NCT01328054 - A Study in Cancer Patients to Evaluate the Effect of Lapatinib on the QTc Interval | Crick

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

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.

Time frame: 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

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.

Time frame: 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.

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.

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.

Time frame: 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.