A Study in Cancer Patients to Evaluate the Effect of Lapatinib on the QTc Interval
Condition: Cancer
Intervention: lapatinib; placebo matching lapatinib
Intervention description: lapatinib commercial tablet, 2000mg, will be given as three separate doses (8 tablets/dose) given 12 hours apart over a 2 day period; placebo matching lapatinib will be given as three separate doses (8 tablets/dose) given 12 hours apart over a 2 day period
Intervention MeSH terms: Lapatinib
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: Single (Participant)
Enrollment: 58.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: cancer; cardiac repolarization; Holter monitor; pharmacokinetics; GW572016; lapatinib; QTc interval; safety; ECG

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.