1) Signed Written Informed Consent

a) Participants or their legally acceptable representatives (see Appendix 2), must have signed and dated an (IRB)/Independent Ethics Committee (IEC)–approved written ICF in
accordance with regulatory, local, and institutional guidelines. This must be obtained before the performance of any protocol-related procedures that are not part of normal
patient care.

b) Participants must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study.

2) Type of Participant and Target Disease Characteristics

a) A fresh pre-treatment and on-treatment tumor biopsy must be provided for biomarkeranalysis. Participants must have a tumor that can be biopsied at an acceptable clinical risk
as judged by the investigator to be eligible. An unsuccessful fresh tumor biopsy at screening will not exclude participants from receiving study treatment. For participants in Parts 2A and 2B, a repeat biopsy at screening or on-treatment from the same or an alternative site will be required if clinically feasible (at the discretion of the investigator), and the initial attempt was unsuccessful in obtaining adequate tissue for biomarker analysis. Only 1 repeat attempt may be performed at each time point, if clinically feasible. An unsuccessful fresh tumor biopsy at screening (whether or not repeat is clinically feasible) will not exclude participants from receiving study treatment. Please refer to the laboratory manual for additionaldetails. The biopsy must be a core biopsy, an excisional biopsy, or a surgical specimen.

b) Participants must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (Appendix 5) and, in addition, have at least 1 lesion accessible for biopsy. Fine needle biopsy, cytology, and bone lesion biopsies are not acceptable.

c) Participants must have an Eastern Cooperative Oncology Group Performance Status of 0 or 1 (Appendix 6).

d) Participants must have experienced radiographically documented progressive disease on or after the most recent therapy.

e) Study participants will be expected to have received standard-of-care therapies (except forPart 1C, where participants with prior docetaxel use for the advanced/metastatic setting will be excluded), including an available PD-(L)1 inhibitor known to be effective in the tumor type for which they are being evaluated.

f) Participants must have advanced or metastatic disease and have received, be refractory to, not be a candidate for, or be intolerant to existing therapy(ies) known to provide clinical benefit for the condition of the participant. Eligible tumor types for each Part are listed below:
- Parts 1A and 1B: NSCLC, SCCHN, MSS-CRC, gastric/GEJ adenocarcinoma, cervical cancer (SCC or adenocarcinoma), RCC, UC, PDAC, melanoma, OC, orTNBC.
- Parts2A and 2B: NSCLC, SCCHN, gastric/GEJadenocarcinoma, orup to 3 additional tumor types from Parts 1A and 1B may be considered based on emerging data.
- Part 1C: NSCLC, SCCHN, gastric/GEJ adenocarcinoma, OC, or TNBC.

g) Participants with NSCLC:
i) Histologically confirmed NSCLC meeting stage criteria for stage IIIB, stage IV, or recurrent disease.
ii) Participants must have recurrent or progressive disease during or after platinum doublet-based chemotherapy for advanced or metastatic disease, OR must have recurrent or progressive disease within 6 months after completing platinum-based chemotherapy for local disease.
iii) Participants must have received and progressed on or after anti-PD-(L)1 therapy, if available.
iv) Status for actionable mutations (eg, epidermal growth factor [EGFR], anaplastic lymphoma kinase [ALK], ROS oncogene 1 [ROS1], rearranged during transfection [RET], etc.) must be known (when testing is available as per country/region standard of care practices); participants with actionable mutations must have received and progressed on, have been intolerant to, or not be a candidate for standard tyrosine kinase inhibitors (as available per country/region standard-of-care practices)

h) Participants with SCCHN:
i) Participants must have histologically confirmed, recurrent, or metastatic SCCHN (oral cavity, pharynx, larynx), andnot amenable to local therapy with curative intent. Any other cancers of the head and neck, including nasopharyngeal cancer, salivary gland, and neuroendocrine tumors, are excluded.
ii) Participants must have progressed on or after, or been intolerant to a platinum containing regimen.
iii) Prior curative radiation therapy must have been completed at least 4 weeks prior to first study drug administration. Prior focal palliative radiotherapy must have been completed at least 2 weeks before study drug administration.
iv) Historical human papillomavirus (HPV) status for oropharyngeal cancers must be documented. HPV status should have been determined using p16 immunohistochemistry (IHC) or HPV polymerase chain reaction (PCR).
v) Participants must have received and progressed on or after anti-PD-(L)1 therapy, if available.

i) Participants with MSS-CRC:

i) Participants must have received and then progressed on or after, or have been intolerant or refractory to at least 1 standard systemic therapy for metastatic and/or unresectable disease (or have progressed within 6 months of adjuvant therapy).
(1) Prior treatment with fluoropyrimidine, oxaliplatin, and irinotecan given as a single regimen or over multiple regimens is required.
(2) Prior treatment with an anti-angiogenic therapy (eg, bevacizumab) is required.

ii) Participants must have known MSI status or mismatch repair status.
(1) If the MSI molecular test and MMR IHC test results are both available, then both MSS and MMR proficiency will be required for study entry. Patients with MSIhigh or MSI-low or MMR deficiency will not be eligible.

iii) KRAS, NRAS and BRAF status, if known, should be documented.
(1) If RAS wild-type, prior treatment with an anti-EGFR therapy (eg, cetuximab or panitumumab) is required.

j) Participants with gastric/GEJ adenocarcinoma:

i) Participants must have received and then progressed, relapsed, or been intolerant to at least 1 standard treatment regimen in the advanced or metastatic setting (or have progressed within 6 months of adjuvant therapy).

ii) Participants with known human epidermal growth factor receptor 2 (HER2)-positive gastric cancer must have received prior treatment with a HER2 inhibitor (eg, trastuzumab).

iii) If available, MSI status or mismatch repair status should be documented.

k) Participants with cervical cancer (SCC or adenocarcinoma):

i) Must have received and then progressed, relapsed, or been intolerant to platinum-based chemotherapy with or without bevacizumab in the advanced or metastatic setting.

ii) If available, MSI status or mismatch repair status should be documented.

l) Participants with renal cell carcinoma (RCC):

i) Participants must have histologically confirmed, recurrent, or metastatic RCC, and not amenable to local therapy with curative intent.

ii) Participant had progression or refractory disease during or after at least 2 lines of therapy, including a prior anti-PD-(L)1 therapy.

m) Participants with urothelial carcinoma (UC):

i) Participants must have histologically confirmed, recurrent, or metastatic UC, and not amenable to local therapy with curative intent.

ii) Must have received and then progressed, relapsed, been intolerant to, or ineligible for at least 1 platinum-containing chemotherapy regimen OR be within 12 months of perioperative (neo-adjuvant or adjuvant) treatment with a platinum agent in the setting of cystectomy for localized muscle-invasive UC.

iii) Must be resistant or refractory to anti-PD-(L)1-based immunotherapy.

n) Participants with pancreatic adenocarcinomas (PDAC):

i) Participants must have histologically confirmed, recurrent, unresectable or metastatic PDAC, and not amenable to local therapy with curative intent.

ii) Participants must have received and progressed or been intolerant to (or not be a candidate for) at least 1 prior standard
chemotherapy.

o) Participants with melanoma:

i) Participants must have cutaneous, acral, mucosal, or unknown primary melanoma.Participants with uveal/ocular melanoma are not eligible.

ii) Participants must have histologically confirmed, recurrent, or metastatic melanoma, and not amenable to local therapy with curative intent.

iii) Participants must have received and then progressed, relapsed, or been intolerant to at least 1 standard treatment regimen in the advanced or metastatic setting, including a prior anti-PD-(L)1 therapy, if available.

iv) Participants must have known BRAF status. If indicated, participants must have been offered mutation-directed therapy that has proven survival benefit.

p) Participants with ovarian carcinomas (OC):

i) Participants must have histologically or cytologically confirmed, recurrent, or metastatic epithelial ovarian cancer, primary peritoneal carcinoma or fallopian tube cancer, and not amenable to local therapy with curative intent.

ii) Participants must have received and then progressed, relapsed, or been intolerant to platinum-based chemotherapy, OR must have recurrent or progressive disease within 6 months after completing platinum-based chemotherapy.

iii) Participants with BRCA1/2 mutation must have received treatment with a PARP inhibitor, if available.

q) Participants with triple negative breast cancer (TNBC):

i) Participants must have histologically confirmed, recurrent, or metastatic TNBC, and not amenable to local therapy with curative intent.

ii) Must have progression or refractory disease during or after at least 1 chemotherapy regimen for the treatment of locally advanced or metastatic disease.

iii) Participants with BRCA1/2 mutation must have received treatment with a platinum-containing regimen (if eligible) and a PARP inhibitor, if available.

iv) If PD-L1 positive (defined as combined positive score = 10), prior treatment with immune checkpoint inhibitor is required.

3) Age and Reproductive Status

Investigators shall counsel women of childbearing potential (WOCBP) on the importance of pregnancy prevention, the implications of an unexpected pregnancy, and the potential of fetal toxicity occurring due to transmission of study drug to a developing fetus.

- The investigator shall evaluate the effectiveness of the contraceptive method in relationship to the first dose of study treatment.

- Local laws and regulations may require the use of alternative and/or additional contraception methods.

a) Female Participants

i) Females, ages = 18 or local age of majority at the time of consent.

ii) Women who are not of childbearing potential are exempt from contraceptive requirements.

iii) Women participants must have documented proof that they are not of childbearing potential.

iv) WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [hCG]) within 24 hours prior to the start of study treatment. An extension up to 72 hours prior to the start of study treatment is permissible in situations where results cannot be obtained within the standard 24-hour window.

v) Additional requirements for pregnancy testing during and after study treatment are located in Section 2, Schedule of Activities.

vi) The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.

vii) WOCBP must agree to follow instructions for method(s) of contraception defined in Appendix 4 and as described below and included in the ICF.

viii) WOCBP are permitted to use hormonal contraception methods (as described in Appendix 4).

ix) A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least 1 of the following conditions applies:

(1) Is not a WOCBP OR

(2) Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, as described in Appendix 4 during the treatment period and for at least 3 months after the last treatment with BMS-986340 monotherapy or for at least 6 months after the last dose of study treatment if receiving BMS 986340 in combination with nivolumab or with docetaxel and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction for the same time period.

b) Male Participants

i) Males, age = 18 years or local age of majority at the time of consent.

ii) Male participants receiving BMS-986340 monotherapy and BMS-986340 in combination with nivolumab should maintain their usual practice with regard to contraception (if any); however, no specific contraceptive measures are required.

iii) Male participants receiving BMS-986340 in combination with docetaxel who are sexually active with a WOCBP must agree to follow instructions for method(s) of contraception as defined in Appendix 4 and as described below.

(1) Male participants will be required to always use latex or other synthetic condom during any sexual activity (eg, vaginal, anal, oral) with WOCBP, even if the participants have undergone a successful vasectomy or if their partner is already pregnant or breastfeeding. Males should continue to use a condom during the intervention period and for at least 3 months after the last dose of study intervention.

(2) Female partners of males participating in the study should be advised to use highly effective methods of contraception during the intervention period and for at least 3 months after the last dose of study intervention in the male participant.

(3) Male participants must refrain from donating sperm during the intervention period and for at least 3 months after the last dose of study intervention.

(4) Breastfeeding partners should be advised to consult their health care providers about using appropriate highly effective contraception during the time participant is required to use condoms.

1) Medical Conditions

a) Women who are pregnant or breastfeeding.

2) Medical History and Concurrent Diseases

a) Primary central nervous system (CNS) malignancy.

b) Untreated CNS metastases. Participants are eligible if CNS metastases have been treated and participants have neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment). In addition, participants must have been either off corticosteroids, or on a stable or decreasing dose of = 10 mg daily prednisone (or equivalent) for at least 2 weeks prior to the first dose of study treatment. Imaging performed within 28 days prior to the first dose of study treatment must document radiographic stability of CNS lesions and be performed after completion of any CNS-directed therapy

c) Leptomeningeal metastases.

d) Concurrent malignancy (present during screening) requiring treatment or history of prior malignancy active within 2 years prior to the first dose of study treatment (ie, participants with a history of prior malignancy are eligible if treatment was completed at least 2 years before the first dose of study treatment and the participant has no evidence of disease). Participants with history of prior early-stage basal/squamous cell skin cancer or noninvasive or in situ cancers who have undergone definitive treatment at any time are also eligible.

e) Participants with an active, known, or suspected autoimmune disease. Participants with type 1 diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.

f) Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) within 14 days or other immunosuppressive medications within 30 days of the first dose of study treatment. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.

g) Prior organ or tissue allograft.

h) Toxicity (except for alopecia) related to prior anti-cancer therapy and/or surgery, unless the toxicity is either resolved, returned to baseline or Grade 1, or deemed irreversible.

i) Any major surgery within 4 weeks of study drug administration. Participants must have recovered from the effects of major surgery or significant traumatic injury at least 14 days before the first dose of study treatment.

j) Uncontrolled or significant cardiovascular disease including, but not limited to, any of the following:

i) Myocardial infarction or stroke/transient ischemic attack within the past 6 months.

ii) Uncontrolled angina within the past 3 months.

iii) Any history of clinically significant arrhythmias (such as ventricular tachycardia,ventricular fibrillation, or torsades de pointes).

iv) History of other clinically significant heart disease (eg, cardiomyopathy, congestiveheart failure with New York Heart Association functional classification III to IV pericarditis or significant pericardial effusion).

v) Cardiovascular disease-related requirement for daily supplemental oxygen therapy.

vi) QT interval corrected for heart rate using Fridericia’s formula (QTcF) prolongation> 480 msec, except for right bundle branch block.

vii) History of myocarditis, regardless of etiology.

k) History of or with active interstitial lung disease or pulmonary fibrosis.

l) Evidence of active infection that requires systemic antibacterial, antiviral, or antifungal therapy = 7 days prior to the first dose of study treatment (except for viral infections that
are presumed to be associated with the underlying tumor type required for study entry).

m) Known human immunodeficiency virus (HIV) positive with an acquired immune deficiency syndrome (AIDS)-defining opportunistic infection within the last year, or a current CD4 count <350 cells/µL. Participants with HIV are eligible if:

i)They have received antiretroviral therapy for at least 4 weeks prior to the first dose of study treatment, as clinically indicated, while enrolled on study.

ii) They continue on antiretroviral therapy as clinically indicated while enrolled on study.

iii) CD4 counts and viral load are monitored per standard of care by a local health care provider.

NOTE: Testing for HIV must be performed at sites where mandated locally. HIV positive participants must be excluded where mandated locally.

n) Participants with serious or uncontrolled medical disorders.

o) Receipt of packed red blood cells or platelet transfusion within 2 weeks of the first dose of study treatment.

p) Any significant acute or chronic medical illness which would interfere with study treatment or follow-up.

q) Any known or underlying medical or psychiatric condition and/or social reason that, in the opinion of the Investigator or Sponsor, could make the administration of studytreatment hazardous to the participants or could adversely affect the ability of the participant to comply with or tolerate the study.

r) Any condition, including active or uncontrolled infection, or the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.

s) Previous SARS-CoV-2 infection within 10 days for mild or asymptomatic infections or 20 days for severe/critical illness prior to Cycle 1 Day 1.

i) Acute symptoms must have resolved, and, based on investigator assessment in consultation with the Medical Monitor, there are no sequelae that would place the participant at a higher risk of receiving study treatment.

3) Prior/Concomitant Therapy

a) Cytotoxic agents, unless at least 4 weeks have elapsed from last dose of prior anti-cancer therapy and prior to the first administration of study drug.

b) Non-cytotoxic agents, unless at least 4 weeks or 5 half-lives (whichever is shorter) have elapsed from the last dose of prior anti-cancer therapy and prior to the first administration of study drug. If 5 half-lives is shorter than 4 weeks, agreement with the Sponsor/Medical Monitor (or designee) is mandatory.

c) Prior immune therapy treatments, unless at least 4 weeks or 5 half-lives (whichever is shorter) have elapsed from the last dose of immune therapy and initiation of study therapy.
See Section 6.1 for additional requirements for prior immunotherapy treatments.

d) Treatment with any live / attenuated vaccine within 30 days of first study treatment.

e) Previous SARS-CoV-2 vaccine within 7 days of Cycle 1 Day 1. For vaccines requiring more than 1 dose, the full series (eg, both doses of a 2-dose series) should be completed prior to Cycle 1 Day 1, when feasible, and when a delay in Cycle 1 Day 1 would not put the study participant at risk.

f) Has participated in a study of an investigational agent and has received study therapy or has used an investigational device within 28 days or 5 half-lives (whichever is shorter) of administration of BMS-986340.

g) Treatment with complementary medications (eg, herbal supplements or traditional Chinese medicines) to treat the disease under study within 2 weeks prior to first study treatment. Refer to Section 7.7.1 for prohibited therapies.

h) Prior radiation therapy within 2 weeks prior to first study treatment. Participants must have recovered (ie, Grade = 1 or at baseline) from radiation-related toxicities prior to first study treatment.

i) Prior therapy with an anti-CCR8 antibody.

j) For Part 1C only: Participants must not have been previously treated with docetaxel in the unresectable or metastatic setting.

4) Physical and Laboratory Test Findings

a) White blood cells (WBC) < 2000/µL.

b) Neutrophils < 1500/µL (stable off any growth factor within 4 weeks of first study treatment administration).

c) Platelets < 100 x 10^3/µL (transfusion to achieve this level is not permitted within 2 weeks of first study treatment administration).

d) Hemoglobin < 9.0 g/dL (transfusion to achieve this level is not permitted within 2 weeks of first study treatment administration).

e) Serum creatinine > 1.5 x ULN, unless creatinine clearance = 40 mL/min (measured or calculated using the Cockroft-Gault formula).

f) Aspartate aminotransferase (AST)/alanine aminotransferase (ALT): > 3.0 x ULN. For participants in Part 1C receiving docetaxel: AST and/or ALT > 1.5 x ULN concomitant with alkaline phosphatase > 2.5 x ULN.

g) Total bilirubin > 1.5 x ULN (except participants with Gilbert’s syndrome, who must have a total bilirubin level of < 3.0 x ULN). For participants in Part 1C receiving docetaxel: total bilirubin > 1 x ULN.

h) Any positive test result for hepatitis B virus (HBV) indicating presence of virus; eg, hepatitis B surface antigen (HBsAg, Australia antigen) positive.

i) Any positive test result for hepatitis C virus (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

5) Allergies and Adverse Drug Reaction

a) History of allergy, hypersensitivity, or serious adverse reaction to monoclonal antibodies or related compounds.

b) History of life-threatening toxicity related to prior immune therapy (eg, anti-CTLA-4 or anti-PD-1/PD-L1 treatment or any other antibody or drug specifically targeting T cell co stimulation or immune checkpoint pathways) except those that are unlikely to re-occur with standard countermeasures (eg, hypothyroidism).

c) History of any significant drug allergy (such as anaphylaxis or hepatotoxicity) except for history of infusion reaction to paclitaxel or oxaliplatin.

d) History of allergy or hypersensitivity to study drug components.

6) Other Exclusion Criteria

a) Prisoners or participants who are involuntarily incarcerated. (Note: Under specific circumstances and only in countries where local regulations permit, a person who has been
imprisoned may be included as a participant. Strict conditions apply and BMS approval is required.)

b) Participants who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness.

Eligibility criteria for this study have been carefully considered to ensure the safety of the study participants and that the results of the study can be used. It is imperative that participants fully meet all eligibility criteria.

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.

Dose escalation

Participants are eligible to be enrolled in the dose escalation study only if all of the following criteria apply:

Demographic characteristics

1. Male or female participant aged = 18 years of age.

General criteria

2. Estimated life expectancy = 3 months.

3. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1

Sex and contraceptive/barrier requirements

4a. Women of childbearing potential (WOCBP) must use a highly effective method of birth control (described in Appendix 7) during study treatment and for at least 6 months after the last dose of S095035 when administered as a single agent, and for at least 7 months after the last dose when S095035 is given in combination with TNG462. In case of oral contraceptive use, women should have been stable on the same contraceptive drug (i.e., same active principle) for at least 3 months prior to the first IMP administration. Ovum donation will not be allowed during the study and for at least 6 months after the last dose of S095035 when administered as a single agent, and for at least 7 months after the last dose when S095035 is given in combination with TNG462.

5b. Male participants with WOCBP partners must use a condom during the study and until at least 3 months after the last dose of S095035 when administered as a single agent, and for at least 4 months after the last dose when S095035 is given in combination with TNG462. In addition, the same contraception duration should be considered for their female partners. Sperm donation will not be allowed during the study and for at least 3 months after the last dose of S095035 when administered as a single agent, and for at least 4 months after the last dose when S095035 is given in combination with TNG462.

Contraceptive measures do not apply if the participant is sterile, has undergone a vasectomy or hysterectomy or is sexually abstinent from heterosexual contact.

Please refer to Appendix 7 for further contraception considerations.

Informed consent

6. Obtained prior to any study-specific procedure as described in Section 13.3 of the protocol.

Medical and therapeutic criteria

7b. Participants with histologically confirmed advanced or metastatic solid tumors (excluding CNS tumors other than IDHwt glioblastoma [as per World Health Organization (WHO) 2021 classification]), with measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or Response Assessment in Neuro-oncology (RANO) 2.0 criteria for participants with IDHwt glioblastoma, that have progressed (documented disease progression) after receiving at least one prior treatment regimen given for advanced/metastatic disease, and for whom additional effective standard therapy is not available. For this study, effective standard therapy is defined as treatment that has been shown to be curative and/or to prolong survival. In addition, participants who are considered to not be candidates for standard therapy are eligible for this study; in such cases, documentation of the reason for omitting a standard therapy is required.

8. Participants with pre-existing documented MTAP homozygous gene deletion in their tumor tissue, determined using an NGS IVD test (please refer to the laboratory manual for the tests authorized by the Sponsor in the frame of this clinical study) prior to screening.

9a. Participants, except those with IDHwt glioblastoma, must be willing to provide newly collected tumor biopsies prior to Cycle 1 Day 1 (C1D1), and while receiving treatment (i.e., at C1D28 +/- 6 days) unless not medically feasible. Participants with IDHwt glioblastoma must provide archival tissue from their most recent surgery or biopsy, collected before screening.

10. Adequate hematological function based on the last assessment performed within 7 days prior to the first IMP administration, defined as:
- Absolute neutrophil count (ANC) = 1.10^9/L.
- Hemoglobin = 9 g/dL. In case of blood transfusion, the hemoglobin assessment must be performed 2 weeks or more after the transfusion.
- Platelet count = 100 x 10^9/L.

11a. Adequate coagulation function, defined as international normalized ratio (INR), prothrombin time (PT) or activated partial thromboplastin time (aPTT) = 1.5 x the upper limit of normal (ULN) unless participant is receiving anticoagulant therapy and the PT or aPTT is within the therapeutic range for such anticoagulants. For participants receiving coumadin/warfarin, the INR should be determined and = 2.0 x ULN.

12a. Adequate renal function, defined as a glomerular filtration rate (GFR) or creatinine clearance (CrCl) =60 mL/min, must be confirmed based on the most recent assessment conducted within 7 days prior to the first administration of IMP. Renal function may be assessed using the Cockcroft-Gault formula, the Modification of Diet in Renal Disease (MDRD) formula, or the Chronic Kidney Disease Epidemiology Collaboration (CKD EPI) formula.

13. Adequate hepatic function based on the last assessment performed within 7 days prior to the first IMP administration, defined as:
- Total serum bilirubin <- 1.5 x ULN.
- Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) < 3 x ULN.
- AST and/or ALT = 5 x ULN if increase due to underlying liver metastasis.

36. Participants with IDHwt glioblastoma must be stable. If they are on corticosteroids for reasons related to their CNS tumor, they must be on a stable or decreasing dose (= 4mg/day of dexamethasone or equivalent) for = 5 days before the first IMP administration.

Dose expansion

Participants are eligible to be enrolled in one of the single-agent or combination dose expansion Arms only if they meet all of the inclusion criteria listed in Section 5.1.1, unless otherwise specified, as well as the criteria (general and cohort-specific) listed below:

37. Participants in dose expansion, except those with IDHwt glioblastoma, must provide newly collected tumor biopsies at screening, unless not medically feasible and archival tissue was collected within 3 months before study entry and no treatment has been received since the most recent biopsy.

38. Participants with IDHwt glioblastoma must provide archival tissue from their most recent surgery or biopsy, collected before screening, even if that occurred > 3 months before study entry.

Inclusion criteria specific to S095035 single-agent dose expansion

Arm 1a:

39b. Participants with histologically or cytologically confirmed metastatic or unresectable locally advanced NSCLC with homozygous deletion of MTAP, with measurable disease as per RECIST version 1.1, who have progressed or experienced disease recurrence during or after at least 1 prior line of standard-of-care systemic therapy in the advanced/metastatic setting. Participants must have exhausted available standard-of-care treatments known to be beneficial for this tumor type or would be unlikely to tolerate or derive clinically benefit from available standard-of-care therapy, and for whom this trial is a reasonable option. Prior neoadjuvant or adjuvant systemic therapy may be considered for eligibility only if the participant progressed during or within 6 months of completing the therapy.

Arm 1b:

40b. Participants with histologically or cytologically confirmed metastatic or unresectable locally advanced BTC with homozygous deletion of MTAP, with measurable disease as per RECIST version 1.1, who have progressed or experienced disease recurrence during or after at least 1 prior line of standard-of-care systemic therapy in the advanced/metastatic setting. Participants must have exhausted available standard-of-care treatments known to be beneficial for this tumor type or would be unlikely to tolerate or derive clinically benefit from available standard-of-care therapy, and for whom this trial is a reasonable option. Prior neoadjuvant or adjuvant systemic therapy may be considered for eligibility only if the participant progressed during or within 6 months of completing the therapy.

Arm 1c:

41b. Participants with histologically or cytologically confirmed metastatic or unresectable locally advanced PDAC with homozygous deletion of MTAP, with measurable disease as per RECIST version 1.1, who have progressed or experienced disease recurrence during or after at least 1 prior line of standard-of-care systemic therapy in the advanced/metastatic setting. Participants must have exhausted available standard-of-care treatments known to be beneficial for this tumor type or would be unlikely to tolerate or derive clinically benefit from available standard-of-care therapy, and for whom this trial is a reasonable option. Prior neoadjuvant or adjuvant systemic therapy may be considered for eligibility only if the participant progressed during or within 6 months of completing the therapy.

Arm 1d:

42b. Participants with locally advanced or metastatic malignancies with homozygous deletion of MTAP, with measurable disease as per RECIST version 1.1 or RANO 2.0 criteria for participants with IDHwt glioblastoma, who have received and progressed of experienced recurrence during or after receiving at least 1 prior line of standard-of-care systemic therapy in the advanced/metastatic setting. Participants must have exhausted available standard-of-care treatments known to be beneficial for this tumor type or would be unlikely to tolerate or derive clinically benefit from available standard-of-care therapy, and for whom this trial is a reasonable option. Enrollment in Arm 1d will be limited to the following tumor types: IDHwt glioblastoma (as per WHO 2021 classification), gastroesophageal cancer, urothelial cancer, head and neck (including salivary) cancers, and melanoma. However, other locally advanced or metastatic homozygously MTAP deleted solid tumor types may be considered following discussion with the Sponsor. Prior neoadjuvant or adjuvant systemic therapy may be considered for eligibility only if the participant progressed during or within 6 months of completing the therapy.

Inclusion criteria specific to S095035–TNG462 combination dose expansion

Arm 2a:

43b. Participants with histologically or cytologically confirmed metastatic or unresectable locally advanced BTC with homozygous deletion of MTAP, with measurable disease as per RECIST version 1.1, who have progressed or experienced disease recurrence during or after receiving at least 1 prior line of standard-of care systemic therapy in the advanced/metastatic setting. Participants must have exhausted available standard-of-care treatments known to be beneficial for this tumor type or would be unlikely to tolerate or derive clinically benefit from available standard-of-care therapy, and for whom this trial is a reasonable option. Prior neoadjuvant or adjuvant systemic therapy may be considered for eligibility only if the participant progressed during or within 6 months of completing the therapy.

Arm 2b:

44b. Participants with histologically or cytologically confirmed metastatic or unresectable locally advanced gastroesophageal cancer with homozygous deletion of MTAP, with measurable disease as per RECIST version 1.1, who have progressed or experienced disease recurrence during or after receiving at least 1 prior line of standard-of-care systemic therapy in the advanced/metastatic setting. Participants must have exhausted available standard-of-care treatments known to be beneficial for this tumor type or would be unlikely to tolerate or derive clinically benefit from available standard-of-care therapy, and for whom this trial is a reasonable option. Prior neoadjuvant or adjuvant systemic therapy may be considered for eligibility only if the participant progressed during or within 6 months of completing the therapy.

Arm 2c:

45b. Participants with histologically or cytologically confirmed metastatic or unresectable locally advanced PDAC with homozygous deletion of MTAP, with measurable disease as per RECIST version 1.1, who have progressed or experienced disease recurrence during or after receiving at least 1 prior line of standard-of-care systemic therapy in the advanced/metastatic setting. Participants must have exhausted available standard-of-care treatments known to be beneficial for this tumor type or would be unlikely to tolerate or derive clinically benefit from available standard-of-care therapy, and for whom this trial is a reasonable option. Prior neoadjuvant or adjuvant systemic therapy may be considered for eligibility only if the participant progressed during or within 6 months of completing the therapy.

Dose escalation

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

General criteria

14. Inability to take an orally administered drug, or medical disorder or prior surgical resection that may affect the absorption of the IMP. Examples of medical conditions that may affect IMP absorption include (but are not limited to) inflammatory bowel disease (e.g., Crohn’s disease) and gastrointestinal diseases such as ulcerative diseases, uncontrolled nausea, vomiting, diarrhea and malabsorption syndrome.

15. Pregnant or lactating women.

16. WOCBP who have a positive pregnancy test within 7 days prior to the first day of IMP administration.

17. Unlikely to cooperate in the study.

18. Participation in another interventional study at the same time or less than 5 half-lives of the investigational drug of the other study. Participation in non-interventional registry or epidemiological studies is allowed.

19. Participant already enrolled in the study (informed consent signed) who had received at least 1 dose of IMP.

Medical and therapeutic criteria

20. Active second primary malignancy other than non-melanoma skin cancers, nonmetastatic prostate cancer, in situ cervical cancer, ductal or lobular carcinoma in situ of the breast, or other malignancy that the Sponsor’s Medical monitor and investigator agree and document that it should not be exclusionary.

21. Known prior severe hypersensitivity to any component of the IMP(s) formulation.

22. Failure to recover to = Grade 1 (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI-CTCAE] version 5.0) from acute non-hematologic toxicity (or to = Grade 2 for neuropathy or alopecia), due to previous therapy, prior to screening.

23. Major surgery within 4 weeks prior to the first IMP administration or participants who have not recovered from side effects of the surgery.

24. Have a known history of Gilbert’s syndrome.

25. History of gastrointestinal perforation and /or fistula or aorto-esophageal fistula within 6 months prior to first IMP intake.

26. Severe or uncontrolled active acute or chronic infection.

27. Participants with a known clinically significant cardiovascular disease or condition, including:
- Uncontrolled arterial hypertension per the investigator’s judgment.
- Congestive heart failure (corresponding to New York Heart Association class III or IV).
- Congenital or substance-induced long QT defined as heart rate–corrected QT (QTc) interval > 470 ms according to Frederica’s formula.
- Uncontrolled cardiac arrhythmia (e.g., participants with rate-controlled atrial fibrillation are eligible).
- Severe conduction disturbances (e.g., 3rd degree heart block).
- Acute coronary syndrome (including unstable angina pectoris, acute myocardial infarction), coronary angioplasty or bypass grafting within 6 months prior to the first IMP administration.

28. Participants with thrombosis, or a history of deep vein thrombosis or pulmonary embolism, within 4 weeks prior to first IMP administration.

29. Active brain metastases, i.e., symptomatic brain metastases or known leptomeningeal disease. Asymptomatic brain metastases are allowed if they meet the following criteria:
- Have been treated and have been stable for = 4 weeks as documented by radiographic imaging.
- Have not required increasing doses of corticosteroids within 2 weeks prior to initiation of study treatment.
- Participants who have had complete surgical resection or received stereotactic radiosurgery or whole brain radiotherapy may enroll in the study provided that they have completed treatment > 2 weeks prior to initiation of study treatment, have recovered, are clinically/neurologically stable and do not require escalating corticosteroid therapy as noted above. If local treatment was completed > 4 weeks prior to study entry, participants must not have new findings on CNS imaging.

30. Participants who have received systemic anticancer treatment or radiotherapy less than 2 weeks before the first dose of IMP. Continuation of supportive therapy with bisphosphonates or denosumab is allowed, regardless of the underlying malignancy.

31. Any clinically significant medical condition (e.g., organ dysfunction) or laboratory abnormality likely to jeopardize the participant’s safety or to interfere with the conduct of the study, in the investigator’s opinion.

32. Participants who have already received a MAT2A or PRMT5 inhibitor.

33. For prohibited concomitant medication, refer to Section 6.3.

35. A medical condition that results in increased clinically significant photosensitivity (e.g., solar urticaria, lupus erythematosus, etc.).

- 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

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.

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

- Patientinnen und Patienten, die eine viszeralchirurgische Operation mit kurativer In-tention aufgrund eines primären oder sekundären Malignom erhalten

- vorliegender Tumorboardbeschluss

- Alter = 18 Jahre

- Mündliche und schriftliche Einwilligungserklärung

- Schwangerschaft

- ASA = 4

- Geistige Einschränkung, welche eine Erfassung von Wesen, Art und Umfang des For-schungsprojekt verhindert

- Zu erwartende fehlende Wahrnehmung der Empfehlungen

- Fehlende Einwilligungsfähigkeit

- Teilnahme an einer anderen Studie, die das Studienergebnis beeinträchtigt

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

1. Age 18 years or above

2. Planned elective esophagectomy, gastrectomy, colectomy, rectal resection, pancreatic resection, or hepatectomy

3. Adequate renal function with serum creatinine < 250 µmol/L (2.82 mg/dL)

4. The patient has the capability to understand the character and individual consequences of trial participation

5. Written informed consent obtained before randomization

6. Negative pregnancy test for women of childbearing potential within 72 hours of commencing study treatment. Females of reproductive potential must agree to practice highly effective contraceptive measures during the study. These comprise measures with a failure rate of < 1% per year when used consistently and correctly, such as in travaginal and transdermal combined (oestrogen and progestogen containing) hormonal contraception, injectable and implantable progestogen-only hormonal contraception, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion; vasectomised partner, sexual abstinence (defined as refraining from heterosexual intercourse during the entire study period).

1. Severe anaemia, defined as a haemoglobin concentration <8 g/dL (< 5 mmol/L) or anaemia with haemoglobin concentration = 8 to < 10 g/dL (= 5.0 < to < 6.2 mmol/l) and one or several of the following symptoms suggesting hypoxemia:
- Clinical signs of tachycardia, e.g., resting heart rate > 100 beats/minute, palpitation etc.
- Clinical signs of hypotension, e.g., resting systolic blood pressure < 100 mmHg, orthostatic dysregulation etc.
- Clinical signs of dyspnea, e.g., speech dyspnea, resting respiratory rate > 20 breaths/min.

2. Thrombocytopenia with platelets < 60 x 10^9 /L

3. Confirmed bleeding disorder with the need for specific preventive perioperative treatment (e.g., factor deficiency with the need of perioperative substitution)

4. A priori refusal of blood transfusions

5. Confirmed thrombophilia with a pertinent need for perioperative anticoagulation

6. Allergy / hypersensitivity to TXA

7. Recent (< 30 days) thromboembolic event

8. History of medically confirmed convulsions

9. In female subjects: pregnancy or lactation.

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. 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:
f) Absolute number of neutrophils (ANC) = 1.5 x 10^9/L
g) Platelets = 100 x 10^3/µL
h) 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.
i) AST (SGOT) and ALT (SGPT) = 3.0 x ULN (or = 5.0 x ULN if liver metastases are present)
j) 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 Paragraph 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 [Paragraph 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.