Patients with histologically or cytologically confirmed unresectable, locally advanced or metastatic, HER2+ overexpressing or amplified BC, GEAC, or CRC who are previously treated with the standard of care first line and/or second line treatment (depending on the cohort)

MAIN INCLUSION CRITERIA:

- Patients = 18 years of age or over the legal age of consent in countries where that is greater than 18 years at the time of signature of the informed consent form (ICF)

- Cohorts A to K and Cohort O: Documented HER2+ mBC or mGEAC according to ASCO-CAP guidelines [R23-3591, R23-3707], for the respective cancer indication according to the
result of local testing from the latest available biopsy.

- Cohorts L (L-ext), M, and N (mCRC): Documented HER2 overexpression/amplification according to ASCO/CAP gastric cancer guidelines [R23-3591] and according to the result of local testing:
testing:
- HER2 IHC 3+ by gastric algorithm, or
- HER2 IHC 2+ and HER2 amplification by ISH, or
- HER2 amplification in archival tissue by next generation sequencing (NGS) assay (copy number = 6), or
- HER2 amplification in ctDNA by blood based NGS assay and investigator confirmation by IHC/ISH or tissue NGS prior to or in parallel with the screening process

- For dose optimization and justification (Phase II): Patient must provide tumor tissue from locations not radiated prior to biopsy, if possible, collected through archival tissue

- History of prior treatment lines in palliative setting:

- For cohorts A, B, C, D, E, F, G, H, I, I-ext, J, J-ext, K and O documented investigator assessed progression after HER2-directed treatment for unresectable locally advanced or metastatic disease (For Cohorts D, H, I (I-ext), J (J-ext) - patients must have been pretreated with T-DXd and have progressed or have been intolerant to previous T-DXd).

- For cohorts L, L-ext, M and N documented progression or recurrence of disease during or following their latest line of therapy. Patients must have had at least one prior line of
therapy for locally advanced unresectable disease or metastatic disease (adjuvant and neoadjuvant therapy excluded) and documented disease progression or recurrence of disease during or following their latest line of therapy. In the opinion of the Investigator, patients must be unlikely to tolerate or derive clinically meaningful benefit from further standard of care therapy known to prolong survival.

- Presence of at least one measurable lesion according to RECIST 1.1

- Eastern Cooperative Oncology Group (ECOG) score of 0 or 1

- Adequate organ function based on laboratory values


INCLUSION CRITERIA

1. Signed and dated written ICF in accordance with ICH-GCP and local legislation prior to admission to the trial.

2. Patients = 18 years of age or over the legal age of consent in countries where that is greater than 18 years at the time of signature of the ICF.

3. HER2 status:

i. For mBC and mGEAC (Cohorts A to K and Cohort O): Documented HER2+ mBC or mGEAC according to ASCO-CAP guidelines [R23-3591, R23-3707], for the respective cancer indication according to the result of local testing from the latest available biopsy. For specific requirements in Phase II, see Section 6.2.1.

ii. For mCRC (Cohorts L,L-ext, M, and N): Documented HER2 overexpression/amplification according to ASCO/CAP gastric cancer guidelines [R23-3591] according to the result of local testing:
- HER2 IHC 3+ by gastric algorithm, or
- HER2 IHC 2+ and HER2 amplification by ISH, or
- HER2 amplification in archival tissue by next generation sequencing (NGS) assay (copy number =6), or
- HER2 amplification in ctDNA by blood based NGS assay and investigator confirmation by IHC/ISH or tissue NGS prior to or in parallel with the screening process.
For specific requirements in Phase II, see Sections 5.4 and 6.2.1.

4. For dose optimization (Phase II): Patient must provide tumor tissue from locations not radiated prior to biopsy, if possible, collected through archival tissue, see Sections 5.4.3 and 6.2.1 for details regarding acceptable tissue

5. History of prior treatment lines in palliative setting – Cohorts A, B, C, D, E, F, G, H, I, I-ext, J, J-ext, K and O:
Documented investigator assessed progression after HER2-directed treatment for unresectable, locally advanced, or metastatic disease:

i. For Cohorts A, B, C, G, K, and O, (dose escalation), one line of prior therapy is required, and additional lines of therapy are allowed.

ii. For Cohort D (dose optimization, combination with T-DM1 in mBC), one line of prior therapy is required, and two prior lines of therapy are allowed.
However, previous treatment with small molecule HER2 inhibitors, including, but not limited to, tucatinib, pyrotinib, lapatinib, and neratinib in the palliative setting and/or treatment with capecitabine (or other fluoropyromidine [e.g. 5-fluorouracil]) for metastatic disease for more than 21 days is allowed in up to 15 patients in each dose level (see
exclusion criterion 1.i and 1. iv). For these patients, up to three prior lines of therapy are allowed.
All patients must have been pretreated with T-DXd and have progressed or have been intolerant to previous T-DXd.

iii. For Cohort E (dose optimization, combination with T-DXd in mBC), one line of prior therapy is allowed, which must be trastuzumab with or without pertuzumab and taxane. Additional prior lines of therapy are not allowed. However, previous treatment with T-DXd in the palliative setting is allowed for up to 15 patients in each dose level. For these patients, up to three prior lines of therapy are allowed, including also treatment with small molecule HER2 inhibitors, including, but not limited to, tucatinib, pyrotinib, lapatinib and neratinib, capecitabine (or other fluoropyromidine [e.g. 5-fluorouracil]) and/or T-DM1 in the palliative setting. For Cohort F (dose optimization, combination with T-DXd in mGEAC), one line of prior therapy is required, and 2 or 3 prior lines of therapy are allowed, which can be trastuzumab or other anti-HER2 antibody containing the same epitope as trastuzumab in combination with chemotherapy and with or without a checkpoint inhibitor.

iv. For Cohort H (dose optimization, combination with capecitabine and trastuzumab in mBC) one line of prior therapy is required, and two prior lines of therapy are allowed. However, previous treatment with T-DM1 in the palliative setting is allowed for up to 15 patients in each dose level. For these patients, up to three prior lines of therapy are allowed.
All patients must be pretreated with T-DXd and progressed on or are intolerant to previous T-DXd.

v. For Cohort I (dose optimization, zongertinib monotherapy in mBC, and I-ext, respectively) and Cohort J (dose optimization, zongertinib combination with trastuzumab in mBC, and J-ext, respectively) a maximum of 5 lines of prior therapy are allowed. All patients must have previously received taxane-trastuzumab and been pretreated with T-DXd, having either progressed on it or been unable to tolerate it.

vi. For Cohorts D, E, H, I (I-ext), and J (J-ext) at least 7 patients in each zongertinib dose level should have brain metastases at baseline, defined as patients with a history of brain metastases, current brain metastases, or equivocal brain lesions at baseline, using RECIST 1.1 and RANO based on investigator assessment.

History of prior treatment lines in palliative setting – Cohorts L, L-ext, M, and N:
Documented progression or recurrence of disease during or following their latest line of therapy. In the opinion of the Investigator, patients must be unlikely to tolerate or derive clinically meaningful benefit from further standard of care therapy known to prolong survival. HER2-targeted mAB and prior HER2-targeted antibody-drug conjugates (ADCs) are allowed.

