Clinical trial NCT02873650: Pharmacokinetics of Dabrafenib in Subjects With Hepatic Impairment
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Hepatic Impairment
Keywords: Hepatic impairment
Healthy volunteers
Clinical pharmacology study
DRB436
dabrafenib
normal hepatic function
impaired hepatic function
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2016-08-19
Enrollment: 5
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: open-label, parallel group
Primary purpose: BASIC_SCIENCE

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


Eligibility criteria: 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.

Primary outcomes:
measure: Maximum plasma concentration (Cmax)
timeFrame: Predose through 96 hours postdose
measure: Area under the curve (AUClast)
timeFrame: Predose through 96 hours postdose
measure: Area under the curve (AUFinf)
timeFrame: Predose through 96 hours postdose
measure: Systemic drug clearance (CL/F)
timeFrame: Predose through 96 hours postdose
measure: Time to reach maximum concentration (Tmax)
timeFrame: Predose through 96 hours postdose
measure: Terminal elimination rate (Lambda_z)
timeFrame: Predose through 96 hours postdose
measure: Elimination half-life (T1/2)
timeFrame: Predose through 96 hours postdose
measure: Volume of distribution (Vz/F)
timeFrame: Predose through 96 hours postdose
Secondary outcomes:
measure: Number of subjects with adverse events
timeFrame: Time of study drug administration through 30 days postdose
measure: Number of subjects with abnormal lab values related to study drug
timeFrame: Time of study drug administration through 30 days postdose
measure: Number of subjects with abnormal blood pressure related to study drug
timeFrame: Time of study drug administration through 30 days postdose
measure: Number of subjects with abnormal pulse rate related to study drug
timeFrame: Time of study drug administration through 30 days postdose
measure: Number of subjects with abnormal respiratory rate related to study drug
timeFrame: Time of study drug administration through 30 days postdose
measure: Number of subjects with abnormal body temperature related to study drug
timeFrame: Time of study drug administration through 30 days postdose
measure: Changes in electrocardiogram (ECG)
timeFrame: Time of study drug administration through 30 days postdose
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: American Institute of Research
state: California
city: DeBary
country: United States
facility: Omega Research Consultants LLC
state: Florida
city: Berlin
country: United States
facility: Hassman Research Institute
state: New Jersey
city: Raleigh
country: United States
facility: Wake Research Associates Oncology
state: North Carolina
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: