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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 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 |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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) |
| Measure | Description | Time Frame |
|---|---|---|
| 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) | Day 1, Day 8 (initiation of dabrafenib dosing) and Day 22 (steady state) |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| GSK Clinical Trials | GlaxoSmithKline | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| GSK Investigational Site | Lebanon | New Hampshire | 03756 | United States | ||
| GSK Investigational Site |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 33932130 | Derived | 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. |
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| ID | Term |
|---|---|
| D009369 | Neoplasms |
| D008545 | Melanoma |
| ID | Term |
|---|---|
| D018358 | Neuroendocrine Tumors |
| D017599 | Neuroectodermal Tumors |
| D009373 | Neoplasms, Germ Cell and Embryonal |
| D009370 | Neoplasms by Histologic Type |
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| ID | Term |
|---|---|
| D008874 | Midazolam |
| C561627 | dabrafenib |
| ID | Term |
|---|---|
| D001569 | Benzodiazepines |
| D001552 | Benzazepines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
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| 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 |
|
| 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. |
|
| PK parameters of dabrafenib and dabrafenib metabolites | Blood samples will be collected for assessment of concentration of dabrafenib and its 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 | 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. | 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 | Any abnormal laboratory test results (haematology, clinical chemistry, or urinalysis) | Screening, Day 1, Day 22 and Follow-up |
| 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. | Screening, Day 1, Day 2, Day 8, Day 9, Day 22 , Day 23 and Follow-up |
| Change from baseline in cardiac assessments | Cardiac assessments include 12-lead Electrocardiogram (ECG) | Screening, Day 1, Day 22,and Follow-up |
| Barcelona |
| 08035 |
| Spain |
| GSK Investigational Site | Madrid | 28040 | Spain |
| GSK Investigational Site | Seville | 41013 | Spain |
| D009380 | Neoplasms, Nerve Tissue |
| D018326 | Nevi and Melanomas |
| D012878 | Skin Neoplasms |
| D009371 | Neoplasms by Site |
| D012871 | Skin Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D006571 | Heterocyclic Compounds |