First-Time-in-Human Study of GSK4381562 in Participants With Advanced Solid Tumors

Inclusion criteria:

• A female participant is eligible to participate if she is not pregnant orbreastfeeding, and at least 1 of the following conditions applies:

• Is not a woman of childbearing potential (WOCBP) or

• Is a WOCBP and using a contraceptive method that is highly effective with afailure rate of less than (<)1 percent ([%] per year), during the interventionperiod and for specified time after end of study treatment.

• A WOCBP must have a negative highly sensitive pregnancy test within 24-48 hoursbefore the first dose of study intervention.

• Requirement for Arm I only: Male participants agree to use contraception andfor their female partner to use contraception, if applicable.

• Histological or cytological documentation of loco-regionally recurrent solid tumorswhere curative treatment options have been exhausted, or metastatic solid tumors;types as follows:

• head and neck squamous cell carcinoma (HNSCC)

• non-small-cell lung cancer (NSCLC)

• breast cancer (BC)

• clear cell renal cell cancer (ccRCC)

• gastric cancer (GC)

• colorectal cancer (CRC)

• endometrial cancer (EC)

• epithelial ovarian, fallopian tube, and primary peritoneal cancers- Diseasethat has progressed after standard therapy for the specific tumor type, or forwhich standard therapy has proven to be ineffective, intolerable, or isconsidered inappropriate, or if no further standard therapy exists.

• Measurable disease per RECIST 1.1.

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1.

• Life expectancy of at least 12 weeks.

• Adequate organ function, as defined in the protocol.

• For participants enrolled in a PK/PD cohort, participant agrees to a fresh tumorbiopsy during Screening and at approximately 6-weeks after treatment initiation.

Exclusion Criteria:

• Prior treatment with the following therapies (specified time periods are from lastdose of prior treatment to first dose of study intervention):

• Any therapy directed against Polio virus receptor (PVR)-related immunoglobulindomain-containing (PVRIG) (COM701 or other anti-PVRIG monoclonal antibody [mAb]) or other cluster of differentiation (CD)226 axis receptor (T-cellimmunoglobulin and immunoreceptor tyrosine-based inhibition motif domain [TIGIT] or CD96) at any time.

• For Arm I only, prior treatment with orlotamab, enoblituzumab, I-Dxd, or otherB7-H3 targeted agents.

• Other prior immunotherapy, chemotherapy, targeted therapy, biological therapyor radiation therapy within specified periods as defined in the protocol.

• Investigational therapy: if the participant has participated in a clinicalstudy and has received an investigational product within 4 weeks or 5half-lives of the investigational product (whichever is shorter).

• Prior allogenic or autologous bone marrow transplantation or other solid organtransplantation.

• Toxicity from previous anticancer treatment, including:

• Greater than or equal to Grade 3 immune-mediated toxicity considered related toprior immunotherapy and that led to treatment discontinuation; or

• History of myocarditis of any grade during a previous treatment withimmunotherapy

• Toxicity related to prior treatment that has not resolved to less than or equalto (<=) Grade 1. Non clinically relevant Grade 2 toxicities, not constituting asafety risk by investigator judgment are allowed.

• Participant has a known additional malignancy that progressed or required activetreatment within the last 2 years.