Clinical trial NCT00258050: To Examine The Effects Of Lapatinib On Orally And Intravenously Administered Midazolam In Cancer Patients
Official title: A Four-Way Cross-Over Study to Examine the Effects of Lapatinib on the Pharmacokinetics of Orally and Intravenously Administered Midazolam in Cancer Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Neoplasms, Breast
Keywords: midazolam
pharmacokinetics
lapatinib
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2005-11-24
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: To characterize the effect of repeat oral dose of lapatinib treatment on the pharmacokinetics of a single oral and single intravenous dose of midazolam in adult cancer patients. Also to assess the safety and tolerability of chronic oral lapatinib therapy in cancer patients.


Eligibility criteria: Inclusion criteria:

* Histologically confirmed, solid tumor refractory to standard therapy.
* Tumor for which there is no standard therapy.
* Able to swallow and retain oral medication.
* ECOG (Eastern Cooperative Oncology Group) performance status 0 to 2.
* Provided written informed consent.
* Adequate bone marrow function.
* Serum creatinine is less than or equal to 1.5 mg/dL.
* Calculated creatinine clearance is greater than or equal to 60 ml/min based on Cockcroft and Gault.
* Total bilirubin is greater than or equal to the upper limit of normal of institutional values.
* Aspartate and alanine transaminase is less than or equal to 3 times the upper limit of the institutional values.
* Have a left ventricular ejection fraction (LVEF) greater than or equal to 40% based on electrocardiogram (ECHO) or multiple gated acquisition scan (MUGA).
* Resting oxygen saturations of greater than 90%.

Exclusion criteria:

* Pregnant or lactating female.
* Have malabsorption syndrome, a disease affecting gastrointestinal function.
* Resection of the stomach or small bowel.
* Evidence of symptomatic or uncontrolled brain metastases or leptomeningeal disease.
* Is considered medically unfit for the study by the investigator as a result of the medical interview, physical exam, or screening investigations.
* Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the investigational product.
* Use of anilinoquinazolines, such as gefitinib \[Iressa™\], erlotinib \[Tarceva™\].
* Immediate or delayed hypersensitivity reaction to midazolam or any component of the formulation, including benzyl alcohol (cross-sensitivity with other benzodiazepines may exist).
* Has narrow-angle glaucoma which is a contraindication to midazolam use.
* Has received treatment with any investigational drug in the previous 4 weeks.
* Received chemotherapy, immunotherapy, biologic therapy or hormonal therapy within the past 14 days, with the exception of mitomycin C within the past 6 weeks.
* Currently receiving amiodarone or has received amiodarone in the 6 months prior to screening.
* Is taking regular doses of opiates that in the opinion of the investigator would put the patient at risk of clinically significant respiratory compromise when midazolam is administered.
* Physiological, familial, sociological, or geographical conditions that do not permit compliance with the protocol.
* Has Class II to IV heart failure as defined by the New York Heart Association (NYHA) functional classification system.
* Clinically significant electrocardiogram (ECG) abnormality.
* Clinically assessed to have inadequate venous access for protocol-related blood draws.

Primary outcomes:
measure: Area under the concentration versus time curve (AUC) of midazolam
timeFrame: Pre-dose, 2 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours post-dose on Day 1, Day 3, Day 9 and Day 11
measure: Maximum observed concentration (Cmax) of midazolam
timeFrame: Pre-dose, 2 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours post-dose on Day 1, Day 3, Day 9 and Day 11
measure: Clearance (CL) of midazolam
timeFrame: Pre-dose, 2 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours post-dose on Day 1, Day 3, Day 9 and Day 11
measure: Half-life (t½) of midazolam
timeFrame: Pre-dose, 2 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours post-dose on Day 1, Day 3, Day 9 and Day 11
measure: Absolute bioavailability (F) of midazolam
timeFrame: Pre-dose, 2 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours post-dose on Day 1, Day 3, Day 9 and Day 11
Secondary outcomes:
measure: Time of maximum observed concentration (tmax) of midazolam
timeFrame: Pre-dose, 2 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours post-dose on Day 1, Day 3, Day 9 and Day 11
measure: Volume of distribution (Vss) of midazolam
timeFrame: Pre-dose, 2 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours post-dose on Day 1, Day 3, Day 9 and Day 11
measure: Number of subjects with adverse events (AEs) and serious adverse events (SAEs)
timeFrame: Up to Month 7
measure: Number of subjects with abnormal clinical chemistry parameters
timeFrame: Up to Month 7
measure: Number of subjects with abnormal hematology parameters
timeFrame: Up to Month 7
measure: Number of subjects with abnormal blood pressure
timeFrame: Up to Month 7
measure: Number of subjects with abnormal heart rate
timeFrame: Up to Month 7
Other outcomes:
Locations:
city: Lebanon
country: United States
facility: GSK Investigational Site
state: New Hampshire
city: Chapel Hill
country: United States
facility: GSK Investigational Site
state: North Carolina
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: