An Open-label, Dose Escalation Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of GSK3326595 in Participants With Solid Tumors and Non-Hodgkin's Lymphoma

Study Overview
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Brief Summary
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This first time in human (FTIH) open-label, dose escalation study will assess the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity of GSK3326595 in participants with advanced or recurrent solid tumors, as well as clinical activity in participants with a subset of solid tumors and non-Hodgkin's lymphoma (NHL).

Official Title
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A Phase I, Open-label, Dose Escalation Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of GSK3326595 in Subjects With Solid Tumors and Non-Hodgkin's Lymphoma

Conditions
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Neoplasms

Intervention / Treatment
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* Drug: GSK3326595
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Males and females greater than or equal to (>=)18 years of age (at the time consent is obtained) Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 or 2 Diagnosis of non-resectable or metastatic solid malignancy (as defined in the protocol) or NHL Presence of evaluable disease Adequate organ function (as defined in the protocol) Reproductive criteria (as defined in the protocol). Exclusion Criteria: Malignancy attributed to prior solid organ transplant Leptomeningeal disease, spinal cord compression, or brain metastases that require immediate central nervous system (CNS)-specific treatment in the opinion of the Investigator (for example [e.g.], for symptomatic disease) History of a second malignancy, excluding non-melanoma skin cell cancer within the last three years Evidence of severe or uncontrolled systemic diseases, or serious and/or pre-existing medical or other condition that could interfere with participant's safety, obtaining informed consent or compliance to the study procedures, in the opinion of the Investigator Any clinically significant gastrointestinal (GI) abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach and/or bowels. Select cardiac abnormalities (as defined in the protocol) History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates their participation. History of optic nerve neuropathy or neuritis.

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: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This will be a three-part study where Part 1 is dose escalation, including assessment of Food Effect and Relative Bioavailability, Part 2 is disease specific expansion cohorts to better characterize the clinical activity and safety profile of GSK3326595 and Part 3 is dose determination of GSK3326595 in combination with pembrolizumab.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: Dose Escalation, Food effect and Relative Bioavailability of Capsule formulation to Tablet<br>Participants will receive escalating doses of GSK3326595 until the maximum tolerated dose level is reached. The recommended phase 2 dose (RP2D) will be determined. Participants will be dosed in a fed (high-fat, high-calorie meal) and fasted state to determine the effect of food on bioavailability of GSK3326595, and will be dosed with tablet and capsule to compare two formulations of GSK3326595 (capsule versus tablet). | Drug: GSK3326595<br>* GSK3326595 will be administered with and without food, in tablet and capsule formulation.<br>|
| Experimental: Part 2: Disease-Specific Expansion cohort<br>Participants with triple-negative breast cancer (TNBC), metastatic transitional cell carcinoma of the urinary system (mTCC), Grade IV anaplastic astrocytoma (glioblastoma multiforme [GBM]), non-Hodgkin's lymphoma (NHL), adenoid cystic carcinoma (ACC), hormone receptor-positive adenocarcinoma of the breast (ER+BC), human papillomavirus (HPV)-positive solid tumors of any histology, and p53-wild type non-small cell lung cancer (NSCLC) will be administered GSK3326595 at the recommended phase 2 dose (RP2D) as determined in Part 1. | Drug: GSK3326595<br>* GSK3326595 will be administered with and without food, in tablet and capsule formulation.<br>|
| Experimental: Part 3: GSK3326595 in combination with pembrolizumab<br>Participants with selected solid tumors will be administered GSK3326595 in combination with pembrolizumab as part of this dose determination study. | Drug: GSK3326595<br>* GSK3326595 will be administered with and without food, in tablet and capsule formulation.<br>Drug: Pembrolizumab<br>* Pembrolizumab will be administered.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Parts 1 and 3: Number of participants with any adverse events (AEs), serious adverse events (SAEs), withdrawal due to AEs, dose interruptions and reductions | All AEs, SAEs and dose modifications will be collected. | Up to approximately 2 years | 
| Part 1: Number of participants with dose limiting toxicities (DLTs) | An event is considered to be a DLT if the event occurs within the first 21 days of treatment and meets the dose-limiting toxicity criteria, unless it can be clearly established that the event is unrelated to treatment. | Up to 21 days | 
| Parts 1 and 3: Number of participants with clinically significant changes in laboratory parameters, vital signs, physical examination and organ-specific parameters. | Blood and urine samples will be collected for analysis of lab parameters. Vital signs, physical examinations and organ-specific parameters will be collected at specified time points. | Up to approximately 2 years | 
| Part 2: Participants with solid tumors (non-GBM): Overall response rate (ORR) based on Evaluation Criteria In Solid Tumors (RECIST) 1.1 | ORR is defined as the percentage of participants achieving a confirmed complete response (CR) or partial response (PR) based on RECIST 1.1 criteria. | Up to approximately 2 years | 
| Part 2: Participants with NHL: ORR based on Lugano criteria | ORR is defined as the percentage of participants achieving CR or PR based on Lugano criteria. | Up to approximately 2 years | 
| Part 2: GBM cohort: Six-month progression free survival (PFS) rate | PFS is defined as the percentage of participants free from radiographic progression per Response Assessment in Neuro-Oncology (RANO) criteria, or death due to any cause, for six months after starting GSK3326595. | Up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Parts 1 and 3: Maximum observed plasma concentration (Cmax) of GSK3326595 | Blood samples will be collected at given time points to determine the Cmax of GSK3326595. | Baseline and up to approximately 2 years | 
| Parts 1 and 3: Area under the plasma concentration-time curve (AUC) extrapolated from time zero to infinity (AUC[0-inf]) of GSK3326595 | Blood samples will be collected at given time points to determine the AUC (0-inf) of GSK3326595. | Up to approximately 2 years | 
| Parts 1 and 3: AUC from time zero to the last quantifiable concentration after dosing (AUC[0-t]) of GSK3326595 | Blood samples will be collected at given time points to determine the AUC (0-t) of GSK3326595. | Up to approximately 2 years | 
| Parts 1 and 3: AUC over the dosing interval tau (AUC[0-tau]) of GSK3326595 | Blood samples will be collected at given time points to determine the AUC (0-tau) of GSK3326595. | Up to approximately 2 years | 
| Parts 1 and 3: Terminal phase half-life (t1/2) of GSK3326595 | Blood samples will be collected at given time points to determine the half-life of GSK3326595. | Up to approximately 2 years | 
| Parts 1 and 3: Oral clearance (CL/F) of GSK3326595 | Blood samples will be collected at given time points to determine the CL/F of GSK3326595. | Up to approximately 2 years | 
| Parts 1 and 3: Accumulation ratio (AR) of GSK3326595 | Blood samples will be collected at given time points to determine the AR of GSK3326595. | Up to approximately 2 years | 
| Parts 1 and 3: Time invariance (TI) of GSK3326595 | Blood samples will be collected at given time points to determine the TI of GSK3326595. | Up to approximately 2 years | 
| Part 1: Participants with solid tumors: Overall response rate (ORR) based on Evaluation Criteria In Solid Tumors (RECIST) 1.1 | ORR is defined as the percentage of participants achieving a confirmed complete response (CR) or partial response (PR) based on RECIST 1.1 criteria. | Up to approximately 2 years | 
| Part 3: ORR based on immune-based RECIST (iRECIST) criteria | ORR is defined as the percentage of participants achieving confirmed CR or confirmed PR based on immune-based RECIST (iRECIST) criteria. | Up to approximately 2 years | 
| Part 2: PFS | Progression-free survival (PFS) is defined as the time from first dose until radiographic progression per standard criteria or death due to any cause, whichever is earlier. | Up to approximately 2 years | 
| Part 2: ORR in participants with GBM based on Response Assessment Neuro-Oncology (RANO) Working group criteria | ORR is defined as the percentage of participants achieving a confirmed complete response (CR) or partial response (PR) based on RANO working group criteria. | Up to approximately 2 years | 
| Part 2: (Participants in ACC tablet cohort): Duration of Response (DOR) | DOR is defined as the time from first evidence of response (CR or PR per RECIST 1.1) to earlier date of disease progression or death due to any cause, as determined by Investigator Assessment. | Up to approximately 2 years | 
| Part 2: (Participants in ACC tablet cohort): Overall survival (OS) | OS is defined as the time from first dose until death from any cause. | Up to approximately 2 years | 
| Part 2: Number of participants with any AEs, SAEs, withdrawal due to AEs, dose reductions or delays | All AEs, SAEs and dose modifications will be collected. | Up to approximately 2 years | 
| Part 2: Number of participants with clinically significant changes in laboratory parameters, vital signs, physical examination and organ-specific parameters | Blood and urine samples will be collected for analysis of lab parameters. Vital signs, physical examinations and organ-specific parameters will be collected at specified time points. | Up to approximately 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GSK3326595, Solid tumor, Non-Hodgkin's lymphoma (NHL), Urinary tract cancer, Dose escalation, Adenoid cystic carcinoma (ACC), Non small-cell lung cancer (NSCLC), Squamous cell carcinoma of the head and neck (HNSCC), Melanoma