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 –

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Frankfurter Institut Fuer Klinische Krebsforschung IKF GmbH

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04], Diseases [C] - Digestive System Diseases [C06]

Trial duration

13 Feb 2023 → ongoing

Decision date (initial)

2024-10-11

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Organon Healthcare GmbH · MSD Sharp & Dohme GmbH

External identifiers

EU CT number

2024-513610-34-00

EudraCT number

2021-006512-87

ClinicalTrials.gov

NCT05504720

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy, Safety

Assessment of co-primary objectives of disease-free survival and the pathological complete response rate

Secondary objectives 5

1. Assessment of overall response rate (ORR) according to RECIST v1.1
2. Assessment of R0 resection rate
3. Assessment of Overall survival (OS)
4. Assessment of Feasibility
5. Assessment of Safety and toxicity

Conditions and MedDRA coding

HER2-positive, localized esophagogastric adenocarcinoma

Study design 1 period

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. The participant provides written informed consent for the trial.
2. 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.
3. In the investigator’s judgement, participant is willing and able to comply with the study protocol including the planned surgical treatment
4. Histologically confirmed adenocarcinoma of the GEJ (Type I-III according to Siewert´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.
5. 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
6. Participants must be candidates for potential curative resection as determined by the treating surgeon
7. No prior systemic-anti cancer therapy (e.g. cytotoxic or targeted agents or radiotherapy)
8. No prior partial or complete esophagogastric tumor resection
9. ECOG (Eastern Cooperative Oncology Group) performance status score of 0 or 1
10. 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.
11. 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).

Exclusion criteria 25

1. Participants with involved retroperitoneal (e.g. para-aortal, paracaval or interaortocaval lymph nodes) or mesenterial lymph nodes (distant metastasis!)
2. 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.
3. 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).
4. 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.
5. Major surgery within 2 weeks of starting study intervention and patients must have recovered from any effects of any major surgery.
6. 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.
7. Inadequate cardiac function (LVEF value < 55 %) as determined by echocardiography
8. 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.
9. 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.
10. Participant is currently participating in or has participated in a study of an investigational agent within 4 weeks or within less than 5 half-lives of the investigational agent (whichever is longer) or has used an investigational device within 4 weeks prior to the first dose of study intervention.
11. 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.
12. 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.
13. Participant has myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or with features suggestive of MDS/AML.
14. Participant has severe dyspnea at rest requiring supplementary oxygen therapy.
15. 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
16. Any known contraindication (including hypersensitivity) to docetaxel, 5-FU, folinic acid/leucovorin, or oxaliplatin.
17. 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/]
18. 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.
19. Participant has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
20. Participant has an active infection requiring systemic therapy.
21. Participant has a known history of Human Immunodeficiency Virus (HIV) infection
22. 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.
23. 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.
24. 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.
25. Participant has had an allogenic tissue/solid organ transplant.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. disease-free survival and the pathological complete response rate (co-primary)

Secondary endpoints 4

1. ORR – percentage of patients with CR or partial response (PR) according to RECIST 1.1.
2. R0 resection - microscopically margin negative resection with no gross or microscopic tumor remains in the areas of the primary tumor and/or sampled regional lymph nodes.
3. OS – time from enrolment to the date of death of any cause Feasibility rate - severe toxicity/withdrawal rate before the last postoperative administration of pembrolizumab/trastuzumab/FLOT has been completed.
4. (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.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 6

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Frankfurter Institut Fuer Klinische Krebsforschung IKF GmbH

Sponsor organisation

Frankfurter Institut Fuer Klinische Krebsforschung IKF GmbH

Address

Steinbacher Hohl 2-26, Praunheim Praunheim

City

Frankfurt Am Main

Postcode

60488

Country

Germany

Scientific contact point

Organisation

Frankfurter Institut Fuer Klinische Krebsforschung IKF GmbH

Contact name

Clinical Trial project manager

Public contact point

Organisation

Frankfurter Institut Fuer Klinische Krebsforschung IKF GmbH

Contact name

Clinical Trial project manager

Third parties 2

Locations

1 EU/EEA country · 11 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 13 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications