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A Phase I, Single-Sequence, Placebo-Controlled, Single-Blind Study to Evaluate the Effect of Repeat Oral Dosing of GSK1120212 on Cardiac Repolarization in Subjects With Solid Tumors

Phase 1
18 Years
Open (Enrolling)

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Trial Information

A Phase I, Single-Sequence, Placebo-Controlled, Single-Blind Study to Evaluate the Effect of Repeat Oral Dosing of GSK1120212 on Cardiac Repolarization in Subjects With Solid Tumors

GSK1120212 is an orally administered, potent and highly selective small molecule inhibitor
of MEK1(mitogen-activated extracellular signal-regulated kinase-1)/MEK2 (mitogen-activated
extracellular signal-regulated kinase-2) activation and kinase activity. As monotherapy,
GSK1120212 has shown an acceptable risk-benefit profile with encouraging efficacy in various
oncologic settings. This Phase I, single-sequence, placebo-controlled, singleblind,
multicenter study is designed to evaluate the effects of repeat oral dosing of GSK1120212 on
electrocardiographic parameters with a particular focus on its effect on cardiac
repolarization (Corrected QT interval [QTc] duration) as compared to placebo in subjects
with solid tumor cancers. A single dose of placebo will be administered on Study Day 1
followed by administration of a once-daily 2 mg dose of GSK1120212 for 13 days (Study Days 2
through 14) and on Study Day 15 a dose of 3 mg of GSK1120212 will be given. Digital 12-lead
electrocardiograms (ECGs) will be extracted from continuous ECG recordings obtained via
Holter monitor on Study Days 1 and 2 after the administration of placebo and on Study Days
15 and 16 after the administration of GSK1120212. Pharmacokinetic samples will be
time-matched with the Holter ECGs. This study will also assess the exposure-QTc relationship
between plasma concentrations of GSK1120212 and its effect, if any, on cardiac
repolarization, specifically on the QTc interval. Continuous 24-hour ambulatory blood
pressure monitoring will be conducted to assess the effect of GSK1120212 on blood pressure
parameters on Study Days 1 and 15. Safety assessments, including assessment of adverse
events, clinical laboratory tests (hematology and clinical chemistry) and vital signs, will
be performed throughout the study. Following completion of study treatment, eligible
subjects may transition to the open-label, rollover study MEK114375 to continue treatment
with GSK1120212.

Inclusion Criteria

Inclusion Criteria

- Has provided signed, written informed consent.

- Male or female, age greater than and equal to 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

- Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

- Able to swallow and retain oral medication.

- Has adequate baseline organ function as follows: System: Hematologic - absolute
neutrophil count, Laboratory values: greater than and equal to 1.2 × 109/L;System:
Hematologic - Hemoglobin, laboratory values: greater than and equal to 9 g/dL;
System: Hematologic-platelets, laboratory values: greater than and equal to 75 ×
109/L; System: Hematologic - Prothrombin time (PT), INR (international normalizing
ratio - a blood clotting test))and Partial thromboplastin time (PTT), laboratory
values: less than and equal to 1.5 times ULN(Upper limit of normal); System -
Hepatic - Total bilirubin, laboratory values: less than and equal to 1.5 times ULN;
System: Hepatic-ALT(Alanine aminotransferase), laboratory values: less than and
equal to 2.5 times ULN; System: Renal-Creatine, laboratory values: less than anad
equal to 1.5 times ULN; or System: Renal-Calculated creatinine clearance, laboratory
values: greater than and equal to 50 mL/min; or System: Renal-24hour urine creatine
clearance, laboratory values: greater than and equal to 50 mL/min; System:
Cardiac-LVEF, laboratory values: greater than and equal to LLN (Lower limit of
normal) by ECHO or MUGA(Multigated acquisition scan). Abbreviations: ALT, alanine
aminotransferase; AST, aspartate aminotransferase; ECHO, echocardiogram; INR;
LLN,lower limit of normal; LVEF, left ventricular ejection fraction; MUGA; PT,
prothrombin time; PTT, partial thromboplastin time; ULN, upper limit of normal. INR
greater than 1.5 times ULN will be acceptable in case of subjects receiving
therapeutic anticoagulants such as warfarin as long as INR is monitored during the
study according to clinical practice; Calculated by the Cockcroft-Gault formula; If
LLN is not defined for a given institution, then ejection fraction must be greater
than and equal to 50%. NOTE: Subjects with aspartate aminotransferase (AST), ALT or
bilirubin values outside the range(s) in the table due to Gilbert's syndrome or
asymptomatic gallstones are not excluded. Laboratory results obtained during
Screening should be used to determine eligibility criteria. In situations where
laboratory results are outside the permitted range, the investigator may opt to
retest the subject and the subsequent within-range screening result may be used to
confirm eligibility.

- Have serum potassium, serum magnesium, and total serum calcium levels within normal
limits. NOTE: If total serum calcium is below the LLN, then it will be necessary to
determine the albumin-corrected total serum calcium level. Use the following
calculation: Calcium (mg/dL) = measured total Calcium (mg/dL) + 0.8 (4.0 - serum
albumin [g/dL]) NOTE: If serum potassium or magnesium level is below the LLN,
supplementation is permitted in order to meet the inclusion criterion. Subject should
be retested following supplementation. In order to avoid a situation where the
subject cannot be dosed during the study due to electrolyte levels falling below the
LLN, it is strongly recommended to maintain serum potassium levels greater than 4
mEq(Milliequivalent )/L and serum magnesium levels greater than 2.2 mg/dL whenever
possible. Slight elevations of potassium or magnesium above the upper limit of normal
may be seen during supplementation and will not exclude subjects from study entry.

