Effects of Dabrafenib on the Single Dose Pharmacokinetics (PK) of Rosuvastatin and Midazolam

Sponsor

GlaxoSmithKline (Industry)

Overall Status

Completed

CT.gov ID

NCT02082665

Collaborator

(none)

Enrollment

Locations

Arm

17.4

Duration (Months)

1.5

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is an open-label, multi-center, fixed sequence study in subjects with BRAF V600 mutation positive tumors. Subjects will receive single oral doses of 10 milligram (mg) of rosuvastatin and 3 mg of midazolam in the morning of Day 1 (alone), Day 8 (with first dose of dabrafenib 150 mg), and Day 22 (during repeat dose dabrafenib 150 mg twice daily [BID]). Dabrafenib 150 mg BID will be administered from Day 8 to Day 23. Blood samples for PK analysis will be obtained over 32 hours post-dose on Day 1, Day 8, and Day 22. The last dose of dabrafenib will be taken in the morning of Day 23 and the last blood sample in the evening of Day 23. Subjects will be considered to have completed the study once the 32 hour PK sample has been collected on Day 23. Once they have completed the study, eligible subjects may have the option to enter study BRF114144, an open-label roll-over study of dabrafenib (no follow-up visit required) and continue receiving dabrafenib.

Condition or Disease	Intervention/Treatment	Phase
Cancer	Drug: Rosuvastatin10 mg tablet Drug: Midazolam 3 mg syrup Drug: Dabrafenib 75 mg capsule	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

6 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

An Open-label Phase 1 Study to Evaluate the Effects of Dabrafenib (GSK2118436) on the Single Dose Pharmacokinetics of an OATP1B1/1B3 Substrate and of a CYP3A4 Substrate in Subjects With BRAF V600 Mutation Positive Tumors

Study Start Date :

Feb 19, 2015

Actual Primary Completion Date :

Jul 1, 2016

Actual Study Completion Date :

Aug 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm 1 On Day 1 subjects will simultaneously receive single dose of Rosuvastatin 10 mg tablet and Midazolam 3 mg syrup administered orally in the morning.	Drug: Rosuvastatin10 mg tablet Commercially available Rosuvastatin 10 mg tablets will be supplied. Single oral dose of Rosuvastatin 10 mg will be administered on Day 1, 8 and 22 Drug: Midazolam 3 mg syrup Commercially available Midazolam syrup will be supplied.Single oral dose of Midazolam 3 mg syrup will be administered on Days 1, 8 and 22 Drug: Dabrafenib 75 mg capsule Dabrafenib 75mg will be supplied in the form of capsules. Oral dose Dabrafenib 150 mg (2 x 75 mg) BID will be administered at 12 h apart on Days 8 through 22 and 150 mg (2 x 75 mg) OD on Day 23.

Arm

Intervention/Treatment

Experimental: Arm 1

On Day 1 subjects will simultaneously receive single dose of Rosuvastatin 10 mg tablet and Midazolam 3 mg syrup administered orally in the morning.

Drug: Rosuvastatin10 mg tablet

Commercially available Rosuvastatin 10 mg tablets will be supplied. Single oral dose of Rosuvastatin 10 mg will be administered on Day 1, 8 and 22

Drug: Midazolam 3 mg syrup

Commercially available Midazolam syrup will be supplied.Single oral dose of Midazolam 3 mg syrup will be administered on Days 1, 8 and 22

Drug: Dabrafenib 75 mg capsule

Dabrafenib 75mg will be supplied in the form of capsules. Oral dose Dabrafenib 150 mg (2 x 75 mg) BID will be administered at 12 h apart on Days 8 through 22 and 150 mg (2 x 75 mg) OD on Day 23.

