Trial Outcomes & Findings for Phase II Biomarker Study Comparing the Combination of BRAF Inhibitor Dabrafenib With MEK Inhibitor Trametinib Versus the Combination After Monotherapy With Dabrafenib or Trametinib (NCT NCT02314143)

This is an open label, randomized, phase II study to compare the combination of dabrafenib with trametinib versus the combination after eight weeks of monotherapy with dabrafenib or trametinib in metastatic and unresectable stage III or IV melanoma. The study was terminated early due to slow enrollment and limited numbers of viable tissue samples.

This study was planned to enroll 54 participants randomized in 1:1:1 ratio into the three treatment arms; dabrafenib followed by combination therapy, trametinib followed by combination therapy and only combination therapy. The study was early terminated with 48 participants enrolled.

Phase II Biomarker Study Comparing the Combination of BRAF Inhibitor Dabrafenib With MEK Inhibitor Trametinib Versus the Combination After Monotherapy With Dabrafenib or Trametinib

Intra-tumoral expression levels of ERK measured using immunohistochemistry methods. The H score value ranged from 0 to a maximum score of 300 (strongest expression) was derived by summing the percentages of cells staining at each intensity multiplied by the weighted intensity of staining (0 \[no staining\], 1+ \[weak staining\], 2+ \[medium staining\] and 3+ \[strongest staining\]). Baseline was defined as the most recent non-missing value prior to the first dose of study treatment. Percentage change from Baseline was calculated by dividing change from Baseline value by Baseline value and multiplied by 100. The data has been presented for combination therapy calculated from Week 0 to Week 2. The analysis was based on the biomarker Population which included all participants with biopsy performed at screening and at least once during treatment.

Intra-tumoral expression levels of ERK were measured using immunohistochemistry methods. The H score value ranged from 0 to a maximum score of 300 (strongest expression) was derived by summing the percentages of cells staining at each intensity multiplied by the weighted intensity of staining (0 \[no staining\], 1+ \[weak staining\], 2+ \[medium staining\] and 3+ \[strongest staining\]). Baseline was defined as the most recent non-missing value prior to the first dose of study treatment. Percentage change from Baseline was calculated by dividing change from Baseline value by Baseline value and multiplied by 100. The data has been presented for dabrafenib followed by combination therapy and trametinib followed by combination therapy, calculated from Week 8 to Week 10.

Clinical response was evaluated by ORR, which was defined as the number of participants with a confirmed or an unconfirmed complete response (CR) or partial response (PR) at any time per Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. CR was defined as disappearance of all target lesions. PR was defined as at least a 30 percent decrease in the sum of the diameters of target lesions. Number of participants with ORR (CR+PR) has been presented. The analysis was based on the Intent-to-Treat Population (ITT) which included all the randomized participants whether or not randomized treatment was administered.

Vital signs including systolic blood pressure (SBP), diastolic blood pressure (DBP) and heat rate (HR) were measured. Baseline was defined as the most recent non-missing value prior to the first dose of study treatment. Change from Baseline was defined as any visit value minus the Baseline value. The number of participants with heart rate "decrease to \< 60" and "increase to \>100" have been presented. For SBP and DBP, "any grade increase" have been presented. Any grade increase in SBP, including grade 0 (\<120), grade 1 (120-139), grade 2 (140-159), grade 3 (\>=160) and DBP including grade 0 (\<80), grade 1 (80-89), grade 2 (90-99), grade 3 (\>=100) have been presented. The analysis was based on the Safety Population which included all participants who received at least one dose of randomized treatment and was based on the actual treatment received. Only those participants available at specified time point were analyzed (represented by n=x in category titles).

Complete physical examination included assessments of eyes, neurological and cardiovascular systems, lungs, abdomen, and any other areas with signs and symptoms of disease, and of the head, neck, ears, nose, mouth, throat, thyroid, lymph nodes, extremities, and a full skin exam to assess cutaneous malignancies and proliferative skin diseases. This analysis was planned but data was not captured in the database. Abnormal changes were captured as adverse events if they were clinically significant.

The ECOG scale of performance status describes the level of functioning of participants in terms of their ability to care for themselves, daily activity, and physical ability. The ECOG performance was recorded as per ECOG performance status grades ranging from 0 (fully active, able to carry on all pre-disease performance without restriction) to 5 (dead). Baseline was defined as the most recent non-missing value prior to the first dose of study treatment. Change from Baseline was defined as any visit value minus Baseline value. The Baseline performance status of participants with respect to worst-case on-therapy performance status has been presented.

Single measurements of 12-lead ECGs were obtained using an ECG machine that automatically calculates the heart rate and measures PR, QRS, corrected QT interval (QTc), Bazett's Corrected QT interval (QTcB), Friderica's Corrected QT interval (QTcF). Number of participants with abnormal ECG findings (Abnormal - Not Clinically Significant and Abnormal - Clinically Significant ) at any time post-Baseline visit have been presented.

Echocardiograms (ECHO) was performed to assess cardiac ejection fraction and cardiac valve morphology. Baseline was defined as the most recent non-missing value prior to the first dose of study treatment. Change from Baseline was defined as any visit value minus Baseline value. The worst-case on-therapy value has been presented.

Blood samples were collected for evaluation of clinical chemistry parameters including sodium, potassium, calcium, albumin, total protein, blood urea nitrogen (BUN), creatinine, lactate dehydrogenase (LDH), gamma-glutamyl transpeptidase (GCT), phosphate, C-reactive protein (CRP), hypercalcemia, hyperkalemia, hypernatremia, hypocalcemia, hypokalemia, hyponatremia, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, total bilirubin, direct bilirubin and estimated creatinine clearance (CRTCE). Baseline was defined as the most recent non-missing value from a central laboratory prior to the first dose of study treatment. Change from Baseline was defined as any visit value minus Baseline value. The worst-case on therapy value for number of participants with any grade increase in clinical chemistry parameters for has been presented. Only those participants available at specified time point were analyzed (represented by n=x in category titles).

Blood samples were collected for evaluation of hematology parameters including hemoglobin, white blood cell (WBC), platelet count, basophils, eosinophils, lymphocytes, monocytes, total neutrophils, lymphocytopenia and lymphocytosis. Baseline was defined as the most recent non-missing value from a central laboratory prior to the first dose of study treatment. Change from Baseline was defined as any visit value minus Baseline value. The worst-case on therapy value for number of participants with any grade increase in hematology parameters for has been presented.

The safety profile of dabrafenib and trametinib in monotherapy as well as in combination therapy was characterized by determining the number of participants with incidence of squamous cell carcinoma and keratoacanthoma.

An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability, is a congenital anomaly/ birth defect, other situations and is associated with liver injury or impaired liver function.

Blood samples were collected for pharmacokinetic analysis of trametinib at indicated time points. Pharmacokinetic analysis was performed using standard non-compartmental method.

Blood samples were collected for pharmacokinetic analysis of Dabrafenib at indicated time points. Pharmacokinetic analysis was performed using standard non-compartmental method.