First-Time-in-Human Study of GSK4381562 in Participants With Advanced Solid Tumors

Study Overview
=================
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

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

Conditions
-----------------
Neoplasms

Intervention / Treatment
-----------------
* Drug: GSK4381562
* Drug: Dostarlimab
* Drug: GSK4428859A


Participation Criteria
=================
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. 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) ovarian epithelial cancer (OEC) 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. Exclusion Criteria: Prior treatment with the following therapies (specified time periods are from last dose of prior treatment to first dose of GSK4381562): 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. 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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: 3 Dose Escalation arms (GSK4381562 alone and GSK4381562 plus dostarlimab and GSK4381562 plus dostarlimab plus GSK4428859A); additional participants may be enrolled in any study arms in PK/Pharmacodynamic (PD) cohorts at putative recommended Phase 2 dose (RP2D) level and/or at previously cleared dose levels (up to 15 participants)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Participants receiving GSK4381562 monotherapy<br> | Drug: GSK4381562<br>* GSK4381562 will be administered.<br>|
| Experimental: Participants receiving GSK4381562 plus dostarlimab<br> | Drug: GSK4381562<br>* GSK4381562 will be administered.<br>Drug: Dostarlimab<br>* Dostarlimab will be administered.<br>|
| Experimental: Participants receiving GSK4381562 plus dostarlimab plus GSK4428859A<br> | Drug: GSK4381562<br>* GSK4381562 will be administered.<br>Drug: Dostarlimab<br>* Dostarlimab will be administered.<br>Drug: GSK4428859A<br>* GSK4428859A will be administered.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with dose-limiting toxicities (DLTs) |  | Up to 21 days | 
| Number of participants with adverse events (AEs) and serious adverse events (SAEs) |  | Up to 27 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with clinically significant changes in laboratory parameters, electrocardiogram (ECG) and vital signs |  | Up to 24 months | 
| Number of participants with dose reductions or delays |  | Up to 24 months | 
| Number of participants with withdrawals due to AEs | Number of participants with adverse events leading to permanent discontinuation of study treatment or withdrawal from study by overall frequency will be assessed. | Up to 27 months | 
| Overall response rate (ORR) | Objective response rate will be calculated as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria. It is defined as the percentage of participants with a best overall confirmed complete response (CR) or partial response (PR) at any time as per disease-specific criteria. | Up to 24 months | 
| Number of participants with positive antidrug antibodies (ADA) to GSK4381562 |  | Up to 27 months | 
| Titers of ADA to GSK4381562 |  | Up to 27 months | 
| Number of participants with positive ADA to dostarlimab |  | Up to 27 months | 
| Titers of ADA to dostarlimab |  | Up to 27 months | 
| Number of participants with positive ADA to GSK4428859A |  | Up to 27 months | 
| Titers of ADA to GSK4428859A |  | Up to 27 months | 
| Plasma concentrations of GSK4381562 |  | Up to 4 months | 
| Maximum observed plasma concentration (Cmax) of GSK4381562 monotherapy |  | Up to 27 months | 
| Cmax of GSK4381562 in combination with dostarlimab |  | Up to 27 months | 
| Cmax of GSK4381562 in combination with GSK4428859A |  | Up to 27 months | 
| Minimum observed plasma concentration (Cmin) of GSK4381562 monotherapy |  | Up to 27 months | 
| Cmin of GSK4381562 in combination with dostarlimab |  | UP to 27 months | 
| Cmin of GSK4381562 in combination with GSK4428859A |  | Up to 27 months | 
| Area under the plasma concentration curve from time zero to last time of quantifiable concentration (AUC[0-t]) of GSK4381562 |  | Up to 27 months | 
| AUC(0-t) of GSK4381562 in combination with dostarlimab |  | Up to 27 months | 
| AUC(0-t) of GSK4381562 in combination with GSK4428859A |  | Up to 27 months | 
| AUC from time zero to infinity (AUC[0-infinity]) of single dosing of GSK4381562 |  | Up to 27 months | 
| AUC(0-infinity) of single dosing of GSK4381562 in combination with dostarlimab |  | Up to 27 months | 
| AUC(0-infinity) of single dosing of GSK4381562 in combination with GSK4428859A |  | Up to 27 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Advanced solid tumors, Metastatic solid tumor, Anticancer agents, Dostarlimab, GSK4381562, GSK4428859A, 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), Ovarian epithelial cancer (OEC)