| Eligibility |
Inclusion Criteria:
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 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.
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 (see Appendix 4)
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).
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.
Exclusion Criteria:
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 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. 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
15. Any known contraindication (including hypersensitivity) to docetaxel, 5-FU, folinic
acid/leucovorin, or oxaliplatin.
16. 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/]
17. 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.
18. Participant has a history of (non-infectious) pneumonitis/interstitial lung disease
that required steroids or has current pneumonitis/interstitial lung disease.
19. Participant has an active infection requiring systemic therapy.
20. Participant has a known history of Human Immunodeficiency Virus (HIV) infection
21. 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.
22. 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.
23. 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.
24. Participant has had an allogenic tissue/solid organ transplant.
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