Clinical trial NCT05277051: First-Time-in-Human Study of GSK4381562 in Participants With Advanced Solid Tumors
Official title: A Phase 1 First-Time-in-Human, Open-Label Study of GSK4381562 Administered as Monotherapy and in Combination With Anticancer Agents in Participants With Selected Advanced Solid Tumors
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Neoplasms
Keywords: Advanced solid tumors
Metastatic solid tumor
Anticancer agents
Dostarlimab
GSK4381562
GSK4428859A
Belrestotug
Nelistotug
GSK5764227
Head and neck squamous cell carcinoma (HNSCC)
Non-small-cell lung cancer (NSCLC)
Breast cancer (BC)
Clear cell renal cell cancer (ccRCC)
Gastric cancer (GC)
Colorectal cancer (CRC)
Endometrial cancer (EC)
Epithelial ovarian, fallopian tube and primary peritoneal cancers
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2022-03-14
Enrollment: 141
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: 4 Dose Escalation arms (Arm A: GSK4381562 alone; Arm B: GSK4381562 plus dostarlimab; Arm C: GSK4381562 plus dostarlimab plus belrestotug; Arm I: GSK5764227 plus dostarlimab) and 5 other arms (Arm D: dostarlimab plus belrestotug; Arm E: dostarlimab plus belrestotug plus GSK4381562; Arm F: dostarlimab plus belrestotug plus nelistotug; Arm G: China cohort: dostarlimab; Arm H: China cohort: dostarlimab plus belrestotug).
Primary purpose: TREATMENT

Brief summary: This is a first time in-human (FTIH) study designed to investigate the safety, tolerability, pharmacokinetics (PK), and immunogenicity of GSK4381562 in participants with select loco-regionally recurrent solid tumors or metastatic solid tumors where curative or standard treatment options have been exhausted.


Eligibility criteria: Inclusion criteria:

* A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least 1 of the following conditions applies:

  * Is not a woman of childbearing potential (WOCBP) or
  * Is a WOCBP and using a contraceptive method that is highly effective with a failure rate of less than (\<)1 percent (\[%\] per year), during the intervention period and for specified time after end of study treatment.
  * A WOCBP must have a negative highly sensitive pregnancy test within 24-48 hours before the first dose of study intervention.
  * Requirement for Arm I only: Male participants agree to use contraception and for their female partner to use contraception, if applicable.
* Histological or cytological documentation of loco-regionally recurrent solid tumors where curative treatment options have been exhausted, or metastatic solid tumors; types as follows:

  * head and neck squamous cell carcinoma (HNSCC)
  * non-small-cell lung cancer (NSCLC)
  * breast cancer (BC)
  * clear cell renal cell cancer (ccRCC)
  * gastric cancer (GC)
  * colorectal cancer (CRC)
  * endometrial cancer (EC)
  * epithelial ovarian, fallopian tube, and primary peritoneal cancers- Disease that has progressed after standard therapy for the specific tumor type, or for which standard therapy has proven to be ineffective, intolerable, or is considered inappropriate, or if no further standard therapy exists.
  * Measurable disease per RECIST 1.1.
* Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1.
* Life expectancy of at least 12 weeks.
* Adequate organ function, as defined in the protocol.
* For participants enrolled in a PK/PD cohort, participant agrees to a fresh tumor biopsy during Screening and at approximately 6-weeks after treatment initiation.

Exclusion Criteria:

* Prior treatment with the following therapies (specified time periods are from last dose of prior treatment to first dose of study intervention):

  * Any therapy directed against Polio virus receptor (PVR)-related immunoglobulin domain-containing (PVRIG) (COM701 or other anti-PVRIG monoclonal antibody \[mAb\]) or other cluster of differentiation (CD)226 axis receptor (T-cell immunoglobulin and immunoreceptor tyrosine-based inhibition motif domain \[TIGIT\] or CD96) at any time.
  * For Arm I only, prior treatment with orlotamab, enoblituzumab, I-Dxd, or other B7-H3 targeted agents.
  * Other prior immunotherapy, chemotherapy, targeted therapy, biological therapy or radiation therapy within specified periods as defined in the protocol.
  * Investigational therapy: if the participant has participated in a clinical study and has received an investigational product within 4 weeks or 5 half-lives of the investigational product (whichever is shorter).
* Prior allogenic or autologous bone marrow transplantation or other solid organ transplantation.
* Toxicity from previous anticancer treatment, including:

  * Greater than or equal to Grade 3 immune-mediated toxicity considered related to prior immunotherapy and that led to treatment discontinuation; or
  * History of myocarditis of any grade during a previous treatment with immunotherapy
  * Toxicity related to prior treatment that has not resolved to less than or equal to (\<=) Grade 1. Non clinically relevant Grade 2 toxicities, not constituting a safety risk by investigator judgment are allowed.
* Participant has a known additional malignancy that progressed or required active treatment within the last 2 years.

