* Participant has received other investigational agents, or antineoplastic therapy including other immunotherapy or devices concurrently or within 21 days or 5 times the half-life, whichever is shorter, prior to first dose of study intervention administration.
* Participant has any condition which makes the participant unsuitable for study participation.
* Participant has known immediate or delayed hypersensitivity or contraindication to any component of study intervention.
* Participant has had prior severe allergic reaction or intolerance to known ingredients of ASP2138 or other antibodies, including humanized or chimeric antibodies.
* Participant weighs < 40 kg.
* Participant has received systemic immunosuppressive therapy, including systemic corticosteroids 14 days prior to first dose of study intervention. Participant using a physiologic replacement dose of hydrocortisone or its equivalent (defined as up to 10 mg per day of prednisone or equivalent), receiving a single daily dose of systemic corticosteroids or receiving systemic corticosteroids as pre-medication for radiologic imaging contrast use are allowed.
* Participant has a complete gastric outlet syndrome or a partial gastric outlet syndrome with persistent/recurrent vomiting.
* Participant has significant gastric bleeding &/or untreated gastric ulcers that exclude the participant from participation.
* Participant has symptomatic CNS metastases or participant has evidence of unstable CNS metastases even if asymptomatic (e.g., progression on scans). Participants with previously treated CNS metastases are eligible, if they are clinically stable & have no evidence of CNS progression by imaging for at least 4 weeks prior to start of study intervention & are not requiring immunosuppressive doses of systemic steroids (> 10 mg per day of prednisone or equivalent) for longer than 2 weeks.
* Participant is known to have HIV infection. However, participants with cluster of differentiation (CD4) + T cell counts >= 350 cells/µL & no history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections within the past 6 months are eligible. NOTE: Screening for human immunodeficiency virus (HIV) infection should be conducted per local requirements.
* Participant is known to have active hepatitis B (positive hepatitis B surface antigen [HBsAg]) or hepatitis C infection. Testing is required for known history of these infections or as mandated by local requirements. NOTE: Screening for these infections should be conducted per local requirements.
* For participant who is negative for HBsAg, but hepatitis B core antibody (HBc Ab) positive, a hepatitis B virus (HBV) deoxyribonucleic acid (DNA) test will be performed & if positive the participant will be excluded.
* Participant with positive hepatitis C virus (HCV) serology, but negative HCV ribonucleic acid (RNA) test results are eligible.
* Participant treated for HCV with undetectable viral load results are eligible
* Participant has had within 6 months prior to first dose of study intervention any of the following: unstable angina, myocardial infarction, ventricular arrhythmia requiring intervention or hospitalization for heart failure.
* Participant has active infection requiring systemic therapy that has not completely resolved within 7 days prior to the start of study intervention.
* Participant has active autoimmune disease that has required systemic immunosuppressive treatment within the past 1 month prior to the start of study intervention.
* Participant has a clinically significant disease or co-morbidity that may adversely affect the safe delivery of treatment within this study or make the participant unsuitable for study participation.
* Participant has psychiatric illness or social situations that would preclude study compliance.
* Participant has had a major surgical procedure 28 days before start of study intervention & has not fully recovered.
* Participant has received radiotherapy metastatic or for locally advanced unresectable gastric/GEJ or metastatic pancreatic adenocarcinoma 14 days prior to start of study intervention & has NOT recovered from any related toxicity.
* Participant has another malignancy for which treatment is required.
* Participant who has received CLDN18.2-targeted therapy (e.g., zolbetuximab or chimeric antigen receptor CLDN18.2-specific T cells) prior to first dose of study intervention administration is not eligible for dose escalation cohorts. However, a participant who has received CLDN18.2-targeted therapy greater than 28 days or 5 half-lives (whichever is longer) prior to first dose study intervention administration is eligible for dose expansion cohorts only, with the exception of participants who have experienced Grade >= 3 gastrointestinal toxicity after receiving an CLDN18.2-targeted therapy.
* Participant has a history or complication of interstitial lung disease.
Participant who has received treatment with herbal medications that have known antitumor activity within 28 days prior to first dose of study treatment.
For all participants in CT administration:
* Participant has prior severe allergic reaction; suspected, known immediate or delayed hypersensitivity; or intolerance or contraindication to any study intervention (i.e., pembrolizumab & mFOLFOX6 [all components], ramucirumab & paclitaxel or mFOLFIRINOX [all components]).
* For 5 FU (fluorouracil): Participant has known dihydropyrimidine dehydrogenase (DPD) deficiency. (NOTE: Screening for DPD deficiency should be conducted per local requirements).
* Participant is known to have HIV infection.
* NOTE: Differing from monotherapy administration, participants with CD4+ T cell counts ≥ 350 cells/µL & no history of AIDS-defining opportunistic infections within the past 6 months remain ineligible.
* NOTE: Screening for HIV infection should be conducted per local requirements.
* Participant has had uncontrolled high blood pressure within 6 months prior to the first dose of study intervention (Unique to EU: high blood pressure Stage 2 is defined as ≥ 140/90 mmHg).
* Participant has a history of ascites requiring drainage more than twice in the past 7 days.
CTDS Exclusion Criteria: ASP2138 in Combination with Pembrolizumab & mFOLFOX6 as First-line Therapy in Gastric/GEJ Cancer:
* Participant has history of (non-infectious) pneumonitis that required steroids, current pneumonitis, or has a history of interstitial lung disease.
* Participant received live-virus vaccination within 30 days prior to the first dose of study intervention.
* Participant has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study intervention or has been diagnosed with an autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Patients that require replacement therapy (e.g., thyroxine [T4], insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) may be enrolled.
CTDS Exclusion Criteria: ASP2138 in Combination with Ramucirumab & Paclitaxel as Second-line Therapy in Gastric/GEJ Cancer:
* History of cerebrovascular accident or transient ischemic attack within 6 months prior to study intervention.
* Participant has significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to study intervention.
* Participant has evidence of a bleeding diathesis or significant coagulopathy.
* Participant has initiated new treatment with medications that affect the coagulation cascade with an INR ≥ 2 such as vitamin K antagonists, heparins & direct thrombin inhibitors or the use of factor Xa inhibitors within 28 days prior to the start of study intervention.
Note: If the participant started receiving such medications more than 28 days prior to the start of study intervention & needs to continue, this is allowed. However, new anticoagulation medications may not be initiated within 28 days prior to the start of study intervention.
For All Participants in ASP2138 in Combination with Pembrolizumab & CAPOX:
* Participant has prior severe allergic reaction; suspected, known immediate or delayed hypersensitivity; or intolerance or contraindication to any study intervention (i.e., pembrolizumab & CAPOX [all components]).
* Participant is known to have HIV infection.
* NOTE: Differing from monotherapy administration, participants with CD4+ T cell counts ≥ 350 cells/μL & no history of AIDS-defining opportunistic infections within the past 6 months remain ineligible.
* NOTE: Screening for HIV infection should be conducted per local requirements.
* Participant has had uncontrolled high blood pressure within 6 months prior to the first dose of study intervention.
* Participant has a history of ascites requiring drainage more than twice in the past 7 days.
* Participant has known DPD deficiency. (NOTE: Screening for DPD deficiency should be conducted per local requirements).
ASP2138 in Combination with Pembrolizumab & CAPOX as First-line Therapy in Gastric/GEJ Cancer:
* Participant has history of (noninfectious) pneumonitis that required steroids, current pneumonitis, or has a history of interstitial lung disease.
* Participant received live-virus vaccination within 30 days prior to the first dose of study intervention.
* Participant has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study intervention or has been diagnosed with an autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Participants who require replacement therapy (e.g., thyroxine [T4], insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) may be enrolled.