To Examine The Effects Of Lapatinib On Orally And Intravenously Administered Midazolam In Cancer Patients

NCT00258050 | Completed Phase 1

• 1 other identifier: EGF10015
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 2

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.

Conditions

Neoplasms, Breast

Keywords

midazolam; pharmacokinetics; lapatinib

Outcome Measures

Primary Outcomes (5)

• Area under the concentration versus time curve (AUC) of midazolam

  Blood samples will be collected at indicated time points for the determination of midazolam concentration. AUC of midazolam in the presence and absence of lapatinib will be determined.

  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

• Maximum observed concentration (Cmax) of midazolam

  Blood samples will be collected at indicated time points for the determination of midazolam concentration. Cmax of midazolam in the presence and absence of lapatinib will be determined.

  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

• Clearance (CL) of midazolam

  Blood samples will be collected at indicated time points for the determination of midazolam concentration. CL of midazolam in the presence and absence of lapatinib will be determined.

  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

• Half-life (t½) of midazolam

  Blood samples will be collected at indicated time points for the determination of midazolam concentration. t1/2 of midazolam in the presence and absence of lapatinib will be determined.

  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

• Absolute bioavailability (F) of midazolam

  Blood samples will be collected at indicated time points for the determination of midazolam concentration. Absolute bioavailability of midazolam in the presence and absence of lapatinib will be determined.

  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 (7)

• Time of maximum observed concentration (tmax) of midazolam

  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

• Volume of distribution (Vss) of midazolam

  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

• Number of subjects with adverse events (AEs) and serious adverse events (SAEs)

  Up to Month 7

• Number of subjects with abnormal clinical chemistry parameters

  Up to Month 7

• Number of subjects with abnormal hematology parameters

  Up to Month 7

Study Arms (1)

Subjects with cancer

EXPERIMENTAL

In Part 1 of the study, subjects will be randomized to one of four sequences. All subjects will receive oral or intravenous (IV) midazolam on Days 1, 3, 9 and 11 as per assigned randomization scheme. Starting on Day 4 through Day 11, subjects will receive a daily dose of 1500 milligrams (mg) of oral lapatinib. In Part 2, which will begin on Day 12, the subjects will be required to take 1500 mg of lapatinib daily until removed from the study for disease progression, adverse events, withdrawal of consent, or transfer to another lapatinib study.

Drug: Midazolam; Drug: Lapatinib

Interventions

Midazolam DRUG

Subjects will receive midazolam by oral or IV route on Days 1, 3, 9 and 11. Oral midazolam was supplied as 3 mg tablets; IV midazolam was supplied as 1 milligram per milliliter (mg/L) sterile solution.

Also known as: GW572016 oral tablets

Subjects with cancer

Lapatinib DRUG

Subjects will receive 1500 mg lapatinib by oral route once daily from Day 4.

Subjects with cancer

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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%.

You may not qualify if:

• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (2)

GSK Investigational Site

Lebanon, New Hampshire, 03756, United States

Location

GSK Investigational Site

Chapel Hill, North Carolina, 27599, United States

Location

Related Links

• Results for study EGF10015 can be found on the GSK Clinical Study Register.

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Midazolam; Lapatinib

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

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

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 22, 2005
• First Posted: November 24, 2005
• Study Start: November 21, 2005
• Primary Completion: February 8, 2007
• Study Completion: February 8, 2007
• Last Updated: December 6, 2017

Record last verified: 2017-12

Locations

US (2)