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Esophagogastric AdenocarcinomaPhase 2NCT05504720

Evaluating Pembrolizumab, Trastuzumab and FLOT as Perioperative Treatment of HER2-positive, Localized Esophagogastric Adenocarcinoma

A Phase 2 study testing Pembrolizumab, Trastuzumab and FLOT in people with Esophagogastric Adenocarcinoma, run by Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest at 13 sites in Germany.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

The study is an open-label, single arm, multicenter phase II trial investigating the clinical activity of a perioperative therapy consisting of a combination of pembrolizumab, trastuzumab and FLOT, followed by pembrolizumab plus trastuzumab alone for a maximum systemic treatment duration of one year in patients with… Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Esophagogastric Adenocarcinoma
What is being tested?
Pembrolizumab, Trastuzumab and FLOT
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
31 participants
Where
13 sitesGermany
Study dates
13 Feb 2023to 5 Aug 2026
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • The participant provides written informed consent for the trial.
  • Male/female* participants who are at least 18 years of age on the day of signing informed consent.
  • There are no data that indicate special gender distribution. Therefore, patients will be enrolled in the study gender-independently.
  • In the investigator's judgement, participant is willing and able to comply with the study protocol including the planned surgical treatment
  • Histologically confirmed adenocarcinoma of the GEJ (Type I-III according to Sievert´s classification) 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
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  • 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.
  • Participants must have HER2-positive disease defined as either IHC 3+ or IHC 2+, the latter in combination with ISH+, as assessed locally by a certified test on primary tumor (see Appendix 4)
  • Participants must be candidates for potential curative resection as determined by the treating surgeon
  • No prior systemic-anti cancer therapy (e.g. cytotoxic or targeted agents or radiotherapy)
  • No prior partial or complete esophagogastric tumor resection
  • ECOG (Eastern Cooperative Oncology Group) performance status score of 0 or 1
  • Male participants: A male participant must agree to use a contraception as detailed in Appendix 2 of this protocol during the treatment period and for at least 6 months after the last dose of study intervention and refrain from donating sperm during this period.
  • Female participants: A female participant is eligible to participate if she is not pregnant (see Appendix 2), not breastfeeding, and at least one of the following conditions applies:
  • Not a woman of childbearing potential (WOCBP) as defined in Appendix 2 OR
  • A WOCBP who agrees to follow the contraceptive guidance as given in Appendix 2 during the treatment period and for at least 7 months after the last dose of study intervention.
  • Participants have adequate organ function as defined in the following table (Table 2). Specimens must be collected within 14 days prior to enrolment (also to be repeated if older than 14 days at day of first treatment).
  • Hematological:
  • Absolute neutrophil count (ANC) ≥ 1500/μL
  • leucocytes ≥ 3000/μL
  • Thrombocytes ≥ 100 000/μL
  • Hemoglobin ≥ 9.0 g/dL or ≥ 5.6 mmol/L (Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within the last 2 weeks)
  • Renal:
  • Measured or calculated (b) creatinine clearance≥ 50 mL/min
  • Hepatic:
  • Total bilirubin ≤ 1.5 ×ULN OR direct bilirubin ≤ ULN for participants with total bilirubin levels > 1.5 × ULN
  • AST (SGOT) and ALT (SGPT) ≤ 2.5 × ULN Coagulation
  • International normalized ratio (INR) OR prothrombin time (PT) and
  • Activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper limit of normal.

Who cannot join

  • Participants with involved retroperitoneal (e.g. para-aortal, paracaval or interaortocaval lymph nodes) or mesenterial lymph nodes (distant metastasis!)
  • A WOCBP who has a positive urine pregnancy test within 72 hours prior to start of study intervention (see Appendix 2). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
  • Received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX-40, CD137).
  • Participant received colony-stimulating factors (e.g. granulocyte colony-stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor [GM-CSF] or recombinant erythropoietin) within 28 days prior to the first dose of study intervention.
  • Major surgery within 2 weeks of starting study intervention and patients must have recovered from any effects of any major surgery.
  • Concomitant use of drugs inhibiting (dihydropyrimidine dehydrogenase) DPD activity (including sorivudine, brivudine), the required wash out phase is 4 weeks before start of the study intervention.
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  • Inadequate cardiac function (LVEF value < 55 %) as determined by echocardiography
  • Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (e.g., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, QTcF prolongation > 500 ms, electrolyte disturbances, etc.), or patients with congenital long QT syndrome.
  • Participant has received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of study drug. Administration of killed vaccines is allowed.
  • Participant is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention.
  • Participant has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
  • Participant has a known additional malignancy that is progressing or has required active treatment within the past 2 years. Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.
  • Participant has myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or with features suggestive of MDS/AML.
  • 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 pembrolizumab or trastuzumab formulation
  • Any known contraindication (including hypersensitivity) to docetaxel, 5-FU, folinic acid/leucovorin, or oxaliplatin.
  • Known 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 [https://cpicpgx.org/guidelines/guideline-for-fluoropyrimidines-and-dpyd/]
  • Participant has active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed.
  • Participant has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
  • Participant has an active infection requiring systemic therapy.
  • Participant has a known history of Human Immunodeficiency Virus (HIV) infection
  • Participant has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA is detected) infection.
  • Participant is considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on High Resolution Computed Tomography (HRCT) scan, previous allogenic bone marrow/blood transplantation or any psychiatric disorder or substance abuse that prohibits obtaining informed consent.
  • Participant is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 6 months after the last dose of study intervention.
  • Participant has had an allogenic tissue/solid organ transplant.

Trial locations and contacts

13 sites in 1 country.

13 sites in 1 country

Germany13 sites

  • Charité - Universitätsmedizin Berlin / Campus Virchow Klinikum (CVK)

    Berlin, 13353

  • MVZ Onkologischer Schwerpunkt

    Berlin, 14195

  • KEM | Klinik für Internistische Onkologie gGmbH

    Essen, 45136

  • Institut für Klinisch-Onkologische Forschung am Krankenhaus Nordwest

    Frankfurt am Main, 60488

  • Hämatologisch-Onkologische Praxis Eppendorf

    Hamburg, 20249

  • Nationales Centrum für Tumorerkrankungen

    Heidelberg, 69120

  • St. Anna Hospital Herne

    Herne, 44649

  • Tagestherapiezentrum (TTZ) am Interdisziplinären Tumorzentrum (ITM)

    Mannheim, 68167

  • Klinikum rechts der Isar der TU München

    München, 81675

  • Klinikum Nürnberg

    Nuremberg, 90419

  • Krankenhaus Barmherzige Brüder

    Regensburg, 93049

  • Universitätsklinikum Ulm

    Ulm, 89070

  • Klinikum Wolfsburg

    Wolfsburg, 38440

Other trials in Germany

About this study

Official title: Pembrolizumab and Trastuzumab in Combination With FLOT in the Perioperative Treatment of HER2-positive, Localized Esophagogastric Adenocarcinoma - A Phase II Trial of the AIO Study Group - PHERFLOT -

The study is an open-label, single arm, multicenter phase II trial investigating the clinical activity of a perioperative therapy consisting of a combination of pembrolizumab, trastuzumab and FLOT, followed by pembrolizumab plus trastuzumab alone for a maximum systemic treatment duration of one year in patients with Her-2 positive localized esophagogastric adenocarcinoma.

Read the detailed description

Her-2 positive patients suffering from localized esophagogastric adenocarcinoma (≥ T2 any N+ or any T N+) without evidence of metastatic disease will be included in the study. Eligible subjects will receive a combination of pembrolizumab and trastuzumab with FLOT 8 weeks pre- as well as post-surgery, followed by pembrolizumab and trastuzumab treatment for up to one year (maximum of 17 administrations of systemic treatment with pembrolizumab and trastuzumab incl. pre- and postoperative chemo-immunotherapy) or until tumor relapse/progression or occurrence of limiting toxicity.

The primary objective of this phase II study is to demonstrate the efficacy of the FLOT/trastuzumab/pembrolizumab regimen in terms of an improvement in disease free survival (DFS) according to RECIST v1.1 and an increase in the pathological complete response (pCR) rate compared to historical controls (interim read out after surgery of last patient in study with 18 months recruitment after 24 months). Secondary objectives are further efficacy and tolerability parameters, including overall response rate according to RECIST v1.1, R0 resection rate, overall survival, safety, and tolerability (including perioperative morbidity).

The exploratory objective is to assess whether clinical efficacy correlates with molecularly-defined subgroups (PD-L1 expression, MSI subtypes, and others).

30 patients will be enrolled in this trial.

Being tested
Pembrolizumab, Trastuzumab, FLOT
Keywords
gastric adenocarcinoma, GEJ adenocarcinoma, Her-2 positive esophagogastric adenocarcinoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • PembrolizumabDrug

    Also called Keytruda

    200 mg flat dose, IV, over 30 minutes; day 1, 22, 43 (8 weeks) pre- and post-surgery, followed by post chemotherapy phase day 1 q3w for 11 cycles; max. 17 applications

  • TrastuzumabDrug

    Also called Ontruzant

    loading dose 8 mg/kg IV over 90 min: day 1 pre- and post-surgery; maintenance dose 6 mg/kg IV over 30 min: Day 22, 43 pre- and post-surgery; followed by 6 mg/kg post chemotherapy phase, day 1 q3w for 11 cycles; max. 17 applications

  • FLOTDrug

    Docetaxel 50 mg/m² IV over 1 hour plus Oxaliplatin 85 mg/m² IV over 2 hours plus Folinic Acid 200 mg/m² IV over 1 hour plus 5-FU 2600 mg/m² IV over 24 hours every 2 weeks (day 1, 15, 29, 43) for 8 weeks pre- and 8 weeks post-surgery

Study groups in NCT05504720
Study groupRoleWhat they receive
Pembrolizumab TrastuzumabExperimentalSingle arm with pembrolizumab (200 mg flat dose over 30 min IV) on day 1, 22 and 43 plus trastuzumab (loading dose 8 mg/kg IV over 90 min at day 1 and maintenance dose 6 mg/kg IV over 30 min) on day 22 and 43 plus FLOT in four 2-week treatment cycles prior to undergoing surgery. Following surgery, patients will receive four further 2-week cycles of pembrolizumab+trastuzumab + FLOT followed by pembrolizumab (200 mg flat dose) and trastuzumab (6 mg/kg) alone for up to 11 further cycles (Q3W).
Receives: Drug: Pembrolizumab; Drug: Trastuzumab; Drug: FLOT

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Disease-free survival after 2 years co-primary endpoint

    Disease-free survival is defined as the proportion of patients being tumor/disease free and alive 2 years after enrolment.

    Measured: 2 years after enrolment

  2. Pathological complete response rate co-primary endpoint

    The pCR rate is defined as the absence of residual tumor based on evaluation of the resected esophagogastric specimen in the primary tumor by local pathology.

    Measured: after surgery, i.e. approx. 12 weeks after enrolment

Secondary outcomes (5)

  1. Overall response rate (ORR)

    Overall response rate, defined as percentage of patients with CR and PR according to RECIST v1.1

    Measured: up to 1 year after enrolment

  2. Overall survival (OS)

    Overall survival is defined as time from enrolment to the date of death of any cause. If no event is observed (e.g., lost to follow-up) OS is censored at the date of last subject contact. Subjects who are alive will be censored at the last known alive dates.

    Measured: up to 52 months

  3. R0 resection rate

    R0 resection is defined as a microscopically margin negative resection with no gross or microscopic tumor remains in the areas of the primary tumor and/or sampled regional lymph nodes based on evaluation by the local pathologist

    Measured: after surgery, i.e. approx. 12 weeks after enrolment

  4. Feasibility rate

    Feasibility rate - severe toxicity/withdrawal rate before the last postoperative administration of pembrolizumab/trastuzumab/FLOT has been completed.

    Measured: up to 32 weeks

  5. Incidence and severity of adverse events according to CTC criteria

    (Serious) adverse events - recorded and graded according to NCI-CTCAE V5.0. Occurrence of (serious) adverse events at any time during the study. Description by nature (System Organ Class and Preferred Term), severity and causal relationship to drug administration.

    Measured: up to 18 months (max. 1 year treatment plus 90 days after last treatment)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted17 Aug 2022
  2. Study start13 Feb 2023
  3. Primary completion15 Jul 2026
  4. Study completion5 Aug 2026

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Model description
All eligible patients will receive pembrolizumab at a dosage of 200 mg flat dose in combination with trastuzumab (6 mg/kg after loading dose of 8 mg/kg) every 3 weeks and 5-FU 2600 mg/m2 for 24 h, folinic acid 200 mg/m2, oxaliplatin 85 mg/m2 and docetaxel 50 mg/m2 (FLOT regimen) every 2 weeks for 8 weeks, followed by surgical resection 4 weeks after last preoperative treatment at the earliest, followed (within 4-10 weeks) by further 8 weeks of the same regime, followed by pembrolizumab 200 mg and trastuzumab 6 mg/kg alone for up to 11 cycles. In total 1 year of systemic treatment (17 pembrolizumab/ trastuzumab administrations max. per patient incl. pre- and postoperative chemo-immunotherapy).
Masking
None (open label)
Enrolment
31 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05504720
Sponsor's protocol ID
PHERFLOT
Other IDs
2021-006512-87, AIO-STO-0321
Status last verified
Aug 2026
First submitted
15 Aug 2022
Last updated
10 Aug 2026
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No: No IPD will be shared.

Publications

  • Stein A, Goekkurt E, Al-Batran SE, Moosmann N, Ettrich TJ, Goetze T, Gruen B, Homann N, Lorenzen S, Hofheinz RD, Rempel V, Siegler G, Muller C, Thiele B, Broering T, Cruz MS, Pauligk C, Binder M, Tintelnot J. Perioperative pembrolizumab, trastuzumab and FLOT in HER2-positive localized esophagogastric adenocarcinoma: a phase 2 trial. Nat Med. 2025 Dec;31(12):4197-4204. doi: 10.1038/s41591-025-03979-y. Epub 2025 Oct 18.

    PubMed 41109919

  • Tintelnot J, Stein A, Al-Batran SE, Ettrich T, Gotze T, Grun B, Haag GM, Heuer V, Hofheinz RD, Homann N, Broring TS, Cruz MS, Kurreck A, Lorenzen S, Moosmann N, Muller C, Schuler M, Siegler G, Binder M, Gokkurt E. Pembrolizumab and trastuzumab in combination with FLOT in the perioperative treatment of HER2-positive, localized esophagogastric adenocarcinoma-a phase II trial of the AIO study group (AIO STO 0321). Front Oncol. 2023 Oct 16;13:1272175. doi: 10.3389/fonc.2023.1272175. eCollection 2023.

    PubMed 37909020

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Pembrolizumab, Trastuzumab and FLOT in people with Esophagogastric Adenocarcinoma, run by Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest at 13 sites in Germany.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 30 inclusion and 24 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 10 Aug 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 13 sites in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Disease-free survival after 2 years co-primary endpoint (time frame: 2 years after enrolment). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05504720, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Aug 2026.

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