Clinical trial NCT01328054: A Study in Cancer Patients to Evaluate the Effect of Lapatinib on the QTc Interval
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Cancer
Keywords: cancer
cardiac repolarization
Holter monitor
pharmacokinetics
GW572016
lapatinib
QTc interval
safety
ECG
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2011-04-04
Enrollment: 58
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Treatment Difference in Duration of Cardiac Ventricular Depolarization and Repolarization Interval (QT) in Fridericia-corrected QT Interval (QTcF) Values Between Placebo and Lapatinib 2000mg
timeFrame: Baseline (BL) (Day1) and pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24-hours (hr) post-dose on Day 2 for placebo (PBO). Baseline (Day 3) and pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24-hours post-dose on Day 4 for lapatinib (LAP).
Secondary outcomes:
measure: Change From Baseline in the Holter ECG Parameters of QT Interval, Corrected QT Interval (QTc), Bazett Corrected QTc Interval (QTcB), Individual-corrected QT Interval (QTcI), RR Interval, PR Interval, and QRS Duration at Indicated Time Points
timeFrame: Baseline (Day1) and pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24-hours post-dose on Day 2 for placebo. Baseline (Day 3) and pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24-hours post-dose on Day 4 for lapatinib.
measure: Number of Participants With 12-lead Holter ECG Findings at the Indicated Time Points
timeFrame: Baseline (Day1) and pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24-hours post-dose on Day 2 for placebo. Baseline (Day 3) and pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24-hours post-dose on Day 4 for lapatinib.
measure: Number of Participants With the Worst-case Post-Baseline 12-lead Holter ECG Findings With Significant ST, T Wave, and U Wave Abnormalities
timeFrame: Baseline (Day1) and pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24-hours post-dose on Day 2 for placebo. Baseline (Day 3) and pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24-hours post-dose on Day 4 for lapatinib.
measure: Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE)
timeFrame: From the start of study treatment until follow-up (within approximately 28 days following the last dose of study medication [up to end of Study Week 4])
measure: Mean Albumin, and Hemoglobin at the Indicated Time Points
timeFrame: Baseline; Day 5 and end of study visit on Day 8-11
measure: Mean Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), and Aspartate Aminotransferase (AST) at the Indicated Time Points
timeFrame: Baseline; Day 5 and end of study visit on Day 8-11
measure: Mean Direct Bilirubin, Total Bilirubin, and Creatinine at the Indicated Time Points
timeFrame: Baseline; Day 5 and end of study visit on Day 8-11
measure: Mean Calcium, Chloride, Carbon Dioxide (CO2), Potassium, Sodium, Magnesium and Urea at the Indicated Time Points
timeFrame: Baseline; Day 5 and end of study visit on Day 8-11
measure: Mean Total Neutrophils (ANC [Absolute Neutrophil Count]), Platelets and Leukocyte Count at the Indicated Time Points
timeFrame: Baseline; Day 5 and end of study visit on Day 8-11
measure: Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at the Indicated Time Points
timeFrame: Baseline; on Day 2 (at pre-dose, 4, 8, 12 and 24 hours post-dose), and on Day 4 (at pre-dose, 4, 8, 12 and 24 hours post-dose)
measure: Change From Baseline in Heart Rate at the Indicated Time Points
timeFrame: Baseline; on Day 2 (at pre-dose, 4, 8, 12 and 24 hours post dose), and on Day 4 (at pre-dose, 4, 8, 12 and 24 hours post dose
measure: Number of Participants With 12-lead ECG Findings at Indicated Time Points
timeFrame: BL;Day 1 (at pre-dose);Day 2 (at pre-dose, 4, 8, 12 and 24 hr post dose);Day 4 (at pre-dose, 4, 8, 12 and 24 hr post dose);End of Study visit (Day 8-11); and Follow-up (within approx 28 days following last dose of study trt [up to end of Study Week 4])
measure: Mean Area Under the Plasma Drug Concentration-time Curve (AUC) From Time Zero (Pre-dose) to the Last Time of Quantifiable Concentration (AUC[0-t]) and From Time Zero (Pre-dose) to 24 Hours Post Dose (AUC[0-24]) for Lapatinib
timeFrame: Day 1 pre-dose; on Day 2 (at pre-dose, then 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-last-dose), and on Day 4 (at pre-dose, then 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-last-dose)
measure: Mean Maximum Plasma Concentration (Cmax) and Observed Plasma Concentration at 24 Hours Post-dose (C24) of Lapatinib
timeFrame: Day1 pre-dose; on Day 2 (at pre-dose, then 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose), and on Day 4 (at pre-dose, then 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose)
measure: Median Time to Cmax (Tmax) and the Time Prior to the First Quantifiable (Non-zero) Lapatinib Plasma Concentration (Tlag) Following the Last (3rd) Lapatinib Dose
timeFrame: Day 1 pre-dose; on Day 2 (at pre-dose, then 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose), and on Day 4 (at pre-dose, then 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose)
Other outcomes:
Locations:
city: Detroit
country: United States
facility: GSK Investigational Site
state: Michigan
city: Lebanon
country: United States
facility: GSK Investigational Site
state: New Hampshire
city: Durham
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Salt Lake City
country: United States
facility: GSK Investigational Site
state: Utah
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Coker SA, Hurwitz HI, Sharma S, Wang D, Jordaan P, Zarate JP, Lewis LD. The effects of lapatinib on cardiac repolarization: results from a placebo controlled, single sequence, crossover study in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2019 Aug;84(2):383-392. doi: 10.1007/s00280-019-03880-9. Epub 2019 Jun 11.