A Study of ASP2138 Together With Chemotherapy and Pembrolizumab in Adults With Gastric Cancer

Inclusion Criteria:

* Participant has histologically or cytologically confirmed gastric or GEJ adenocarcinoma.
* Participant has radiographically confirmed, locally advanced unresectable or metastatic disease within 28 days prior to randomization.
* Participant has predicted life expectancy \>= 12 weeks.
* Female participant is not pregnant and at least 1 of the following conditions apply:

  * Not a women of childbearing potential (WOCBP)
  * WOCBP who has a negative serum pregnancy test at screening and agrees to follow the contraceptive guidance from the time of informed consent through at least 9 months after the final oxaliplatin administration and 6 months after the final administration of all other study intervention. (Note: For screening, participants with elevated serum human chorionic gonadotropin (HCG) and a demonstrated nonpregnant status through additional testing are eligible.)
* Female participant must not be breastfeeding or lactating starting at screening and throughout the investigational period, and at least 9 months after the final oxaliplatin administration and 6 months after the final administration of all other study intervention.
* Female participant must not donate ova starting at first administration of study intervention and throughout the investigational period, and for 9 months after the final oxaliplatin administration and 6 months after the final administration of all other study intervention.
* Male participant must agree to use contraception with female partner(s) of childbearing potential (including breastfeeding partner) throughout the treatment period and for 6 months after the final administration of study intervention.
* Male participant must agree to remain abstinent or use a condom with pregnant partner(s) for the duration of the pregnancy throughout the investigational period and for 6 months after the final administration of study intervention.
* Male participant must not donate sperm during the treatment period and for 6 months after the final administration of study intervention.
* Participant has radiologically evaluable disease (measurable and/or non measurable) according to RECIST V1.1, per investigator assessment, \<= 28 days prior to randomization. For participants with only 1 evaluable lesion and prior radiotherapy \<= 3 months before randomization, the lesion must either be outside the field of prior radiotherapy or have documented progression following radiation therapy.
* Participant's tumor is HER2-negative (HER2 immunohistochemistry (IHC) score 0+/1+ or HER2 IHC score 2+/in situ hybridization (ISH) negative) as determined by local or central testing.
* Participant has provided an formalin-fixed paraffin-embedded (FFPE) tumor sample which meets the requirements of the study as specified in the laboratory manual.
* Participant has CLDN18.2-positive tumor as determined by central testing.
* Participant has a valid programmed death-ligand 1 (PD-L1) result as determined by central testing of a tumor sample.
* Participant with known microsatellite instability-high or mismatch repair deficient status may enroll as long as their tumor expresses PD-L1 combined positive score (CPS) \>= 1 as determined by central IHC testing.
* Participant has ECOG performance status 0 to 1.
* Participant must meet all of the criteria based on the centrally or locally analyzed laboratory tests collected within 14 days prior to randomization. In case of multiple central laboratory data within this period, the most recent data should be used (transfusion is allowed, but posttransfusion hemoglobin \[24 hours or later following transfusion\] must be \>= 9 g/dL).

South Korea Specific:

* Participant is \>= 19 years of age at the time of signing informed consent.
* Female participant is not pregnant and at least 1 of the following conditions apply:

  * Not a WOCBP
  * WOCBP who has a negative serum pregnancy test at screening and agrees to follow the contraceptive guidance from the time of informed consent through at least 15 months after the final oxaliplatin administration and 6 months after the final administration of all other study intervention. (Note: For screening, participants with elevated serum HCG) and a demonstrated nonpregnant status through additional testing are eligible.)
* Female participant must not be breastfeeding or lactating starting at screening and throughout the investigational period, and at least 15 months after the final oxaliplatin administration and 6 months after the final administration of all other study intervention.
* Female participant must not donate ova starting at first administration of study intervention and throughout the investigational period, and for at least 15 months after the final oxaliplatin administration and 6 months after the final administration of all other study intervention.
* Male participant must agree to use contraception with female partner(s) of childbearing potential (including breastfeeding partner) throughout the treatment period, and for 12 months after the final oxaliplatin administration and 6 months after the final administration of all other study intervention.
* Male participant must agree to remain abstinent or use a condom with pregnant partner(s) for the duration of the pregnancy throughout the investigational period and for 12 months after the final oxaliplatin administration and 6 months after the final administration of all other study intervention.
* Male participant must not donate sperm during the treatment period and for 12 months after the final oxaliplatin administration and 6 months after the final administration of all other study intervention.

