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

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT00258050
First Posted: November 24, 2005
Last Update Posted: December 6, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
GlaxoSmithKline
  Purpose
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.

Condition Intervention Phase
Neoplasms, Breast Drug: Midazolam Drug: Lapatinib Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Area under the concentration versus time curve (AUC) of midazolam [ Time Frame: 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 ]
    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.

  • Maximum observed concentration (Cmax) of midazolam [ Time Frame: 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 ]
    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.

  • Clearance (CL) of midazolam [ Time Frame: 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 ]
    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.

  • Half-life (t½) of midazolam [ Time Frame: 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 ]
    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.

  • Absolute bioavailability (F) of midazolam [ Time Frame: 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 ]
    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.


Secondary Outcome Measures:
  • Time of maximum observed concentration (tmax) of midazolam [ Time Frame: 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 ]
    Blood samples will be collected at indicated time points for the determination of midazolam concentration.

  • Volume of distribution (Vss) of midazolam [ Time Frame: 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 ]
    Blood samples will be collected at indicated time points for the determination of midazolam concentration.

  • Number of subjects with adverse events (AEs) and serious adverse events (SAEs) [ Time Frame: Up to Month 7 ]
    An AE is any untoward medical occurrence in a clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is any untoward medical occurrence that at any dose: results in death; is life-threatening; requires hospitalization or prolongation of existing hospitalization; results in disability/incapacity; is a congenital anomaly/birth defect; important medical events may require medical or surgical intervention to prevent one of the other outcomes listed above.

  • Number of subjects with abnormal clinical chemistry parameters [ Time Frame: Up to Month 7 ]
    The following clinical chemistry parameters were evaluated: sodium, potassium, total carbon dioxide (CO2), calcium, total bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine and blood urea nitrogen (BUN).

  • Number of subjects with abnormal hematology parameters [ Time Frame: Up to Month 7 ]
    The following hematology parameters were evaluated: hemoglobin, hematocrit, red blood cell count, white blood cell count, neutrophil count, lymphocyte count, monocyte count, eosinophil count and basophil count.

  • Number of subjects with abnormal blood pressure [ Time Frame: Up to Month 7 ]
    Systolic and diastolic blood pressure will be measured.

  • Number of subjects with abnormal heart rate [ Time Frame: Up to Month 7 ]
    Heart rate will be measured.


Enrollment: 24
Actual Study Start Date: November 21, 2005
Study Completion Date: February 8, 2007
Primary Completion Date: February 8, 2007 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Subjects with cancer

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
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.
Other Name: GW572016 oral tablets
Drug: Lapatinib
Subjects will receive 1500 mg lapatinib by oral route once daily from Day 4.

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 70 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00258050


Locations
United States, New Hampshire
GSK Investigational Site
Lebanon, New Hampshire, United States, 03756
United States, North Carolina
GSK Investigational Site
Chapel Hill, North Carolina, United States, 27599
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

Additional Information:
Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT00258050     History of Changes
Other Study ID Numbers: EGF10015
First Submitted: November 22, 2005
First Posted: November 24, 2005
Last Update Posted: December 6, 2017
Last Verified: December 2017

Keywords provided by GlaxoSmithKline:
midazolam
pharmacokinetics
lapatinib

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Midazolam
Lapatinib
Adjuvants, Anesthesia
Hypnotics and Sedatives
Central Nervous System Depressants
Physiological Effects of Drugs
Anti-Anxiety Agents
Tranquilizing Agents
Psychotropic Drugs
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
GABA Modulators
GABA Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors