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VEG111485: A Phase I, Randomized, Double-Blinded, Placebo-Controlled Study to Evaluate the Effect of Repeat Oral Doses ofPazopanib (GW786034) on Cardiac Conduction in Subjects withSolid Tumors

Phase 1
18 Years
Not Enrolling
Carcinoma, Renal Cell, Solid Tumors

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Trial Information

VEG111485: A Phase I, Randomized, Double-Blinded, Placebo-Controlled Study to Evaluate the Effect of Repeat Oral Doses ofPazopanib (GW786034) on Cardiac Conduction in Subjects withSolid Tumors

This is a Phase I, randomized, double-blind, placebo-controlled, parallel group study
designed to estimate the effects of repeated, once daily oral dosing of pazopanib on
electrocardiographic parameters with a particular focus on its effect on cardiac
repolarization (QTc interval duration) as compared with placebo in subjects with solid
tumors. Moxifloxacin, a drug known to cause mild QTc interval prolongation, is included as a
positive control to validate the ability of the study to detect a small prolongation in the
QTc interval. Digital 12-lead electrocardiograms (ECGs) will be extracted from continuous
ECG recordings obtained via a Holter monitor. The effects of pazopanib and moxifloxacin on
cardiac repolarization will be compared with placebo.

This study will also assess the pharmacokinetic-pharmacodynamic relationship between plasma
concentrations of pazopanib and its metabolites and their effects, if any, on cardiac
repolarization, specifically on the QT interval.

Inclusion Criteria:

- Male or female, age 18 years or older, at the time of signing of the informed

- Has histologically or cytologically confirmed advanced solid tumor malignancy.

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

- Able to swallow and retain oral medication.

- Adequate organ systems function.

- Serum potassium level >4 mEq/L, magnesium level >1.7 mg/dL and total serum calcium
level within normal limits (if albumin is <4.5 g/dL, albumin-corrected total serum
calcium level should be within normal limits [see Appendix 7]). NOTE: Supplementation
is permitted in order to meet this criterion. Subject should be retested following

- Subject is a woman of non-childbearing potential or willing to use acceptable

- Subject is a man with a female partner of childbearing potential agrees to use

- Subject, if sexually active, agrees to continue the recommended contraception method
for the duration of treatment and for 28 days following discontinuation of treatment.

- Capable of giving written informed consent.

- The subject is able to understand and comply with protocol requirements, instructions
and protocol-stated restrictions.

Exclusion Criteria:

- Any of the following ECG findings, QTcF interval >470 msec, PR interval >240 msec or
≤110msec, Bradycardia defined as sinus rate <50 beats per minute

- 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), Intraventricular conduction delay with QRS duration >120 msec,
Atrial fibrillation, Presence of cardiac pacemaker.

- History of any one of the following cardiovascular conditions within the past 6
months: Class III or IV congestive heart failure as defined by the New York Heart
Association (NYHA), cardiac angioplasty or stenting, myocardial infarction, unstable
angina, symptomatic peripheral vascular disease or other clinically significant
cardiac disease.

- For subjects with a history of myocardial infarction (>6 months ago), congestive
heart failure (>6 months ago) or prior anthracycline exposure, left ventricular
ejection fraction (LVEF) must be assessed within 28 days prior to the first dose of
study drug by one of the following methods: multiple gated acquisition (MUGA) scan or
echocardiogram (ECHO). Subjects with a measurement of LVEF <50% are excluded from
participation in the study.

- Personal or family history of long-QT syndrome.

- History or clinical evidence of CNS metastases or leptomeningeal carcinomatosis,
except for individuals who have previously treated CNS metastases, are asymptomatic,
and have had no requirement for steroids or anti-seizure medication for 2 months
prior to beginning study treatment.

- Clinically significant gastrointestinal (GI) abnormalities that may affect the
absorption of study drug including, but not limited to: malabsorption syndrome, major
resection of the stomach or small bowel.

- Clinically significant GI abnormalities that may increase the risk for GI bleeding
including, but not limited to: active peptic ulcer disease, known intra-luminal
metastatic lesion(s) with suspected bleeding, inflammatory bowel disease, ulcerative
colitis or other GI conditions with increased risk of perforation, history of
abdominal fistula, GI perforation or intra-abdominal abscess within 28 days prior to
beginning study treatment.

- Presence of uncontrolled infection.

- Unable or unwilling to discontinue use of prohibited medications listed in Section
9.2 for at least 14 days prior to the first dose of study drug (see Section 9.2).

- Poorly controlled hypertension [systolic blood pressure (SBP) >140 mmHg, or diastolic
blood pressure (DBP) >90 mmHg].

- History of cerebrovascular accident, pulmonary embolism or untreated deep venous
thrombosis (DVT) within the past 6 months.

- Evidence of active bleeding or bleeding diathesis.

- Hemoptysis within 6 weeks prior to the first dose of study drug.

- Known endobronchial lesion(s) or involvement of large pulmonary vessel(s) by tumor.

- History of sensitivity or allergic reaction to moxifloxacin or any member of the
quinolone class of antimicrobial agents.

- Treatment with anti-cancer therapy (including chemotherapy, radiation therapy,
immunotherapy, biologic therapy, investigational therapy, hormonal therapy, surgery
or tumor embolization) within 14 days prior to the first dose of pazopanib.

- History or presence of hepatic or renal disease or any other condition known to
interfere with the absorption, distribution, metabolism or excretion of drugs.

- Prior major surgery or trauma within the past 28 days prior to the first dose of
study drug and/or presence of any non-healing wound, fracture or ulcer.

- Any serious and/or unstable pre-existing medical, psychiatric, or other conditions
that could interfere with subject's safety, obtaining informed consent or compliance
to the study.

Type of Study:


Study Design:

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Outcome Measure:

Change from baseline in QTcF interval at each time point on Study Day 9 (average of at least 3 Holter ECG replicates per time point) as compared with time-matched placebo.

Outcome Time Frame:

11 days

Safety Issue:


Principal Investigator

GSK Clinical Trials

Investigator Role:

Study Director

Investigator Affiliation:



United States: Food and Drug Administration

Study ID:




Start Date:

March 2009

Completion Date:

February 2010

Related Keywords:

  • Carcinoma, Renal Cell
  • Solid Tumors
  • GW786034, pazopanib, moxifloxacin, ECG intervals and morphology, QTc, Holter monitor, pharmacokinetics, safety, cancer
  • Carcinoma
  • Carcinoma, Renal Cell



GSK Investigational Site Bakersfield, California  93309
GSK Investigational Site Royal Oak, Michigan  48073
GSK Investigational Site Hooksett, New Hampshire  03106
GSK Investigational Site Columbia, South Carolina  29210
GSK Investigational Site Germantown, Tennessee  38138
GSK Investigational Site Edison, New Jersey  08837
GSK Investigational Site Seattle, Washington  98133