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

NCT02082665 | Completed Phase 1

• 1 other identifier: 200919
• Study Type: interventional
• Target: 6
• Locations: 2 countries
• Sites: 4

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.

Conditions

Cancer

Keywords

rosuvastatin; BRAF V600; Melanoma; dabrafenib; midazolam

Outcome Measures

Primary Outcomes (1)

• Pharmacokinetics (PK) parameter of rosuvastatin and midazolam

  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\[0-infinity\])

  Day 1, Day 8 (initiation of dabrafenib dosing) and Day 22 (steady state)

Secondary Outcomes (6)

• Secondary PK parameters of rosuvastatin and midazolam

  Day 1, Day 8 (initiation of dabrafenib dosing) and Day 22 (steady state)

• 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

• 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.

• Changes in clinical laboratory measurements to access safety

  Screening, Day 1, Day 22 and Follow-up

• Changes in vital sign measurements to access safety

  Screening, Day 1, Day 2, Day 8, Day 9, Day 22 , Day 23 and Follow-up

Study Arms (1)

Arm 1

EXPERIMENTAL

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; Drug: Midazolam 3 mg syrup; Drug: Dabrafenib 75 mg capsule

Interventions

Rosuvastatin10 mg tablet DRUG

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

Arm 1

Midazolam 3 mg syrup DRUG

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

Arm 1

Dabrafenib 75 mg capsule DRUG

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 1

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (4)

GSK Investigational Site

Lebanon, New Hampshire, 03756, United States

Location

GSK Investigational Site

Barcelona, 08035, Spain

Location

GSK Investigational Site

Madrid, 28040, Spain

Location

GSK Investigational Site

Seville, 41013, Spain

Location

Related Publications (1)

• Nebot N, Won CS, Moreno V, Munoz-Couselo E, Lee DY, Gasal E, Bouillaud E. Evaluation of the Effects of Repeat-Dose Dabrafenib on the Single-Dose Pharmacokinetics of Rosuvastatin (OATP1B1/1B3 Substrate) and Midazolam (CYP3A4 Substrate). Clin Pharmacol Drug Dev. 2021 Sep;10(9):1054-1063. doi: 10.1002/cpdd.937. Epub 2021 May 1.

  PMID: 33932130 DERIVED

MeSH Terms

Conditions

Neoplasms; Melanoma

Interventions

Midazolam; dabrafenib

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 6, 2014
• First Posted: March 10, 2014
• Study Start: February 19, 2015
• Primary Completion: July 1, 2016
• Study Completion: August 1, 2016
• Last Updated: July 24, 2017

Record last verified: 2017-07

Locations

US (1); ES (3)