A Study to Test the Safety and Effectiveness of GSK5764227, Alone or With Other Treatments, in Participants With Advanced Gastrointestinal Cancers That Cannot be Surgically Removed

Inclusion criteria:

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

• Is at least 18 or the legal age of consent in the jurisdiction in which the study is taking place years of age at the time of signing the informed consent form (ICF).

CRC Cohort

• Has histologically confirmed unresectable/, locally advanced or unresectablemetastatic adenocarcinoma of the colon or rectum (histology defined by World HealthOrganization (WHO) classification).

• Must have received at least 1 and no more than 2 lines of systemic treatment foradvanced colorectal cancer (CRC), with documented progression on most recent priorline of therapy.

• Must provide tumor tissue from a newly obtained fresh biopsy or an archival tumortissue.

PDAC Cohort

• Has histologically or cytologically confirmed unresectable, locally advanced ormetastatic adenocarcinoma of the pancreas (histology defined by WHO classification).

• Must have received 1 and no more than 1 line of therapy for advanced PDAC, withdocumented progression.

• Should provide tumor tissue at screening, where available or medically feasible.

All Cohorts

• Has at least 1 target lesion per RECIST 1.1, as determined by the investigator.

• Is willing to use adequate contraception.

• Is capable of giving signed informed consent, including compliance with therequirements and restrictions listed in the ICF and in the protocol.

• Has an ECOG performance status of 0 or 1.

• Has adequate organ function.

Exclusion criteria:

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

• Has a malignancy (except disease under study) that has progressed or required activetreatment within the past 24 months except for basal cell or squamous cellcarcinomas of the skin or in-situ carcinomas [e.g., breast, cervix, bladder] thathave been resected with no evidence of disease.

• Has had any major surgery within 28 days prior to randomization (CRC Cohort) orfirst dose of study intervention (PDAC Cohort).

• Has any history of prior allogenic or autologous bone marrow transplant or othersolid organ transplant.

• Has known sensitivity to study intervention components or excipients or otherallergy that, in the opinion of the investigator or medical monitor, contraindicatesparticipation in the study.

• Has severe, uncontrolled or active cardiovascular disorders.

• Has serious or poorly controlled hypertension.

• Has clinically significant bleeding symptoms or significant bleeding tendency within 1 month prior to the first dose.

• Has serious infection within 4 weeks prior to the first dose.

• Known active infectious diseases requiring systemic treatment or known Humanimmunodeficiency virus (HIV).

• Has serious arteriovenous thromboembolic events (such as deep vein thrombosis,pulmonary embolism, etc.) within 3 months prior to the first dose.

• Has untreated brain or Central nervous system (CNS) metastases or brain/CNSmetastases that have progressed.

• Has current active pneumonitis or any history of pneumonitis requiring steroids orimmunomodulatory treatment within 90 days of planned [randomization] or any historyof drug-induced pneumonitis.

• Has a history of autoimmune disease that has required systemic treatments in the 2years prior to screening.

• Has any active renal condition (e.g., infection, requirement for dialysis, or anyother significant renal condition that could affect the participant's safety).

• Has ongoing adverse reaction(s) from prior therapy that has(have) not recovered toGrade 1 or to the baseline status preceding prior therapy.

• Has any serious and/or unstable medical or psychiatric disorder or othercondition(s) (including laboratory assessment abnormalities) that could interferewith the participant's safety, obtainment of informed consent, or compliance to thestudy procedures.

• Has cirrhosis or current unstable liver or biliary disease per investigatorassessment defined by the presence of ascites, encephalopathy, coagulopathy,hypoalbuminemia, esophageal/gastric varices, or persistent jaundice.

• Has documented presence of Hepatitis B surface antigen (HBsAg) or HBcAb at screeningor within 3 months prior to the first dose of study intervention.

• Has a positive Hepatitis C virus (HCV) antibody test result at screening or within 3months prior to the first dose of study intervention.

• Has a positive HCV RNA test result at screening or within 3 months prior to thefirst dose of study intervention.

• Has received immunosuppressive agents within 30 days prior to first dose of studyintervention (or requires long-term [30 days or longer]).

• Has received any prior therapy with an Antibody-drug conjugate (ADC) with aTopoisomerase-1 (TOPO1)-inhibitor payload.

• Has received any live vaccine within 30 days of randomization (CRC Cohort) or beforefirst dose of study intervention (PDAC Cohort).

• Is currently enrolled or has participated in any other clinical study involving aninvestigational study intervention or any other type of interventional medicalresearch and/or has received treatment with any anticancer or investigational agentwithin 4 weeks prior to randomization.

• Is pregnant or breastfeeding.

• Is unable to adhere to the protocol defined SoA, including requirements for theFollow-up Period of the study.