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A Phase 1 Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Clinical Activity of GSK5764227 as Monotherapy and in Combination in Participants with Advanced Solid Tumors

(EMBOLD PanTumor-101
)

A Study of GSK5764227 in Participants With. Advanced Solid Tumors (EMBOLD PanTumor-101) (PanTumor-101)

Ishibashi Hideyasu

GlaxoSmithKline K.K.

Akasaka Intercity AIR, 1-8-1 Akasaka, Minato-ku, Tokyo, Japan

jp.gskjrct@gsk.com

Ishibashi Hideyasu

GlaxoSmithKline K.K.

Akasaka Intercity AIR, 1-8-1 Akasaka, Minato-ku, Tokyo, Japan

+81-120-561-007

jp.gskjrct@gsk.com

Recruiting

Oct. 31, 2024

Interventional

non-randomized controlled trial

open(masking not used)

uncontrolled control

single assignment

treatment purpose

-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

-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) 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. Bevacizumab as monotherapy (for combination 3 only)
4. 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:
- 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.
-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-Barre 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.

Both

Advanced solid tumors

Drug: GSK5764227
GSK5764227 will be administered as an IV infusion

Drug: Cisplatin
Cisplatin will be administered as an IV infusion

Drug: Carboplatin
Carboplatin will be administered as an IV infusion

Drug: Atezolizumab
Atezolizumab will be administered as an IV infusion

Drug: Pembrolizumab
Pembrolizumab will be administered as an IV infusion

Drug: Durvalumab
Durvalumab will be administered as an IV infusion

Drug: Bevacizumab
Bevacizumab will be administered as an IV infusion

Drug: Cetuximab
Cetuximab will be administered as an IV infusion

Phase 1a:
-Number of participants with Adverse Events (AEs)
-Number of participants with Dose Limiting Toxicities (DLTs)
-Number of participants with AEs and serious adverse events (SAEs) and adverse events of special interest (AESIs) by severity
-Number of participants with AEs leading to dose modifications
-Number of participants with changes in vital signs, body weight, laboratory tests, electrocardiogram (ECG) and Eastern Cooperative Oncology Group (ECOG) performance status

Phase 1b:
-Objective Response Rate (ORR)

Phase 1a and Phase 1b:
-Maximum concentration (Cmax) of GSK5764227
-Time to reach maximum concentration (Tmax) of GSK5764227
-Area under the curve (AUC) of GSK5764227
-Trough concentration (Ctrough) of GSK5764227 (conjugated antibody, total antibody, small-molecule toxin)

Phase 1a:
-Objective Response Rate
-Disease control rate (DCR)
-Duration of Response (DoR)

Phase 1b:
-Disease control rate (DCR)
-Duration of Response (DoR)
-Prostate-specific Antigen Decrease From Baseline >=50% (PSA50) response rate

Phase 1a and Phase 1b:
-Number of participants with Antidrug antibody (ADA) or Neutralizing Antibody (NAb)
-Titers of ADA against GSK5764227

Phase 1b:
-Number of participants with AEs, SAEs and AESI by severity
-Number of participants with AEs leading to dose modifications
-Number of participants with changes in vital signs, body weight, laboratory tests, ECG, ECHO and ECOG performance status
-Progression-Free Survival (PFS)

+81-3-3542-2511

Oct. 11, 2024

No

United States/Argentina/Canada/France/Italy/Spain/United Kingdom/Hong Kong/South Korea/Panama/Taiwan