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

A female participant is eligible to participate if she is not pregnant or breastfeeding, 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 a failure rate of less than (<)1 percent ([%] per year), during the intervention period and for specified time after end of study treatment.
• A WOCBP must have a negative highly sensitive pregnancy test within 24-48 hours before the first dose of study intervention.
• Requirement for Arm I only: Male participants agree to use contraception and for their female partner to use contraception, if applicable.

Histological or cytological documentation of loco-regionally recurrent solid tumors where 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- Disease that has progressed after standard therapy for the specific tumor type, or for which standard therapy has proven to be ineffective, intolerable, or is considered 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 tumor biopsy during Screening and at approximately 6-weeks after treatment initiation.

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

• Any therapy directed against Polio virus receptor (PVR)-related immunoglobulin domain-containing (PVRIG) (COM701 or other anti-PVRIG monoclonal antibody [mAb]) or other cluster of differentiation (CD)226 axis receptor (T-cell immunoglobulin 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 other B7-H3 targeted agents.
• Other prior immunotherapy, chemotherapy, targeted therapy, biological therapy or radiation therapy within specified periods as defined in the protocol.
• Investigational therapy: if the participant has participated in a clinical study and has received an investigational product within 4 weeks or 5 half-lives of the investigational product (whichever is shorter).

Prior allogenic or autologous bone marrow transplantation or other solid organ transplantation.

Toxicity from previous anticancer treatment, including:

• Greater than or equal to Grade 3 immune-mediated toxicity considered related to prior immunotherapy and that led to treatment discontinuation; or
• History of myocarditis of any grade during a previous treatment with immunotherapy
• Toxicity related to prior treatment that has not resolved to less than or equal to (<=) Grade 1. Non clinically relevant Grade 2 toxicities, not constituting a safety risk by investigator judgment are allowed.

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