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 (Meteor 1)

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

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).

Study Overview

• Status: Completed
• Conditions: Neoplasms
• Intervention / Treatment: Drug: GSK3326595; Drug: Pembrolizumab

• Study Type: Interventional
• Enrollment (Actual): 297
• Phase: Phase 1

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 1Z2
      • GSK Investigational Site
  • Ontario
    • Ottawa, Ontario, Canada, K1H 8L6
      • GSK Investigational Site
    • Toronto, Ontario, Canada, M5G 1Z5
      • GSK Investigational Site
• France
  • Bordeaux, France, 33076
    • GSK Investigational Site
  • Lyon Cedex 08, France, 69373
    • GSK Investigational Site
  • Villejuif cedex, France, 94805
    • GSK Investigational Site
• Netherlands
  • Amsterdam, Netherlands, 1066 CX
    • GSK Investigational Site
  • Leiden, Netherlands, 2333 ZA
    • GSK Investigational Site
  • Rotterdam, Netherlands, 3015 GD
    • GSK Investigational Site
• United States
  • Colorado
    • Denver, Colorado, United States, 80218
      • GSK Investigational Site
  • Florida
    • Miami, Florida, United States, 33136
      • GSK Investigational Site
  • New York
    • New York, New York, United States, 10065
      • GSK Investigational Site
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • GSK Investigational Site
  • Texas
    • Dallas, Texas, United States, 75230
      • GSK Investigational Site
    • San Antonio, Texas, United States, 78229
      • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1: Dose Escalation, Food effect and Relative Bioavailability of Capsule formulation to Tablet; 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; GSK3326595 will be administered with and without food, in tablet and capsule formulation.
Experimental: Part 2: Disease-Specific Expansion cohort; 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; GSK3326595 will be administered with and without food, in tablet and capsule formulation.
Experimental: Part 3: GSK3326595 in combination with pembrolizumab; Participants with selected solid tumors will be administered GSK3326595 in combination with pembrolizumab as part of this dose determination study.	Drug: GSK3326595; GSK3326595 will be administered with and without food, in tablet and capsule formulation.; Drug: Pembrolizumab; Pembrolizumab will be administered.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1: Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs)	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. SAE is defined as any untoward medical occurrence that, at any dose resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent disability/incapacity, or is a congenital anomaly/birth defect, other situations which involved medical or scientific judgment or is associated with liver injury and impaired liver function. SAEs are subset of AEs. A summary of number of participants with any AEs and SAEs is presented. AEs were coded using the Medical Dictionary for Regulatory Affairs (MedDRA dictionary).	Up to 30 months
Part 1: Number of Participants Withdrawn Due to AEs	The data for number of participants withdrawn due to AEs have been presented.	Up to 30 months
Part 1: Number of Participants With Dose Limiting Toxicities (DLTs)	DLT is considered to be clinically relevant AE by investigator if it met at least one of the criteria: Grade(G)3 neutropenia for >=5 days/G4 neutropenia of any duration, G3 or greater febrile neutropenia, G4 or greater anemia of any duration and thrombocytopenia, or G3 thrombocytopenia with bleeding, Alanine aminotransferase (ALT) >3x upper limit of normal (ULN)+bilirubin, >=2xULN or ALT between 3-5 X ULN with bilirubin < 2Xuln but with hepatitis symptoms/rash, G3 nausea/vomiting/diarrhea that does not improve within 72 hour, G4 or greater nausea/vomiting/diarrhea, G3 or greater hypertension, G3 or greater clinically significant non-hematologic toxicity per National Cancer Institute -- Common Terminology Criteria for Adverse Events (NCICTCAE), Inability to receive at least 80% of scheduled doses in the DLT observation period due to toxicity, G2 or higher toxicity that occurs beyond 21 days which in the judgment of the investigator and GSK Medical Monitor was considered to be a DLT.	Up to 21 days
Part 1: Number of Participants With Dose Modifications of GSK3326595	The number of participants who experienced any dose modifications (interruptions and reductions) of GSK3326595 have been presented.	Up to 30 months