Primary outcomes:
measure: Arms A, B, C, I: Number of Participants with dose-limiting toxicities (DLTs)
timeFrame: Up to 21 days
measure: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Up to 27 months
Secondary outcomes:
measure: Number of Participants With Clinically Significant Changes in Laboratory Parameters, Electrocardiogram (ECG) and Vital Signs
timeFrame: Up to 24 months
measure: Number of Participants With Dose Reductions or Delays
timeFrame: Up to 24 months
measure: Number of Participants With Withdrawals due to AEs
timeFrame: Up to 27 months
measure: Overall Response Rate (ORR)
timeFrame: Up to 24 months
measure: Number of Participants With Positive Antidrug Antibodies (ADA) to GSK4381562
timeFrame: Up to 27 months
measure: Titres of ADA to GSK4381562
timeFrame: Up to 27 months
measure: Number of Participants With Positive ADA to Dostarlimab
timeFrame: Up to 27 months
measure: Titers of ADA to Dostarlimab
timeFrame: Up to 27 months
measure: Number of Participants With Positive ADA to belrestotug
timeFrame: Up to 27 months
measure: Titers of ADA to belrestotug
timeFrame: Up to 27 months
measure: Number of Participants With Positive ADA to nelistotug
timeFrame: Up to 27 months
measure: Titers of ADA to nelistotug
timeFrame: Up to 27 months
measure: Number of Participants With Positive ADA to GSK5764227
timeFrame: Up to 27 months
measure: Titers of ADA to GSK5764227
timeFrame: Up to 27 months
measure: Serum Concentrations of GSK4381562
timeFrame: Up to 4 months
measure: Serum Concentrations of dostarlimab
timeFrame: Up to 4 months
measure: Serum Concentrations of belrestotug
timeFrame: Up to 4 months
measure: Serum Concentrations of nelistotug
timeFrame: Up to 4 months
measure: Serum Concentrations of GSK5764227
timeFrame: Up to 4 months
measure: Maximum Observed Plasma Concentration (Cmax) of GSK4381562 Monotherapy
timeFrame: Up to 27 months
measure: Cmax of GSK4381562 in Combination With Dostarlimab
timeFrame: Up to 27 months
measure: Cmax of GSK4381562 in Combination With dostarlimab and belrestotug
timeFrame: Up to 27 months
measure: Cmax following administration of dostarlimab with belrestotug
timeFrame: Up to 27 months
measure: Minimum Observed Plasma Concentration (Cmin) of GSK4381562 Monotherapy
timeFrame: Up to 27 months
measure: Cmin of GSK4381562 in Combination With Dostarlimab
timeFrame: Up to 27 months
measure: Cmin of GSK4381562 in Combination With dostarlimab and belrestotug
timeFrame: Up to 27 months
measure: Cmin following administration of dostarlimab with belrestotug
timeFrame: Up to 27 months
measure: Area Under the Plasma Concentration Curve From Time Zero to Last Time of Quantifiable Concentration (AUC[0-t]) of GSK4381562
timeFrame: Up to 27 months
measure: AUC(0-t) of GSK4381562 in Combination With Dostarlimab
timeFrame: Up to 27 months
measure: AUC(0-t) of GSK4381562 in Combination With dostarlimab and belrestotug
timeFrame: Up to 27 months
measure: AUC(0-t) following administration of dostarlimab with belrestotug
timeFrame: Up to 27 months
measure: AUC From Time Zero to Infinity (AUC[0-infinity]) of Single Dosing of GSK4381562
timeFrame: Up to 27 months
measure: AUC(0-infinity) of Single Dosing of GSK4381562 in Combination with Dostarlimab
timeFrame: Up to 27 months
measure: AUC(0-infinity) of Single Dosing of GSK4381562 in Combination With dostarlimab and belrestotug
timeFrame: Up to 27 months
measure: AUC(0-infinity) following administration of dostarlimab with belrestotug
timeFrame: Up to 27 months
measure: Cmax of dostarlimab in Combination With GSK4381562
timeFrame: Up to 27 months
measure: Cmax of dostarlimab in combination with GSK5764227
timeFrame: Up to 27 months
measure: Cmax of dostarlimab in combination with GSK4381562 followed by belrestotug
timeFrame: Up to 27 months
measure: Cmax of dostarlimab in combination with belrestotug
timeFrame: Up to 27 months
measure: Cmax of dostarlimab in combination with belrestotug and GSK4381562
timeFrame: Up to 27 months
measure: Cmax of dostarlimab in combination with belrestotug and nelistotug
timeFrame: Up to 27 months
measure: China cohort: Cmax of dostarlimab monotherapy
timeFrame: Up to 27 months
measure: China cohort: Cmax of dostarlimab in combination with belrestotug
timeFrame: Up to 27 months
measure: Cmin of dostarlimab in Combination With GSK4381562
timeFrame: Up to 27 months
measure: Cmin of dostarlimab in combination with GSK5764227
timeFrame: Up to 27 months
measure: Cmin of dostarlimab in combination with GSK4381562 followed by belrestotug
timeFrame: Up to 27 months
measure: Cmin of dostarlimab in combination with belrestotug
timeFrame: Up to 27 months
measure: Cmin of dostarlimab in combination with belrestotug and GSK4381562
timeFrame: Up to 27 months
measure: Cmin of dostarlimab in combination with belrestotug and nelistotug
timeFrame: Up to 27 months
measure: China cohort: Cmin of dostarlimab monotherapy
timeFrame: Up to 27 months
measure: China cohort: Cmin of dostarlimab in combination with belrestotug
timeFrame: Up to 27 months
measure: AUC(0-t) of dostarlimab in Combination With GSK4381562
timeFrame: Up to 27 months
measure: AUC(0-t) of dostarlimab in combination with GSK5764227
timeFrame: Up to 27 months
measure: AUC(0-t) of dostarlimab in combination with GSK4381562 followed by belrestotug
timeFrame: Up to 27 months
measure: AUC(0-t) of dostarlimab in combination with belrestotug
timeFrame: Up to 27 months
measure: AUC(0-t) of dostarlimab in combination with belrestotug and GSK4381562
timeFrame: Up to 27 months
measure: AUC(0-t) of dostarlimab in combination with belrestotug and nelistotug
timeFrame: Up to 27 months
measure: China cohort: AUC(0-t) of dostarlimab monotherapy
timeFrame: Up to 27 months
measure: China cohort: AUC(0-t) of dostarlimab in combination with belrestotug
timeFrame: Up to 27 months
measure: AUC(0-infinity) of dostarlimab in Combination With GSK4381562
timeFrame: Up to 27 months
measure: AUC(0-infinity) of dostarlimab in combination with GSK5764227
timeFrame: Up to 27 months
measure: AUC(0-infinity) of dostarlimab in combination with GSK4381562 followed by belrestotug
timeFrame: Up to 27 months
measure: AUC(0-infinity) of dostarlimab in combination with belrestotug
timeFrame: Up to 27 months
measure: AUC(0-infinity) of dostarlimab in combination with belrestotug and GSK4381562
timeFrame: Up to 27 months
measure: AUC(0-infinity) of dostarlimab in combination with belrestotug and nelistotug
timeFrame: Up to 27 months
measure: China cohort: AUC(0-infinity) of dostarlimab monotherapy
timeFrame: Up to 27 months
measure: China cohort: AUC(0-infinity) of dostarlimab in combination with belrestotug
timeFrame: Up to 27 months
measure: Mean terminal half-life (t1/2) of dostarlimab in Combination With GSK4381562
timeFrame: Up to 27 months
measure: Mean terminal half-life (t1/2) of dostarlimab in combination with GSK5764227
timeFrame: Up to 27 months
measure: China cohort: t1/2 of dostarlimab monotherapy
timeFrame: Up to 27 months
measure: China cohort: t1/2 of dostarlimab in combination with belrestotug
timeFrame: Up to 27 months
measure: Cmax of belrestotug in combination with dostarlimab followed by GSK4381562
timeFrame: Up to 27 months
measure: Cmax of belrestotug in combination with dostarlimab
timeFrame: Up to 27 months
measure: Cmax of belrestotug in combination with dostarlimab and GSK4381562
timeFrame: Up to 27 months
measure: Cmax of belrestotug in combination with dostarlimab and nelistotug
timeFrame: Up to 27 months
measure: China cohort: Cmax of belrestotug in combination with dostarlimab
timeFrame: Up to 27 months
measure: Cmin of belrestotug in combination with dostarlimab followed by GSK4381562
timeFrame: Up to 27 months
measure: Cmin of belrestotug in combination with dostarlimab
timeFrame: Up to 27 months
measure: Cmin of belrestotug in combination with dostarlimab and GSK4381562
timeFrame: Up to 27 months
measure: Cmin of belrestotug in combination with dostarlimab and nelistotug
timeFrame: Up to 27 months
measure: China cohort: Cmin of belrestotug in combination with dostarlimab
timeFrame: Up to 27 months
measure: AUC (0-t) of belrestotug in combination with dostarlimab followed by GSK4381562
timeFrame: Up to 27 months
measure: AUC (0-t) of belrestotug in combination with dostarlimab
timeFrame: Up to 27 months
measure: AUC (0-t) of belrestotug in combination with dostarlimab and GSK4381562
timeFrame: Up to 27 months
measure: AUC (0-t) of belrestotug in combination with dostarlimab and nelistotug
timeFrame: Up to 27 months
measure: China cohort: AUC (0-t) of belrestotug in combination with dostarlimab
timeFrame: Up to 27 months
measure: AUC (0-infinity) of belrestotug in combination with dostarlimab followed by GSK4381562
timeFrame: Up to 27 months
measure: AUC (0- infinity) of belrestotug in combination with dostarlimab
timeFrame: Up to 27 months
measure: AUC (0- infinity) of belrestotug in combination with dostarlimab and GSK4381562
timeFrame: Up to 27 months
measure: AUC (0- infinity) of belrestotug in combination with dostarlimab and nelistotug
timeFrame: Up to 27 months
measure: China cohort: AUC (0- infinity) of belrestotug in combination with dostarlimab
timeFrame: Up to 27 months
measure: China cohort: t1/2 of belrestotug in combination with dostarlimab
timeFrame: Up to 27 months
measure: Cmax of nelistotug in combination with dostarlimab and belrestotug
timeFrame: Up to 27 months
measure: Cmin of nelistotug in combination with dostarlimab and belrestotug
timeFrame: Up to 27 months
measure: AUC (0-t) of nelistotug in combination with dostarlimab and belrestotug
timeFrame: Up to 27 months
measure: AUC (0-infinity) of nelistotug in combination with dostarlimab and belrestotug
timeFrame: Up to 27 months
measure: Cmax of GSK5764227 in combination with dostarlimab
timeFrame: Up to 27 months
measure: Cmin of GSK5764227 in combination with dostarlimab
timeFrame: Up to 27 months
measure: AUC (0-t) of GSK5764227 conjugated antibody (Ab) in combination with dostarlimab
timeFrame: Up to 27 months
measure: AUC (0-t) of GSK5764227 small molecule toxin in combination with dostarlimab
timeFrame: Up to 27 months
measure: AUC (0-infinity) of GSK5764227 conjugated Ab in combination with dostarlimab
timeFrame: Up to 27 months
measure: AUC (0-infinity) of GSK5764227 small molecule toxin in combination with dostarlimab
timeFrame: Up to 27 months
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: GSK Investigational Site
state: California
city: Charlotte
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Oklahoma City
country: United States
facility: GSK Investigational Site
state: Oklahoma
city: Philadelphia
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Dallas
country: United States
facility: GSK Investigational Site
state: Texas
city: San Antonio
country: United States
facility: GSK Investigational Site
state: Texas
city: Salt Lake City
country: United States
facility: GSK Investigational Site
state: Utah
city: Nedlands
country: Australia
facility: GSK Investigational Site
state: Western Australia
city: Ottawa
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Toronto
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Jinan
country: China
facility: GSK Investigational Site
city: Shanghai
country: China
facility: GSK Investigational Site
city: Dijon Cedex
country: France
facility: GSK Investigational Site
city: Lille
country: France
facility: GSK Investigational Site
city: Chiba
country: Japan
facility: GSK Investigational Site
city: Tokyo
country: Japan
facility: GSK Investigational Site
city: Seoul
country: Korea, Republic of
facility: GSK Investigational Site
city: Seoul
country: Korea, Republic of
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: MAlaga
country: Spain
facility: GSK Investigational Site
city: Manchester
country: United Kingdom
facility: GSK Investigational Site
city: Sutton
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: