A study of GSK5764227 in participants with. advanced solid tumors (EMBOLD PanTumor-101)PanTumor-101

Male or female participants at least 18 years of age (≥18 years)

• Participants with histologically confirmed advanced/metastatic solid tumors, as defined per study phase and cohort, as follows: o Phase 1a: -Participants with advanced/metastatic solid tumors. -For monotherapy dose escalation: participants must have progressed on or become intolerant to all available SOC therapies.

For combination dose escalation: participants must have received 3 or fewer prior lines of systemic anticancer therapy in the advanced/metastatic setting

• Has at least 1 target lesion per RECIST 1.1, as determined by the investigator.
• Has an ECOG performance status of 0 or 1, with no deterioration in the 2 weeks before first dose.
• Has adequate organ function.
• Where available, participants should provide a formalin fixed and paraffin embedded (FFPE) tumor sample from the most recent biopsy of primary cancer or from a metastatic site for central testing. Tumor tissue is necessary for retrospective detection of B7 homolog 3 protein (B7-H3) expression by Immunohistochemistry (IHC) and other biomarker analysis.
• At least one of the following treatment combinations/monotherapy (a, b, c, or d) is clinically indicated: a. Atezolizumab, durvalumab, or pembrolizumab in combination with cisplatin or carboplatin (for combination 1 only). b. Atezolizumab, durvalumab, or pembrolizumab as monotherapy (for combination 2 only) c. Bevacizumab as monotherapy (for combination 3 only) d. Cetuximab as monotherapy (for combination 4 only)
• Additional inclusion criteria for Phase 1b Chinese participants: Chinese participants are considered eligible if they meet all of the following:
• Born in mainland China, Hong Kong or Taiwan
• Descendant of 2 ethnic Chinese parents and 4 ethnic Chinese grandparents
• All participants who do not meet either of the above-mentioned inclusion criteria for Chinese participants will be considered as global (non-Chinese) participants.

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

• Prior treatment with orlotamab, enoblituzumab, I-Dxd, or other B7-H3 targeted agents.
• Primary brain tumor or evidence of brain metastasis (unless meeting the following criteria at the same time: asymptomatic; medically stable for at least 4 weeks prior to initial dosing; no steroid treatment required for at least 4 weeks prior to initial dosing; and no midline shift due to herniation); or untreated progression due to brain metastasis or primary brain tumor during or after the last treatment prior to screening; or evidence of meningeal/brainstem involvement; or evidence of spinal cord compression (detected by radiographic examination, symptomatic or not).
• Any of the following cardiac examination abnormality:

Left ventricular ejection fraction (LVEF) <50%.

• Has severe, uncontrolled or active CV disorders, serious or poorly controlled hypertension, clinically significant bleeding symptoms or serious arteriovenous thromboembolic events Any evidence of current interstitial lung disease (ILD) or pneumonitis or a prior history of ILD or non-infectious pneumonitis requiring high-dose glucocorticoids.
• Has donated blood or blood products in excess of 500 mL (approximately 1 pint) within one month prior to first dose of study treatment.
• Has a history of autoimmune disease that has required systemic treatments in the 2 years prior to screening. Participants with prior history of autoimmune disease must be discussed with the medical monitor. Replacement therapy is not considered a form of systemic therapy (e.g., thyroid hormone for autoimmune thyroiditis or insulin is not exclusionary).
• Has any history of prior allogenic or autologous bone marrow transplant or other solid organ transplant.
• Has received immunosuppressive agents within 30 days prior to first dose of study treatment (or requires long-term (30 days or longer) glucocorticoid therapy). Low-dose corticosteroids (prednisone ≤10 mg/day or equivalent) may be administered. Use of inhaled or topical steroids and prophylactic corticosteroids for procedures are permitted.
• Participants in dehydrated condition.
• Participant with history of nephrotic syndrome or Grade 3 proteinuria. Participants discovered to have ≥2 proteinuria on dipstick at screening should undergo a 24‑hour urine collection and must demonstrate <2 g of protein in 24 hours to be eligible.
• History of abdominal or gastrointestinal fistula, tracheoesophageal fistula or any Grade 4 fistula, gastrointestinal perforation, intra‑abdominal abscess or active clinical concern for bowel obstruction.
• Has any active renal condition (e.g., requirement for dialysis, or any other significant renal condition that could affect the participant’s safety). NOTE: renal obstruction successfully managed by stenting is permitted. Additional exclusion criteria for participants receiving combination therapy
• Has received prior systemic anticancer therapy within 28 days of first dose of study treatment (combinations 1, 3 and 4 only).
• Has experienced any of the following with prior immunotherapy: any immune-mediated adverse event [imAE] ≥ Grade 3, immune-mediated severe neurologic events of any-grade (e.g., myasthenic syndrome/myasthenia gravis, encephalitis, Guillain-Barré Syndrome, or transverse myelitis), exfoliative dermatitis of any grade (Stevens-Johnson syndrome [SJS], Toxic epidermal necrolysis [TEN], or Drug reaction with eosinophilia and systemic symptoms [DRESS] syndrome), symptomatic pericarditis of any etiology within 6 months prior to the administration of study intervention, or myocarditis of any grade. Clinically significant laboratory abnormalities, as judged by investigator, are not exclusionary.