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

NCT01328054 | Completed Phase 4 Results

• 1 other identifier: 114271
• Study Type: interventional
• Target: 58
• Locations: 1 country
• Sites: 4

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.

Conditions

Cancer

Keywords

cancer; cardiac repolarization; Holter monitor; pharmacokinetics; GW572016; lapatinib; QTc interval; safety; ECG

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (15)

• 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

  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

  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

  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)

  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

  Baseline; Day 5 and end of study visit on Day 8-11

Study Arms (1)

lapatinib/placebo

EXPERIMENTAL

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; Drug: placebo matching lapatinib

Interventions

lapatinib DRUG

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

lapatinib/placebo

placebo matching lapatinib DRUG

placebo matching lapatinib will be given as three separate doses (8 tablets/dose) given 12 hours apart over a 2 day period

lapatinib/placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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%).

You may not qualify if:

• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (4)

GSK Investigational Site

Detroit, Michigan, 48202, United States

Location

GSK Investigational Site

Lebanon, New Hampshire, 03756, United States

Location

GSK Investigational Site

Durham, North Carolina, 27710, United States

Location

GSK Investigational Site

Salt Lake City, Utah, 84112, United States

Location

Related Publications (1)

• 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.

  PMID: 31187169 DERIVED

MeSH Terms

Conditions

Neoplasms

Interventions

Lapatinib

Intervention Hierarchy (Ancestors)

Quinazolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 10, 2011
• First Posted: April 4, 2011
• Study Start: December 1, 2011
• Primary Completion: March 1, 2015
• Study Completion: March 1, 2015
• Last Updated: June 8, 2016
• Results First Posted: June 8, 2016

Record last verified: 2016-05

Locations

US (4)