6. Recovered from any previous therapy-related toxicity to = CTCAE Grade 1 at start of treatment with the exception of the following, which are permitted if = CTCAE Grade 2 and stable: alopecia, stable sensory neuropathy, and hypothyroidism (on stable thyroid hormone replacement). Stable, irreversible endocrine immune-related adverse events (e.g., adrenal insufficiency, insulin-dependent diabetes mellitus) that are well-controlled with appropriate hormone replacement therapy are permitted.
For Cohort O, recovered from prior therapy-related congestive heart failure to Grade 0.

7. Presence of at least one measurable lesion according to RECIST 1.1, as determined by the local site investigator/radiology assessment.

8. Eastern Cooperative Oncology Group (ECOG) score of 0 or 1 [R01-0787].

9. Adequate organ function defined as all the following:

i. Absolute neutrophil count =.5 x 10^9/L (= 1.5 x 10^3/MikroL) (= 1500/mm^3); platelets = 100 x 10^9/L (100 x 10^3/MikroL) (100 x 10^3/mm^3) without the use of hematopoietic growth factors within 3 weeks of start of trial drugs.
Cohorts M and N: Absolute neutrophil count = 2.0 x 10^9/L (= 2.0 x 10^3/MikroL) (= 2000/mm^3) without the use of hematopoietic growth factors within 3 weeks of start of trial drugs;

ii. Hemoglobin = 9.0 g/dL (= 90 g/L) (= 5.6 mmol/L) without the use of hematopoietic growth factors or transfusion within 1 week prior to start of trial drugs. If a transfusion is needed because of bone marrow depletion, a washout period of 3 weeks is required prior to starting the trial drugs.

iii. Total bilirubin = 1.5 times the upper limit of normal (ULN), except for patients with Gilbert’s syndrome: total bilirubin = 3 times ULN or direct bilirubin = 1.5 times ULN.

iv.Estimated glomerular filtration rate =30 mL/min - calculated using Chronic Kidney Disease Epidemiology (CKD-EPI) formula.

v. Aspartate transaminase and alanine transaminase = 2.5 times ULN or = 5.0 times ULN for patients with liver metastases.

vi. Alkaline phosphatase < 5 times ULN

vii. PTT/aPTT < 1.5 times ULN unless on a stable dose of an anticoagulant and no unexplained elevation of INR.

10. Life expectancy of at least 12 weeks at the start of treatment in the opinion of the investigator.

11. Male or female participants. Women of childbearing potential (WOCB)1 and men able to father a child must be ready and able to use highly effective methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly in combination with a barrier method. A list of contraception methods meeting these criteria and instructions on the duration of their use will be provided in the patient information and in Section 4.2.2.3.

MAIN EXCLUSION CRITERIA:

- Previous treatment with:
- Any small molecule HER2 inhibitor in the palliative setting in Cohorts D, E, F, H, L, L-ext, M, and N. In Cohort D allowed in up to 15 patients in each DL.
- T-DXd in Cohorts E and F. In Cohort E allowed in up to 15 patients in each DL.
- T-DM1 in the palliative setting in Cohort D and H. In Cohort H allowed in up to 15 patients in each DL.
- Capecitabine in Cohort D and H. In Cohort D allowed in up to 15 patients in each DL

- Presence of uncontrolled and/or symptomatic brain metastases, or leptomeningeal disease

- Mean resting corrected QT interval (QTcF) > 470 msec.

- Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, personal or family history of long QT syndrome or unexplained sudden death under 40 years-of-age.

- Ejection fraction < 50% or the lower limit of normal of the institutional standard within 28 days prior to randomization

- History of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening


EXCLUSION CRITERIA

1. Previous treatment with:

i. Any small molecule HER2 inhibitors (including, but not limited to, tucatinib, pyrotinib, lapatinib, and neratinib) in the palliative setting in Cohorts D, E, F, H, L, L-ext, M and N. Twelve months must have passed after use in the curative setting. For Cohorts L and L-ext, previous use of any small molecule HER2 inhibitor is not allowed, regardless of palliative or curative setting. Note: In Cohort D, previous treatment with small molecule HER2 inhibitors in the palliative setting and/or treatment with capecitabine (or other fluoropyromidine [e.g. 5-fluorouracil] for metastatic disease for more than 21 days is allowed in up to 15 patients in each dose level.

ii. T-DXd in Cohorts E and F. Note: In Cohort E, previous treatment with T-DXd in the palliative setting is allowed for up to 15 patients in each dose level in Cohort E. For these patients, up to three prior lines of therapy are allowed, including also treatment with small molecule HER2 inhibitors, including, but not limited to, tucatinib, pyrotinib, lapatinib and neratinib, capecitabine (or other fluoropyromidine [e.g. 5-fluorouracil]) and/or T-DM1 in the palliative setting.

iii. T-DM1 in the palliative setting in Cohort D and H (but allowed in Cohort H in up to 15 patients in each dose level, for these patients, up to three prior lines of therapy are allowed)

iv. For Cohort D and H: Have previously been treated with capecitabine (or other fluoropyrimidine [e.g., 5-fluorouracil]) for metastatic disease (except in cases where capecitabine was given for = 21 days and was discontinued for reasons other than disease progression or severe toxicity).
Note: In Cohort D, pretreatment with small molecule HER2 inhibitors in the palliative setting and/or treatment with capecitabine (or other fluoropyromidine [e.g. 5-fluorouracil] for metastatic disease for more than 21 days is allowed in up to 15 patients in each dose level.
Note: Patients who have received capecitabine for adjuvant or neoadjuvant treatment at least 12 months prior to starting study treatment are eligible.

v. For Cohort O: See exclusion criterion 33.

2. Previous or concomitant malignancies other than the one treated in this trial within the previous 2 years, which require current systemic therapy except:

i. effectively treated non-melanoma skin cancers
ii. effectively treated carcinoma in situ of the cervix
iii. effectively treated ductal carcinoma in situ
iv. other effectively treated malignancy that is considered cured by local treatment

3. Uncontrolled and/or symptomatic brain metastases. Patients with known central nervous system (CNS) lesions must not have any of the following:

- Any untreated brain lesions > 2.0 cm in size, unless discussed with medical monitor and approval for enrolment is given

- Ongoing use of systemic corticosteroids for control of symptoms of brain metastases at a total daily dose of >2 mg of dexamethasone (or equivalent).

- However, patients on a chronic stable dose of = 2 mg total daily of dexamethasone (or equivalent) may be eligible with discussion and approval by the medical monitor

- Any brain lesion thought to require immediate local therapy, including (but not limited to) a lesion in an anatomic site where increase in size or possible treatment-related edema may pose risk to patient (e.g. brain stem lesions).

- Patients who undergo local treatment for such lesions identified by screening contrast brain MRI may still be eligible for the study if treated with CNS local therapy for newly identified lesions found on contrast brain MRI performed during screening for this study if all of the following criteria are met:
- Time since WBRT is =21 days prior to first dose of treatment, time since SRS is = 7 days prior to first dose of treatment, or time since surgical resection is = 28 days
- Other sites of disease assessable by RECIST 1.1 are present

- Known or suspected leptomeningeal disease as documented by the investigator

- Have poorly controlled (> 1/week) generalized or complex partial seizures, or manifest neurologic progression due to brain metastases notwithstanding CNS-directed therapy

4. Patients who must or wish to continue the intake of restricted medications (see Section 4.2) or any drug considered likely to interfere with the safe conduct of the trial.

