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Trametinib

Protein Kinase Inhibitors

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GSK2256098, orally, at 0.375 or 0.5 mg, once daily, continuously every 28 day cycles.

Trametinib, orally at 250 mg or 500 mg, twice daily, continuously every 28 day cycles.

Small molecule inhibitor of focal adhesion kinase (FAK)

GSK2256098

Allosteric inhibitor of mitogen-activated extracellular signal-regulated kinase (MEK)1 and MEK2 activation and kinase activity.

Philippe Bedard, M.D.

This is a phase 2 study (the second phase in testing a new drug or combination to see how effect the drug or combination is) of investigational drugs GSK2256098 and Trametinib.

The purpose of the study is to evaluate the antitumor activity of GSK2256098 and Trametinib in patients with advanced pancreatic cancer.

Trametinib is a drug that works by binding to and blocking certain proteins called mitogen-activated protein kinase kinase (MEK) 1 and MEK2 from working. MEK1 and MEK2 are important proteins that contribute to the growth of cancer cells.

GSK2256098 is a drug that blocks a protein called focal adhesion kinase-1 (FAK) which is an important protein that contribute to the growth of cancer cells.

A Study of GSK2256098 and Trametinib in Advanced Pancreatic Cancer

Molecular Basket Trial In Multiple Malignancies With Common Target Pathway Aberrancies: A Phase II Trial of GSK2256098 and Trametinib in Patients With Advanced Pancreatic Cancer

GlaxoSmithKline

University Health Network, Toronto

Symptoms and General Pathology

Respiratory Tract (Lung and Bronchial) Diseases

Tissue Adhesions

Mesothelioma

Mesothelioma, Malignant

Malignant Mesothelioma

Part 1 will determine the MTD and RP2D based on the safety and tolerability of GSK2256098 administered with trametinib. Subject will be administered starting dose of 1.0 mg OD trametinib combined with 500 mg BID GSK2256098. Dose escalation will continue until the MTD is established.

Based on determination of combination dose regimen in Part 1, dose expansion cohorts for Part 2 will be opened.

GSK2256098 250 mg will be supplied as white to off-white, round, biconvex tablets with no markings. GSK2256098 will be administered 30 minutes after a light meal with approximately 240 milliliter of water.

Trametinib 0.5 mg will be supplied as capsules with no identifying markings. Trametinib will be administered orally under fasting conditions two hours after a meal.

GSK Clinical Trials

The purpose of this study is to assess the safety of combination treatment of GSK2256098 and trametinib in mesothelioma subjects and subjects with other selected tumor types. Also, the study will identify a maximum tolerated combination dose of GSK2256098 and trametinib. This study is a Phase I, open-label, dose-escalation study to determine maximal tolerated dose (MTD) and the recommended Phase 2 dose (RP2D) and regimens for oral MEK inhibitor trametinib (once daily \[OD\]dosing) and the oral FAK inhibitor GSK2256098 (twice daily \[BID\] dosing). The synergy of the combination was observed over a wide range of concentrations and results in several-fold reduction in compound concentration to achieve equivalent biological responses compared to either single agent. The dose and schedule of dosing may be modified based on emerging safety, pharmacokinetic (PK), and pharmacodynamic (PD) data. The study will be conducted in two parts; Part 1 Dose Escalation to determine the MTD and RP2D and Part 2 Expansion Cohort to further evaluate the safety and tolerability of trametinib and GSK2256098 at the RP2D and determine clinical activity. Additionally, in Part 1 Dose Escalation, additional subjects with malignant pleural mesothelioma (MPM) will be recruited at doses that are considered tolerable in order to assess PD in MPM subjects at each dose (the Pharmacodynamic Cohort). The Expansion Cohort will be limited to subjects with MPM who have progressed or are intolerant to first-line therapy.

A Dose Escalation Study to Assess Safety of GSK2256098 (FAK Inhibitor) in Combination With Trametinib (MEK Inhibitor) in Subjects With Advanced Solid Tumors

A Phase 1b, Multi-center, Open-label, Dose Escalation Study of GSK2256098 (FAK Inhibitor) in Combination With Trametinib (MEK Inhibitor) in Subjects With Advanced Solid Tumors

IPD for this study will be made available via the Clinical Study Data Request site.

AEs and SAEs will be assessed to determine the MTD and RP2D combination of GSK2256098 and trametinib.

Twelve lead ECGs will be obtained to determine the MTD and RP2D combination of GSK2256098 and trametinib.

Vital sign measurements will include systolic and diastolic blood pressure, pulse rate, and temperature

Clinical laboratory assessments will include hematology, clinical chemistry, routine urinalysis and additional parameters

Echocardiograms will be performed to assess cardiac ejection fraction.

A standard ophthalmic exam will be performed by an ophthalmologist.

Urine samples will be collected for the analyses of UPC ratio.

AEs and SAEs will be recorded to assess longer term safety of the GSK2256098/trametinib combination at the RP2D in a larger cohort of subjects with MPM.

Twelve lead ECGs will be obtained to assess longer term safety of the GSK2256098/trametinib combination at the RP2D in a larger cohort of subjects with MPM

Blood sample will be collected for measurements of GSK2256098 and trametinib PK parameters including AUC(0-tau), Ctau, Cmax, and tmax.

PD markers pFAK/FAK, and pERK/ERK levels will be analyzed in fresh tumor tissue to assess the level of target inhibition by GSK2256098 and trametinib, respectively. Tumor tissue will be collected at screening (before the first dose on Day 1) and between 1 and 6 hours after GSK2256098 dosing on a day between Day 15 and Day 22, inclusive.

The LCSS- mesothelioma is a disease- and site-specific quality of life instrument to measure physical and functional dimensions in patients with lung cancer. The LCSS- mesothelioma will be completed by the investigator at each scheduled disease assessment and at progression.

Forced vital capacity will be measured at each scheduled disease assessment using standard methods.

PFS is defined as the interval between first dose and the earliest date of disease progression or death due to any cause by investigator assessment.

The LCSS- mesothelioma is a disease- and site-specific quality of life instrument to measure physical and functional dimensions in patients with lung cancer. The LCSS- mesothelioma will be completed by the by the subjects with mesothelioma at each scheduled disease assessment and at progression.

Blood samples will be collected to analyze the PK parameters including AUC (0 tau), Ctau, Cmax, and tmax . If data permitting, population PK parameters, such as oral clearance (CL/F) and oral volume of distribution (Vz/F) of GSK2256098 and trametinib may be determined.

The relationship between GSK2256098 and trametinib PK, PD and clinical endpoints in subjects with MPM will be assessed.

Blood samples will be collected to analyses PK parameters includes area under the concentration-time curve from time zero (pre-dose) to last time of quantifiable concentration within a subject across all treatments \[AUC(0-tau)\], maximum observed plasma concentration (Cmax), time to Cmax (tmax), and trough concentration (Ctau) of GSK2256098 DBS and whole blood following repeat-dose (Day15 and 22) administration of GSK2256098 and trametinib.

single dose administration escalating doses starting at 20 mg and continue escalation; the highest dose in this study will not exceed the mean Day 1 exposure in male dogs at the NOAEL dose (6 mg/kg/day).

Dose to be selected based on emerging safety and PK data; subjects will be given FDA standard high fat meal followed by single dose of study drug.

focal adhesion kinase inhibitor given as a single dose

Placebo to be used as comparator for GSK2256098

Placebo

The purpose of this study is to test the safety of a new drug and to look at how the drug is handled by your body. This is the first time the drug will be given to people, the drug has been safely given to animals over many days at higher doses than will be given in the study. The study will be done in healthy men and woman to determine what effects, good or bad, it has on thier health. This study will find out:

If the drug has any side effects after one dose of the drug is given? How much of the drug gets into the bloodstream, and how long does the body take to get rid of it? If the drug causes any changes to a substance that is in skin, hair or blood.

This study represents the first administration of the focal adhesion kinase (FAK) inhibitor GSK2256098 to humans to evaluate the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary food effect following single oral doses in adult healthy subjects before proceeding to studies in subjects with cancer that will be given at higher doses over an extended period of time. FAK is a protein in the body that is important in cancer development. Objectives of the study will be to characterize the safety of single doses of GSK2256098; to characterize the single dose PK of GSK2256098 in the presence and absence of food; to examine the dose proportionality of GSK2256098 PK parameters following single dose administration; and to characterize the effect of single doses of GSK2256098 on phospho-FAK (pFAK) tyrosine 397 (Y397) levels in skin and hair follicles. Dose- and concentration-effect relationships for various safety parameters will be explored as appropriate.

Phase I Study to Evaluate Safety, Pharmacokinetics and Pharmacodynamics of GSK2256098 in Healthy Volunteers

A Phase I, Randomized, Single-Blind, Placebo-Controlled Dose-Escalation Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics and Preliminary Food Effect Following Single Oral Doses of the Focal Adhesion Kinase Inhibitor, GSK2256098, in Healthy Subjects

Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Study of GSK2256098 and Trametinib in Advanced Pancreatic Cancer	NCT02428270	Pancreatic Canc... Adenocarcinoma	GSK2256098 Trametinib	18 Years -	University Health Network, Toronto
A Dose Escalation Study to Assess Safety of GSK2256098 (FAK Inhibitor) in Combination With Trametinib (MEK Inhibitor) in Subjects With Advanced Solid Tumors	NCT01938443	Cancer Neoplasms	GSK2256098 Trametinib	18 Years -	GlaxoSmithKline
A Dose Escalation Study to Assess Safety of GSK2256098 (FAK Inhibitor) in Combination With Trametinib (MEK Inhibitor) in Subjects With Advanced Solid Tumors	NCT01938443	Cancer Neoplasms	GSK2256098 Trametinib	18 Years -	GlaxoSmithKline
Phase I Study to Evaluate Safety, Pharmacokinetics and Pharmacodynamics of GSK2256098 in Healthy Volunteers	NCT00996671	Cancer	GSK2256098 Placebo	18 Years - 65 Years	GlaxoSmithKline
Phase I Study to Evaluate Safety, Pharmacokinetics and Pharmacodynamics of GSK2256098 in Healthy Volunteers	NCT00996671	Cancer	GSK2256098 Placebo	18 Years - 65 Years	GlaxoSmithKline
A Study of GSK2256098 and Trametinib in Advanced Pancreatic Cancer	NCT02428270	Pancreatic Canc... Adenocarcinoma	GSK2256098 Trametinib	18 Years -	University Health Network, Toronto

Spots Global Cancer Trial Database for gsk2256098

Every month we try and update this database with for gsk2256098 cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for gsk2256098

Every month we try and update this database with for gsk2256098 cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for gsk2256098 cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.