A Study in Cancer Patients to Evaluate the Effect of Lapatinib on the QTc Interval

Cancer Clinical Trial

Official title:

A Phase IV, Placebo-controlled Single Sequence Crossover Study to Evaluate the Effect of Repeat Oral Doses of Lapatinib on Cardiac Repolarization in Patients With Advanced Cancer

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01328054
• Other study ID #: 114271
• Status: Completed
• Phase: Phase 4
• First received: March 10, 2011
• Last updated: July 30, 2015
• Start date: December 2011
• Est. completion date: March 2015

Study information

• Verified date: July 2015
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

This study will estimate the effect of lapatinib on cardiac repolarization (QTc interval duration) in subjects with advanced solid tumors. The study treatment period will occur over five days and an End of Study visit will be conducted on Day 8 (or no later than 3 days beyond Day 8). Subjects will receive placebo that mimics lapatinib for 2 days as three separate doses given 12 hours apart (8 tablets/dose) and lapatinib (2000mg) for 2 days as three separate doses given 12 hours apart (8 tablets/dose). Subjects will not know when they are receiving placebo vs. lapatinib. Digital 12-lead ECG recordings will be extracted from continuous ECG recordings obtained via a Holter monitor to measure QTc interval duration. Triplicate ECG measurements of QTc interval will be taken at pre-specified times at Day 1 (Baseline) and pre-dose and up to 24 hours after the third dose of placebo or lapatinib on Study Days 2 and 4. Pharmacokinetic sampling will occur immediately following each pre-specified QTc measurement in subjects dosed with placebo or lapatinib. Subjects who complete participation in this study, if they are eligible, will be offered the option to continue treatment with lapatinib, either alone or in combination with other oncology drugs in pre-selected anticancer regimens, in a continuation protocol, EGF111767.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 58
• Est. completion date: March 2015
• Est. primary completion date: March 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Histologically or cytologically confirmed diagnosis of: Metastatic breast cancer that over-expresses ErbB2 OR Recurrent, advanced, or metastatic solid tumor malignancy (including breast cancer that does not over-express ErbB2) that is refractory to standard therapies, for which there is no approved therapy, or for which lapatinib in combination with one of the permitted anti-cancer regimens specified in the continuation study EGF111767 may provide clinical benefit.

• A female subject must be of non-childbearing potential or willing to use acceptable contraception.

• A male subject with a female partner of childbearing potential must agree to use acceptable contraception.

• Is able to swallow and retain oral medication and does not have uncontrolled emesis.

• ECOG performance status 0 to 1.

• Adequate bone marrow function: ANC (absolute neutrophil count) >/=1.5 x 10^9/L, Hemoglobin >/=9 g/dL, Platelets >/=75 x 10^9/L.

• Albumin >/=3 g/dL.

• Serum bilirubin </=1.5 x ULN.

• AST and ALT </=3 x ULN .

• Serum Creatinine </=1.5 mg/dL or Calculated Creatinine Clearance >/= 50 mL/min.

• Serum potassium and magnesium levels within normal limits.

• Has a LVEF within the normal institutional range (or >/=50%).

Exclusion Criteria:

• Any of the following ECG findings: QTcF interval >480 msec, PR interval >240 msec or </=110 msec, 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.

• Personal history of long-QT syndrome.

• Is pregnant or lactating.

• Has malabsorption syndrome, or has undergone a resection or bypass of the distal stomach and pylorus, or small bowel.

• Has acute or currently active/requiring anti-viral therapy hepatic or biliary disease (with the exception of subjects with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment).

• Has evidence of symptomatic or uncontrolled brain metastases or leptomeningeal disease. Subjects with brain metastases treated by surgery and/or radiotherapy are eligible if neurologically stable and do not require steroids or anticonvulsants for at least 28 days prior to the first dose of study drug.

• Has known immediate or delayed hypersensitivity reaction or idiosyncratic reaction to drugs chemically related to the investigational product.

• Has received anti-cancer therapy (including chemotherapy, radiation therapy, immunotherapy, biologic therapy, investigational therapy, surgery, or hormonal therapy) within 14 days prior to the first dose of study medication.

• Is receiving any prohibited medication or consuming any food or beverage within the timeframe indicated on the prohibited medication list in the protocol.

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Crossover Assignment, Masking: Single Blind (Subject), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Cancer

Intervention

Drug:
• lapatinib
lapatinib commercial tablet, 2000mg, will be given as three separate doses (8 tablets/dose) given 12 hours apart over a 2 day period
• placebo matching lapatinib
placebo matching lapatinib will be given as three separate doses (8 tablets/dose) given 12 hours apart over a 2 day period

Locations

Country	Name	City	State
United States	GSK Investigational Site	Detroit	Michigan
United States	GSK Investigational Site	Durham	North Carolina
United States	GSK Investigational Site	Lebanon	New Hampshire
United States	GSK Investigational Site	Salt Lake City	Utah

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	• The primary enpoint will be the change in baseline adjusted QTcF interval at each time point for lapatinib (average of at least 3 Holter ECG replicates per time point) as compared with time-matched placebo		From Study Day 1 until Study Day 5	Yes
Secondary	• ECG parameters: RR interval, QT, QTcB, QTci, heart rate, PR, QRS intervals and morphology		From Study Day 1 until Study Day 5	Yes
Secondary	• Plasma lapatinib concentrations and pharmacokinetic parameters AUC(0-t), AUC(0-24), C24, Cmax, tlag, and tmax		From Study Day 1 until Study Day 5	No
Secondary	• Safety parameters: AEs, vital signs, ECGs and clinical laboratory assessments		From Study Day 1 until completion of the study	Yes