Japan Specific:

* Female participant is not pregnant and at least 1 of the following conditions apply:

  * Not a WOCBP
  * WOCBP who has a negative serum pregnancy test at screening with a medical interview and agrees to follow the contraceptive guidance from the time of informed consent through at least 9 months after the final oxaliplatin administration and 6 months after the final administration of all other study intervention. (Note: For screening, participants with elevated serum HCG and a demonstrated nonpregnant status through additional testing are eligible.)

Exclusion Criteria:

* Participant has mixed histology or non-adenocarcinoma gastric or GEJ cancer.
* Participant has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable (i.e., without evidence of progression) for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to randomization.
* Participant has gastrointestinal (GI) perforation, fistulae, untreated gastric ulcers that would preclude the participant from study participation, or any arterial thromboembolic event within 6 months, or any significant GI bleeding or any significant venous thromboembolism within 3 months prior to randomization.
* Participant has a complete gastric outlet syndrome or a partial gastric outlet syndrome with persistent/recurrent vomiting.
* Participant has pre existing peripheral neuropathy \> Grade 1.
* Participant has poorly controlled hypertension.
* Participant has significant cardiovascular disease, including any of the following:

  * Congestive heart failure (defined as New York Heart Association Class III or IV), myocardial infarction, unstable angina, coronary angioplasty, stenting, coronary artery bypass graft, cerebrovascular accident or hypertensive crisis within 6 months prior to randomization.
  * corrected QT (QTc) interval \> 450 msec for male participants; QTc interval \> 470 msec for female participants.
  * Documented history or family history of congenital long QT syndrome.
  * Cardiac arrhythmias requiring anti-arrhythmic medications (Exception: Participant with rate-controlled atrial fibrillation for \> 1 month prior to randomization is eligible), obligate use of cardiac pacemaker, or a history of clinically significant ventricular arrhythmias (i.e., sustained ventricular tachycardia, ventricular fibrillation or Torsades de Pointes).
* Participant has a diagnosis of immunodeficiency 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 that require replacement therapy (e.g., thyroxine (T4), insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) may be enrolled.
* Participant has psychiatric illness or social situations that would preclude study compliance.
* Participant has history of another malignancy within 3 years prior to randomization, or any evidence of residual disease from a previously diagnosed malignancy. Participants with nonmelanoma skin cancer, localized prostate cancer treated with curative intent with no evidence of progression, low-risk or very low-risk (per standard guidelines) localized prostate cancer under active surveillance/watchful waiting without intent to treat, or carcinoma in situ of any type (if complete resection was performed) are allowed.
* Participant has history of (non-infectious) pneumonitis that required steroids, current pneumonitis, or has a history of interstitial lung disease.
* Participant has known, existing uncontrolled coagulopathy. Concomitant treatment with medications that affect the coagulation cascade with an international normalized ratio (INR) \> 2 (e.g., vitamin K antagonists) is not allowed.
* Participant may receive low molecular weight heparin (LMWH) (such as enoxaparin and dalteparin) and direct oral anticoagulant (DOAC) for management of deep venous thrombosis (DVT).
* Participant has a history of bleeding diathesis or recent major bleeding events (i.e. Grade \>= 2 bleeding events 28 days prior to randomization).
* Participant has uncontrolled intercurrent illness.
* Participant has active infection requiring systemic therapy that has not completely resolved within 7 days prior to randomization.
* Participant is known to have human immunodeficiency virus (HIV) infection except for those with cluster of differentiation (CD) 4+ T cell counts \>= 350 cells/microliter (µL) and no history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections within the past 12 months are eligible. NOTE: Screening for HIV infection should be conducted if indicated 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 if indicated per local requirements.

  * For participant who is negative for HBsAg, but hepatitis B core (HBc) antibody positive, an hepatitis B virus (HBV) DNA test will be performed and if positive the participant will be excluded.
  * Participant with positive hepatitis C virus (HCV) serology, but negative HCV RNA test results is eligible.
  * Participant treated for HCV with undetectable viral load results is eligible.
* Participant has a known history of a positive test for tuberculosis or known active tuberculosis infection. NOTE: Screening for these infections should be conducted per local requirements.
* Participant has known complete dihydropyrimidine dehydrogenase (DPD) deficiency (screening for DPD deficiency should be conducted per local requirements).
* Participant has pernicious anemia or other anemias due to vitamin B12 deficiency.
* Participant has received prior systemic chemotherapy and/or immunotherapy for locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma. However, a maximum of 1 cycle of mFOLFOX6 or CAPOX with or without immunotherapy (for those participants with CPS \>= 1) is allowed to be administered prior to randomization (Note: No dose modifications are allowed for the lead-in treatment). Participants may have received either neoadjuvant or adjuvant chemotherapy, immunotherapy, or other systemic anticancer therapies as long as they were completed at least 6 months prior to randomization and there was disease progression occurs at least 6 months after the last dose. Participant may have received treatment with herbal medications that have known antitumor activity \> 28 days prior to randomization. NOTE: Participants must have recovered from all AEs due to previous therapies to \<= Grade 1 or baseline.
* Participant has received systemic immunosuppressive therapy, including systemic corticosteroids \<= 7 days prior to randomization. Participants 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 dose of systemic corticosteroids or receiving systemic corticosteroids as premedication for radiologic imaging contrast use are allowed.
* Participant has had a major surgical procedure \<= 28 days before randomization and has not fully recovered.
* Participant has received a CLDN18.2-targeted therapy \<= 28 days or 5 half-lives (whichever is longer) prior to randomization, or participant has experienced Grade \>= 3 GI toxicity after receiving a CLDN18.2-targeted therapy.
* Participant has received radiotherapy for locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma \<= 14 days prior to randomization and has NOT recovered from any related toxicity. A 7-day washout is permitted for palliative radiation (\<= 14 days duration time for radiotherapy) to non-CNS disease.
* Participant has received prior therapy with an anti-PD-1, anti-PD-L1 or anti-PD-L2 agent, or with an agent directed to another stimulatory or coinhibitory T-cell receptor (e.g., cytotoxic T-lymphocyte-associated protein 4 \[CTLA-4\], OX-40, CD137) unless received in the perioperative setting.
* Participant received a live or live-attenuated vaccine within 30 days prior to randomization. NOTE: Inactivated seasonal influenza vaccines are allowed.
* Participant has received treatment with brivudine, sorivudine or their chemically related analogues within 28 days prior to randomization or within 5 half-lives of the drug, whichever is shorter.
* Participant has received any investigational therapy within 28 days prior to randomization or within 5 half-lives of the investigational medicinal product (IMP), whichever is longer.
* Participant has any condition including 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 prior severe allergic reaction; suspected, known immediate or delayed hypersensitivity; or intolerance or contraindication to any study intervention.

EU Specific:

* Participant has known complete DPD deficiency (screening for DPD deficiency should be conducted per local requirements). All participants in the EU must be tested for DPD deficiency before receiving fluoropyrimidine-based chemotherapy, in accordance with European Society for Medical Oncology and European Medicines Agency (EMA) recommendations.