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

NCT05504720 | Active Not Recruiting Phase 2

• 3 other identifiers: PHERFLOT2021-006512-87AIO-STO-0321
• Study Type: interventional
• Target: 31
• Locations: 1 country
• Sites: 13

Brief 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 Her-2 positive localized esophagogastric adenocarcinoma.

Conditions

Esophagogastric Adenocarcinoma

Keywords

gastric adenocarcinoma; GEJ adenocarcinoma; Her-2 positive esophagogastric adenocarcinoma

Outcome Measures

Primary Outcomes (2)

• 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.

  2 years after enrolment

• 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.

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

Secondary Outcomes (5)

• Overall response rate (ORR)

  up to 1 year after enrolment

• Overall survival (OS)

  up to 52 months

• R0 resection rate

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

• Feasibility rate

  up to 32 weeks

• Incidence and severity of adverse events according to CTC criteria

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

Study Arms (1)

Pembrolizumab Trastuzumab

EXPERIMENTAL

Single 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).

Drug: Pembrolizumab; Drug: Trastuzumab; Drug: FLOT

Interventions

Pembrolizumab DRUG

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

Also known as: Keytruda

Pembrolizumab Trastuzumab

Trastuzumab DRUG

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

Also known as: Ontruzant

Pembrolizumab Trastuzumab

FLOT DRUG

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

Pembrolizumab Trastuzumab

Eligibility Criteria

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

You may qualify if:

• 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
• 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:

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest: lead
• Merck Sharp & Dohme LLC: collaborator
• Organon Healthcare GmbH: collaborator

Study Sites (13)

Charité - Universitätsmedizin Berlin / Campus Virchow Klinikum (CVK)

Berlin, 13353, Germany

Location

MVZ Onkologischer Schwerpunkt

Berlin, 14195, Germany

Location

KEM | Klinik für Internistische Onkologie gGmbH

Essen, 45136, Germany

Location

Institut für Klinisch-Onkologische Forschung am Krankenhaus Nordwest

Frankfurt am Main, 60488, Germany

Location

Hämatologisch-Onkologische Praxis Eppendorf

Hamburg, 20249, Germany

Location

Nationales Centrum für Tumorerkrankungen

Heidelberg, 69120, Germany

Location

St. Anna Hospital Herne

Herne, 44649, Germany

Location

Tagestherapiezentrum (TTZ) am Interdisziplinären Tumorzentrum (ITM)

Mannheim, 68167, Germany

Location

Klinikum rechts der Isar der TU München

München, 81675, Germany

Location

Klinikum Nürnberg

Nuremberg, 90419, Germany

Location

Krankenhaus Barmherzige Brüder

Regensburg, 93049, Germany

Location

Universitätsklinikum Ulm

Ulm, 89070, Germany

Location

Klinikum Wolfsburg

Wolfsburg, 38440, Germany

Location

Related Publications (2)

• 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.

  PMID: 41109919 DERIVED

• 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.

  PMID: 37909020 DERIVED

MeSH Terms

Interventions

pembrolizumab; Trastuzumab; Ontruzant

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Salah Al-Batran, Prof. Dr.

  Institut für Klinische Krebsforschung IKF GmbH

  STUDY DIRECTOR

Study Design

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

Model Details: 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).

Study Record Dates

• First Submitted: August 15, 2022
• First Posted: August 17, 2022
• Study Start: February 13, 2023
• Primary Completion (Estimated): October 1, 2027
• Study Completion (Estimated): December 1, 2027
• Last Updated: June 6, 2025

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will not share

Locations

DE (13)