5. Radiotherapy within 4 weeks prior to randomization except for palliative radiotherapy for symptomatic metastasis within 2 weeks prior to randomization, but this must be discussed with the sponsor.

6. Not completely recovered from major surgery (major according to the investigator’s assessment) performed prior to randomization or planned within 6 months after screening, e.g. hip replacement.

7. Any history of or concomitant condition that, in the opinion of the investigator, would compromise the patient’s ability to comply with the trial or interfere with the evaluation of the safety and efficacy of the test drug.

8. History or presence of cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure NYHA classification of = III or IV, unstable angina or poorly controlled arrhythmia which are considered as clinically relevant by the investigator. Myocardial infarction, stroke, or pulmonary embolism within 6 months prior to randomization.

9. Any clinically important abnormalities (as assessed by the investigator) in rhythm, conduction, or morphology of resting electrocardiograms, e.g. complete left bundle branch block, third degree heart block.

10. Mean resting corrected QT interval (QTcF) > 470 msec.

11. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, personal or family history of long QT syndrome or unexplained sudden death under 40 years-of-age.

12. Ejection fraction < 50% or the lower limit of normal of the institutional standard within 28 days prior to randomization.

13. Women who are pregnant or nursing or who plan to become pregnant or nurse during the trial or within 9 months after last dose of mFOLFOX6 with or without trastuzumab, within 7 months after the last dose of trial treatment with T-DXd, T-DM1, trastuzumab or capecitabine and trastuzumab, within 4 months after last dose of zanidatamab or within 10 days after last dose of zongertinib monotherapy.

14. Patients with chronic HBV infection with active disease who meet the criteria for anti-HBV therapy (according to local or institutional standard) who have not been treated with suppressive antiviral therapy prior to initiation of study treatment OR patients with a history of HCV infection who meet one or both of the following criteria:
criteria:
i. Currently receiving curative antiviral treatment
ii, HCV viral load is above the limit of quantification (HCV RNA positive)

15. Known history of allergy to the trial drugs or any excipients of the trial drugs.

16. History of severe hypersensitivity reactions and infusion-related reactions to mAbs.

17. Patients not expected to comply with the protocol requirements or not expected to complete the trial as scheduled (e.g. chronic alcohol or drug abuse or any other condition that, in the investigator’s opinion, makes the patient an unreliable patient).

18. History of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.

19. Patients with history of human immunodeficiency virus (HIV) infection who meet one or more of the following criteria:
i. CD4+ count < 350 cells/MikroL
ii. Viral load > 400 copies/mL (local lab assessment)
iii. Not receiving antiretroviral therapy
iv. Receiving established antiretroviral therapy for less than 4 weeks prior to the start of trial treatment
v. History of AIDS-defining opportunistic infections within 12 months prior to start of trial treatment

20. Patients with a history of HIV who do not meet any of the criteria above are eligible to participate but the patient must be under the care of a HIV/Infectious Diseases specialist, or an HIV/Infectious Diseases specialist must be consulted prior to inclusion.

21. Any history or presence of uncontrolled gastrointestinal disorders that could affect the intake and/or absorption of the trial drug (e.g. nausea, vomiting, Crohn’s disease, ulcerative colitis, chronic diarrhea, malabsorption) in the opinion of the investigator.

22. Previous enrolment in this trial.

23. Previous enrolment in this trial.
Currently enrolled in another investigational device or drug trial, or less than 30 days since ending another investigational device or drug trial(s) or receiving other investigational treatment(s). Patients may enroll in this trial if they are in follow-up and have completed study treatment for another trial.

24. Have known complete dihydropyrimidine dehydrogenase (DPD) deficiency (only for Cohorts G, H, M, and N)

25. History of severe and unexpected reactions to fluoropyrimidine therapy (only for Cohort G, H, M, and N)

26. Hypersensitivity to capecitabine or to any of the excipients or to fluorouracil or to any of the excipients (only for Cohorts G, H, M, and N).

27. Severe dyspnea at rest due to complications of advanced malignancy or requiring supplementary oxygen therapy (Cohorts G, H, J, K, N, L, J-ext, and L-ext).

28. Need for concomitant treatment with Brivudine and/or treatment with Brivudine within 4 weeks prior to start of study medication for Cohorts G, H, M, and N.

29. Serious infection (e.g. Herpes zoster, chickenpox) (only for Cohorts M and N).

30. Peripheral sensitive neuropathy with functional impairment (only for Cohorts M and N)

31. Pernicious anemia or other anemias due to vitamin B12 deficiency (only for Cohorts M and N)

32. Hypersensitivity reactions to platinum-based drugs (only for Cohorts M and N)

33. Patients who have previously participated in another trial of zanidatamab (only for Cohort O)

34. Patients with prior treatment-related congestive heart failure CTC AE Grade = 2 (only for Cohort O)

Patients eligible for inclusion in this study must meet all of the following criteria:

1. Signed informed consent must be obtained prior to participation in the study.

2. Male or female patients must be = 18 years of age.

3. Eastern Cooperative Oncology Group (ECOG) performance status of = 2. (Inclusion criterion 3 has been replaced with 3a and is no longer applicable with protocol amendment v03).
3a. Eastern Cooperative Oncology Group (ECOG) performance status of = 1.

4. Patients with one of the following indications:

- Histologically and/or cytologically confirmed diagnosis of estrogen-receptor positive and/or progesterone receptor positive and HER2-negative breast cancer based on the most recently analyzed tissue sample; all tested by a local laboratory using an assay that meets applicable local regulations and all data must be available in the patient’s medical record. HER2-negative breast cancer is defined as a negative in situ hybridization (ISH) test or an IHC status of 0 or 1+, or an IHC status of 2+ in conjunction with a negative in situ hybridization test [such as fluorescence in situ hybridization (FISH), chromogenic in situ hybridization (CISH), silver-enhanced in situ hybridization (SISH) or dual in situ hybridization (DISH)].

- Histologically and/or cytologically confirmed diagnosis of cancer with a CCNE1 amplification (only solid tumor data is allowed). CCNE1 amplifications must have been previously identified through local molecular assays that meet applicable local regulations and data must be available in the patient’s medical record.

Phase I:

- BC: Patients with HR+/HER2- breast cancer must have had disease progression on or following, or have been intolerant to, at least one line of hormone-based therapy in combination with a CDK4/6 inhibitor (CDK4/6i) and at least one additional line of systemic therapy (including cytotoxic chemotherapy, targeted therapies, and/or antibody-drug conjugate therapies) for metastatic disease and not be a candidate for any available standard therapy, in the investigator's judgement.

- CCNE1 amplified solid tumors: Patients must have received, but are not benefitting from standard therapies, are intolerant or ineligible to receive such therapy, or have no standard therapy option. For dose expansion only: no more than 3 prior lines of therapy for advanced or metastatic disease are allowed.

- OC: Patients must have received platinum-based chemotherapy and be considered to have platinum-resistant or refractory disease. If appropriate, they should have received prior treatment with anti-VEGF therapy or PARP inhibitor in accordance with local standard of care, unless the patient was ineligible to receive such therapies. In addition, patients must have received at least one line of chemotherapy in the platinum-resistant setting and not be a candidate for any available standard therapy, in the investigator's judgement.

- GEA: Patients must have received one line of therapy with a fluoropyrimidine and platinum-based regimen, and, if appropriate, prior treatment with HER2 targeted therapy or anti-PD-(L)1 therapy in accordance with local standard of care, unless the patient was ineligible to receive such therapy or not be a candidate for any available standard therapy, in the investigator's judgement.

Phase II:

- BC: Patients with HR+/HER2- breast cancer who have received an aromatase inhibitor or tamoxifen in combination with a CDK4/6 inhibitor (palbociclib, ribociclib, or abemaciclib) for unresectable or metastatic disease and demonstrated evidence of disease progression. They must not have received more than two lines of endocrine therapy in the unresectable/metastatic setting. Patients whose disease progressed while on an adjuvant CDK4/6 inhibitor are permitted without a CDK4/6 inhibitor in the metastatic setting; such patients are permitted only one additional line of endocrine therapy in the unresectable/metastatic setting.

5. Measurable disease as determined by RECIST version 1.1 (refer to Appendix 8).
Tumor lesions previously irradiated or subjected to other locoregional therapy will only be considered measurable if there is documented disease progression at the treated site after completion of therapy.

- BC only: If no measurable disease is present, then at least one predominantly lytic bone lesion must be present that can be accurately assessed at baseline and is suitable for repeated assessment (patients with no measurable disease and only one predominantly lytic bone lesion that has been previously irradiated are eligible if there is documented evidence of disease progression of the bone lesion after irradiation).

6. Patients must be suitable and willing to undergo study required biopsies if safe and medically feasible according to the treating institution’s own guidelines and requirements.
Patient must be willing to undergo a new tumor biopsy at screening (and additionally during treatment for Phase I additional escalation cohorts). If a newly obtained biopsy cannot be safely performed at screening, a recent archival sample may be substituted from patients that have not received systemic therapy since the collection of the biopsy.
Exceptions to the mandatory baseline tumor sample requirement may be allowed following documented discussion with Novartis.

Patients meeting any of the following criteria are not eligible for inclusion in this study.

1. Treatment with any of the following anti-cancer therapies prior to the first dose of study treatment within the stated timeframes:
- Previous treatment with a CDK2 inhibitor at any time.
- = 2 weeks for fluoropyrimidine therapy
- = 4 weeks for extended-field radiotherapy or = 2 weeks for limited field radiation for palliation. For the combination treatment, patients in whom = 25% of the bone marrow has been previously irradiated are also excluded.
- = 4 weeks or = 5 half-lives (whichever is shorter) for chemotherapy or biological therapy (including monoclonal antibodies) or continuous or intermittent small molecule therapeutics or any other investigational agent.
- = 6 weeks for cytotoxic agents with major delayed toxicities, such as nitrosoureas and mitomycin C.
- For the combination treatment: = 5 half-lives wash out period after treatment with tamoxifen or toremifene.

2. Having out of range laboratory values defined as:
- Creatinine clearance (calculated using CKD-EPI 2021 formula, or measured) < 50 mL/min
- Total bilirubin > 1 x ULN, (except for patients with Gilbert’s syndrome who are excluded if total bilirubin > 3.0 x ULN) and direct bilirubin > 1.5 x ULN
- Alanine aminotransferase (ALT) > 2.5 x ULN, except for patients with liver metastasis, who are excluded for ALT = 5 x ULN.
- Aspartate aminotransferase (AST) > 2.5 x ULN except for patients with liver metastasis, who are excluded for AST = 5 x ULN.
- Absolute neutrophil count (ANC) < 1.5 x 10^9/L
- Platelet count < 100 x 109/L
- Hemoglobin < 9 g/dL
- QTcF = 450 msec (as a mean value of triplicates) on screening ECGs, or inability to determine the QTcF interval
- Clinically significant electrolyte abnormalities, including any grade of hypocalcemia, hypokalemia, or hypomagnesemia, that are not corrected before the first dose of the study medication

3. Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality, including any of the following:
- History of documented myocardial infarction (MI), angina pectoris, symptomatic pericarditis, or coronary artery bypass graft (CABG) within 6 months prior to study entry
- Documented cardiomyopathy
- Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome, or any of the following:
- Risk factors for Torsades de Pointe (TdP) including uncorrected hypocalcemia, hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia
- Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia, complete left bundle branch block, high-grade atrioventricular (AV) block, Mobitz type II and third-degree AV block)
- Uncontrolled arterial hypertension with systolic blood pressure (SBP) > 160 mmHg.

4. Presence of Grade = 2 toxicity due to prior cancer therapy according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) that has not resolved, with the exception of Grade 2 neuropathy, any grade alopecia, amenorrhea, skin rash that is adequately treated or endocrinopathies that are adequately treated with replacement therapy.

5. Presence of symptomatic central nervous system (CNS) metastases or CNS metastases that require local CNS-directed therapy (such as radiotherapy or surgery) or increasing doses of corticosteroids within 2 weeks prior to study entry. Patients with treated symptomatic brain metastases must be neurologically stable (for 4 weeks post-treatment and prior to study entry) and at a dose of = 10 mg per day prednisone or equivalent for at least 2 weeks before administration of any study treatment.

6. Has a known additional malignancy that is progressing or requires active treatment.
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer or other tumors that will not affect life expectancy.

7. For the combination treatment:
- Patients with symptomatic visceral disease or any disease burden that makes the patient ineligible for endocrine-based therapy per the investigator’s judgment.
- Patients who could not tolerate the prescribed dose of ribociclib during a previous course of treatment, requiring dose reduction or permanent discontinuation due to adverse events.

8. For patients with breast cancer: Patient is concurrently using hormone replacement therapy.

9. Any serious uncontrolled infection (acute or chronic), such as but not limited to those caused by bacteria, viruses, or fungi, confirmed by clinical evidence, imaging, and/or relevant positive laboratory tests (e.g., blood cultures, Polymerase Chain Reaction (PCR) for DNA/RNA, etc.). Patients with active Hepatitis B (HBV) or Hepatitis C (HCV) infection whose disease is controlled (defined as positive anti-HBc and negative hepatitis B virus surface antigen (HBsAg) for HBV and undetectable viral load by real-time PCR for HCV) under antiviral therapy should not be excluded. Testing for HBV or HCV status is not necessary unless clinically indicated or if the patient has a history of HBV or HCV infection.

10. Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of study drugs (e.g., gastrointestinal perforation, ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome). Patients who have undergone gastrectomy are eligible.

11. Unable or unwilling to swallow oral drugs as per dosing schedule.

12. Patients who have undergone major surgery = 4 weeks prior to first dose of study treatment or who have not recovered from the surgical procedure (mediastinoscopy, insertion of a central venous access device and insertion of a feeding tube are not considered major surgery).

13. Any medical condition that would, in the investigator’s judgment, prevent the patient’s participation in the clinical study due to safety concerns, compliance with clinical study procedures or interpretation of study results.

14. Use of hematopoietic growth factors or transfusion support = 2 weeks prior to start of study treatment. If growth factors were initiated more than 2 weeks prior to the first dose of study treatment and the patient is on a stable dose, they can be maintained.

15. History of hypersensitivity to any of the study treatments or its excipients (for the combination treatment arm: including to peanut and soy) or to drugs of similar chemical classes.

16. Patients taking prohibited therapies as listed in Section 6.6.2 that cannot be stopped within 7 days or 5 half-lives (whichever is longer) prior to study treatment and for the duration of the study treatment.

- Medications with a known risk to prolong the QT interval and/or known to cause TdP that cannot be discontinued or replaced by safe alternative medication
- Strong or moderate inhibitors or inducers of CYP3A4/5
- Substrates of CYP3A4/5 with a narrow therapeutic index
- Proton pump inhibitors (PPIs)
- Herbal products
- Other investigational and antineoplastic therapies

17. Women of childbearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant from menarche until becoming post-menopausal, unless they are using highly effective methods of contraception (failure rate < 1% per year) while taking study treatment and for 7 days plus six (6) months after the last dose of ECI830 if receiving ECI830 alone or in combination with ribociclib, or for 1 year after the last dose of fulvestrant or per approved local label requirements (e.g. fulvestrant USPI, SmPC) if receiving any combination treatment with fulvestrant. WOCBP must not donate eggs for 7 days + 6 months or 1 year after the last dose of study treatment as defined above.

Women are considered post-menopausal and not of childbearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age-appropriate [should be generally age = 40 years], history of vasomotor symptoms [e.g., hot flush]) in the absence of other medical justification or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy at least six weeks prior to enrollment on study. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment is she not considered to be of childbearing potential.

Highly effective contraception methods include:

- Total abstinence (when this is in line with the preferred and usual lifestyle of the patient). Note that periodic abstinence (e.g., calendar, ovulation, symptothermal, post ovulation methods) and withdrawal are not acceptable methods of contraception.
- Bilateral oophorectomy with or without hysterectomy, total hysterectomy or bilateral salpingectomy at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment are they considered to be not of childbearing potential.
- Bilateral tubal occlusion, bilateral tubal ligation (at least six weeks before taking study treatment)
- Sterilization (vasectomy) of male partner(s) of the female patient at least 6 months prior to screening provided partner(s) has(have) received medical confirmation of surgical success.
- For breast cancer patients: Placement of non-hormonal intrauterine device (IUD).
- For non-breast cancer patients: Placement of hormonal or non-hormonal IUD, or IUS, or hormonal vaginal ring.

Note: Use of oral (estrogen and progesterone), injected, or implanted hormonal methods of contraception or any other forms of hormonal contraception (which result in systemic exposure) is not allowed in this study.
If local regulations are more stringent than the contraception methods listed above, local regulations apply and will be described in the informed consent.

18. Sexually active males unwilling to use a condom during intercourse while taking study treatment and for 7 days + three (3) months after stopping study treatment. A condom is required for all sexually active male patients to prevent them from fathering a child AND/OR to prevent delivery of study treatment via seminal fluid to their partner.
In addition, male patients must not donate sperm for the time period specified above.
Male patients must inform female partner(s) of the potential risks of ECI830 and any combination study treatment and the requirement to use a method of highly effective contraception.

19. Pregnant or nursing (breast feeding) women.

- Age >= 18 years

- Indication for elective robotic assistend minimal invasive esophagectomy

- ASA I-III

- Verbal and written consent

- Ability to understand the content and scope of the course and to be able to implement it.

- Emergency Operation

- Participation in another study that interferes with the outcome of the study

- > ASA III

- ECOG > II

- chronic pain syndromes that require routine analgesic therapy

- Participation in an interventional study

- Major abdominal surgery for confirmed or suspected gastrointestinal malignancies
- Age >= 18 years
- Written informed consent

- American Society of Anesthesiologist (ASA) classification >= 4
- Planned re-operation within 30 days after index operation
- Mental impairment that prevents an understanding of nature, type and scope of the research project
- Allergies to rosemary oil (rosemary essential oil, virgin olive oil), citrus oil (citrus essential oil, virgin olive oil), solum oil (peat extract, lavender essential oil, horse chestnut extract, horsetail extract, virgin olive oil, white petrolatum, wool wax) or melissa oil (caraway essential oil, fennel essential oil, melissa, marjoram, refined peanut oil) as used oils for the integrative nursing interventions or hypersensitivity to skincare products
- Acute skin disorders at the abdomen or legs
- Emergency Operations
- Pregnancy or breastfeeding
- Participation in another interventional trial with interference on intervention and/or outcome of this trial
- Expected lack of compliance

The following criteria must be met to be eligible for the study:

1. Patient* has given written informed consent.

2. Patient is = 18 years of age at time of signing the written informed consent.

3. Patient has histologically proven locally advanced (cT2-4, any cN, M0 OR any cT, cN+, M0 stage) gastric, esophagogastric junction or lower esophageal adenocarcinoma that:
a. Is considered technically resectable
b. Does not involve distant sites of the peritoneal cavity
- confirmed by diagnostic laparoscopy for all patients with tumors located in the stomach and those with type 2 and 3 GEJ adenocarcinomas according to guideline recommendations [Lordick et al. 2022].
- Type 1 GEJ and lower esophageal tumors can be enrolled without diagnostic laparoscopy (which is in line with guidelines and the current routine practice in Germany)

4. Patient has a HER2 positive tumor (by local testing) defined by HER2 IHC 3+ or IHC 2+ plus ISH positive with a HER2:CEP17 ratio of = 2 according to classically used criteria for defining HER2 positivity [Lordick et al. 2017].

5. Patient has a ECOG performance status 0 or 1.

6. Patient has adequate blood count, liver-enzymes, and renal function:
1. ANC > 1,500 cells/µL without the use of hematopoietic growth factors
2. Platelet count = 100 x 10^9/L (>100,000 per mm^3)**
3. Hemoglobin = 9 g/dL**,
4. Serum total bilirubin = 1.5 x institutional upper normal limit (ULN)
5. AST (SGOT)/ALT (SGPT) = 2.5 x institutional ULN
6. 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
7. Serum Creatinine = 1.5 x ULN and a calculated creatinine clearance rate = 50 mL/min

7. 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 6 months after last dose of chemotherapy or 7 months after the last dose of T-DXd, whatever is later.

8. 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 4 months after last dose of T-DXd or up to 6 months after last dose of chemotherapy, whatever is later. Male patients must refrain from donating sperm during this same period

* There are no data that indicate special gender distribution. Therefore, patients will be enrolled gender independently in this trial
** 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 who meet at least one of the following criteria are ineligible:

1. Patient received previous (radio)chemotherapy or HER2-targeted therapy for the same condition or within the past five years for any other cancerous condition.

2. Patient received prior partial or complete esophagogastric tumor resection.

3. Patient has known hypersensitivity to any component of the T-DXd 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.

4. Patient has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.

5. 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.).

6. Patient received a prior complete pneumonectomy.

7. Patient has inadequate cardiac function (LVEF value < 50 %) as determined by echocardiography.

8. Patient has a known complete absence of dihydropyrimidine dehydrogenase (DPD) activity.

9. Patient received treatment with brivudine, sorivudine or their chemically related analogues within 28 days prior to stud enrollment.

10. Patient has pernicious anemia or other megaloblastic anemia due to vitamin B12 deficiency

11. Patient has peripheral sensitive neuropathy with functional deficits.

12. 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.

13. Patient has a corrected QT interval (QTc) prolongation to > 470 ms (females) or > 450 ms (males) based on average of the screening triplicate12-lead ECG.

14. Patient has a history of malignancy other than EGA except for:
a. Malignancy treated with curative intent and with no known active disease = 5 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.

15. Patient has an uncontrolled infection requiring IV antibiotics, antivirals or antifungals within 14 days prior to enrolment.

16. Patient has active primary immunodeficiency, known uncontrolled active HIV infection or active hepatitis B or C (HBV/HCV) infection. Patients positive for HCV antibody are eligible only if PCR is negative for HCV RNA. Subjects with past or resolved HBV infection are eligible only if they meet all of the following criteria:
- HBsAg(-) (for > 6 months off anti-viral treatment)
- Anti-HBc(+) (IgG or total Ig)
- HBV DNA undetectable
- Absence of cirrhosis or fibrosis on prior imaging or biopsy
- Absence of HCV co-infection or history of HCV co-infection
- Access to a local hepatitis B expert during and after the study

17. Patient has any autoimmune, connective tissue or inflammatory disorders (e.g., Rheumatoid arthritis, Sjogren's, sarcoidosis etc.) with a documented or suspected pulmonary involvement

18. Patient received live, attenuated vaccine within 30 days prior initiation of study drug

19. 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.

20. 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/ noninterventional study or during the follow-up period of an interventional study.

21. Patient has taken an investigational drug within 28 days prior to initiation of study drug.

22. Female patients, who are pregnant or breast feeding or planning to become pregnant within or up to 7 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.

- Alter = 18 Jahre

- Indikation zur elektiven, roboterassistierten minimal invasiven Ösophagektomie

- ASA I-III

- Mündliche und schriftliche Einwilligung

- Fähigkeit, den Studieninhalt und -umfang zu verstehen und diesen umsetzen zu können

- Teilnahme an einer anderen Studie, die das Studienergebnis beeinträchtigt

- > ASA III

- ECOG > II

- Teilnahme an einer interventionellen Studie

- Notfalloperation

1. Patients diagnosed with cancer

2. Patients planned to undergo or undergoing neoadjuvant treatment before planned curative resection

3. Adult patients (>= 18 years of age)

4. Written informed consent

5. Ability to understand character and individual consequences of the clinical trial

Additional for the online program

6. Stable internet connection

7. Laptop of similar

8. Poultieces utensils and utensils for the other applications

9. Sports mat or similar

1. Participation in another interventional trial with interference on intervention and outcome of this trial

2. Immobility or inability to walk unaided

3. Expected lack of compliance

Alter > 18 Jahre
Zustimmung zur Studienteilnahme
Geschäftsfähigkeit
elektive Operation an Pankreas, Leber, Magen oder Ösophagus
Verlegung von einer anästhesiologischen Überwachungsstation (PACU/IMC/Intensivstation) auf Normalstation

Zurückziehen der Einwilligung
Wunsch auf Studienbeendigung
Sprachbarriere
Verletzung beider Gehörgänge, Schwerhörigkeit beidseits
Intensivstationäre Therapie aufgrund eines Organversagens vor Randomisierung
Vorliegen einer palliativen Behandlungssituation
Ablehnung durch die Patienten

Participants are eligible to be included in the study only if all of the following criteria are met:

Signed Written Informed Consent

1) Participants must have signed and dated an IRB/IEC-approved written ICF in accordance with regulatory, local, and institutional guidelines. The study specific ICF and any optional ICFs (if applicable) must be obtained before performing any protocol-related procedures that are not part of normal patient care.

Note: Participants must agree to comply with the requirements and restrictions listed in the informed consent and in this protocol.

Type of Participant and Target Disease Characteristics

2) Previously untreated with systemic treatment for advanced/metastatic disease, histologically or cytologically confirmed advanced or metastatic GC, GEJC or distal EAC. GEJ involvement
can be confirmed via biopsy, endoscopy, or imaging.

Note: Prior adjuvant or neoadjuvant chemotherapy, immunotherapy with PD-(L)1 and/or chemoradiotherapy for GC, GEJC, or EAC are permitted if the last dose of treatment was completed > 12 months prior to diagnosis of recurrent or metastatic disease. Recruitment of this type of participant will be limited to 20% of total population. Palliative radiotherapy is allowed and must be completed 2 weeks prior to randomization.

3) Documented HER2-negative cancer, as determined according to local guidelines

4) Measurable disease as defined by RECIST v1.1.

5) ECOG performance status score of 0 or 1.

6) Tumor tissue requirements:
Fresh or archival (if obtained within 6 months prior to date of enrollment) must be submitted.
Tumor biopsy having significant risk to the safety and/or well-being of the participant should not be performed. Intervening systemic treatment or radiation to the site of tissue is not allowed. FFPE block specimens are preferred to slides. FFPE tissue blocks must contain sufficient tissue to support the minimum number of slides. If blocks cannot be provided, freshly cut sections (= 4 months old) must be submitted. A minimum of 15 unstained slides is required and must be cut sequentially from the same block; submission of 20 unstained slides is strongly recommended to enable important exploratory biomarker work. If despite best efforts, a minimum of 15 slides is not obtainable, submission of fewer slides may be acceptable upon discussion with the Medical Monitor. Tissue must be submitted prior to randomization for PD-L1 testing using the Sponsor-provided central test, exploratory biomarker testing, and additional CDx-related testing. In exceptional cases, tissue can be submitted after randomization upon discussion with the Medical Monitor.

See APPENDIX 6 for country-specific requirements.

Note: Core needle biopsy, punch biopsy, excisional biopsy, or surgical specimens are acceptable.

Note: Fine needle aspirates, pleural effusion drainage, other cytology samples, and biopsies of bone lesions are not acceptable.

7) Documented PD-L1 = 1 or < 1 status for Phase 2, and document PD-L1 = 1 status for the Phase 3 part of the study as determined by the Sponsor pre-approved local PD-L1 IHC assays or through Sponsor-provided central laboratory testing.

Age of Participant

8) Participant must be = 18 years of age at the time of signing the ICF.

Reproductive Status

Note: The investigator or designee shall counsel IOCBP participants (as defined in APPENDIX 3) and male (as assigned at birth) participants who are sexually active with IOCBP on the importance of pregnancy prevention, the implications of an unexpected pregnancy, and the potential of fetal toxicity occurring due to transmission of study intervention present in seminal fluid to a developing fetus, even if the participant has undergone a successful vasectomy or if the partner is pregnant.

Note: The investigator or designee shall evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention.

Note: Local laws and regulations may require the use of alternative and/or additional contraceptive methods.

Note: Study participants receiving study intervention have the potential risk of infertility, either temporary or permanent. The investigator or designee shall counsel participants on further information about locally available fertility preservation options including cryopreservation of gametes, prior to treatment as clinically appropriate.

9) Female (as assigned at birth) participants:

Note: Female (as assigned at birth) participants who are not of childbearing potential (as defined in APPENDIX 3) must have documented proof of reproductive status.

Note: Documentation can be obtained from the site personnel’s review of the participant’s medical records, medical examination, or medical history interview.

Note: Individuals who are not of childbearing potential are exempt from contraceptive requirements.

a) IOCBP must have a negative highly sensitive urine or serum as required by local regulations pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 (or up to 72) hours prior to the start of study intervention.

Note: If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.

Note: The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to potentially decrease the risk for inclusion of an individual with an undetected pregnancy.

b) IOCBP and male (as assigned at birth) participants who are sexually active with IOCBP must agree to follow instructions for method(s) of contraception as described below and included in the ICF.

(1) IOCBP are permitted to use hormonal contraceptive methods (as described in APPENDIX 3).

c) A female (as assigned at birth) is eligible to participate if they are not pregnant or breastfeeding and at least 1 of the following conditions applies:

(2) Is not an IOCBP
OR
Is an IOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), preferably with user independent methods, as described in APPENDIX 3, during the intervention period and for at least 9 monthsafter the last dose of study intervention and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction for the same period.

10) Male (as assigned at birth) participants

Note: A male (as assigned at birth) who is sexually active with IOCBP must agree to follow instructions for method(s) of contraception as described below and included in the ICF.

Note: Azoospermic males are not exempt from contraceptive requirements and will be required to always use a latex or other synthetic condom during any sexual activity (eg, vaginal, anal, oral) with IOCBP, even if the participant has undergone a successful vasectomy or if the partner is pregnant.

a) Male (as assigned at birth) participants are required to use a condom during the intervention period and for at least 6 months after the last dose of study intervention.

b) IOCBP partners of male (as assigned at birth) participants should be advised to use a highly effective method of contraception during the study intervention period and for at least 6 months after the last dose of study intervention for the male participant.

c) Male (as assigned at birth) participants with a pregnant or breastfeeding partner must agree to remain abstinent from sexual activity or use a male condom during any sexual activity (eg, vaginal, anal, oral) during the intervention period and for at least 6 months after the last dose of study intervention.

d) Male (as assigned at birth) participants must refrain from donating sperm during the intervention period and for at least 6 months after the last dose of study intervention.

e) Breastfeeding partners of male (as assigned at birth) participants should be advised to consult their health care provider about using appropriate highly effective contraception during the time the male participant is required to use condoms.

Participants are excluded from the study if any of the following criteria are met:

Medical Conditions

1) Untreated known CNS metastases.

Note: Participants are eligible if CNS metastases are adequately treated, and participants are neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment) for at least 2 weeks prior to randomization.

Note: Participants must have either discontinued corticosteroids or be on a stable or decreasing dose of = 10 mg prednisone (or equivalent) daily for at least 2 weeks prior to randomization.

Note: Baseline imaging required at screening must be performed 28 days after treatment for CNS metastases is completed. CNS metastases must be radiographically stable.

2) Active, known, or suspected autoimmune disease. A condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study intervention administration.
Inhaled or topical steroids, and adrenal replacement doses > 10 mg prednisone equivalents daily are permitted in the absence of active autoimmune disease.

Note: Participants with history of Grade >3 immune-mediated AEs leading to discontinuation of prior immunotherapy are excluded.

Note: Participants with Type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement, or skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment are permitted to enroll.

See APPENDIX 6 for country-specific requirements

3) Prior malignancy active within the previous 2 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast and considered to be of low risk of recurrence.

4) Significant cardiovascular disease, such as myocardial infarction, unstable angina, arterial thrombosis or cerebrovascular accident within 6 months prior to randomization, uncontrolled hypertension (= 160 systolic, = 100 diastolic mm Hg) despite optimal medical management.
Congenital long QT syndrome or QTc prolongation > 480 msec (the ECG can be repeated at the discretion of the investigator prior to randomization.

5) Major surgery or significant traumatic injury within 28 days prior to randomization, or anticipation of the need for major surgery during the course of study intervention.

6) Serious or non-healing wound, or (incompletely healed) bone fracture.

7) Evidence of major coagulation disorders (eg, hemophilia)

8) Clinically significant hematemesis or clinically significant GI hemorrhage within 28 days prior to randomization, or tumor lesions invading large vessels with significant risk of bleeding by investigator’s assessment.

9) History of deep vein thrombosis, pulmonary embolism, or any other significant thromboembolism within 3 months prior to randomization, unless the participant has been fully treated (eg, inferior vena cava filter placed) and/or adequately anticoagulated on a prophylactic dose.

Note: Participants receiving anticoagulation therapy at a stable dose may be eligible if their PT and aPTT values are stable and within the intended therapeutic range, and if hemorrhagic risk is assessed as low per investigator’s clinical judgement.

10) History of abdominal fistula or GI perforation within 6 months of randomization.

11) Known DPD deficiency.

Note: Systematic screening for DPD deficiency testing must be conducted where locally mandated (see APPENDIX 6 for country-specific requirements).

12) Any serious or uncontrolled medical disorder or active infection that, in the opinion of the investigator, may increase the risk associated with study participation, study intervention administration, or would impair the ability of the participant to receive study intervention.

Prior/Concomitant Therapy

13) Inability to comply with restrictions and prohibited treatments as listed in Section 7.7: Prior and Concomitant Therapy.

14) Treatment with botanical preparations (eg, herbal supplements or traditional Chinese medicines) with an antitumor indication intended to treat the disease under study within 2 weeks prior to randomization.

15) Participants who have received a live/attenuated vaccine within 30 days of randomization (eg, varicella, zoster, yellow fever, rotavirus, oral polio and measles, mumps, rubella).

16) Prior focal palliative radiotherapy must have been completed at least 14 days prior to randomization.

17) Current or recent (within 10 days prior to first dose of study intervention) ongoing treatment with therapeutic-dose anticoagulants.

Note: Prophylactic anticoagulation (eg, for DVT prophylaxis) is permitted if medically indicated.

Note: Participants receiving anticoagulation therapy at a stable dose may be eligible if their PT and aPTT values are stable and within the intended therapeutic range, and if hemorrhagic risk is assessed as low per investigator’s clinical judgement.

Reproductive Status

18) Participant is a IOCBP who is pregnant or breastfeeding, or who intends to become pregnant during participation in the study.

See APPENDIX 6 for country-specific requirementsPhysical and Laboratory Test Findings

19) Screening laboratory values must meet the following criteria:
a) Neutrophils < 1500/MikroL
b) Platelets < 100 x 10^3/MikroL
c) Hemoglobin < 9.0 g/dL
d) Serum albumin < 3.0 g/dL
e) CrCl< 40 mL/min (measured or calculated using the Cockcroft-Gault formula)
f) AST or ALT > 3.0 x ULN (or > 5.0 x ULN if liver metastases are present)
g) Total bilirubin > 1.5 x ULN (except participants with the history of Gilbert Syndrome, bilirubin level of = 3.0 x ULN)
h) Proteinuria = 2+ by urine dipstick or urinalysis at baseline.

Note: For participants with proteinuria = 2+ by urine dipstick or urinalysis at baseline, 24-hour urine must be collected. Proteinuria > 1g/24 hours is exclusionary. It is acceptable to estimate urine UPCR instead of 24-hour urine collection. UPCR > 1000 mg/g is exclusionary.
i) INR or PT aPTT > 1.5 x ULN

20) Active viral hepatitis, defined as follows:

a) Any positive test result for HBV indicating presence of virus (eg, HBsAg or HBV DNA) positive would be excluded.

Note: Participants with anti-hepatitis B antibodies attributed to prior vaccination or resolved infection are eligible to enroll.

See APPENDIX 6 for country-specific requirements.

b) Any positive test for HCV indicating presence of active viral replication (detectable HCV-RNA). Note: Participants with positive HCV antibody and an undetectable HCV RNA are eligible to enroll.

