Trial from ClinicalTrials.gov

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Trial ID
NCT01954043
Ethics application status
Date submitted
26/09/2013
Date registered
26/09/2013
Date last updated
20/07/2017

Titles & IDs
Public title
A Pharmacokinetics (PK) Study of the Effects Rabeprazole and Rifampin on Dabrafenib in Subjects With BRAF V600 Mutation Positive Tumors
Scientific title
An Open-label Study to Evaluate the Effects of a Potent CYP3A4 Inducer and the Effects of a pH Elevating Agent on the Repeat Dose Pharmacokinetics of Dabrafenib (GSK2118436) in Subjects With BRAF V600 Mutation Positive Tumors
Secondary ID [1] 0 0
200072
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cancer 0 0
Condition category
Condition code

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: drugs - Dabrafenib 150 mg twice a day (BID)
Treatment: drugs - Rabeprazole 40 mg once daily (OD)
Treatment: drugs - Rifampin 600 mg OD

Experimental: Arm A - Subjects will administer Dabrafenib from Day 1 to Day 15, Dabrafenib and Rabeprazole from Day 16 to Day 19, Dabrafenib and Rifampin from Day 20 to Day 29. The serial PK samples will be collected for 12 hours following dosing on Day 15 (Dabrafenib alone), Day 19 (Dabrafenib and Rabeprazole), and Day 29 (Dabrafenib and Rifampin).


Treatment: drugs: Dabrafenib 150 mg twice a day (BID)
Dabrafenib dosed at 150mg twice a day from Day 1 to the morning of Day 29

Treatment: drugs: Rabeprazole 40 mg once daily (OD)
Rabeprazole dosed at 40mg each morning on Days 16 to 19

Treatment: drugs: Rifampin 600 mg OD
Rifampin dosed at 600mg each morning on Days 20 to 29

Intervention code [1] 0 0
Treatment: drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
PK assessment (Cmax) of Dabrafenib with and without Rabeprazole or Rifampin - Blood samples will be collected to assess PK parameters including: maximum observed concentration (Cmax)
Timepoint [1] 0 0
Day 15, 19 and Day 29
Primary outcome [2] 0 0
PK assessment (tmax) of Dabrafenib with and without Rabeprazole or Rifampin - Blood samples will be collected to assess PK parameters including: time to Cmax (tmax)
Timepoint [2] 0 0
Day 15, 19 and Day 29
Primary outcome [3] 0 0
PK assessment (AUC[0-tau]) of Dabrafenib with and without Rabeprazole or Rifampin - Blood samples will be collected to assess PK parameters including: area under the concentration-time curve over the dosing interval (AUC[0-tau])
Timepoint [3] 0 0
Day 15, 19 and Day 29
Secondary outcome [1] 0 0
PK assessment of Dabrafenib co administered with rabeprazole or rifampin - Blood samples will be collected to assess PK parameters including: Pre-dose concentration (Ctau) after administration of Dabrafenib co-administered with rabeprazole or rifampin
Timepoint [1] 0 0
Day 15, 19 and Day 29
Secondary outcome [2] 0 0
PK assessment (AUC[0-tau]) of hydroxy-dabrafenib, carboxy-dabrafenib, and desmethyl-dabrafenib - Blood samples will be collected to assess PK parameter (AUC[0-tau]) after administration of Dabrafenib co-administered with rabeprazole or rifampin
Timepoint [2] 0 0
Day 15, 19 and Day 29
Secondary outcome [3] 0 0
PK assessment (Cmax and Ctau,) of hydroxy-dabrafenib, carboxy-dabrafenib, and desmethyl-dabrafenib - Blood samples will be collected to assess PK parameters including: Cmax and Ctau, after administration of Dabrafenib co-administered with rabeprazole or rifampin
Timepoint [3] 0 0
Day 15, 19 and Day 29
Secondary outcome [4] 0 0
PK assessment (tmax) of hydroxy-dabrafenib, carboxy-dabrafenib, and desmethyl-dabrafenib - Blood samples will be collected to assess PK parameter (tmax), after administration of Dabrafenib co-administered with rabeprazole or rifampin
Timepoint [4] 0 0
Day 15, 19 and Day 29
Secondary outcome [5] 0 0
Ratio of metabolite to Dabrafenib - Blood samples will be collected for AUC(0 tau) to estimate ratio of Dabrafenib metabolites to parent Dabrafenib co-administered with rabeprazole or rifampin
Timepoint [5] 0 0
Day 15, 19 and Day 29
Secondary outcome [6] 0 0
Safety and tolerability assessment to measure vital signs - Safety and tolerability assessment for vital signs including systolic and diastolic blood pressure, temperature, and pulse rate for dabrafenib in combination with rabeprazole or rifampin
Timepoint [6] 0 0
Day 15, 19 and Day 29
Secondary outcome [7] 0 0
Safety and tolerability assessment for 12-lead ECG - A single 12-lead ECG will be obtained to assess safety and tolerability of dabrafenib in combination with rabeprazole or rifampin
Timepoint [7] 0 0
From Screening up to follow up visit within 7-10 days of the last dose of study medication
Secondary outcome [8] 0 0
Safety and tolerability assessment for laboratory tests - Safety and tolerability assessment for clinical laboratory tests including hematology, clinical chemistry and other tests for dabrafenib in combination with rabeprazole or rifampin
Timepoint [8] 0 0
From Screening up to follow up visit within 7-10 days of the last dose of study medication
Secondary outcome [9] 0 0
Safety and tolerability assessment of dabrafenib in combination with rabeprazole or rifampin - Safety and tolerability assessment includes adverse events (AEs) and serious adverse events (SAEs)
Timepoint [9] 0 0
From Screening up to follow up visit within 7-10 days of the last dose of study medication
Secondary outcome [10] 0 0
Concentrations of Rabeprazole in the presence of Dabrafenib - Blood sample will be collected to measure concentration of Rabeprazole in the presence of Dabrafenib
Timepoint [10] 0 0
Predose, 1, 2, 3 and 12 hours postdose on Day 19
Secondary outcome [11] 0 0
Concentrations of Rifampin in the presence of Dabrafenib - Blood sample will be collected to measure concentration of Rifampin in the presence of Dabrafenib
Timepoint [11] 0 0
Predose, 1, 2, 3 and 12 hours postdose on Day 29

Eligibility
Key inclusion criteria
- Male or female at least 18 years of age at the time of signing the informed consent
form.

- Provided signed written informed consent.

- Capable of compliance with the requirements and restrictions listed in the consent
form.

- Body weight >=45 kilogram (kg) and a body mass index (BMI) >=19 Kilogram per meter
squared (kg/m^2) and <40 kg/m^2 (inclusive).

- Able to swallow and retain oral medication.

- BRAF V600 mutation-positive tumor as confirmed in a Clinical Laboratory Improvement
Amendments (CLIA)-approved laboratory or equivalent.

- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

- Adequate baseline organ function defined in study protocol.

- Women of child-bearing potential must be willing to practice acceptable methods of
birth control. Additionally, women of childbearing potential must have a negative
serum pregnancy test within 14 days prior to the first dose of study medication.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- History of another malignancy with exceptions below, or any malignancy with confirmed
activating RAS mutation. Exception: (a) Subjects who have been successfully treated
and are disease-free for 5 years, (b) a history of completely resected non-melanoma
skin cancer, (c) successfully treated in situ carcinoma, (d) CLL in stable remission,
or (e) indolent prostate cancer (definition: clinical stage T1 or T2a, Gleason score
<=6, and PSA <10 nanogram per milliliter [ng/mL]) requiring no or only anti-hormonal
therapy, are eligible.

- Cancer therapy (chemotherapy with delayed toxicity, extensive radiation therapy,
immunotherapy, biologic therapy, or major surgery) or investigational anti-cancer
drugs within the last 3 weeks, or chemotherapy without delayed toxicity within the
last 2 weeks, preceding the first dose of dabrafenib.

- Unresolved toxicity greater than Grade 2 from previous anti-cancer therapy except
alopecia.

- Any serious and/or unstable pre-existing medical, psychiatric disorder or other
conditions that could interfere with subject's safety, obtaining informed consent or
compliance to the study procedures.

- Current use of therapeutic warfarin.

- Any prohibited medication(s) or herbal preparation as described in study protocol or
requires any of these medications during the study.

- Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
chemically related to dabrafenib, rabeprazole and rifampin, or excipients that
contraindicates their participation.

- Pregnant or nursing females.

- A history or evidence of cardiovascular risk including any of the following: a QT
interval corrected for heart rate using the Bazett's formula (QTcB) >=480 milliseconds
(msec); a history or evidence of current clinically significant uncontrolled
arrhythmias; a history of acute coronary syndromes (including myocardial infarction or
unstable angina), coronary angioplasty, or stenting within 6 months prior to
randomization; a history or evidence of current >=Class II congestive heart failure
(CHF) as defined by the New York Heart Association (NYHA) guidelines; Abnormal cardiac
valve morphology (>=grade 2) documented by echocardiogram (subjects with grade 1
abnormalities [i.e., mild regurgitation/stenosis] can be entered on study). Subjects
with moderate valvular thickening should not be entered on study.

- Presence of active gastrointestinal (GI) disease or other condition (e.g., small bowel
or large bowel resection) that will interfere significantly with the absorption of
drugs. If clarification is needed as to whether a condition will significantly affect
absorption of drugs, contact the GSK Medical Monitor.

- A history of known Human Immunodeficiency Virus (HIV), Hepatitis B Virus, or Hepatitis
C Virus infection.

- Subjects with brain metastases are excluded if their brain metastases are:
Symptomatic, Treated (surgery, radiation therapy) but not clinically and
radiographically stable one month after local therapy, or asymptomatic and untreated
but >1 centimeter (cm) in the longest dimension. Subjects with small (<=1 cm in the
longest dimension), asymptomatic brain metastases that do not need immediate local
therapy can be enrolled. Subjects on a stable dose of corticosteroids for >1 month, or
those who have been off corticosteroids for at least 2 weeks can be enrolled. Subjects
must also be off of enzyme-inducing anticonvulsants for more than 4 weeks.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Current
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 0 0
GSK Investigational Site - Heidelberg
Recruitment hospital [2] 0 0
GSK Investigational Site - Melbourne
Recruitment postcode(s) [1] 0 0
3084 - Heidelberg
Recruitment postcode(s) [2] 0 0
3004 - Melbourne
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Arizona
Country [2] 0 0
United States of America
State/province [2] 0 0
Texas
Country [3] 0 0
United States of America
State/province [3] 0 0
Washington
Country [4] 0 0
United Kingdom
State/province [4] 0 0
London

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
GlaxoSmithKline
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
The study is being conducted to evaluate the effect of rifampin (a strong CYP3A4 inducer) and
rabeprazole (a pH elevating agent) on the PK of dabrafenib (a CYP3A4/CYP2C8 substrate). The
study will be conducted in subjects with BRAF V600 mutation-positive tumors. Data collected
from this study will be used to inform recommendations regarding use of concomitant
medications with dabrafenib and future clinical pharmacologic evaluation of dabrafenib.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
GSK Clinical Trials
Address 0 0
GlaxoSmithKline
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries
Contact person responsible for updating information