Study to Investigate the Absorption, Distribution, Metabolism and Elimination of [14C]GSK1120212

Study Overview
=================
Brief Summary
-----------------
GSK1120212 is a reversible and highly selective allosteric inhibitor of MEK1 and MEK2 activation and kinase activity currently being developed for the treatment of malignant melanoma. This is a Phase I, open-label, non-randomized, single-dose study designed to characterize the absorption, distribution, metabolism, and elimination (ADME) of a single oral dose of MEK inhibitor [14C]GSK1120212 as a solution in male subjects with solid tumor malignancies. A sufficient number of subjects will be enrolled to complete approximately four evaluable subjects. Following completion of the study, subjects may elect to continue dosing with GSK1120212 in the rollover study, MEK114375.

Official Title
-----------------
An Open-label Mass Balance Study to Investigate the Absorption, Distribution, Metabolism and Elimination of a Single Oral Dose of MEK Inhibitor [14C]GSK1120212 in Male Subjects With Solid Tumors

Conditions
-----------------
Cancer

Intervention / Treatment
-----------------
* Drug: GSK1120212


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male 18 years old or older. Written informed consent provided Body weight greater than or equal to 45 kg and a BMI greater than or equal to 19 kg/m2 and less than or equal to 35 kg/m2 (inclusive). Able to swallow and retain oral medication. Histologically or cytologically confirmed diagnosis of a solid tumor. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. Agree to use one of the contraception methods listed in the protocol from the time of the first dose of study medication until sixteen weeks after the last dose of study medication. A history of regular bowel movements (approximately once per day). Adequate baseline organ function as listed in the protocol. Exclusion Criteria: Currently receiving cancer therapy as specified in the protocol. Serious and/or unstable pre-existing medical psychiatric disorder, or other conditions. Any major surgery within the last four weeks. Unresolved toxicity equal to or greater than Grade 2 from previous anti-cancer therapy except alopecia. An occupation within the past 12 months which requires monitoring for radiation exposure, nuclear medicine procedures or excessive x-rays. Radiation exposure from the previous three year period over 10 mSv if exposed to ionizing radiation above background as a result of work with radiation as category A (classified) workers or as a result of research studies. History of interstitial lung disease or pneumonitis. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to dimethyl sulfoxide (DMSO). Current use of a prohibited medications described in the protocol. • Use of anticoagulants such as warfarin is permitted. History RVO or CSR. Predisposing factors to RVO or CSR. Visible retinal pathology that is considered a risk factor for RVO or CSR such as: - Evidence of new optic disc cupping - Intraocular pressure greater than 21 mm Hg as measured by tonography. 11.1. Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression. (Previously treated and have had stable CNS disease for greater than 3 months, asymptomatic and off corticosteroids, or on stable dose of corticosteroids for at least 1 month prior to study Day 1 are permitted). 11.2. Receiving enzyme inducing anti-epileptic drugs (EIAEDs). 12. History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within the past 6 months. 13. QTcB greater than or equal to 480 msec. 14. History or evidence of current clinically significant uncontrolled arrhythmias. 15. History or evidence of current greater than or equal to Class II congestive heart failure. 16. Active gastrointestinal disease or other condition (e.g., gastrectomy, bariatric surgery, small bowel or large bowel resection, or cholecystectomy). 17. A history of known Human Immunodeficiency Virus (HIV), Hepatitis B Virus, or Hepatitis C Virus. 18. Alcohol or drug abuse within six months prior to screening. 19. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study drugs or excipients. 20. Participated in a clinical trial and has received an investigational product within 30 days or five half-lives or twice the duration of the biological effect of the investigational product (whichever is longer) before the 1st dose. 21. Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period. 22. Mentally or legally incapacitated.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single-Dose, 2 mg [14C]GSK1120212<br>A single 2 mg (2 mg/10mL) oral dose of [14C]GSK1120212 containing approximately 79 μCi of radioactivity will be delivered as a solution. | Drug: GSK1120212<br>* The 2 mg dose is based on clinical data from the ongoing FTIH study in which subjects have been dosed daily for greater than 21 days, as well as preclinical toxicity data.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total excretion of radioactivity | • Total and relative excretion of radioactivity in urine and feces following a single, 2 mg oral solution dose of [14C]GSK1120212 | 11 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total radioactivity concentration in blood and plasma | AUC(0- t), AUC(0-∞), Cmax, tmax and t1/2 | 11 days | 
| Characterize and quantify metabolites in urine plasma and feces | Characterize and quantify metabolites of GSK1120212 in plasma, urine and feces (studied separately under a DMPK protocol). | 11 days | 
| Assess covalent binding of drug related material to plasma proteins | Assess percentage of drug-related material that covalently bonds to plasma proteins (studied separately under a DMPK protocol) | 11 days | 
| Blood:plasma ratio | Blood:plasma ratio of total drug-related material (radioactivity) | 11 days | 
| Pharmacokentic concentrations in plasma | Plasma GSK1120212 concentrations AUC(0-t), AUC(0-∞), Cmax, tmax, and t1/2 | 11 days | 
| AEs | Number of adverse events (AEs) | From dosing on Day 1 to Follow-up | 
| Vital signs | Changes from baseline | Screening, Day -1, Day 1, Day 5, and Follow-up | 
| ECGs | Changes from baseline | Screening, Day 1 pre-dose, 24 hours, Day 11 and Follow-up | 
| Clinical Laboratory assessments | Changes from baslines | Screening, Day -1, and Day 11 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
MEK inhibitor, elimination, Phase 1, GSK1120212, cancer, Pharmacokinetics, oncology, radiolabeled ADME