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)

• ClinicalTrials.gov Identifier: NCT02783300
• Recruitment Status: Active, not recruiting
• First Posted: May 26, 2016
• Last Update Posted: June 28, 2022
• Sponsor: GlaxoSmithKline
• Information provided by (Responsible Party): GlaxoSmithKline

Study Description

Brief Summary:

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).

Condition or disease	Intervention/treatment	Phase
Neoplasms	Drug: GSK3326595; Drug: Pembrolizumab	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 288 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Intervention 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)
• Masking Description: This is an open label study.
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: August 30, 2016
• Estimated Primary Completion Date: August 31, 2023
• Estimated Study Completion Date: August 31, 2023

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures :

1. Parts 1 and 3: Number of participants with any adverse events (AEs), serious adverse events (SAEs), withdrawal due to AEs, dose interruptions and reductions [ Time Frame: Up to approximately 2 years ]
   All AEs, SAEs and dose modifications will be collected.
2. Part 1: Number of participants with dose limiting toxicities (DLTs) [ Time Frame: Up to 21 days ]
   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.
3. Parts 1 and 3: Number of participants with clinically significant changes in laboratory parameters, vital signs, physical examination and organ-specific parameters. [ Time Frame: Up to approximately 2 years ]
   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.
4. Part 2: Participants with solid tumors (non-GBM): Overall response rate (ORR) based on Evaluation Criteria In Solid Tumors (RECIST) 1.1 [ Time Frame: Up to approximately 2 years ]
   ORR is defined as the percentage of participants achieving a confirmed complete response (CR) or partial response (PR) based on RECIST 1.1 criteria.
5. Part 2: Participants with NHL: ORR based on Lugano criteria [ Time Frame: Up to approximately 2 years ]
   ORR is defined as the percentage of participants achieving CR or PR based on Lugano criteria.
6. Part 2: GBM cohort: Six-month progression free survival (PFS) rate [ Time Frame: Up to 6 months ]
   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.

Secondary Outcome Measures :

1. Parts 1 and 3: Maximum observed plasma concentration (Cmax) of GSK3326595 [ Time Frame: Baseline and up to approximately 2 years ]
   Blood samples will be collected at given time points to determine the Cmax of GSK3326595.
2. Parts 1 and 3: Area under the plasma concentration-time curve (AUC) extrapolated from time zero to infinity (AUC[0-inf]) of GSK3326595 [ Time Frame: Up to approximately 2 years ]
   Blood samples will be collected at given time points to determine the AUC (0-inf) of GSK3326595.
3. Parts 1 and 3: AUC from time zero to the last quantifiable concentration after dosing (AUC[0-t]) of GSK3326595 [ Time Frame: Up to approximately 2 years ]
   Blood samples will be collected at given time points to determine the AUC (0-t) of GSK3326595.
4. Parts 1 and 3: AUC over the dosing interval tau (AUC[0-tau]) of GSK3326595 [ Time Frame: Up to approximately 2 years ]
   Blood samples will be collected at given time points to determine the AUC (0-tau) of GSK3326595.
5. Parts 1 and 3: Terminal phase half-life (t1/2) of GSK3326595 [ Time Frame: Up to approximately 2 years ]
   Blood samples will be collected at given time points to determine the half-life of GSK3326595.
6. Parts 1 and 3: Oral clearance (CL/F) of GSK3326595 [ Time Frame: Up to approximately 2 years ]
   Blood samples will be collected at given time points to determine the CL/F of GSK3326595.
7. Parts 1 and 3: Accumulation ratio (AR) of GSK3326595 [ Time Frame: Up to approximately 2 years ]
   Blood samples will be collected at given time points to determine the AR of GSK3326595.
8. Parts 1 and 3: Time invariance (TI) of GSK3326595 [ Time Frame: Up to approximately 2 years ]
   Blood samples will be collected at given time points to determine the TI of GSK3326595.
9. Part 1: Participants with solid tumors: Overall response rate (ORR) based on Evaluation Criteria In Solid Tumors (RECIST) 1.1 [ Time Frame: Up to approximately 2 years ]
   ORR is defined as the percentage of participants achieving a confirmed complete response (CR) or partial response (PR) based on RECIST 1.1 criteria.
10. Part 3: ORR based on immune-based RECIST (iRECIST) criteria [ Time Frame: Up to approximately 2 years ]
    ORR is defined as the percentage of participants achieving confirmed CR or confirmed PR based on immune-based RECIST (iRECIST) criteria.
11. Part 2: PFS [ Time Frame: Up to approximately 2 years ]
    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.
12. Part 2: ORR in participants with GBM based on Response Assessment Neuro-Oncology (RANO) Working group criteria [ Time Frame: Up to approximately 2 years ]
    ORR is defined as the percentage of participants achieving a confirmed complete response (CR) or partial response (PR) based on RANO working group criteria.
13. Part 2: (Participants in ACC tablet cohort): Duration of Response (DOR) [ Time Frame: Up to approximately 2 years ]
    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.
14. Part 2: (Participants in ACC tablet cohort): Overall survival (OS) [ Time Frame: Up to approximately 2 years ]
    OS is defined as the time from first dose until death from any cause.
15. Part 2: Number of participants with any AEs, SAEs, withdrawal due to AEs, dose reductions or delays [ Time Frame: Up to approximately 2 years ]
    All AEs, SAEs and dose modifications will be collected.
16. Part 2: Number of participants with clinically significant changes in laboratory parameters, vital signs, physical examination and organ-specific parameters [ Time Frame: Up to approximately 2 years ]
    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.

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Locations

United States, Colorado

GSK Investigational Site

Denver, Colorado, United States, 80218

United States, Florida

GSK Investigational Site

Miami, Florida, United States, 33136

United States, New Jersey

GSK Investigational Site

Middletown, New Jersey, United States, 07748

United States, New York

GSK Investigational Site

Harrison, New York, United States, 10604

GSK Investigational Site

New York, New York, United States, 10065

United States, Tennessee

GSK Investigational Site

Nashville, Tennessee, United States, 37203

United States, Texas

GSK Investigational Site

Dallas, Texas, United States, 75230

GSK Investigational Site

San Antonio, Texas, United States, 78229

Canada, Alberta

GSK Investigational Site

Edmonton, Alberta, Canada, T6G 1Z2

Canada, Ontario

GSK Investigational Site

Ottawa, Ontario, Canada, K1H 8L6

GSK Investigational Site

Toronto, Ontario, Canada, M5G 1Z5

France

GSK Investigational Site

Bordeaux Cedex, France, 33076

GSK Investigational Site

Lyon Cedex 08, France, 69373

GSK Investigational Site

Villejuif cedex, France, 94805

Netherlands

GSK Investigational Site

Amsterdam, Netherlands, 1066 CX

GSK Investigational Site

Leiden, Netherlands, 2333 ZA

GSK Investigational Site

Rotterdam, Netherlands, 3015 GD

Sponsors and Collaborators

GlaxoSmithKline

Investigators

• Study Director: GSK Clinical Trials; GlaxoSmithKline

More Information

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT02783300
• Other Study ID Numbers: 204653; 2016-000278-39 ( EudraCT Number )
• First Posted: May 26, 2016
• Last Update Posted: June 28, 2022
• Last Verified: June 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: IPD for this study will be made available via the Clinical Study Data Request site.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)
• 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.
• 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.
• URL: http://clinicalstudydatarequest.com

Keywords provided by GlaxoSmithKline:

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

Additional relevant MeSH terms:

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