficacy of total neoadjuvant treatment consisting of pre‑operative administration of durvalumab combined with the FLOT chemotherapy regimen and postoperative durvalumab in patients with resectable gastroesophageal adenocarcinoma, aiming to enhance tumor regression and improve survival outcomes. Secondary objectives are to further characterize efficacy, to assess safety of the combined regimen, and to evaluate quality of life of the treated patients.
Participants
The trial enrolled ten adult participants (≥ 18 years) of both sexes with histologically confirmed, locally advanced, resectable gastroesophageal adenocarcinoma. Candidates were selected on the basis of clinical staging (cT2‑4, any cN, M0 or any cT, cN+, M0), documented PD‑L1 status, and an ECOG performance status of 0 or 1, indicating good functional capacity. Required baseline laboratory values included neutrophil count ≥1.0 × 10⁹ cells/L, platelet count ≥75 × 10⁹/L, hemoglobin ≥9 g/dL, and adequate hepatic and renal function. Participants were required to have a life expectancy of at least 12 weeks and a body weight >30 kg. Lifestyle considerations mandated the use of effective contraception or abstinence for women of childbearing potential and their male partners, with additional barrier methods, and prohibited sperm donation during treatment and follow‑up periods. Enrollment was gender‑independent and included patients deemed medically and technically resectable, with stable therapeutic anticoagulation limits when applicable.
Plans and Procedures
The trial is a phase IV therapeutic‑exploratory study evaluating total neoadjuvant treatment (TNT) with pre‑operative combination of durvalumab and the FLOT regimen (5‑fluorouracil, calcium folinate, oxaliplatin, and docetaxel) followed by post‑operative durvalumab in patients with resectable Gastroesophageal Adenocarcinoma. After written informed consent, eligible participants undergo a screening visit to confirm histologic diagnosis, PD‑L1 status, performance status, and laboratory eligibility. Baseline assessments are performed before the first infusion of FLOT plus durvalumab, which is administered in repeated cycles according to standard dosing (5‑FU 2600 mg/m², calcium folinate 200 mg/m², oxaliplatin 85 mg/m², docetaxel 50 mg/m²) together with durvalumab 1500 mg. Treatment cycles are followed by scheduled study visits for safety monitoring, laboratory tests, and imaging. After completion of the neoadjuvant phase, patients undergo surgical resection; a post‑operative visit records operative outcomes and pathology, including assessment of pathological complete response. Subsequent visits administer adjuvant durvalumab for a predefined number of cycles, with periodic evaluation of adverse events, quality‑of‑life questionnaires, and disease status. The study concludes with an end‑of‑study visit after the final durvalumab dose, at which overall survival, event‑free survival, and long‑term safety are documented. Participant involvement extends from the screening visit through the end‑of‑study assessment, typically encompassing several months of treatment and follow‑up. Early termination may occur if disease progression precludes surgery, unacceptable toxicity per NCI CTCAE v6.0, withdrawal of consent, or non‑compliance with protocol‑required assessments.
Treatment
5‑FU medac is supplied as a 50 mg/mL solution for injection and is administered by intravenous infusion at a dose of 2600 mg/m² per cycle. The infusion is given on day 1 of each chemotherapy cycle as part of the FLOT regimen.
Calcium folinate is provided as a 10 mg/mL solution for injection and is delivered by intravenous infusion at a dose of 200 mg/m² on day 1 of each cycle, concomitantly with 5‑FU.
Oxaliplatin is supplied as a 5 mg/mL concentrate for solution for infusion and is administered intravenously at 85 mg/m² on day 1 of each chemotherapy cycle, in combination with the other FLOT components.
Docetaxel Accord is a 20 mg/1 mL concentrate for solution for infusion and is given by intravenous infusion at 50 mg/m² on day 1 of each cycle, completing the FLOT chemotherapy backbone.
IMFINZI (durvalumab) is a 50 mg/mL concentrate for solution for infusion administered intravenously at a fixed dose of 1500 mg. Preoperatively, durvalumab is infused on the same day as the FLOT chemotherapy, and postoperative durvalumab is given every four weeks for a defined number of cycles. Compliance is monitored through infusion records, dose‑modification guidelines, and scheduled safety assessments.
Efficacy
The primary efficacy parameter is Pathological complete response (pCR), defined as the proportion of patients whose post‑surgical specimen shows ypT0N0M0, indicating complete absence of viable tumor cells in the primary tumor, lymph nodes, and no metastatic disease. pCR is assessed locally by pathological examination of the resection specimen following completion of neoadjuvant therapy and surgery.
