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

Study Overview
=================
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.

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

Conditions
-----------------
Cancer

Intervention / Treatment
-----------------
* Drug: lapatinib
* Drug: placebo matching lapatinib


Participation Criteria
=================
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: lapatinib/placebo<br>This is a crossover study where subjects will receive placebo that mimics lapatinib for 2 days and lapatinib for 2 days. Subjects will not know when they are receiving placebo vs. lapatinib. | Drug: lapatinib<br>* lapatinib commercial tablet, 2000mg, will be given as three separate doses (8 tablets/dose) given 12 hours apart over a 2 day period<br>Drug: placebo matching lapatinib<br>* placebo matching lapatinib will be given as three separate doses (8 tablets/dose) given 12 hours apart over a 2 day period<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment Difference in Duration of Cardiac Ventricular Depolarization and Repolarization Interval (QT) in Fridericia-corrected QT Interval (QTcF) Values Between Placebo and Lapatinib 2000mg | A Holter monitor is an ambulatory portable device used for continuously monitoring the cardiovascular system. Three replicate electrocardiograms (ECGs) were collected at 30, 15, and 0 minutes prior to the administration of study treatment (trt) on Days 1 and 3 and pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hr post-dose on Days 2 and 4. The 3 readings at each time point (TP) were averaged prior to any analysis. BL is the average of the pre-dose QTcF values (triplicate) taken on Day 1 for PBO and on Day 3 for LAP. Mean change from BL was calculated by subtracting the BL values from individual QTcF for each TP. BL adjusted mean difference in absolute QTcF between LAB and PBO (trt difference) with the corresponding 90% confidence interval (CI) was estimated for each TP (pre-dose and 1, 2, 3, 4, 6, 8, 10, 12, and 24-hr post-dose). Trt difference analysis was performed by a repeated measures analysis of variance adjusted for trt group, TP, and trt group*TP interaction. | 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | A Holter monitor is an ambulatory portable device for continuously monitoring the cardiovascular system. Change from Baseline in QT interval, QTc interval, QTcB interval, QTcI interval, RR interval, PR interval, and QRS duration at each time point for lapatinib was assessed in comparison with time-matched placebo. Three replicate ECGs were collected at 30, 15, and 0 minutes prior to the administration of study treatment on Days 1 and 3 and pre-dose and 1, 2, 3, 4, 6, 8, 10, and 24 hours post dose on Days 2 and 4. The three readings at each time point were averaged prior to any analysis. Baseline is the average of the pre-dose ECGs (triplicate) taken on Day 1 for placebo and Day 3 for lapatinib. Change from Baseline was calculated by subtracting the Baseline values from individual post-Baseline values for each time point. | 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. | 
| Number of Participants With 12-lead Holter ECG Findings at the Indicated Time Points | The number of participants with 12-lead Holter ECG findings of normal (NL), abnormal not clinically significant (Abn NCS), and abnormal clinically significant (Abn CS) are reported. Abnormal ECG findings or change in ECG morphological patterns were based on the ECG interpretations provided by the ECG core lab. Three replicate 12-lead Holter ECGs were collected at -30, -15, and 0 minutes prior to the administration of study treatment on Days 1 (Baseline for placebo) and 3 (Baseline for lapatinib) and pre-dose and 1, 2, 3, 4, 6, 8, 10,12, and 24 hours post dose on Days 2 and 4. The three readings at each time point were averaged prior to any analysis. Baseline is the pre-dose ECGs (triplicate) taken on Day 1 for placebo and on Day 3 for lapatinib. | 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. | 
| Number of Participants With the Worst-case Post-Baseline 12-lead Holter ECG Findings With Significant ST, T Wave, and U Wave Abnormalities | Abnormal ECG findings or change in ECG morphological patterns were based on the ECG interpretations provided by the ECG core lab. Three replicate Holter ECGs were collected at 30, 15, and 0 minutes prior to the administration of study treatment on Days 1 (Baseline for placebo) and 3 (Baseline for lapatinib) and pre-dose and 1, 2, 3, 4, 6, 8, 10, and 24 hours post dose on Days 2 and 4. The three readings at each time point were averaged prior to any analysis. Baseline is the pre-dose ECGs (triplicate) taken on Day 1 for placebo and Day 3 for lapatinib. The number of participants with the worst-case post-Baseline 12-lead Holter ECG findings with significant ST, T wave, and U wave abnormalities were analyzed. | 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. | 
| Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) | An AE is defined as any untoward medical occurrence in a participant temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity or is a congenital anomaly/birth defect, or is an important medical eventsthat jeopardizes the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition, new primary cancers, liver events, cardiac dysfunction, pneumonitis, and laboratory abnormalities. | 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]) | 
| Mean Albumin, and Hemoglobin at the Indicated Time Points | Blood samples were collected for the measurement of albumin and hemoglobin at Baseline; Days 5 and 8-11. Baseline is defined as the most recent, non-missing value from a central laboratory prior to or on the first study treatment dose date. | Baseline; Day 5 and end of study visit on Day 8-11 | 
| Mean Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), and Aspartate Aminotransferase (AST) at the Indicated Time Points | Blood samples were collected for the measurement of ALP, ALT, and AST at Baseline; Days 5 and 8-11. Baseline is defined as the most recent, non-missing value from a central laboratory prior to or on the first study treatment dose date. | Baseline; Day 5 and end of study visit on Day 8-11 | 
| Mean Direct Bilirubin, Total Bilirubin, and Creatinine at the Indicated Time Points | Blood samples were collected for the measurement of direct bilirubin, total bilirubin, and creatinine at Baseline; Days 5 and 8-11; Baseline is defined as the most recent, non-missing value from a central laboratory prior to or on the first study treatment dose date. | Baseline; Day 5 and end of study visit on Day 8-11 | 
| Mean Calcium, Chloride, Carbon Dioxide (CO2), Potassium, Sodium, Magnesium and Urea at the Indicated Time Points | Blood samples were collected for the measurement of calcium, chloride, CO2, potassium, sodium, magnesium and urea at Baseline; at Days 5 and 8-11. Baseline is defined as the most recent, non-missing value from a central laboratory prior to or on the first study treatment dose date. | Baseline; Day 5 and end of study visit on Day 8-11 | 
| Mean Total Neutrophils (ANC [Absolute Neutrophil Count]), Platelets and Leukocyte Count at the Indicated Time Points | Blood samples were collected for the measurement of total neutrophils (ANC), platelets, and leukocyte count at Baseline; Days 5 and 8-11. Baseline was defined as the most recent, non-missing value from a central laboratory prior to or on the first study treatment dose date. | Baseline; Day 5 and end of study visit on Day 8-11 | 
| Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at the Indicated Time Points | Blood pressure measurements included SBP and DBP and were obtained at 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). Baseline is defined as the most recent, non-missing value prior to or on the first study treatment dose date. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. | 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) | 
| Change From Baseline in Heart Rate at the Indicated Time Points | Heart rate were measured at 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. Baseline is defined as the most recent, non-missing value prior to or on the first study treatment dose date. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. | 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 | 
| Number of Participants With 12-lead ECG Findings at Indicated Time Points | The number of participants with the 12-lead ECG findings normal (NL), abnormal not clinically significant (Abn NCS), and abnormal clinically significant (Abn CS) are reported. Clinical significance was based on the medical and scientific judgement of the investigator or qualified designee. A single safety 12-lead ECG was performed using a standard 12-lead ECG machine at Baseline; on Day 1 (at pre-dose); on Day 2 (at pre-dose, 4, 8, 12 and 24 hours post-last- dose); on Day 4 (at pre-dose, 4, 8, 12 and 24 hours post-last-dose); at the End of Study visit (Day 8-11); and at the post-treatment Follow-up visit (if applicable). | 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]) | 
| 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 | AUC is defined as the area under the lapatinib concentration-time curve as a measure of drug exposure. AUC(0-t) and AUC(0-24) were determined from the plasma concentration-time data using the linear trapezoidal rule for increased concentrations and the logarithmic trapezoidal rule for decreased concentrations. For PK analysis, one blood sample was collected on Day 1 for placebo Baseline. The 24 hour blood sample on Day 2 also served for lapatinib Baseline. Pre-dose blood samples were collected 30 minutes prior to the administration of study medication on Day 2 (placebo) and Day 4 (lapatinib). Serial blood samples were collected on Day 2 (for placebo) and on Day 4 (for lapatinib) at the following post-last-dose time points 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours. | 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) | 
| Mean Maximum Plasma Concentration (Cmax) and Observed Plasma Concentration at 24 Hours Post-dose (C24) of Lapatinib | The first occurrence of Cmax and C24 was determined directly from the raw concentration-time data. For PK analysis, one blood sample was collected on Day 1 for placebo Baseline. The 24 hour blood sample on Day 2 also served for lapatinib Baseline. Pre-dose blood samples were collected 30 minutes prior to the administration of study medication on Day 2 (placebo) and Day 4 (lapatinib). Serial blood samples were collected on Day 2 (for placebo) and on Day 4 (for lapatinib) at the following post-last-dose time points 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours. | 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) | 
| 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 | For each participant, the time at which Cmax was observed (tmax) was determined directly from the raw concentration-time data. For each participant, the time prior to the first quantifiable (non-zero) concentration (tlag) was determined directly from the raw concentration-time data. Since all participants received 2 doses of study medication prior to the collection of the first (pre-dose) blood sample on Day 4, tlag was expected to be zero. For PK analysis, one blood sample was collected on Day 1 for placebo Baseline. The 24 hour blood sample on Day 2 also served for lapatinib Baseline. Pre-dose blood samples were collected 30 minutes prior to the administration of study medication on Day 2 (placebo) and Day 4 (lapatinib). Serial blood samples were collected on Day 2 (for placebo) and on Day 4 (for lapatinib) at the following post-last-dose time points 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours. | 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) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
cancer, cardiac repolarization, Holter monitor, pharmacokinetics, GW572016, lapatinib, QTc interval, safety, ECG