21) Known HIV infection or known AIDS, with the following exceptions:
a) Participants with CD4+ T cell counts = 350 cells/mL per local laboratory should generally be eligible for the study.
b) Participants who have not had an opportunistic infection within the past 12 months are eligible.

Note: Eligible participants should have adequate virological control and be on ART for at least 4 weeks prior to first dose and continue on ART therapy (as clinically indicated) while enrolled on-study.

Note: HIV testing must be conducted where locally mandated. HIV-positive participants must be excluded where mandated locally.

Allergies and Adverse Drug Reactions

22) History of allergy or hypersensitivity to study intervention components.

23) Any contraindications to nivolumab or any of the study chemotherapy regimen drugs selected by the investigator. Investigators should refer to local package insert of nivolumab and the chemotherapy drugs.

Other Exclusion Criteria

24) Prisoners or participants who are involuntarily incarcerated. (Note: Under certain specific circumstances and only in countries where local regulations permit, a person who has been imprisoned while on study may be permitted to continue as a participant. Strict conditions apply, and Sponsor approval is required.).

1. Patient* has signed and dated a written informed consent form in accordance with regulatory and institutional guidelines and approved by an institutional Review Board / Independent Ethics Committee. This must be obtained before the performance of any protocol-related procedures that are not part of normal subject care.

2. Patient is, in the investigator’s judgement, willing and able to comply with scheduled visits, treatment schedule, laboratory tests and other requirements of the study.

3. Patient is = 18 years of age at time of signing the written informed consent.

4. Patient has been diagnosed with histologically confirmed unresectable advanced/metastatic HER2-positive (defined as IHC 3+ or IHC 2+ with ISH+) and PD-L1- positive (combined positive score CPS = 1) gastroesophageal adenocarcinoma per local standard assessment of new or archival tumor tissue. Results of local HER2 and PD-L1 assessment will be retrospectively confirmed by central pathological re-assessment.
Note: In case of metachronous metastases, particularly in case of prior treatment with PD-(L)1-antibodies, a fresh re-biopsy should be performed for immunohistochemistry testing (local pathology), if feasible.

5. Patient has assessable disease (measurable or non-measurable) per RECIST v1.1.

6. Patient did not receive previous palliative treatment (exception: maximum of one cycle of standard of care treatment with a fluoropyrimidine/platinum based regimen +/- pembrolizumab is acceptable). Prior adjuvant or neoadjuvant chemotherapy, immunotherapy, radiotherapy and/or chemoradiotherapy (but not anti HER2-targeted treatment) are permitted as long as the last administration of the last regimen (whichever was given last) occurred at least 6 months prior to enrolment.

7. Patient has ECOG performance status = 1.

8. Patient has adequate hepatic, renal and hematologic functions:
a) Absolute number of neutrophils (ANC) = 1.5 x 10^9/L
b) Platelets = 100 x 10^3/MikroL
c) Serum creatinine = 1.5 x ULN or creatinine clearance (measured by 24 h urine) = 30 mL/min (i.e., if serum creatinine level is > 1.5 x upper limit of normal (ULN), then a 24-hour urine test must be performed to check the creatinine clearance to be determined.
d) AST (SGOT) and ALT (SGPT) = 3.0 x ULN (or = 5.0 x ULN if liver metastases are present)
e) Total Bilirubin = 1.5 x ULN (or < 3.0 x ULN in case of prior liver involvement or Gilbert’s Syndrome)

9. Patient has adequate coagulation function as defined by International Normalized Ratio (INR) = 1.5, and a partial thromboplastin time (PTT) = 5 seconds above the ULN (unless receiving anticoagulation therapy).

10. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of hCG) within 7 days prior to the start of study drug. Women must not be breastfeeding. WOCBP must use a highly effective method(s) of contraception during the treatment period and for 4 months after last dose of zanidatamab and/or pembrolizumab, or 6 months after the last dose of chemotherapy, whichever occurs last. Males who are sexually active with WOCBP must agree to remain abstinent or follow instructions for method(s) of contraception during the treatment and for 4 months after the last dose of zanidatamab and/or pembrolizumab, or 6 months after the last dose of chemotherapy, whichever occurs last. In addition, male subjects must be willing to refrain from sperm donation during this time.

* There are no data that indicate special gender distribution. Therefore, patients will be enrolled in the study gender-independently.

1. Patient has any known contraindication including allergy or hypersensitivity to the trial drugs or any constituent of the products as well as a known history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies.

2. Patient received prior anti HER2-targeted treatment for GEA.

3. Patient has malignancies other than the disease under study within 5 years prior to inclusion, except for those with a negligible risk of metastasis or death (e.g., expected 5-year OS > 90%) treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated surgically with curative intent, ductal carcinoma in situ treated surgically with curative intent).

4. Patient has untreated known CNS metastases. Patient is eligible, if previous CNS metastases are adequately treated and patient has neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment) for = 2 weeks prior to enrolment, and did not receive corticosteroids, or is on a stable or decreasing dose of < 10 mg daily prednisone (or equivalent) for = 2 weeks prior to inclusion.

5. Patient has abnormal baseline left ventricular ejection fraction (LVEF < 50%), assessed by echocardiogram, multigated acquisition (MUGA) scan, or cardiac magnetic resonance imaging (MRI) scan.

6. Patient has active, known, or suspected autoimmune disease. Exception: Subjects with Type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement, or skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment are permitted to enroll. For any cases of uncertainty, it is recommended that the medical expert/sponsor be consulted prior to signing informed consent.

7. Patient has a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of trial drug administration. Inhaled or topical steroids, and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.

8. Patient with persisting toxicity related to prior therapy (NCI CTCAE v.5.0 Grade > 1); however, alopecia, sensory neuropathy Grade = 2, or other Grade = 2 not constituting a safety risk based on investigator’s judgment are acceptable.

9. Patient with any serious or uncontrolled medical disorder or active infection that, in the opinion of the investigator, may increase the risk associated with trial participation, trial drug administration, or would impair the ability of the patient to receive trial drug.

10. Patient has significant acute or chronic infections including, among others:
- Any positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
- Any positive test result for hepatitis B virus or hepatitis C virus indicating acute or chronic infection.

11. Patient has history of allogeneic tissue / solid organ transplant.

12. Patient has been incarcerated or involuntarily institutionalized by court order or by the authorities § 40 Abs. 1 S. 3 Nr. 4 AMG.

13. Patient is unable to consent because he/she does not understand the nature, significance and implications of the clinical trial and therefore cannot form a rational intention in the light of the facts [§ 40 Abs. 1 S. 3 Nr. 3a AMG].

14. Patient has evidence of any other disease, neurologic or metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of any of the trial medications, puts the patient at higher risk for treatment-related complications or may affect the interpretation of trial results.

15. Patient currently participates in any other interventional clinical study within 30 days before the first administration of the investigational product or at any time during the trial, unless it is an observational (non-interventional) study, or during the follow-up period of an interventional study with last dose of investigational product =28 days prior to enrolment in this trial.

16. Patient has a known complete absence of dihydropyrimidine dehydrogenase (DPD) activity or use of any medications known to inhibit DPD (including brivudine, sorivudine and analogs) within 4 weeks prior to enrolment.

17. Female patients, who are pregnant or breast feeding or planning to become pregnant within and 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 trial treatment.