A Study of GSK5764227 in Participants With Advanced Solid Tumors

Inclusion Criteria:

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

• Participants with histologically confirmed advanced/metastatic solid tumors,irrespective of mutational status, as defined per study phase and cohort, asfollows: o Phase 1a:

• Participants with advanced/metastatic solid tumors.

• For monotherapy dose escalation: participants must have progressed on or becomeintolerant to all available SOC therapies.

• For combination dose escalation: participants must have received 3 or fewerprior 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 weeksbefore first dose.

• Has a life expectancy >12 weeks.

• Has adequate organ function. Screening specimens must be collected at least 3-5 daysprior to pre-dose specimens, and pre-dose specimens must be collected within 24hours prior to first dose.

• Where available, participants should provide a formalin fixed and paraffin embedded (FFPE) tumor sample from the most recent biopsy of primary cancer or from ametastatic site for central testing. Tumor tissue (archival tumor tissue or a freshbiopsy) for all except ES-SCLC participants. Exemptions can be granted by themedical monitor for participants with bladder cancer and mCRPC. Tumor tissue isnecessary for retrospective detection of B7 homolog 3 protein (B7-H3) expression byImmunohistochemistry (IHC) and other biomarker analysis.

• At least one of the following treatment combinations/monotherapy (a, b, c, or d) arenot contraindicated.

1. Atezolizumab, durvalumab, or pembrolizumab in combination with cisplatin orcarboplatin (for combination 1 only).

2. Atezolizumab, durvalumab, or pembrolizumab as monotherapy (for combination 2only)

3. Bevacizumab as monotherapy (for combination 3 only)

4. Cetuximab as monotherapy (for combination 4 only)

• Has received no more than 4 cycles of cisplatin or carboplatin in combination withpembrolizumab, atezolizumab, or durvalumab as most recent treatment regimen, withobjective response (per RECIST 1.1) of SD or better and no PD, and otherwisequalifies for continued treatment with atezolizumab, durvalumab, or pembrolizumabper local practice guidelines (combination 2 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 criteriafor Chinese participants will be considered as global (non-Chinese) participants.

Exclusion Criteria:

• 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 targetedagents.

• Evidence of brain metastasis (unless meeting the following criteria at the sametime: asymptomatic; medically stable for at least 4 weeks prior to initial dosing;no steroid treatment required for at least 2 weeks prior to initial dosing; and nomidline shift due to herniation); or untreated progression due to brain metastasisduring or after the last treatment prior to screening; or evidence ofmeningeal/brainstem metastasis; or evidence of spinal cord compression (detected byradiographic examination, symptomatic or not).

• Any of the following cardiac examination abnormality:

• Has QT interval, corrected for heart rate (QTc) >450 msec or QTc >480 msec forparticipants with bundle branch block.

• Evidence of current clinically significant arrhythmias or ECG abnormalities (e.g., complete left bundle branch block, third-degree atrioventricular [AV]block, second-degree AV block, PR interval >250 msec).

• Risk factors of prolonged QTc or arrhythmia events, such as heart failure,refractory hypokalemia, congenital long QT syndrome, family history of long QTsyndrome, or unexplained sudden death of any direct relative under 40 years oldor any concomitant medications that prolong the QT interval.

• Left ventricular ejection fraction (LVEF) <50%.

• Has severe, uncontrolled or active CV disorders, serious or poorly controlledhypertension, clinically significant bleeding symptoms or serious arteriovenousthromboembolic events Any evidence of current interstitial lung disease (ILD) orpneumonitis or a prior history of ILD or non-infectious pneumonitis requiringhigh-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 2years prior to screening. Participants with prior history of autoimmune disease mustbe discussed with the medical monitor. Replacement therapy is not considered a formof systemic therapy (e.g., thyroid hormone for autoimmune thyroiditis or insulin isnot exclusionary).

• Has any history of prior allogenic or autologous bone marrow transplant or othersolid organ transplant.

• Has received immunosuppressive agents within 30 days prior to first dose of studytreatment (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 proceduresare permitted.

• Participants in dehydrated condition.

• Participant with history of nephrotic syndrome or Grade 3 proteinuria. Participantsdiscovered to have ≥2 proteinuria on dipstick at screening should undergo a 24-hoururine collection and must demonstrate <2 g of protein in 24 hours to be eligible.

• History of abdominal or gastrointestinal fistula, tracheoesophageal fistula or anyGrade 4 fistula, gastrointestinal perforation, or intra-abdominal abscess.

• History of bowel involvement on CT scan or clinical symptoms of bowel obstruction.

• Has any active renal condition (e.g., requirement for dialysis, or any othersignificant renal condition that could affect the participant's safety). NOTE: renalobstruction 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 studytreatment (combinations 1, 3 and 4 only).

• Has experienced any of the following with prior immunotherapy: any immune-mediatedadverse event [imAE] ≥ Grade 3, immune-mediated severe neurologic events ofany-grade (e.g., myasthenic syndrome/myasthenia gravis, encephalitis, Guillain-BarréSyndrome, or transverse myelitis), exfoliative dermatitis of any grade (Stevens-Johnson syndrome [SJS], Toxic epidermal necrolysis [TEN], or Drug reactionwith eosinophilia and systemic symptoms [DRESS] syndrome), or myocarditis of anygrade. Clinically significant laboratory abnormalities, as judged by investigator,are not exclusionary.