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CancerPhase 1NCT02082665

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

A Phase 1 study testing Rosuvastatin10 mg tablet, Midazolam 3 mg syrup and Dabrafenib 75 mg capsule in people with Cancer, run by GlaxoSmithKline at 4 sites in 2 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 18 to 65 years
Conditions the study is for
Cancer
What is being tested?
Rosuvastatin10 mg tablet, Midazolam 3 mg syrup and Dabrafenib 75 mg capsule
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
6 participants
Where
4 sitesin 2 countries
Study dates
19 Feb 2015to 1 Aug 2016
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 65 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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.

Who cannot join

  • 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.
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  • 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.

Trial locations and contacts

4 sites in 2 countries.

4 sites in 2 countries

Spain3 sites

  • GSK Investigational Site

    Barcelona, 08035

  • GSK Investigational Site

    Madrid, 28040

  • GSK Investigational Site

    Seville, 41013

Other trials in Spain

United States1 site

  • GSK Investigational Site

    Lebanon, New Hampshire, 03756

Other trials in United States

About this study

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

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
Being tested
Rosuvastatin10 mg tablet, Midazolam 3 mg syrup, Dabrafenib 75 mg capsule
Keywords
rosuvastatin, BRAF V600, Melanoma, dabrafenib, midazolam
Medical subject headings
Neoplasms, Melanoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Rosuvastatin10 mg tabletDrug

    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

  • Midazolam 3 mg syrupDrug

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

  • Dabrafenib 75 mg capsuleDrug

    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.

Study groups in NCT02082665
Study groupRoleWhat they receive
Arm 1ExperimentalOn Day 1 subjects will simultaneously receive single dose of Rosuvastatin 10 mg tablet and Midazolam 3 mg syrup administered orally in the morning.
Receives: Drug: Rosuvastatin10 mg tablet; Drug: Midazolam 3 mg syrup; Drug: Dabrafenib 75 mg capsule

What is being measured

The primary outcome is the main question the study is designed to answer.

  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])

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

Secondary outcomes (6)

  1. Secondary PK parameters of rosuvastatin and midazolam

    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)

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

  2. PK parameters of dabrafenib and dabrafenib metabolites

    Blood samples will be collected for assessment of concentration of dabrafenib and its metabolites

    Measured: Day 8 and 22; pre-dose, 1 hour (hr), 2 hr, 8 hr and 24 hr after dose

  3. Number of subjects with adverse events as a measure of safety and tolerability

    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.

    Measured: Screening and up to 10 days post last dose. Skin exams may continue through 6 months post study.

  4. Changes in clinical laboratory measurements to access safety

    Any abnormal laboratory test results (haematology, clinical chemistry, or urinalysis)

    Measured: Screening, Day 1, Day 22 and Follow-up

  5. Changes in vital sign measurements to access safety

    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.

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

  6. Change from baseline in cardiac assessments

    Cardiac assessments include 12-lead Electrocardiogram (ECG)

    Measured: Screening, Day 1, Day 22,and Follow-up

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted10 Mar 2014 (estimated)
  2. Study start19 Feb 2015
  3. Primary completion1 Jul 2016
  4. Study completion1 Aug 2016

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
6 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02082665
Sponsor's protocol ID
200919
Status last verified
Jul 2017
First submitted
6 Mar 2014
Last updated
24 Jul 2017
Results posted
No
Data monitoring committee
No

Publications

  • 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.

    PubMed 33932130

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Rosuvastatin10 mg tablet, Midazolam 3 mg syrup and Dabrafenib 75 mg capsule in people with Cancer, run by GlaxoSmithKline at 4 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 9 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 24 Jul 2017. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 4 sites in Spain, United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Pharmacokinetics (PK) parameter of rosuvastatin and midazolam (time frame: Day 1, Day 8 (initiation of dabrafenib dosing) and Day 22 (steady state)). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02082665, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Jul 2017.

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