A Study to Investigate the Safety, Tolerability, Pharmacokinetics (PK), and Preliminary Anticancer Activity of GSK4524101 Alone or With Niraparib in Participants With Solid Tumors

Study Overview
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Brief Summary
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The primary purpose of this study is to determine the maximum tolerated dose of GSK4524101 monotherapy (MTD) and GSK4524101 in combination with niraparib (MTDc). The study consists of two parts - Part 1 (Dose Escalation) and Part 2 (Dose Expansion).

Official Title
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A Phase 1/2 First-Time-in-Human, Open-label, Multicenter, Dose Escalation and Expansion Study of the Oral DNA Polymerase Theta Inhibitor (POLQi) GSK4524101 and the PARP Inhibitor (PARPi) Niraparib in Adult Participants With Solid Tumors

Conditions
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Neoplasms

Intervention / Treatment
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* Drug: GSK4524101
* Drug: Niraparib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: More than or equal to (≥)18 years of age Eastern cooperative oncology group (ECOG) class 0-2 Life expectancy of a minimum of 3 month Participant has histologically diagnosed advanced or metastatic solid tumor and has exhausted all standard of care treatment options. Exclusion Criteria: Participant has not recovered (i.e., to Grade less than or equal to [≤1] or to baseline) from prior chemotherapy-induced AEs. Participant is currently participating in a treatment study or has participated in a study of any investigational agent within 4 weeks of the first dose of treatment. Participant has symptomatic uncontrolled brain or leptomeningeal metastases. Participant has a known additional malignancy that progressed or required active treatment within the last 2 years Participant has a known history of Myelodysplastic syndrome (MDS) or Acute myeloid leukemia (AML). Participant has uncontrolled hypertension with sustained systolic blood pressure (BP) >140 millimetres of mercury (mmHg) or diastolic BP >90 mmHg.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 - GSK4524101 Monotherapy<br> | Drug: GSK4524101<br>* GSK452101 will be administered.<br>|
| Experimental: Part 1 - GSK4524101 plus Niraparib<br> | Drug: GSK4524101<br>* GSK452101 will be administered.<br>Drug: Niraparib<br>* Niraparib will be administered.<br>|
| Experimental: Part 1 - GSK4524101 Food Effect Cohort<br> | Drug: GSK4524101<br>* GSK452101 will be administered.<br>|
| Experimental: Part 2 - GSK4524101 plus Niraparib<br> | Drug: GSK4524101<br>* GSK452101 will be administered.<br>Drug: Niraparib<br>* Niraparib will be administered.<br>|
| Active Comparator: Part 2 - Niraparib<br> | Drug: Niraparib<br>* Niraparib will be administered.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1 - Number of Participants with Dose Limiting Toxicities (DLTs) during DLT Observation Period |  | Up to 28 days | 
| Part 1 - Number of Participants with Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) based on Severity during DLT Observation Period |  | Up to 28 days | 
| Part 1 - Duration of Treatment Emergent AEs and SAEs (Days) during DLT Observation Period |  | Up to 28 days | 
| Part 1 - Percentage of Participants who receive all Planned Doses during DLT Observation Period |  | Up to 28 days | 
| Part 1 -Percentage of Participants who require dosage interruptions, dose reductions, and drug discontinuations due to adverse reactions during DLT Observation Period |  | Up to 28 days | 
| Part 2 - Confirmed Objective Response Rate (ORR) | ORR is the percentage of participants with an Investigator-assessed confirmed complete response and confirmed partial response to treatment, as assessed by Response Evaluation Criteria in Solid Tumor (RECIST) v1.1 | Up to approximately 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1 - Area Under Curve (AUC) of GSK4364973 (Metabolite of GSK4524101) |  | Up to 21 weeks | 
| Part 1 -Maximum Concentration (Cmax) of GSK4364973 (Metabolite of GSK4524101) |  | Up to 21 weeks | 
| Part 1 - Time to Maximum Concentration of GSK4364973 (Metabolite of GSK4524101) |  | Up to 21 weeks | 
| Part 1 - Half-life of GSK4364973 (Metabolite of GSK4524101) (Days) |  | Up to 21 weeks | 
| Part 1 -Plasma Concentration of Niraparib |  | Up to 21 weeks | 
| Part 1 - Number of Participants with TEAEs and SAEs based on Severity beyond DLT Observation Period |  | Up to approximately 24 weeks | 
| Part 1 - Duration of TEAEs and SAEs (Days) beyond DLT Observation Period |  | Up to approximately 24 weeks | 
| Part 2 - Number of Participants with TEAEs and SAEs based on Severity |  | Up to approximately 52 weeks | 
| Part 2 - Duration of Treatment Emergent AEs and SAEs (Days) |  | Up to approximately 52 weeks | 
| Part 2 - Progression-free Survival (PFS) | PFS is time from randomization to progressive disease or death from any cause, whichever is earlier, as assessed via RECIST v1.1 by Investigator assessment | Up to approximately 52 weeks | 
| Part 2 - Duration of Response (DOR) | DOR is defined as time from first documented PR or better to disease progression (as assessed by RECIST v1.1 by investigator assessment) or death whichever is earlier for participants who have achieved a CR or PR | Up to approximately 52 weeks | 
| Part 2 -Maximum Concentration (Cmax) of GSK4364973 (Metabolite of GSK4524101) |  | Up to 21 weeks | 
| Part 2 - Minimum Concentration (Cmin) of GSK4364973 (Metabolite of GSK4524101) |  | Up to 21 weeks | 
| Part 2 -Plasma Concentration of Niraparib |  | Up to 21 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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POLQi, Niraparib, GSK4524101