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 (EMBOLD PanGI-201)

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).

PDAC Cohort

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

All Cohorts

* 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 or first dose of study intervention, depending on sub-cohort/cohort assignment
* Has any history of prior allogenic or autologous bone marrow transplant or other solid organ transplant.
* 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 untreated brain or Central nervous system (CNS) metastases or brain/CNS metastases that have progressed.
* Has evidence of current ILD/non-infectious pneumonitis or a prior history of ILD/non-infectious pneumonitis requiring high-dose glucocorticoids Or suspected ILD/non-infectious pneumonitis that cannot be ruled out by imaging.
* 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 received any prior therapy with an Antibody-drug conjugate (ADC) with a Topoisomerase-1 (TOPO1)-inhibitor payload.
* Is pregnant or breastfeeding.