A Study of GSK5764227 in Participants With. Advanced Solid Tumors

Participation Requirements

• Sex:

  ALL

• Eligible Ages:

  18 and up

Participation Criteria

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, as follows:

* 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.
* Phase 1b:

* Participants with selected solid tumors cohort.

* 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 a life expectancy \>12 weeks.
* Has adequate organ function. Specimens must be collected within 3 days prior to the start of study intervention administration.
* 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 (archival tumor tissue or a fresh biopsy) is required unless an exemption is granted by the medical monitor. Tumor tissue is necessary for retrospective detection of B7 homolog 3 protein (B7-H3) expression by Immunohistochemistry (IHC) in central laboratory and other biomarker analysis.
* For Combinations 1-2 Only - Male participants: Male participants are eligible to participate if they agree to the following during the study intervention period and for at least 6 months after the last dose of study intervention:
* Refrain from donating sperm.

PLUS either:

- Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent.

OR

* Must agree to use contraception/barrier as detailed below:

• Agree to use a male condom with female partner use of an additional highly effective contraceptive method with a failure rate of \<1% per year.

• Prior treatment with 3 or fewer lines of systemic therapy in the locally advanced / metastatic setting.

• At least one of the following treatment combinations (a, b, c, or d) are not contraindicated.
1. Atezolizumab, durvalumab, or pembrolizumab in combination with cisplatin or carboplatin (for combination 1 only).
2. Atezolizumab, durvalumab, or pembrolizumab as monotherapy (for combination 2 only)
3. 5-fluorouracil + leucovorin in combination with bevacizumab (for combination 3 only)
4. 5-fluorouracil + leucovorin in combination with cetuximab (for combination 4 only)

• Has received no more than 4 cycles of cisplatin or carboplatin in combination with pembrolizumab, atezolizumab, or durvalumab as most recent treatment regimen, with objective response (per RECIST 1.1) of SD or better and no PD, and otherwise qualifies for continued treatment with atezolizumab, durvalumab, or pembrolizumab per local practice guidelines (combination 2 only).

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 targeted agents.
* 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 2 weeks prior to initial dosing; and no midline shift due to herniation); or untreated progression due to brain metastasis during or after the last treatment prior to screening; or evidence of meningeal/brainstem metastasis; or evidence of spinal cord compression (detected by radiographic 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 for participants 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 QT syndrome, or unexplained sudden death of any direct relative under 40 years old or any concomitant medications that prolong the QT interval.
* 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.
* 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)
* Participants with solid tumors of squamous histology (combination 3 only).
* Participants with a recent history of hemoptysis of ½ teaspoon or more of red blood.
* 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, or intra-abdominal abscess.
* History of bowel involvement on CT scan or clinical symptoms of bowel obstruction.
* Has known complete dihydropyrimidine hydrogenase (DPD) deficiency.
* 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), or myocarditis of any grade. Clinically significant laboratory abnormalities, as judged by investigator, are not exclusionary.