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Report for Clinical Trial NCT00880321
Developed by Shray Alag, 2020-2021.
SNP Clinical Trial Gene
BRF112680 is a first-time-in-human study to establish the recommended dose and schedule of
the orally administered GSK2118436. The recommended dose and regimen will be selected based
on the safety, pharmacokinetic, and pharmacodynamic profiles observed after the treatment of
subjects with solid tumors. This is a two-part study. Part 1 will identify the recommended
Part 2 dose using a dose-escalation procedure. Escalation may proceed until either a maximum
tolerated dose is established, or the toxicokinetic safety limit is reached. The recommended
Part 2 dose will be expanded to up to 12 patients. Part 2 will explore further the safety,
tolerability, and clinical activity of GSK2118436 in subjects with BRAF mutation-positive
tumors. In addition, the effect of GSK2118436 on midazolam will be assessed in a subset of
patients in Part 2. Biologically active doses will be identified by measurement of
pharmacodynamic markers in tumor tissue and blood across a range of doses and these doses may
be explored in Part 2.
Description: Dose escalation with GSK2118436 may proceed until either a maximum tolerated dose is established, or the toxicokinetic safety limit is reached.
Description: Part 2 will use the recommended Part 2 dose of GSK2118436 identified during Part 1 of the study. Biologically active doses will be identified by measurement of pharmacodynamic markers in tumor tissue and blood across a range of doses and these doses may be explored in Part 2.
Description: Midazolam will be administered alone and with GSK2118436 in a sub-set of subjects in Part 2 to study the effect of GSK2118436 on CYP3A using midazolam as a probe.
Primary Outcomes Measure: PK data, AEs, changes in laboratory values and vital signs, physical exam, clinical testing and PD data Time: 21 days
Secondary Outcomes Measure: GSK2118436 and its metabolite, PK parameters per protocol following single- and repeat-dose administration of GSK2118436 Time: 15 days
Measure: Change in PD markers including IL-8 in blood, pERK and other markers in tumor biopsies. Time: 15 days
Measure: Correlation between PK, PD, and clinical endpoints. Time: 15 days
Measure: Tumor response as defined by Response Evaluation Criteria in Solid Tumors (RECIST v1.0) Time: approximately once every 2 months until the end of participation
Measure: Urinary ratio of 6-beta-hydroxycortisol to cortisol ratio Time: 15 days
Measure: GSK2118436 PK parameters per protocol with and without food Time: 15 days
Measure: Metabolic profiling in plasma and urine Time: 15 days
Measure: Midazolam PK parameters per protocol Time: 15 days
Single Group Assignment
There is one SNP
- Part 2/Cohort C only: Must have BRAF positive melanoma with the V600E mutation. --- V600E ---