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

NCT02783300 | Completed Phase 1 Results

• 2 other identifiers: 2046532016-000278-39
• Study Type: interventional
• Target: 297
• Locations: 4 countries
• Sites: 15

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).

Conditions

Neoplasms

Keywords

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

Outcome Measures

Primary Outcomes (21)

• 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• Part 1: Number of Participants Withdrawn Due to AEs

  The data for number of participants withdrawn due to AEs have been presented.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 Outcomes (45)

• Part 2: Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs)

  Up to 42 months

• Part 2: Number of Participants Withdrawn Due to AEs

  Up to 42 months

• Part 2: Number of Participants With Dose Modifications of GSK3326595

  Up to 42 months

• Part 2: Number of Participants With Worst Case Change From Baseline in Clinical Chemistry Parameters

  Baseline (Day 1) and up to 42 months

• Part 2: Number of Participants With Worst Case Change From Baseline in Hematology Parameters

  Baseline (Day 1) and up to 42 months

Study Arms (3)

Part 1: Dose Escalation, Food effect and Relative Bioavailability of Capsule formulation to Tablet

EXPERIMENTAL

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

Part 2: Disease-Specific Expansion cohort

EXPERIMENTAL

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

Part 3: GSK3326595 in combination with pembrolizumab

EXPERIMENTAL

Participants with selected solid tumors will be administered GSK3326595 in combination with pembrolizumab as part of this dose determination study.

Drug: GSK3326595; Drug: Pembrolizumab

Interventions

GSK3326595 DRUG

GSK3326595 will be administered with and without food, in tablet and capsule formulation.

Part 1: Dose Escalation, Food effect and Relative Bioavailability of Capsule formulation to Tablet; Part 2: Disease-Specific Expansion cohort; Part 3: GSK3326595 in combination with pembrolizumab

Pembrolizumab DRUG

Pembrolizumab will be administered.

Part 3: GSK3326595 in combination with pembrolizumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (15)

GSK Investigational Site

Denver, Colorado, 80218, United States

Location

GSK Investigational Site

Miami, Florida, 33136, United States

Location

GSK Investigational Site

New York, New York, 10065, United States

Location

GSK Investigational Site

Nashville, Tennessee, 37203, United States

Location

GSK Investigational Site

Dallas, Texas, 75230, United States

Location

GSK Investigational Site

San Antonio, Texas, 78229, United States

Location

GSK Investigational Site

Edmonton, Alberta, T6G 1Z2, Canada

Location

GSK Investigational Site

Ottawa, Ontario, K1H 8L6, Canada

Location

GSK Investigational Site

Toronto, Ontario, M5G 1Z5, Canada

Location

GSK Investigational Site

Bordeaux, 33076, France

Location

GSK Investigational Site

Lyon, 69373, France

Location

GSK Investigational Site

Villejuif, 94805, France

Location

GSK Investigational Site

Amsterdam, 1066 CX, Netherlands

Location

GSK Investigational Site

Leiden, 2333 ZA, Netherlands

Location

GSK Investigational Site

Rotterdam, 3015 GD, Netherlands

Location

MeSH Terms

Conditions

Neoplasms; Lymphoma, Non-Hodgkin; Urologic Neoplasms; Carcinoma, Adenoid Cystic; Carcinoma, Non-Small-Cell Lung; Squamous Cell Carcinoma of Head and Neck; Melanoma

Interventions

GSK-3326595; pembrolizumab

Condition Hierarchy (Ancestors)

Lymphoma; Neoplasms by Histologic Type; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Urogenital Neoplasms; Neoplasms by Site; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Urologic Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Squamous Cell; Head and Neck Neoplasms; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Skin Diseases; Skin and Connective Tissue Diseases

Limitations and Caveats

Data was not available for pharmacokinetic parameters in samples that were out of stability or lost in transit.

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Masking Details: This is an open label study.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: April 11, 2016
• First Posted: May 26, 2016
• Study Start: August 30, 2016
• Primary Completion: August 30, 2023
• Study Completion: August 30, 2023
• Last Updated: March 10, 2025
• Results First Posted: March 10, 2025

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, 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.

Locations

CA (3); US (6); FR (3); NL (3)