This study will check how well a new medicine, GSK5764227, works, how safe it is and how the body handles it in participants all around the world with advanced inoperable or metastatic gastrointestinal cancer who have previously received treatment.

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 unresectable metastatic adenocarcinoma of the colon or rectum (histology defined by World Health Organization (WHO) classification).
• Must have received at least 1 and no more than 2 lines of systemic treatment for advanced colorectal cancer (CRC), with documented progression on most recent prior line of therapy.
• Must provide tumor tissue from a newly obtained fresh biopsy or an archival tumor tissue.

PDAC Cohort

• Has histologically or cytologically confirmed unresectable, locally advanced or metastatic adenocarcinoma of the pancreas (histology defined by WHO classification).
• Must have received 1 and no more than 1 line of therapy for advanced PDAC, with documented 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 the requirements 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 active treatment within the past 24 months except for basal cell or squamous cell carcinomas of the skin or in-situ carcinomas [e.g., breast, cervix, bladder] that have been resected with no evidence of disease.
• Has had any major surgery within 28 days prior to randomization (CRC Cohort) or first dose of study intervention (PDAC Cohort).
• Has any history of prior allogenic or autologous bone marrow transplant or other solid organ transplant.
• Has known sensitivity to study intervention components or excipients or other allergy that, in the opinion of the investigator or medical monitor, contraindicates participation 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 Human immunodeficiency 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/CNS metastases that have progressed.
• Has current active pneumonitis or any history of pneumonitis requiring steroids or immunomodulatory treatment within 90 days of planned [randomization] or any history of drug-induced pneumonitis.
• Has a history of autoimmune disease that has required systemic treatments in the 2 years prior to screening.
• Has any active renal condition (e.g., infection, requirement for dialysis, or any other significant renal condition that could affect the participant's safety).
• Has ongoing adverse reaction(s) from prior therapy that has(have) not recovered to Grade 1 or to the baseline status preceding prior therapy.
• Has any serious and/or unstable medical or psychiatric disorder or other condition(s) (including laboratory assessment abnormalities) that could interfere with the participant's safety, obtainment of informed consent, or compliance to the study procedures.
• Has cirrhosis or current unstable liver or biliary disease per investigator assessment 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 screening or 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 3 months prior to the first dose of study intervention.
• Has a positive HCV RNA test result at screening or within 3 months prior to the first dose of study intervention.
• Has received immunosuppressive agents within 30 days prior to first dose of study intervention (or requires long-term [30 days or longer]).
• Has received any prior therapy with an Antibody-drug conjugate (ADC) with a Topoisomerase-1 (TOPO1)-inhibitor payload.
• Has received any live vaccine within 30 days of randomization (CRC Cohort) or before first dose of study intervention (PDAC Cohort).
• Is currently enrolled or has participated in any other clinical study involving an investigational study intervention or any other type of interventional medical research and/or has received treatment with any anticancer or investigational agent within 4 weeks prior to randomization.
• Is pregnant or breastfeeding.
• Is unable to adhere to the protocol defined SoA, including requirements for the Follow-up Period of the study.

Study Sponsor will assess requests from qualified researchers for anonymized individual patient-level data and related study documents. Data sharing is subject to certain criteria, conditions, and exceptions. For further information, refer to https://www.gsk-studyregister.com/About\_GSK\_Patient\_Level\_Data\_Sharing\_Final\_13July2023.pdf

Anonymized IPD will be made available within 6 months of publication of primary, key secondary and safety results for studies in product with approved indication(s) or asset(s) with development terminated across all indications.

Anonymized IPD is shared with researchers whose proposals are approved by an Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months, but an extension may be granted, when justified, for up to 6 months.