Outcome Measures

Primary Outcome Measures

Pharmacokinetics (PK) parameter of rosuvastatin and midazolam [Day 1, Day 8 (initiation of dabrafenib dosing) and Day 22 (steady state)]
Blood samples will be collected for assessment of PK parameters including maximum observed concentration (Cmax), time to Cmax (tmax), and area under the concentration-time curve from pre-dose extrapolated to infinite time (AUC[0-infinity])

Secondary Outcome Measures

Secondary PK parameters of rosuvastatin and midazolam [Day 1, Day 8 (initiation of dabrafenib dosing) and Day 22 (steady state)]
Blood samples will be collected for assessment of PK parameters including area under the concentration-time curve to time of last measurable concentration (AUC[0-t]), area under the concentration-time curve from time zero to a time point determined from the data (AUC (partial), terminal phase half-life (t1/2)
PK parameters of dabrafenib and dabrafenib metabolites [Day 8 and 22; pre-dose, 1 hour (hr), 2 hr, 8 hr and 24 hr after dose]
Blood samples will be collected for assessment of concentration of dabrafenib and its metabolites
Number of subjects with adverse events as a measure of safety and tolerability [Screening and up to 10 days post last dose. Skin exams may continue through 6 months post study.]
AE is defined as Any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.
Changes in clinical laboratory measurements to access safety [Screening, Day 1, Day 22 and Follow-up]
Any abnormal laboratory test results (haematology, clinical chemistry, or urinalysis)
Changes in vital sign measurements to access safety [Screening, Day 1, Day 2, Day 8, Day 9, Day 22 , Day 23 and Follow-up]
Vital sign measurements will include systolic and diastolic blood pressure, respiratory rate, pulse rate and pulse oximetry Vital signs should be measured after sitting in a semi-supine position for at least 5 min.
Change from baseline in cardiac assessments [Screening, Day 1, Day 22,and Follow-up]
Cardiac assessments include 12-lead Electrocardiogram (ECG)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Signed, written informed consent.
BRAF V600 mutation-positive tumor: as confirmed by a Clinical Laboratory Improvement Amendments (CLIA) approved local laboratory or equivalent.
Male or female between 18 to 65 years of age, inclusive, at the time of signing the informed consent form;
Capable of compliance with the requirements and restrictions listed in the consent form;
Body weight >= 45 kilogram (kg) and a body mass index >= 19 kilogram per squaremeter (kg/m^{2)and <40 kg/m}2 (inclusive);
Able to swallow and retain orally administered medication
Eastern Cooperative Oncology Group (ECOG) performance status: 0 or 1. NOTE: Subjects with a performance status of 2 can be enrolled if the subject's confinement to bed and inability to carry out work activities is due solely to cancer-related pain, as assessed by the Investigator.
Adequate baseline organ function defined as: absolute neutrophil count >= 1.2 x 10^{9/Liter (L); hemoglobin>=9 gram per deciliter (g/dL); platelets >= 75 x 10}9/L; prothrombin time /international normalized ratio and partial thromboplastin time =<1.3 x ULN; serum bilirubin=<1.5 times upper limit of normal (ULN); aspartate aminotransferase and alanine aminotransferase =<2.5 times ULN; serum creatinine=<1.5 mg/dL or calculate creatinine clearance >= 50 milliliter per minute; Left ventricular ejection fraction>= lower limit of normal by echocardiography.
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.

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) chronic lymphocytic leukemia in stable remission, or (e) indolent prostate cancer (definition: clinical stage T1 or T2a, Gleason score <=6, and prostate-specific antigen <10 nanogram per milliliter) requiring no or only anti-hormonal therapy, are eligible. Note: Prospective RAS testing is not required. However, if the results of previous RAS testing are known, they must be used in assessing eligibility.
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 study medication.
Unresolved clinically significant toxicity greater than Grade 2 from previous anti-cancer therapy
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. NOTE: Low molecular weight heparin and prophylactic low-dose warfarin are permitted
Any prohibited medication(s) or herbal preparation as described in the 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, rosuvastatin, and midazolam, or excipients that contraindicate their participation; or have an allergy to cherries.
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 millisecond (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 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.
Patients with intra-cardiac defibrillators
Presence of active 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.
Subjects with COPD or subjects with increased risk of respiratory depression
Subjects with narrow angle glaucoma
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 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 more than one 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Lebanon	New Hampshire	United States	03756
2	GSK Investigational Site	Barcelona		Spain	08035
3	GSK Investigational Site	Madrid		Spain	28040
4	GSK Investigational Site	Sevilla		Spain	41013