Secondary efficacy assessments include Event‑free survival, measured from the date of enrollment to the occurrence of any defined progression event (RECIST 1.1 progression precluding surgery, progression/recurrence during adjuvant therapy, non‑RECIST progression precluding surgery, or death). EFS rates are calculated at 1‑year and 2‑year timepoints. The Overall survival endpoint records time from enrollment to death from any cause, with OS rates estimated at 2 years. Surgical outcomes are evaluated by the R0 resection rate, defined as the proportion of patients achieving microscopically negative margins, and by the postoperative ypTNM stage. Safety is monitored using the NCI CTCAE 6.0 for adverse event grading and the Clavien‑Dindo classification for peri‑operative morbidity and mortality. Quality of life is captured with the EORTC QLQ‑C30 questionnaire. Exploratory analyses examine efficacy endpoints in relation to PD‑L1 expression status, presented descriptively without formal hypothesis testing. All assessments are performed according to predefined schedules and using validated instruments as specified.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patient* has given written informed consent (* There are no data that indicate special gender distribution. Therefore, patients will be enrolled gender-independently in this trial).
- Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
- Patient is ≥ 18 years of age at time of signing the written informed consent.
- Patient has histologically proven locally advanced (cT2-4, any cN, M0 OR any cT, cN+, M0 stage) gastric, esophagogastric junction (type 1-3) or lower esophageal adenocarcinoma that is considered medically and technically resectable.
- Patient has a known PD-L1 status according to standardized TAP scoring (by local testing), any PD-L1 status is eligible.
- Patient has a ECOG performance status 0 or 1.
- Patient must have a life expectancy of at least 12 weeks.
- Patient has adequate blood count, liver-enzymes, and renal function: a. ANC ≥ 1.0x10^9 cells/L without the use of hematopoietic growth factors b. Platelet count ≥ 75 x 10^9/L (>75,000 per mm3)** c. Hemoglobin ≥ 9 g/dL** d. Serum total bilirubin ≤ 1.5x institutional upper normal limit (ULN) e. AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional ULN f. Patients not receiving therapeutic anticoagulation must have an INR ≤ 1.5 ULN and aPTT ≤ 1.5 ULN. The use of full dose anticoagulants is allowed as long as the INR or PTT is within therapeutic limits (according to the medical standard in the institution) and the patient has been on a stable dose for anticoagulants for at least three weeks at the time of inclusion. g. Serum Creatinine ≤ 1.5 x ULN and a calculated creatinine clearance rate > 40 mL /min (** Transfusion (red blood cell or platelet) is not allowed within 14 days prior to the day on which bone marrow function is assessed, or at any time after this day and prior to treatment initiation).
- Patients have a body weight > 30 kg.ave a body weight > 30 kg.
- Female patients defined as women of childbearing potential (WOCBP) 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 3 months after last dose of durvalumab or 6 months after last dose of chemotherapy, whatever is later. A barrier contraceptive should be used in addition.
- Male patients with WOCBP partners must agree to remain abstinent (refrain from heterosexual intercourse) or use barrier contraceptive during the treatment period as well as up to 3 months after last dose of durvalumab or up to 6 months after last dose of chemotherapy, whatever is later. Male patients must refrain from donating sperm during this same period.
Exclusion Criteria
- Patient received previous (radio)chemotherapy or checkpoint inhibition for the same condition or within the past five years for any other cancerous condition.
- Patient received prior partial or complete esophagogastric tumor resection.Patient received prior partial or complete esophagogastric tumor resection.
- Patient has known hypersensitivity to any component of the durvalumab formulation as well as a known history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion protein and/or any known contraindication (including hypersensitivity) to one of the study drugs.
- Patient has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
- Patient has lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (e.g., pulmonary emboli within three months of the study enrolment, severe asthma, severe COPD, restrictive lung disease, pleural effusion etc.).
- Patient received a prior complete pneumonectomy
- Patient has inadequate cardiac function (LVEF value < 50 %) as determined by echocardiography.
- Patient has a known complete absence of dihydropyrimidine dehydrogenase (DPD) activity.
- Patient received treatment with brivudine, sorivudine or their chemically related analogues within 28 days prior to study enrollment.
- Patient has pernicious anemia or other megaloblastic anemia due to vitamin B12 deficiency.
- Patient has peripheral sensitive neuropathy with functional deficits.
- Patient has a medical history of myocardial infarction (MI) within 6 months before enrollment, symptomatic congestive heart failure (CHF) (New York Heart Association Class II to IV). Subjects with troponin levels above ULN at screening (as defined by the manufacturer), and without any MI related symptoms should have a cardiologic consultation during screening to rule out MI.
- Patient has a corrected QT interval (QTc) prolongation to > 470 ms (females) or >450 ms (males) based on average of the screening triplicate ECG.
- Patient has a history of malignancy other than EGA except for: a. Malignancy treated with curative intent and cured with no known active disease ≥ 3 years before the first dose of study treatment and of low potential risk for recurrence. b. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease. c. Adequately treated carcinoma in situ without evidence of disease.
- Patient has an uncontrolled infection requiring IV antibiotics, antivirals or antifungals within 14 days prior to enrolment.
- Patient has active HBV infection, which is characterized by positive HBV surface antigen (HBsAg) and/or positive HBc antibodies (anti-HBcAb) with detectable HBV DNA (≥ 10 IU/mL or above the limit of detection per local laboratory standard), unless the participant is treated with antiviral therapy, as per institutional practice. The HBV antiviral therapy must be initiated prior to enrollment, and participants must remain on antiviral therapy for the study duration and for 6 months after the last dose of response (e.g., reduction HBV DNA levels) prior to starting intervention. Note: Patients who test positive for HBsAg or anti-HBc with undetectable HBV DNA (< 10 IU/mL or under the limit of detection per local laboratory standard) do not require antiviral therapy prior to enrollment. These patients are eligible and will be tested at every cycle to monitor HBV DNA levels and initiate antiviral therapy if HBV DNA is detected (≥ 10 IU/mL or above the limit of detection per local laboratory standard). The HBV DNA detectable patients must initiate and remain on antiviral therapy for the trial duration and for 6 months after the last dose of durvalumab.
- Patient has active HCV infection (as characterized by the presence of detectable HCV RNA and anti-HCV antibody [anti-HCV]) unless the patient is managed per local institutional practice for the trial and for 6 months after the last dose of durvalumab.
- Patient has any co-infection with HBV and HDV (HDV-positive infection is indicated by the presence of anti-HDV antibodies).
- Patient has active tuberculosis infection (clinical evaluation that may include clinical history, physical examination, and radiographic findings, or tuberculosis testing in line with local practice).
- Patient has known HIV infection that is not well controlled. All of the following criteria are required to define an HIV infection that is well controlled: a. Undetectable viral RNA b. CD4+ count ≥ 350 cells/mm3 c. No history of acquired immune deficiency syndrome-defining opportunistic infection within the past 12 months, and stable for at least 4 weeks on the same anti-HIV medications (meaning there are no expected further changes in that time to the number or type of antiretroviral drugs in the regimen) If an HIV infection meets the above criteria, monitoring of viral RNA load and CD4+ count is recommended. Patient must be tested for HIV if acceptable by local regulations or an institutional IRB/IEC
- Patient has 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 syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. The following are exceptions to this criterion: a. Patients with vitiligo or alopecia b. Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement c. Any chronic skin condition that does not require systemic therapy d. Patients without active disease in the last 5 years may be included but only after consultation with the study physician e. Patients with celiac disease controlled by diet alone
- Patient currently or priorly used immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion: a. Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection) b. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent c. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
- Patient received live, attenuated vaccine within 30 days prior initiation of study drug.
- Patient has any other serious concomitant or medical condition that, in the opinion of the investigator, presents a high risk of complications to the patient or reduces the likelihood of clinical effect.
- Patient participated in another interventional clinical study within 28 days prior to study enrollment or participation in a clinical study at the same time as this study, unless it is an observational/ non-interventional study or during the follow-up period of an interventional study.
- Patient has taken an investigational drug within 28 days prior to initiation of study drug.
- Female patients, who are pregnant or breast feeding or planning to become pregnant within 6 months after the end of treatment. Female patients of childbearing potential must have a negative serum pregnancy test result within 7 days prior to initiation of study treatment.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Not Yet Recruiting | 01 Jul 2026 | 66 |
 Spain | Not Yet Recruiting | 01 Jul 2026 | 25 |
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 |
|---|---|---|---|---|---|---|
5-FU medac 50 mg/ml, Injektionslösung | Test | INJEKTIONSLÖSUNG | INFUSION | 2600 | 16 | PRD11987344 |
Calcium Folinate 10 mg/ml solution for injection | Test | SOLUTION FOR INJECTION | INFUSION | 200 | 16 | PRD11926118 |
Oxaliplatin 5 mg/ml concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INFUSION | 85 | 16 | PRD11323472 |
IMFINZI 50 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INFUSION | 1500 | 19 | PRD6651398 |
Docetaxel Accord 20 mg/1 ml concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INFUSION | 50 | 16 | PRD3445550 |