Part 1: Number of Participants With Worst Case Change From Baseline in Clinical Chemistry Parameters	Blood samples were collected for evaluation of clinical chemistry parameters. The summaries of worst-case change from Baseline with respect to normal range have been presented for only those laboratory tests that are gradable by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The number of participants with decreases to low, changes to normal or no changes from Baseline, and increases to high values have been presented. Participants were counted twice if the participants have values that changed 'To Low' and 'To High', so the percentages may not add to 100%.	Baseline (Day 1) and up to 30 months
Part 1: Number of Participants With Worst Case Change From Baseline in Hematology Parameters	Blood samples were collected for evaluation of hematology parameters. The summaries of worst-case change from Baseline with respect to normal range have been presented for only those laboratory tests that are gradable by CTCAE v5.0. The number of participants with decreases to low, changes to normal or no changes from Baseline, and increases to high values have been presented. Participants were counted twice if the participants have values that changed 'To Low' and 'To High', so the percentages may not add to 100%.	Baseline (Day 1) and up to 30 months
Part 1: Number of Participants With Worst Case Change From Baseline in Coagulation Parameters	Blood samples were collected for evaluation of coagulation parameters. The summaries of worst-case change from Baseline with respect to normal range have been presented for only those laboratory tests that are gradable by CTCAE v4.0. The number of participants with decreases to low, changes to normal or no changes from Baseline, and increases to high values have been presented. Participants were counted twice if the participants have values that changed 'To Low' and 'To High', so the percentages may not add to 100%.	Baseline (Day 1) and up to 30 months
Part 1: Number of Participants With Worst Case Change From Baseline in Urinalysis Parameters	Urine samples were collected for evaluation of urinalysis parameters. The summaries of worst-case change from Baseline with respect to normal range have been presented for only those laboratory tests that are gradable by CTCAE v5.0. The number of participants with no change or change to negative and change to positive have been presented.	Baseline (Day 1) and up to 30 months
Part 1: Changes From Baseline in Urine Potential of Hydrogen (pH)	Urine samples were collected from participants to assess urine pH levels.	Baseline (Day 1) and up to week 132
Part 1: Changes From Baseline in Urine Specific Gravity	Urine samples were collected from participants to assess urine specific gravity.	Baseline (Day 1) and up to week 132
Part 1: Number of Participants With Maximum Grade Worst Case Increase Post-baseline Relative to Baseline in Vital Signs	The abnormal vital sign ranges are: Heart Rate:- Low (<60 beats per minute (bpm)), Normal (>=60 bpm to <=100 bpm), High (>100 bpm); Temperature:- Low (<=35 degree Celsius (°C)), Normal (>35 °C and <38 °C), High (>=38 °C); Systolic Blood Pressure:- Low (<90 millimeter of mercury (mmHg)), Normal (>=90 mmHg to <120 mmHg), High (>=120 mmHg); Diastolic Blood Pressure:- Low (<60 mmHg), Normal (>=60 mmHg to <80 mmHg), High (>=80 mmHg). Participants were counted in the worst-case category and their value changes to (low, normal or high), unless there is no change in their category. Participants whose value category was unchanged (e.g., High to High), or whose value became normal, are recorded in the "To Normal or No Change" category. Participants were counted twice if the participants have values that changed 'To Low' and 'To High', so the percentages may not add to 100%.	Baseline (Day 1) and up to 30 months
Part 3: Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs)	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. SAE is defined as any untoward medical occurrence that, at any dose resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent disability/incapacity, or was a congenital anomaly/birth defect, other situations which involve medical or scientific judgment or is associated with liver injury and impaired liver function. SAEs are subset of AEs. A summary of number of participants with any AEs and SAEs is presented. AEs were coded using the MedDRA dictionary.	Up to 10 months
Part 3: Number of Participants Withdrawn Due to AEs	The data for number of participants withdrawn due to AEs have been presented.	Up to 10 months