- If a female subject 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, as defined in the protocol. during the study and for 4 months
following the last dose of study treatment.

Exclusion Criteria:

- History of prior exposure to a MEK(activated extracellular signal-regulated kinase)
inhibitor or disease progression while receiving treatment with a MEK inhibitor.

- Any of the following ECG findings: QTcF (preferred) or QTcB(interval corrected for
heart rate by Bazett's formula) interval greater than and equal to 480 msec;
PR(Partial response) interval greater than 220 msec or less than and equal to 110
msec; Bradycardia defined as sinus rate less than 50 beats per minute (bpm)

- Cardiac conduction abnormalities denoted by any of the following: Evidence of
second-degree (type II) or third-degree atrioventricular block; Evidence of
ventricular pre-excitation; Electrocardiographic evidence of complete left bundle
branch block (LBBB) NOTE: Right bundle branch block (RBBB), incomplete LBBB or
incomplete RBBB will be exclusionary ONLY if QRS(a name for the combination of the
graphical deflections seen on a typical electrocardiogram) duration is greater than
120 msec; Intraventricular conduction delay with QRS duration greater than 120 msec;
Evidence of atrial fibrillation or history of atrial fibrillation within the past 6
months; Presence of cardiac pacemaker

- History or evidence of any one of the following cardiovascular conditions within the
past 6 months: Class II, III, IV heart failure as defined by the New York Heart
Association; Cardiac angioplasty or stenting; Myocardial infarction; Unstable angina;
Symptomatic peripheral vascular disease or other clinically significant cardiac
disease; Cardiac metastases

- 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, less than 50%

- Personal or family history of long-QT syndrome.

- Treatment-refractory hypertension defined as a blood pressure of SBP (Systolic blood
pressure) greater than 140 mmHg and/or DBP(Diastolic blood pressure) greater than 90
mmHg which cannot be controlled by anti-hypertensive therapy or lifestyle

- Anti-cancer therapy (e.g., chemotherapy with delayed toxicity, extensive radiation
therapy, immunotherapy, biologic therapy, or major surgery) within 21 days prior to
enrollment; chemotherapy regimens without delayed toxicity within 14 days prior to
enrollment; or use of an investigational anti-cancer drug within 28 days preceding
the first dose of study treatment. NOTE: Subjects with a history of prior
anthracycline exposure are excluded.

- Current use of a prohibited medication(s) or requires any of these medications during
treatment with study treatment. NOTE: This includes medications that are listed as
drugs that are generally accepted by the (Advisory Board of the Arizona
Center for Education and Research on Therapeutics to have a risk of causing Torsade
de pointes (available at:

- Current use of therapeutic warfarin. NOTE: Low molecular weight heparin and
prophylactic low-dose warfarin are permitted.

- Any unresolved toxicity of greater than and equal to Grade 2, except alopecia or
Grade 2 anemia, (NCI-CTCAE), version 4.0, from previous anti-cancer therapy.

- Pre-existing Grade 2 or greater peripheral neuropathy.

- History or current evidence/risk of RVO or CSR: History of RVO (Retinal vein
occlusion) or CSR (Central serous retinopathy), or predisposing factors to RVO or CSR
(i.e., uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease
such as hypertension or diabetes mellitus, or history of hyperviscosity or
hypercoagulability syndromes); Visible retinal pathology as assessed by ophthalmic
examination that is considered a risk factor for RVO or CSR such as: Evidence of new
optic disc cupping; Intraocular pressure >21 mmHg as measured by tonography

- History of interstitial lung disease or pneumonitis.

- Symptomatic or untreated leptomeningeal or brain metastases or spinal cord
compression. NOTE: Subjects previously treated for these conditions that have had
stable central nervous system disease (verified with consecutive imaging studies) for
greater than 3 months, are asymptomatic and are not currently taking corticosteroids,
or are on stable dose of corticosteroids for at least 30 days prior to Study Day 1
are permitted.

- Presence of clinically significant gastrointestinal (GI) abnormalities that may
affect the absorption of study treatment(s) including, but not limited to: Active,
uncontrolled GI disease; Malabsorption syndrome; Substantial resection of the
stomach, small bowel or colon. If clarification is needed as to whether a condition
will significantly affect the absorption of study treatment(s), contact the GSK
Medical Monitor.

- History or presence of hepatic insufficiency (excluding metastatic hepatic

- Uncontrolled medical conditions (i.e., diabetes mellitus, hypertension),
psychological,familial, sociological, or geographical conditions that do not permit
compliance with the protocol; or unwillingness or inability to follow the procedures
required in the protocol.

- Lactating or actively breastfeeding females.

- Known immediate or delayed hypersensitivity reaction or idiosyncrasy to DMSO
(Dimethyl Sulfoxide).

Type of Study:


Study Design:

Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Single Group Assignment, Masking: Single Blind (Subject), Primary Purpose: Basic Science

Outcome Measure:

Compare the effect of GSK1120212 on the baseline-adjusted, placebo-corrected, time-matched QTcF(QT interval corrected for heart rate by Fridericia's formula) interval duration in subjects with solid tumor cancers

Outcome Time Frame:

from baseline to day 15

Safety Issue:


Principal Investigator

GSK Clinical Trials

Investigator Role:

Study Director

Investigator Affiliation:



United States: Food and Drug Administration

Study ID:




Start Date:

September 2011

Completion Date:

March 2014

Related Keywords:

  • Cancer
  • solid tumors



GSK Investigational Site Fort Worth, Texas  76104
GSK Investigational Site Salt Lake City, Utah  84107