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): 288
• 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 Cedex, 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 Jersey
    • Middletown, New Jersey, United States, 07748
      • GSK Investigational Site
  • New York
    • Harrison, New York, United States, 10604
      • GSK Investigational Site
    • 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
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

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 (Estimated): December 13, 2023
• Last Update Submitted That Met QC Criteria: December 12, 2023
• Last Verified: December 1, 2023

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: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma; Lymphoma, Non-Hodgkin; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Pembrolizumab; GSK-3326595
• 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