Clinical trial NCT06551142: A Study of GSK5764227 in Participants With Advanced Solid Tumors
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Neoplasms
Keywords: Solid Tumors
GSK5764227
Neoplasms
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2024-08-13
Enrollment: 281
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: The goal of this study is to assess the safety, tolerability, clinical activity and pharmacokinetics of GSK5764227. The study will also see how the levels of GSK5764227 will change over time at different dose amounts when administered alone and in combination with other medicines like carboplatin, cisplatin, atezolizumab, pembrolizumab, durvalumab, bevacizumab, cetuximab.


Eligibility 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:

  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 a life expectancy \>12 weeks.
* Has adequate organ function. Screening specimens must be collected at least 3-5 days prior to pre-dose specimens, and pre-dose specimens must be collected within 24 hours 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 a metastatic site for central testing. Tumor tissue (archival tumor tissue or a fresh biopsy) for all except ES-SCLC participants. Exemptions can be granted by the medical monitor for participants with bladder cancer and mCRPC. 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)
* 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).
* 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.

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.
* 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 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), or myocarditis of any grade. Clinically significant laboratory abnormalities, as judged by investigator, are not exclusionary.

Primary outcomes:
measure: Phase 1a: Number of participants with Adverse Events (AEs)
timeFrame: Up to approximately 28 months
measure: Phase 1a: Number of participants with Dose Limiting Toxicities (DLTs)
timeFrame: Up to 21 days
measure: Phase 1a: Number of participants with AEs, serious adverse events (SAEs) and adverse events of special interest (AESIs) by severity
timeFrame: Up to approximately 30 months
measure: Phase 1a: Number of participants with AEs leading to dose modifications
timeFrame: Up to approximately 28 months
measure: Phase 1a: Number of participants with changes in vital signs, body weight, laboratory tests, electrocardiogram (ECG) and Eastern Cooperative Oncology Group (ECOG) performance status
timeFrame: Up to approximately 28 months
measure: Phase 1b: Objective Response Rate (ORR)
timeFrame: Up to approximately 27 months
Secondary outcomes:
measure: Phase 1a and Phase 1b: Maximum concentration (Cmax) of GSK5764227
timeFrame: Up to approximately 28 months
measure: Phase 1a and Phase 1b: Time to reach maximum concentration (Tmax) of GSK5764227
timeFrame: Up to approximately 28 months
measure: Phase 1a and Phase 1b: Area under the curve (AUC) of GSK5764227
timeFrame: Up to approximately 28 months
measure: Phase 1a and Phase 1b: Trough concentration (Ctrough) of GSK5764227 (conjugated antibody)
timeFrame: Up to approximately 28 months
measure: Phase 1a and Phase 1b: Trough concentration (Ctrough) of GSK5764227 (total antibody)
timeFrame: Up to approximately 28 months
measure: Phase 1a and Phase 1b: Trough concentration (Ctrough) of GSK5757810 (small-molecule toxin)
timeFrame: Up to approximately 28 months
measure: Phase 1a: Objective Response Rate
timeFrame: Up to approximately 33 months
measure: Phase 1a: Disease control rate (DCR)
timeFrame: Up to approximately 33 months
measure: Phase 1b: Disease control rate (DCR)
timeFrame: Up to approximately 33 months
measure: Phase 1a: Duration of Response (DoR)
timeFrame: Up to approximately 33 months
measure: Phase 1b: Duration of Response (DoR)
timeFrame: Up to approximately 33 months
measure: Phase 1b: Prostate-specific Antigen Decrease From Baseline >=50% (PSA50) response rate
timeFrame: Up to approximately 33 months
measure: Phase 1a and Phase 1b: Number of participants with Antidrug antibody (ADA) or Neutralizing Antibody (NAb)
timeFrame: Up to approximately 30 months
measure: Phase 1a and Phase 1b: Titers of ADA against GSK5764227
timeFrame: Up to approximately 30 months
measure: Phase 1b: Number of participants with AEs,SAEs and AESI by severity
timeFrame: Up to approximately 30 months
measure: Phase 1b: Number of participants with AEs leading to dose modifications
timeFrame: Up to approximately 27 months
measure: Phase 1b: Number of participants with changes in vital signs, body weight, laboratory tests, ECG, ECHO and ECOG performance status
timeFrame: Up to approximately 28 months
measure: Phase 1b: Progression-Free Survival (PFS)
timeFrame: Up to approximately 33 months
Other outcomes:
Locations:
city: Denver
country: United States
facility: GSK Investigational Site
state: Colorado
city: New Haven
country: United States
facility: GSK Investigational Site
state: Connecticut
city: Detroit
country: United States
facility: GSK Investigational Site
state: Michigan
city: Nashville
country: United States
facility: GSK Investigational Site
state: Tennessee
city: Dallas
country: United States
facility: GSK Investigational Site
state: Texas
city: San Antonio
country: United States
facility: GSK Investigational Site
state: Texas
city: Rosario
country: Argentina
facility: GSK Investigational Site
city: Viedma
country: Argentina
facility: GSK Investigational Site
city: Ottawa
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Toronto
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Sherbrooke
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Chiba
country: Japan
facility: GSK Investigational Site
city: Tokyo
country: Japan
facility: GSK Investigational Site
city: Edinburgh
country: United Kingdom
facility: GSK Investigational Site
Study officials:
References: