A Study to Determine the Relative Bioavailability of the MEK Inhibitor, Trametinib, in Subjects With Solid Tumor Malignancies

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by GlaxoSmithKline
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01725100
First received: November 8, 2012
Last updated: July 24, 2014
Last verified: July 2014
  Purpose

This is an open-label, randomized, single-dose, 2-treatment, 2-period, 2-way crossover study with incomplete wash-out in subjects with solid tumors to determine the relative bioavailability of test formulation with lower dimethyl sulfoxide (DMSO) content as compared with standard reference formulation trametinib.

Approximately 18 subjects will be randomized to receive either a single dose of Treatment A (standard target DMSO content [theoretical 11.3%] formulation of GSK1120212B) or a single dose of Treatment B (lower DMSO Content [approximately 9.5%] formulation of GSK1120212B) followed by a 7 day incomplete wash-out period, then a single dose of the other treatment.

Administration of the dose under fasted conditions in Periods 1 and 2 will be only on Day 1 followed by 7 days of serial blood sampling for PK analysis of plasma trametinib. Safety assessments, including assessment of AEs, clinical laboratory (hematology and clinical chemistry) and vital signs, will be made throughout the study.

After a subject completes the study, he or she may be eligible to enter study MEK114375, an open-label rollover study of trametinib (no wash-out period or follow-up visit required) and continue receiving trametinib. For those subjects who wish to discontinue or complete the current study and choose not enter the rollover study, a follow-up visit should be performed within 21 days after receiving the last dose of study treatment.


Condition Intervention Phase
Cancer
Drug: GSK1120212B (Standard DMSO content)
Drug: GSK1120212B (Lower DMSO content)
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Bio-availability Study
Intervention Model: Crossover Assignment
Masking: Open Label
Official Title: An Open-label, Randomized, 2-treatment, 2-period, 2-way Crossover, Single-dose Study to Determine the Relative Bioavailability of the MEK Inhibitor, Trametinib, in Subjects With Solid Tumor Malignancies

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Corrected Cmax of GSK1120212B [ Time Frame: Period 1 and 2: Day 1 pre-dose within 15 minutes (mins) of planned study treatment administration (serves as the 168-hour [hr] sample for Period 1), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 10 hrs post-dose; Days 2 to 7: post dose at 24 hrs (Day 2), 48 hrs ( ] [ Designated as safety issue: No ]
    Pharmacokinetic data will include corrected maximum plasma concentration (Cmax) of GSK1120212B. Comparison of Cmax will enable to determine the relative bioavailability of the test formulation with lower DMSO content (Treatment B) and the standard reference formulation (Treatment A). Period 2 PK parameters will be corrected for residual concentrations from Period 1 (based on individual estimates of t1/2) to remove the carry-over effect.

  • Corrected AUC(0-t) and AUC(0-inf) of GSK1120212B [ Time Frame: Period 1 and 2: Day 1 pre-dose within 15 mins of planned study treatment administration (serves as the 168-hr sample for Period 1), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 10 hrs post-dose; Days 2 to 7: post dose at 24 hrs (Day 2), 48 hrs (Day 3), 72 hrs ( ] [ Designated as safety issue: No ]
    Pharmacokinetic data will include corrected area under the time-concentration curve from time zero (pre-dose) to last time of quantifiable concentration (AUC(0-t)) and AUC from zero to infinity (AUC(0-inf)) of GSK1120212B. Period 2 PK parameters will be corrected for residual concentrations from Period 1 (based on individual estimates of t1/2) to remove the carry-over effect.

  • Corrected tmax of GSK1120212B [ Time Frame: Period 1 and 2: Day 1 pre-dose within 15 mins of planned study treatment administration (serves as the 168-hr sample for Period 1), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 10 hrs post-dose; Days 2 to 7: post dose at 24 hrs (Day 2), 48 hrs (Day 3), 72 hrs ( ] [ Designated as safety issue: No ]
    Pharmacokinetic data will include corrected time of occurrence of Cmax (tmax) of GSK1120212B. Period 2 PK parameters will be corrected for residual concentrations from Period 1 (based on individual estimates of t1/2) to remove the carry-over effect.


Secondary Outcome Measures:
  • Uncorrected Cmax of GSK1120212B [ Time Frame: For Period 1 and 2 on Day 1: pre-dose within 15 mins of planned study treatment administration (serves as the 168-hr sample for Period 1), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 10 hrs post-dose; Days 2 to 7: post dose at 24 hrs (Day 2), 48 hrs (Day 3), 72 ] [ Designated as safety issue: No ]
    Pharmacokinetic data will include uncorrected Cmax of GSK1120212B.

  • Uncorrected AUC(0-t), AUC(0-inf) and AUC(0-24) of GSK1120212B [ Time Frame: For Period 1 and 2 on Day 1: pre-dose within 15 mins of planned study treatment administration (serves as the 168-hr sample for Period 1), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 10 hrs post-dose; Days 2 to 7: post dose at 24 hrs (Day 2), 48 hrs (Day 3), 72 ] [ Designated as safety issue: No ]
    Pharmacokinetic data will include uncorrected AUC(0-t), AUC(0-inf) and AUC from zero to 24 hrs AUC(0-24) of GSK1120212B.

  • Pre-dose concentration (C0) of GSK1120212B [ Time Frame: Period 2: Day 1 pre-dose within 15 minutes (mins) of planned study treatment administration (serves as the 168-hour [hr] sample for Period 1. ] [ Designated as safety issue: No ]
    Pharmacokinetic data will include uncorrected C0 of GSK1120212B in Period 2

  • Elimination half life (t½) of GSK1120212B [ Time Frame: Period 1 and 2: Day 1 pre-dose within 15 mins of planned study treatment administration (serves as the 168-hr sample for Period 1), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 10 hrs post-dose; Days 2 to 7: post dose at 24 hrs (Day 2), 48 hrs (Day 3), 72 hrs ( ] [ Designated as safety issue: No ]
    Pharmacokinetic data will include t1/2 of GSK1120212B.

  • Safety of GSK1120212B as assessed by changes in vital signs measurements [ Time Frame: Through Day 36. ] [ Designated as safety issue: No ]
    Safety data will include measurements of vital signs (blood pressure, pulse rate and temperature) at Baseline and end of the study.

  • Safety of GSK1120212B as assessed by changes in clinical laboratory tests [ Time Frame: Through Day 36. ] [ Designated as safety issue: No ]
    Safety data will include assessments of clinical laboratory tests (hematology, clinical chemistry, coagulation and at Baseline and end of the study.

  • Safety of GSK1120212B as assessed by number of subjects with adverse events (AE)s [ Time Frame: Through Day 36 ] [ Designated as safety issue: No ]
    Safety data will include recording of number of subjects with AEs.


Estimated Enrollment: 80
Study Start Date: February 2013
Estimated Study Completion Date: October 2014
Estimated Primary Completion Date: October 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment A: GSK1120212B (Standard DMSO content)
Subjects will receive Treatment A in Period 1 or 2 as single oral dose on Day 1 of Period 1 or 2 in fasting condition with water.
Drug: GSK1120212B (Standard DMSO content)
Each tablet contains GSK1120212B equivalent to 2 mg of GSK1120212 as drug substance. The coated tablets have a standard DMSO content of theoretical 11.3%.
Experimental: Treatment B: GSK1120212B (Lower DMSO content)
Subjects will receive Treatment B in Period 1 or 2 as single oral dose on Day 1 of Period 1 or 2 in fasting condition with water.
Drug: GSK1120212B (Lower DMSO content)
Each tablet contains GSK1120212B equivalent to 2 mg of GSK1120212 as drug substance. The coated tablets have a lower DMSO content approximately 9.5%.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Has provided signed, written informed consent.
  • Male or female, age >=18 years of age at the time of signing the informed consent form.
  • Has histologically or cytologically confirmed diagnosis of a solid tumor malignancy that is not responsive to standard therapy (ies) or for which there is no approved therapy.
  • Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
  • Able to swallow and retain orally administered medication and does not have any clinically significant gastrointestinal (GI) abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels.
  • All prior treatment-related toxicities must be National Cancer Institute - Common Toxicity Criteria for Adverse Events (NCI-CTCAE), version 4.0 <=Grade 1 (except alopecia) at the time of enrollment.
  • Has adequate baseline organ function as defined: ANC >=1.2×10^9/liter (L), hemoglobin>=9 gram (g)/deciliter (dL), Platelets>=75×10^9/L, partial thromboplastin time (PTT), prothrombin time (PT) and International normalization ratio (INR) <=1.5 times upper limit of normal (ULN), albumin >=2.5 g/dL, total bilirubin <=1.5 times ULN alanine aminotransferase (ALT) <=2.5 times ULN, Creatinine or calculated creatinine clearance >=50 milliliter (mL)/minute (min) and left ventricular ejection fraction (LVEF)>=lower limit of normal (LLN) by echocardiogram (ECHO) or multigated acquisition scan (MUGA).
  • Women of childbearing potential must have a negative serum pregnancy test within 14 days of first dose of study treatment and agree to use effective contraception, during the study and for 4 months following the last dose of study treatment.

Exclusion Criteria:

  • Prior exposure to a mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor.
  • Anti-cancer therapy (e.g., chemotherapy with delayed toxicity, extensive radiation therapy, immunotherapy, biologic therapy, or major surgery) within 21 days prior to randomization; chemotherapy regimens without delayed toxicity within 14 days prior to randomization.
  • Female Subjects: Lactating or actively breastfeeding.
  • Has participated in a clinical trial and received investigational drug within 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (IP), whichever is longer, prior to randomization in this study.
  • Has participated in a study that resulted in or made a donation of blood or blood products in excess of 500 mL within 56 days of the first dose of study treatment.
  • History or presence of hepatic insufficiency (excluding metastatic hepatic carcinoma).
  • History of interstitial lung disease or pneumonitis.
  • Known Human Immunodeficiency Virus, Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection
  • Subjects with laboratory evidence of cleared HBV and HCV infection will be permitted.
  • Has a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to study treatment, or excipients, or to DMSO.
  • Currently using a prohibited medication or requires the use of any of the prohibited medications during the study. Use of anticoagulants such as warfarin is permitted provided INR must be monitored in accordance with local institutional practice.
  • Has a history of another malignancy. Subjects who have been disease-free for 3 years or subjects with a history of a completely resected non-melanoma skin cancer and/or subjects with indolent second malignancies are eligible.
  • Any serious and/or unstable pre-existing medical disorder (aside from malignancy exception above), psychiatric disorder, or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures.
  • Has a history or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR).
  • Symptomatic or untreated leptomeningeal or brain metastases, or spinal cord compression.
  • Left ventricular ejection fraction (LVEF), as measured by ECHO or MUGA scan, below the institutional LLN, or if a LLN does not exist at an institution, <50%.
  • QT interval corrected for heart rate using the Bazett formula (QTcB) >=480 millisecond (msec).
  • History or current evidence of cardiovascular risk including any of the following: current clinically significant uncontrolled arrhythmias, acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization, current >= Class II congestive heart failure as defined by New York Heart Association (NYHA), treatment-refractory hypertension defined as a blood pressure of systolic blood pressure (SBP) >140 millimeters of mercury (mmHg) and/or diastolic blood pressure (DBP) >90 mmHg which cannot be controlled by anti-hypertensive therapy, has an intra-cardiac defibrillator or permanent pacemaker and known cardiac metastases.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01725100

Contacts
Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com

Locations
United States, Arizona
GSK Investigational Site Recruiting
Goodyear, Arizona, United States, 85338
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
GSK Investigational Site Recruiting
Scottsdale, Arizona, United States, 85259
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
United States, Florida
GSK Investigational Site Recruiting
Sarasota, Florida, United States, 34232
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
United States, Tennessee
GSK Investigational Site Recruiting
Nashville, Tennessee, United States, 37203
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01725100     History of Changes
Other Study ID Numbers: 114656
Study First Received: November 8, 2012
Last Updated: July 24, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by GlaxoSmithKline:
GSK1120212
DMSO content
pharmacokinetics
solid tumors
MEK inhibitor
dissolution
trametinib
relative bioavailability

Additional relevant MeSH terms:
Trametinib
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on September 30, 2014