Phase 4
Completed N=57
A Study in Cancer Patients to Evaluate the Effect of Lapatinib on the QTc Interval
Source: ClinicalTrials.gov NCT01328054 ↗Enrolled (actual)
57
Serious AEs
3.5%
Results posted
Jun 2016
Primary outcomePrimary: Treatment Difference in Duration of Cardiac Ventricular Depolarization and Repolarization Interval (QT) in Fridericia-corrected QT Interval (QTcF) Values Between Placebo and Lapatinib 2000mg — -3.71; 2.60; 0.66; 7.09 Milliseconds
◆ Published Evidence
Emerging
3citations · ~0 / year
The effects of lapatinib on cardiac repolarization: results from a placebo controlled, single sequence, crossover study in patients with advanced solid tumors.
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.
Linked Publications
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The effects of lapatinib on cardiac repolarization: results from a placebo controlled, single sequence, crossover study in patients with advanced solid tumors.
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Treatment Difference in Duration of Cardiac Ventricular Depolarization and Repolarization Interval (QT) in Fridericia-corrected QT Interval (QTcF) Values Between Placebo and Lapatinib 2000mg |
-3.71; 2.60; 0.66; 7.09; 0.49; 8.20 | — |
| SECONDARY 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 |
-6.24; 1.05; 0.10; 7.69; 1.24; 10.66 | — |
| SECONDARY Number of Participants With 12-lead Holter ECG Findings at the Indicated Time Points |
35; 32; 0; 0; 0; 0 | — |
| SECONDARY Number of Participants With the Worst-case Post-Baseline 12-lead Holter ECG Findings With Significant ST, T Wave, and U Wave Abnormalities |
11; 14 | — |
| SECONDARY Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) |
16; 44; 0; 4 | — |
| SECONDARY Mean Albumin, and Hemoglobin at the Indicated Time Points |
38.8; 35.5; 37.5; 123.7; 114.8; 117.6 | — |
| SECONDARY Mean Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), and Aspartate Aminotransferase (AST) at the Indicated Time Points |
116.9; 111.2; 116.7; 25.9; 23.1; 24.2 | — |
| SECONDARY Mean Direct Bilirubin, Total Bilirubin, and Creatinine at the Indicated Time Points |
2.683; 3.123; 2.502; 10.496; 13.450; 9.980 | — |
| SECONDARY Mean Calcium, Chloride, Carbon Dioxide (CO2), Potassium, Sodium, Magnesium and Urea at the Indicated Time Points |
2.344; 2.231; 2.303; 103.6; 104.4; 104.7 | — |
| SECONDARY Mean Total Neutrophils (ANC [Absolute Neutrophil Count]), Platelets and Leukocyte Count at the Indicated Time Points |
23.959; 25.802; 23.848; 262.6; 239.3; 263.7 | — |
| SECONDARY Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at the Indicated Time Points |
-3.5; -2.1; -7.0; -4.2; -2.2; -9.4 | — |
| SECONDARY Change From Baseline in Heart Rate at the Indicated Time Points |
3.9; -1.7; 3.2; 3.3; 0.8; 3.5 | — |
| SECONDARY Number of Participants With 12-lead ECG Findings at Indicated Time Points |
36; 22; 0; 35; 23; 0 | — |
| SECONDARY 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 |
56000; 59200 | — |
| SECONDARY Mean Maximum Plasma Concentration (Cmax) and Observed Plasma Concentration at 24 Hours Post-dose (C24) of Lapatinib |
3920; 1410 | — |
| SECONDARY 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 |
3.55; 0 | — |
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 /= 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 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.
Data sourced from ClinicalTrials.gov (NCT01328054) and the linked publication. Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication. Informational only — not medical advice.