Pharmacokinetics of Dabrafenib in Subjects With Hepatic Impairment

A Phase I, Open Label, Multicenter, Single Dose Study to Evaluate the Pharmacokinetics of Dabrafenib in Healthy Subjects With Normal Hepatic Function and Subjects With Impaired Hepatic Function

To characterize the pharmacokinetics and safety of dabrafenib following a single 100 mg oral dose in subjects with moderate and severe hepatic impairment.

Study Overview

• Status: Terminated
• Conditions: Hepatic Impairment
• Intervention / Treatment: Drug: dabrafenib

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 900017
      • American Institute of Research
  • Florida
    • DeBary, Florida, United States, 32713
      • Omega Research Consultants LLC
  • New Jersey
    • Berlin, New Jersey, United States, 08009
      • Hassman Research Institute
  • North Carolina
    • Raleigh, North Carolina, United States, 27612
      • Wake Research Associates Oncology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion criteria (for all subjects)

• Male and/or female subjects 18-75 years of age
• Females must be of non-childbearing potential . All non-postmenopausal females must have a confirmed negative serum pregnancy
• Subjects in good health condition as determined by no clinically significant findings from medical history and physical examination.
• Body mass index (BMI) between ≥18.0 and ≤38.0 kg/m2, with body weight ≥ 50 kg and no more than 140 kg
• Laboratory values must be within normal limits (correction allowed) or considered clinically insignificant
• Do not participate in any other clinical trials with a BRAF or other RAF inhibitors

Additional inclusion criteria for patients with normal hepatic function (Control group):

• Absence of clinically significant deviation from normal in medical history, physical examination, vital signs, electrocardiograms and clinical laboratory determinations.
• Must match to at least one hepatic impairment subject by age, gender and bodyweight

Additional inclusion criteria for hepatic impaired subjects:

• Confirmed hepatic disease
• Stable Child-Pugh status within 28 days prior to dosing.

Exclusion criteria for all subjects

• Participation in any clinical investigation within 4 weeks prior to dosing
• Significant acute illness within the two weeks prior to dosing
• History of immunodeficiency diseases, including a positive HIV
• History of malignancy of any organ system, treated or untreated, within 5 years
• Any prior history of keratoacanthoma and/or cutaneous squamous cell carcinoma
• A known diagnosis of any of the RASopathies, such as NF-1, Noonan syndrome, or related conditions.
• History of drug or alcohol abuse within the 6 months prior to dosing
• Smoking: urine cotinine levels below 500 ng/mL on Day -1.
• Use of drugs known to affect CYP3A4 and/or CYP2C8 including both (strong or moderate) inhibitors and inducers, within 7 days prior to dosing
• Administration of medications that prolong the QT interval within 4 weeks prior to dosing and until EOT.
• History or current diagnosis of cardiac disease indicating significant risk of safety
• Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism or excretion of drugs.

Additional exclusion criteria for healthy subjects (control group):

• Clinical evidence of liver disease or liver injury
• History or presence of renal impairment as indicated by abnormal creatinine or BUN values
• A positive Hepatitis B surface antigen (HBsAg) or Hepatitis C antibody

Additional exclusion criteria for subjects with hepatic impairment:

• Alcohol or drug abuse within one month prior to dosing or evidence of such
• History of liver transplantation at any time in the past and is on immunosuppressant therapy.
• Encephalopathy Grade 3 or worse within 28 days of dosing.
• History of surgical portosystemic shunt.
• Life expectancy ≤3 months

Other protocol-defined inclusion/exclusion may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Group 1 - Control group	Drug: dabrafenib; Single dose of 100 mg dabrafenib on Day 1; Other Names: DRB436
EXPERIMENTAL: Group 2-Moderate hepatic impairment	Drug: dabrafenib; Single dose of 100 mg dabrafenib on Day 1; Other Names: DRB436
EXPERIMENTAL: Group 3-Severe hepatic impairment	Drug: dabrafenib; Single dose of 100 mg dabrafenib on Day 1; Other Names: DRB436

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Maximum plasma concentration (Cmax)	Predose through 96 hours postdose
Area under the curve (AUClast)	Predose through 96 hours postdose
Area under the curve (AUFinf)	Predose through 96 hours postdose
Systemic drug clearance (CL/F)	Predose through 96 hours postdose
Time to reach maximum concentration (Tmax)	Predose through 96 hours postdose
Terminal elimination rate (Lambda_z)	Predose through 96 hours postdose
Elimination half-life (T1/2)	Predose through 96 hours postdose
Volume of distribution (Vz/F)	Predose through 96 hours postdose

Secondary Outcome Measures

Outcome Measure	Time Frame
Number of subjects with adverse events	Time of study drug administration through 30 days postdose
Number of subjects with abnormal lab values related to study drug	Time of study drug administration through 30 days postdose
Number of subjects with abnormal blood pressure related to study drug	Time of study drug administration through 30 days postdose
Number of subjects with abnormal pulse rate related to study drug	Time of study drug administration through 30 days postdose
Number of subjects with abnormal respiratory rate related to study drug	Time of study drug administration through 30 days postdose
Number of subjects with abnormal body temperature related to study drug	Time of study drug administration through 30 days postdose
Changes in electrocardiogram (ECG)	Time of study drug administration through 30 days postdose

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 20, 2016
• Primary Completion (ACTUAL): October 12, 2018
• Study Completion (ACTUAL): April 8, 2019

Study Registration Dates

• First Submitted: August 16, 2016
• First Submitted That Met QC Criteria: August 16, 2016
• First Posted (ESTIMATE): August 19, 2016

Study Record Updates

• Last Update Posted (ACTUAL): December 8, 2020
• Last Update Submitted That Met QC Criteria: December 6, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: Healthy volunteers; dabrafenib; Clinical pharmacology study; DRB436; Hepatic impairment; normal hepatic function; impaired hepatic function
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Dabrafenib
• Other Study ID Numbers: CDRB436A2107

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No