Part 3: Number of Participants With Dose Modifications of GSK3326595 and Pembrolizumab	The number of participants who experienced any dose modifications (interruptions and reductions) of GSK3326595 and pembrolizumab have been presented.	Up to 10 months
Part 3: Number of Participants With Worst Case Change From Baseline in Clinical Chemistry Parameters	Blood samples were collected for evaluation of clinical chemistry parameters. The summaries of worst case change from Baseline with respect to normal range have been presented for only those laboratory tests that are gradable by CTCAE v5.0. The number of participants with decreases to low, changes to normal or no changes from Baseline, and increases to high values have been presented.	Baseline (Day 1) and up to 10 months
Part 3: Number of Participants With Worst Case Change From Baseline in Hematology Parameters	Blood samples were collected for evaluation of hematology parameters. The summaries of worst case change from Baseline with respect to normal range have been presented for only those laboratory tests that are gradable by CTCAE v5.0. The number of participants with decreases to low, changes to normal or no changes from Baseline, and increases to high values have been presented.	Baseline (Day 1) and up to 10 months
Part 3: Number of Participants With Worst Case Change From Baseline in Coagulation Parameters	Blood samples were collected for evaluation of coagulation parameters. The summaries of worst case change from Baseline with respect to normal range have been presented for only those laboratory tests that are gradable by CTCAE v5.0. The number of participants with 'decreases to low', 'changes to normal' or 'no changes from Baseline', and 'increases to high' values have been presented.	Baseline (Day 1) and up to 10 months
Part 3: Number of Participants With Worst Case Change From Baseline in Urinalysis Parameters	Urine samples were collected for evaluation of urinalysis parameters. The summaries of worst case change from Baseline with respect to normal range have been presented for only those laboratory tests that are gradable by CTCAE v5.0. The number of participants with no change or change to negative and change to positive values have been presented.	Baseline (Day 1) and up to 10 months
Part 3: Changes From Baseline in Urine Potential of Hydrogen (pH)	Urine samples were collected from participants to assess urine pH levels.	Baseline (Day 1) and up to Week 42
Part 3: Changes From Baseline in Urine Specific Gravity	Urine samples were collected from participants to assess urine specific gravity.	Baseline (Day 1) and up to Week 42
Part 3: Number of Participants With Maximum Worst-case Increase Post-baseline Relative to Baseline in Vital Signs	The abnormal vital sign ranges are: Heart Rate:- Low [<60 bpm], Normal (>=60 bpm to <=100 bpm), High (>100 bpm); Temperature:- Low (<=35 C), Normal (>35 C and <38 C), High (>=38 C); Systolic Blood Pressure:- Low (<90 mmHg), Normal (>=90 mmHg to <120 mmHg), High (>=120 mmHg); Diastolic Blood Pressure:- Low (<60 mmHg), Normal (>=60 mmHg to <80 mmHg), High (>=80 mmHg). Participants were counted in the maximum worst case increase category that their value changes to (low, normal or high), unless there is no change in their category. Participants whose value category was unchanged (e.g., High to High), or whose value became normal, are recorded in the "To Normal or No Change" category. Participants were counted twice if the participants have values that changed 'To Low' and 'To High', so the percentages may not add to 100%.	Baseline (Day 1) and up to 10 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 2: Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs)	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. SAE is defined as any untoward medical occurrence that, at any dose resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent disability/incapacity, or is a congenital anomaly/birth defect, other situations which involved medical or scientific judgment or was associated with liver injury and impaired liver function. SAEs are subset of AEs. AEs were coded using the MedDRA dictionary.	Up to 42 months
Part 2: Number of Participants Withdrawn Due to AEs	The data for number of participants withdrawn due to AEs have been presented.	Up to 42 months
Part 2: Number of Participants With Dose Modifications of GSK3326595	The number of participants who had any dose modifications (interruptions and reductions) of GSK3326595 have been presented.	Up to 42 months
Part 2: Number of Participants With Worst Case Change From Baseline in Clinical Chemistry Parameters	Blood samples were collected for evaluation of clinical chemistry parameters. The summaries of worst case change from Baseline with respect to normal range have been presented for only those laboratory tests that are gradable by CTCAE v5.0. The number of participants with 'decreases to low', 'changes to normal' or 'no changes from Baseline', and 'increases to high' values have been presented. Participants were counted twice if the participants have values that changed 'To Low' and 'To High', so the percentages may not add to 100%.	Baseline (Day 1) and up to 42 months
Part 2: Number of Participants With Worst Case Change From Baseline in Hematology Parameters	Blood samples were collected for evaluation of hematology parameters. The summaries of worst case change from Baseline with respect to normal range have been presented for only those laboratory tests that are gradable by CTCAE v5.0. The number of participants with 'decreases to low', 'changes to normal' or 'no changes from Baseline', and 'increases to high values' have been presented. Participants were counted twice if the participants have values that changed 'To Low' and 'To High', so the percentages may not add to 100%.	Baseline (Day 1) and up to 42 months
Part 2: Number of Participants With Worst Case Change From Baseline in Coagulation Parameters	Blood samples were collected for evaluation of coagulation parameters. The summaries of worst case change from Baseline with respect to normal range have been presented for only those laboratory tests that are gradable by CTCAE v5.0. The number of participants with 'decreases to low', 'changes to normal' or 'no changes from Baseline', and 'increases to high' values have been presented. Participants were counted twice if the participants have values that changed 'To Low' and 'To High', so the percentages may not add to 100%.	Baseline (Day 1) and up to 42 months
Part 2: Number of Participants With Worst Case Change From Baseline in Urinalysis Parameters	Urine samples were collected for evaluation of urinalysis parameters. The summaries of worst case change from Baseline with respect to normal range have been presented for only those laboratory tests that are gradable by CTCAE v5.0. The number of participants with 'decreases to low', 'changes to normal' or 'no changes from Baseline', and 'increases to high' values have been presented.	Baseline (Day 1) and up to 42 months
Part 2: Changes From Baseline in Urine Potential of Hydrogen (pH)	Urine samples were collected from participants to assess urine pH levels.	Baseline (Day 1) and up to week 184
Part 2: Changes From Baseline in Urine Specific Gravity	Urine samples were collected from participants to assess urine specific gravity.	Baseline (Day 1) and up to week 184
Part 2: Number of Participants With Maximum Grade Worst Case Increase Post-baseline Relative to Baseline in Vital Signs	The abnormal vital sign ranges are: Heart Rate:- Low (<60 beats per minute (bpm)), Normal (>=60 bpm to <=100 bpm), High (>100 bpm); Temperature:- Low (<=35 degree Celsius (C)), Normal (>35 C and <38 C), High (>=38 C); Systolic Blood Pressure:- Low (<90 millimeter of mercury (mmHg)), Normal (>=90 mmHg to <120 mmHg), High (>=120 mmHg); Diastolic Blood Pressure:- Low (<60 mmHg), Normal (>=60 mmHg to <80 mmHg), High (>=80 mmHg). Participants were counted in the worst-case category and their value changes to (low, normal or high), unless there is no change in their category. Participants whose value category was unchanged (e.g., High to High), or whose value became normal, are recorded in the "To Normal or No Change" category. Participants were counted twice if the participants have values that changed 'To Low' and 'To High', so the percentages may not add to 100%.	Baseline (Day 1) and up to 42 months
Part 1: Maximum Observed Plasma Concentration (Cmax) of GSK3326595	Blood samples were collected for pharmacokinetic (PK) analysis of GSK3326595. PK parameter was determined using standard non-compartmental methods.	Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 hours (h) post-dose; pre-dose on day 8; pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 h post-dose on day 15
Part 3: Maximum Observed Plasma Concentration (Cmax) of GSK3326595	Blood samples were collected for pharmacokinetic (PK) analysis of GSK3326595. PK parameter was determined using standard non-compartmental methods.	Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24h post-dose
Part 1: Area Under the Plasma Concentration-time Curve (AUC) Extrapolated From Time Zero to Infinity (AUC[0-inf]) of GSK3326595	Blood samples were collected for pharmacokinetic (PK) analysis of GSK3326595. PK parameter was determined using standard non-compartmental methods.	Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 h post-dose
Part 3: Area Under the Plasma Concentration-time Curve (AUC) Extrapolated From Time Zero to Infinity (AUC[0-inf]) of GSK3326595	Blood samples were collected for pharmacokinetic (PK) analysis of GSK3326595. PK parameter was determined using standard non-compartmental methods.	Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24h post-dose
Part 1: AUC From Time Zero to the Last Quantifiable Concentration After Dosing (AUC[0-t]) of GSK3326595	Blood samples were collected for pharmacokinetic (PK) analysis of GSK3326595. PK parameter was determined using standard non-compartmental methods.	Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 h post-dose; pre-dose on day 8; pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 h post-dose on day 15
Part 3: AUC From Time Zero to the Last Quantifiable Concentration After Dosing (AUC[0-t]) of GSK3326595	Blood samples were collected for pharmacokinetic (PK) analysis of GSK3326595. PK parameter was determined using standard non-compartmental methods.	Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24h post-dose
Part 1: AUC Over the Dosing Interval Tau (AUC[0-tau]) of GSK3326595	Blood samples were collected for pharmacokinetic (PK) analysis of GSK3326595. PK parameter was determined using standard non-compartmental methods.	Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 h post-dose; pre-dose on day 8; pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 h post-dose on day 15
Part 3: AUC Over the Dosing Interval Tau (AUC[0-tau]) of GSK3326595	Blood samples were collected for pharmacokinetic (PK) analysis of GSK3326595. PK parameter was determined using standard non-compartmental methods.	Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24h post-dose
Part 1: Terminal Phase Half-life (t1/2) of GSK3326595	Blood samples were collected for pharmacokinetic (PK) analysis of GSK3326595. PK parameter was determined using standard non-compartmental methods.	Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 h post-dose; pre-dose on day 8; pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 h post-dose on day 15
Part 3: Terminal Phase Half-life (t1/2) of GSK3326595	Blood samples were collected for pharmacokinetic (PK) analysis of GSK3326595. PK parameter was determined using standard non-compartmental methods.	Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24h post-dose
Part 1: Oral Clearance (CL/F) of GSK3326595	Blood samples were collected for pharmacokinetic (PK) analysis of GSK3326595. PK parameter was determined using standard non-compartmental methods.	Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24h post-dose
Part 3: Oral Clearance (CL/F) of GSK3326595	Blood samples were collected for pharmacokinetic (PK) analysis of GSK3326595. PK parameter was determined using standard non-compartmental methods.	Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24h post-dose
Part 1: Accumulation Ratio (AR) of GSK3326595	Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3326595	Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24h post-dose on Day 1 and Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24h post-dose on Day 15
Part 3: Accumulation Ratio (AR) of GSK3326595	Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3326595	Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24h post-dose
Part 1: Time Invariance (TI) of GSK3326595	Blood samples were collected for pharmacokinetic (PK) analysis of GSK3326595. PK parameter was determined using standard non-compartmental methods. Time invariance was calculated as AUC(0-tau) at Day 15 divided by AUC(0-infinity) at Day 1 for GSK3326595.	Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24h post-dose on Day 1 and Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24h post-dose on Day 15
Part 3: Time Invariance (TI) of GSK3326595	Blood samples were collected for pharmacokinetic (PK) analysis of GSK3326595.	Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24h post-dose
Part 1: Overall Response Rate (ORR) Based on RECIST 1.1	ORR was defined as the percentage of participants with a confirmed complete response (CR) or confirmed partial response (PR) per RECIST version 1.1. PR was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (<)10 mm.	Up to 30 months
Part 2: Overall Response Rate (ORR) (Non-glioblastoma Multiforme [GBM] Cohorts)	Overall response rate (ORR) was defined as the percentage of participants with a confirmed complete response (CR) or confirmed partial response (PR) per Response Evaluation Criteria in Solid Tumors Criteria (RECIST) version 1.1. Partial response (PR) was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Complete response (CR) was defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (<)10 millimeters (mm).	Up to 42 months
Part 2: Six-month Progression Free Survival (PFS) Rate (GBM Cohort)	Six-month progression free survival (PFS) rate was 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. The RANO criteria were used to ascertain response (Wen, 2010).	At month 6
Part 2: Duration of Response (DOR) (ACC Tablet Cohort)	Duration of response (DOR) was defined as 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 42 months
Part 3: ORR Based on Immune-based RECIST (iRECIST) Criteria	ORR was defined as the percentage of participants with irCR or irPR per irRECIST. irCR is defined as disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 millimeters (mm). irPR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the baseline sum of the diameters.	Up to 10 months
Part 2: ORR (GBM Cohort) Based on Response Assessment Neuro-Oncology (RANO) Working Group Criteria	ORR was defined as the percentage of participants with a CR or PR, confirmed no less than 4 weeks based on the RANO criteria. CR was defined as complete disappearance of all enhancing measurable and non-measurable disease sustained for at least 4 weeks, stable or improved non-enhancing (T2/FLAIR) lesions, no new lesions, participants must be off corticosteroids (or on physiologic replacement doses only), and clinically stable or improved. PR was defined as at least 50% decrease compared to Baseline in the size of all measurable enhancing lesions sustained for at least 4 weeks, no progression of non-measurable disease or any new lesions, stable of lower dose of corticosteroids than Baseline dose, and stable or improved non-enhancing (T2/FLAIR) lesions.	Up to 42 months
Part 2: ORR (Non-Hodgkin's Lymphoma (NHL) Cohorts) Based on Lugano Criteria	ORR was defined as the percentage of participants with a confirmed complete response (CR) or confirmed partial response (PR) based on Lugano Criteria for Non-Hodgkin's lymphoma cohorts.	Up to 42 months
Part 2: Overall Survival (OS) (ACC Tablet Cohort)	Overall survival (OS) was defined as time from first dose until death from any cause in ACC participants who are systemic-treatment naïve.	Up to 42 months
Part 2: Progression-free Survival	PFS was defined as time from first dose until radiographic progression per standard criteria or death due to any cause, whichever is earlier.	Up to 42 months
RP2D Phase: Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs)	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. SAE is defined as any untoward medical occurrence that, at any dose resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent disability/incapacity, or is a congenital anomaly/birth defect, other situations which involve medical or scientific judgment or was associated with liver injury and impaired liver function. SAEs are subset of AEs. AEs were coded using the MedDRA dictionary.	Up to maximum 42 months
RP2D Phase: Number of Participants Withdrawn Due to AEs	The data for number of participants withdrawn due to AEs have been presented.	Up to maximum 42 months
RP2D Phase: Number of Participants With Dose Modifications of GSK3326595	The number of participants who experienced any dose modifications (interruptions and reductions) of GSK3326595 have been presented.	Up to maximum 42 months
RP2D Phase: Number of Participants With Worst Case Change From Baseline in Clinical Chemistry Parameters	Blood samples were collected for evaluation of clinical chemistry parameters. The summaries of worst case change from Baseline with respect to normal range have been presented for only those laboratory tests that are gradable by CTCAE v5.0. The number of participants with 'decreases to low', 'changes to normal' or 'no changes from Baseline', and 'increases to high' values have been presented. Participants were counted twice if the participants have values that changed 'To Low' and 'To High', so the percentages may not add to 100%.	Baseline (Day 1) and up to maximum 42 months
RP2D Phase: Number of Participants With Worst Case Change From Baseline in Hematology Parameters	Blood samples were collected for evaluation of hematology parameters. The summaries of worst case change from Baseline with respect to normal range have been presented for only those laboratory tests that are gradable by CTCAE v5.0. The number of participants with 'decreases to low', 'changes to normal' or 'no changes from Baseline', and 'increases to high' values have been presented. Participants were counted twice if the participants have values that changed 'To Low' and 'To High', so the percentages may not add to 100%.	Baseline (Day 1) and up to maximum 42 months
RP2D Phase: Number of Participants With Worst Case Change From Baseline in Coagulation Parameters	Blood samples were collected for evaluation of coagulation parameters. The summaries of worst case change from Baseline with respect to normal range have been presented for only those laboratory tests that are gradable by CTCAE v5.0. The number of participants with 'decreases to low', 'changes to normal' or 'no changes from Baseline', and 'increases to high' values have been presented. Participants were counted twice if the participants have values that changed 'To Low' and 'To High', so the percentages may not add to 100%.	Baseline (Day 1) and up to maximum 42 months
RP2D Phase: Number of Participants With Worst Case Change From Baseline in Urinalysis Parameters	Urine samples were collected for evaluation of urinalysis parameters. The summaries of worst case change from Baseline with respect to normal range have been presented for only those laboratory tests that are gradable by CTCAE v4.0. The number of participants with 'decreases to low', 'changes to normal' or 'no changes from Baseline', and 'increases to high' values have been presented.	Baseline (Day 1) and up to maximum 42 months
RP2D Phase: Changes From Baseline in Urine Potential of Hydrogen (pH)	Urine samples were collected from participants to assess urine pH levels.	Baseline (Day 1) and up to Week 184
RP2D Phase: Changes From Baseline in Urine Specific Gravity	Urine samples were collected from participants to assess urine specific gravity.	Baseline (Day 1) and up to Week 184
RP2D Phase: Number of Participants With Worst-case Increase Post-baseline Relative to Baseline in Vital Signs	Vital signs were measured. The abnormal vital sign ranges are: Heart Rate:- Low [<60 beats per minute (bpm)], Normal (>=60 bpm to <=100 bpm), High (>100 bpm); Temperature:- Low (<=35 C), Normal (>35 C and <38 C), High (>=38 C); Systolic Blood Pressure:- Low (<90 mmHg), Normal (>=90 mmHg to <120 mmHg), High (>=120 mmHg); Diastolic Blood Pressure:- Low (<60 mmHg), Normal (>=60 mmHg to <80 mmHg), High (>=80 mmHg). Participants were counted in the worst-case category that their value changes to (low, normal or high), unless there is no change in their category. Participants whose value category was unchanged (e.g., High to High), or whose value became normal, are recorded in the "To Normal or No Change" category. Participants were counted twice if the participants have values that changed 'To Low' and 'To High', so the percentages may not add to 100%.	Baseline (Day 1) and up to maximum 42 months

Collaborators and Investigators

• Sponsor: GlaxoSmithKline
• Investigators: Study Director: GSK Clinical Trials, GlaxoSmithKline

Study record dates

Study Major Dates

• Study Start (Actual): August 30, 2016
• Primary Completion (Actual): August 30, 2023
• Study Completion (Actual): August 30, 2023

Study Registration Dates

• First Submitted: April 11, 2016
• First Submitted That Met QC Criteria: May 23, 2016
• First Posted (Estimated): May 26, 2016

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 15, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: Non-Hodgkin's lymphoma (NHL); Melanoma; Dose escalation; Solid tumor; Urinary tract cancer; GSK3326595; Squamous cell carcinoma of the head and neck (HNSCC); Adenoid cystic carcinoma (ACC); Non small-cell lung cancer (NSCLC)
• Additional Relevant MeSH Terms: Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Lymphoma; Lymphoma, Non-Hodgkin; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; GSK-3326595; Pembrolizumab
• Other Study ID Numbers: 204653; 2016-000278-39 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: IPD for this study will be made available via the Clinical Study Data Request site.
• IPD Sharing Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints, key secondary endpoints and safety data of the study.
• IPD Sharing Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR