Clinical trial NCT02783300: 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
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
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
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2016-05-26
Enrollment: 297
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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).


Eligibility 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.

Primary outcomes:
measure: Part 1: Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Up to 30 months
measure: Part 1: Number of Participants Withdrawn Due to AEs
timeFrame: Up to 30 months
measure: Part 1: Number of Participants With Dose Limiting Toxicities (DLTs)
timeFrame: Up to 21 days
measure: Part 1: Number of Participants With Dose Modifications of GSK3326595
timeFrame: Up to 30 months
measure: Part 1: Number of Participants With Worst Case Change From Baseline in Clinical Chemistry Parameters
timeFrame: Baseline (Day 1) and up to 30 months
measure: Part 1: Number of Participants With Worst Case Change From Baseline in Hematology Parameters
timeFrame: Baseline (Day 1) and up to 30 months
measure: Part 1: Number of Participants With Worst Case Change From Baseline in Coagulation Parameters
timeFrame: Baseline (Day 1) and up to 30 months
measure: Part 1: Number of Participants With Worst Case Change From Baseline in Urinalysis Parameters
timeFrame: Baseline (Day 1) and up to 30 months
measure: Part 1: Changes From Baseline in Urine Potential of Hydrogen (pH)
timeFrame: Baseline (Day 1) and up to week 132
measure: Part 1: Changes From Baseline in Urine Specific Gravity
timeFrame: Baseline (Day 1) and up to week 132
measure: Part 1: Number of Participants With Maximum Grade Worst Case Increase Post-baseline Relative to Baseline in Vital Signs
timeFrame: Baseline (Day 1) and up to 30 months
measure: Part 3: Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Up to 10 months
measure: Part 3: Number of Participants Withdrawn Due to AEs
timeFrame: Up to 10 months
measure: Part 3: Number of Participants With Dose Modifications of GSK3326595 and Pembrolizumab
timeFrame: Up to 10 months
measure: Part 3: Number of Participants With Worst Case Change From Baseline in Clinical Chemistry Parameters
timeFrame: Baseline (Day 1) and up to 10 months
measure: Part 3: Number of Participants With Worst Case Change From Baseline in Hematology Parameters
timeFrame: Baseline (Day 1) and up to 10 months
measure: Part 3: Number of Participants With Worst Case Change From Baseline in Coagulation Parameters
timeFrame: Baseline (Day 1) and up to 10 months
measure: Part 3: Number of Participants With Worst Case Change From Baseline in Urinalysis Parameters
timeFrame: Baseline (Day 1) and up to 10 months
measure: Part 3: Changes From Baseline in Urine Potential of Hydrogen (pH)
timeFrame: Baseline (Day 1) and up to Week 42
measure: Part 3: Changes From Baseline in Urine Specific Gravity
timeFrame: Baseline (Day 1) and up to Week 42
measure: Part 3: Number of Participants With Maximum Worst-case Increase Post-baseline Relative to Baseline in Vital Signs
timeFrame: Baseline (Day 1) and up to 10 months
Secondary outcomes:
measure: Part 2: Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Up to 42 months
measure: Part 2: Number of Participants Withdrawn Due to AEs
timeFrame: Up to 42 months
measure: Part 2: Number of Participants With Dose Modifications of GSK3326595
timeFrame: Up to 42 months
measure: Part 2: Number of Participants With Worst Case Change From Baseline in Clinical Chemistry Parameters
timeFrame: Baseline (Day 1) and up to 42 months
measure: Part 2: Number of Participants With Worst Case Change From Baseline in Hematology Parameters
timeFrame: Baseline (Day 1) and up to 42 months
measure: Part 2: Number of Participants With Worst Case Change From Baseline in Coagulation Parameters
timeFrame: Baseline (Day 1) and up to 42 months
measure: Part 2: Number of Participants With Worst Case Change From Baseline in Urinalysis Parameters
timeFrame: Baseline (Day 1) and up to 42 months
measure: Part 2: Changes From Baseline in Urine Potential of Hydrogen (pH)
timeFrame: Baseline (Day 1) and up to week 184
measure: Part 2: Changes From Baseline in Urine Specific Gravity
timeFrame: Baseline (Day 1) and up to week 184
measure: Part 2: Number of Participants With Maximum Grade Worst Case Increase Post-baseline Relative to Baseline in Vital Signs
timeFrame: Baseline (Day 1) and up to 42 months
measure: Part 1: Maximum Observed Plasma Concentration (Cmax) of GSK3326595
timeFrame: 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
measure: Part 3: Maximum Observed Plasma Concentration (Cmax) of GSK3326595
timeFrame: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24h post-dose
measure: Part 1: Area Under the Plasma Concentration-time Curve (AUC) Extrapolated From Time Zero to Infinity (AUC[0-inf]) of GSK3326595
timeFrame: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 h post-dose
measure: Part 3: Area Under the Plasma Concentration-time Curve (AUC) Extrapolated From Time Zero to Infinity (AUC[0-inf]) of GSK3326595
timeFrame: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24h post-dose
measure: Part 1: AUC From Time Zero to the Last Quantifiable Concentration After Dosing (AUC[0-t]) of GSK3326595
timeFrame: 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
measure: Part 3: AUC From Time Zero to the Last Quantifiable Concentration After Dosing (AUC[0-t]) of GSK3326595
timeFrame: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24h post-dose
measure: Part 1: AUC Over the Dosing Interval Tau (AUC[0-tau]) of GSK3326595
timeFrame: 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
measure: Part 3: AUC Over the Dosing Interval Tau (AUC[0-tau]) of GSK3326595
timeFrame: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24h post-dose
measure: Part 1: Terminal Phase Half-life (t1/2) of GSK3326595
timeFrame: 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
measure: Part 3: Terminal Phase Half-life (t1/2) of GSK3326595
timeFrame: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24h post-dose
measure: Part 1: Oral Clearance (CL/F) of GSK3326595
timeFrame: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24h post-dose
measure: Part 3: Oral Clearance (CL/F) of GSK3326595
timeFrame: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24h post-dose
measure: Part 1: Accumulation Ratio (AR) of GSK3326595
timeFrame: 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
measure: Part 3: Accumulation Ratio (AR) of GSK3326595
timeFrame: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24h post-dose
measure: Part 1: Time Invariance (TI) of GSK3326595
timeFrame: 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
measure: Part 3: Time Invariance (TI) of GSK3326595
timeFrame: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24h post-dose
measure: Part 1: Overall Response Rate (ORR) Based on RECIST 1.1
timeFrame: Up to 30 months
measure: Part 2: Overall Response Rate (ORR) (Non-glioblastoma Multiforme [GBM] Cohorts)
timeFrame: Up to 42 months
measure: Part 2: Six-month Progression Free Survival (PFS) Rate (GBM Cohort)
timeFrame: At month 6
measure: Part 2: Duration of Response (DOR) (ACC Tablet Cohort)
timeFrame: Up to 42 months
measure: Part 3: ORR Based on Immune-based RECIST (iRECIST) Criteria
timeFrame: Up to 10 months
measure: Part 2: ORR (GBM Cohort) Based on Response Assessment Neuro-Oncology (RANO) Working Group Criteria
timeFrame: Up to 42 months
measure: Part 2: ORR (Non-Hodgkin's Lymphoma (NHL) Cohorts) Based on Lugano Criteria
timeFrame: Up to 42 months
measure: Part 2: Overall Survival (OS) (ACC Tablet Cohort)
timeFrame: Up to 42 months
measure: Part 2: Progression-free Survival
timeFrame: Up to 42 months
measure: RP2D Phase: Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Up to maximum 42 months
measure: RP2D Phase: Number of Participants Withdrawn Due to AEs
timeFrame: Up to maximum 42 months
measure: RP2D Phase: Number of Participants With Dose Modifications of GSK3326595
timeFrame: Up to maximum 42 months
measure: RP2D Phase: Number of Participants With Worst Case Change From Baseline in Clinical Chemistry Parameters
timeFrame: Baseline (Day 1) and up to maximum 42 months
measure: RP2D Phase: Number of Participants With Worst Case Change From Baseline in Hematology Parameters
timeFrame: Baseline (Day 1) and up to maximum 42 months
measure: RP2D Phase: Number of Participants With Worst Case Change From Baseline in Coagulation Parameters
timeFrame: Baseline (Day 1) and up to maximum 42 months
measure: RP2D Phase: Number of Participants With Worst Case Change From Baseline in Urinalysis Parameters
timeFrame: Baseline (Day 1) and up to maximum 42 months
measure: RP2D Phase: Changes From Baseline in Urine Potential of Hydrogen (pH)
timeFrame: Baseline (Day 1) and up to Week 184
measure: RP2D Phase: Changes From Baseline in Urine Specific Gravity
timeFrame: Baseline (Day 1) and up to Week 184
measure: RP2D Phase: Number of Participants With Worst-case Increase Post-baseline Relative to Baseline in Vital Signs
timeFrame: Baseline (Day 1) and up to maximum 42 months
Other outcomes:
Locations:
city: Denver
country: United States
facility: GSK Investigational Site
state: Colorado
city: Miami
country: United States
facility: GSK Investigational Site
state: Florida
city: New York
country: United States
facility: GSK Investigational Site
state: New York
city: Nashville
country: United States
facility: GSK Investigational Site
state: Tennessee
city: Dallas
country: United States
facility: GSK Investigational Site
state: Texas
city: San Antonio
country: United States
facility: GSK Investigational Site
state: Texas
city: Edmonton
country: Canada
facility: GSK Investigational Site
state: Alberta
city: Ottawa
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Toronto
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Bordeaux
country: France
facility: GSK Investigational Site
city: Lyon Cedex 08
country: France
facility: GSK Investigational Site
city: Villejuif cedex
country: France
facility: GSK Investigational Site
city: Amsterdam
country: Netherlands
facility: GSK Investigational Site
city: Leiden
country: Netherlands
facility: GSK Investigational Site
city: Rotterdam
country: Netherlands
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: