Melanoma
Conditions
Keywords
dabrafenib, MEK, trametinib, BRAF, melanoma, Oncology
Brief summary
This is a three-arm, open-label, randomised Phase II study to evaluate whether the different sequencing of dabrafenib and trametinib monotherapies and the upfront combination has an impact on translational or clinical activity in subjects with BRAF mutant metastatic unresectable stage IIIc or IV melanoma. Both dabrafenib and trametinib have demonstrated clinical activity as monotherapies and in combination in BRAF-mutant melanoma. However, duration of responses seem to be limited due to acquired drug resistance. The goal of this protocol is to study the sequential effects of BRAF and MEK inhibition on skin, blood and tumour biomarkers and to study the correlation between biomarkers and response to treatment and intrapatient toxicity. Approximately 54 eligible subjects will be randomised in the ratio of 1:1:1 to one of the three treatment arms.
Interventions
DRUGDabrafenib
Dabrafenib will be provided as 50 mg and 75 mg capsules.
DRUGTrametinib
Trametinib study medication will be provided as 0.5 mg and 2.0 mg tablets.
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participant with signed written informed consent; * Participants of age \>=18 years; * Participants with histologically confirmed cutaneous melanoma that is either Stage IIIc (unresectable) or Stage IV (metastatic) (according to American Joint Committee on Cancer \[AJCC\] staging 7th edition). * BRAF (proto-oncogene B-Raf) V600E/K mutation-positive confirmed by a local laboratory. * Accessible melanoma tumours for biopsies (locally advanced primary melanoma or metastases) * Measurable disease according to Response Evaluation Criteria in Solid Tumours (RECIST 1.1) on not biopsied lesions. * All prior anti-cancer treatment-related toxicities (except alopecia) must be \<= Grade 1 according to the Common Terminology Criteria for Adverse Events version 4 (CTCAE version 4.0) at the time of randomisation. * Able to swallow and retain orally administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels. * Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to randomisation and agree to use effective contraception, throughout the treatment period, and for 4 months after the last dose of study treatment. * Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1. * Adequate baseline organ function as defined : absolute neutrophil count \>= 1.2 × 109/Liters (L); Haemoglobin \>= 9 grams(g)/Deciliter (dL); Platelet count \>= 75 x 109/L; prothrombin time(PT)/ international normalized ratio (INR) and partial thromboplastin time (PTT) \<= 1.5 x Upper limit of normal (ULN); Albumin \>= 2.5 g/dL; Total bilirubin- \<= 1.5 x ULN; aspartate aminotransferase(AST) and alanine transaminase (ALT) \<= 2.5 x ULN; Calculated creatinine clearance \>=50 mL/min; Left Ventricular Ejection fraction (LVEF) \>= Lower limit of normal (LLN) by Echocardiogram (ECHO)
Exclusion criteria
* Prior treatment with a BRAF or MEK inhibitor * Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity, biologic therapy, or immunotherapy within 21 days prior to randomisation and/or daily or weekly chemotherapy without the potential for delayed toxicity within 14 days prior to randomisation. * Taken an investigational drug within 28 days or 5 half-lives (minimum 14 days), whichever is shorter, prior to randomisation * Current use of a prohibited medication. * Refusal of tumour and skin biopsies. * History of another malignancy. * Any serious and/or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), psychiatric disorders, or other conditions that could interfere with the participant's safety, obtaining informed consent, or compliance with study procedures. * Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection (with the exception of chronic or cleared HBV and HCV infection which will be allowed). * A history of glucose-6-phosphate dehydrogenase (G6PD) deficiency. * Brain metastases are excluded unless: All known lesions were previously treated with surgery or stereotactic surgery (whole-brain radiation is not allowed unless given after definitive treatment with surgery or stereotactic surgery), OR Brain lesion(s), if still present, must be confirmed stable (i.e., no increase in lesion size) for \>= 12 weeks prior to randomisation (stability must be confirmed with two consecutive magnetic resonance image (MRI) or computed tomography (CT) scans with contrast, AND Asymptomatic with no corticosteroid requirements for \>= 4 weeks prior to randomisation, AND No enzyme inducing anticonvulsants for \>= 4 weeks prior to randomisation. * A history or evidence of cardiovascular risk including any of the following: LVEF \< LLN; A QT interval corrected for heart rate using the Bazett's formula (QTcB) \>= 480 milliseconds (msec); A history or evidence of current clinically significant uncontrolled arrhythmias; Exception: Participants with atrial fibrillation controlled for \> 30 days prior to randomisation are eligible; A history (within 6 months prior to randomisation) of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty; A history or evidence of current \>= Class II congestive heart failure as defined by the New York Heart Association (NYHA) guidelines; Treatment refractory hypertension defined as a blood pressure of systolic \> 140 millimetres of mercury (mmHg) and/or diastolic \> 90 mmHg which cannot be controlled by anti-hypertensive therapy; Participants with intra-cardiac defibrillators or permanent pacemakers; Known cardiac metastases; Abnormal cardiac valve morphology (\>=grade 2) documented by echocardiogram (Participants with grade 1 abnormalities \[i.e., mild regurgitation/stenosis\] can be entered on study). Participants with moderate valvular thickening should not be entered on study. * A history or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR) including: Presence of predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled hypertension, uncontrolled diabetes mellitus, or a history of hyperviscosity or hypercoagulability syndromes); or Visible retinal pathology as assessed by ophthalmic examination that is considered a risk factor for RVO or CSR such as: Evidence of new optic disc cupping; Evidence of new visual field defects on automated perimetry; Intraocular pressure \>21 mmHg as measured by tonography. * Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO). * Pregnant or lactating females * Interstitial lung disease or pneumonitis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Percentage Change From Baseline in Extracellular Signal-regulated Kinase (ERK) Phosphorylation (p-ERK) H Score From Week 0 to Week 2 | Baseline (Week 0) and up to 2 weeks | 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. |
| Number of Participants With Percentage Change in p-ERK H Score From Week 8 to Week 10 | Week 8 and up to 10 weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Clinically Significant Abnormal Findings Undergoing Physical Examinations | Up to 3.2 years | 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. |
| Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | Baseline and up to 3.2 years | 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. |
| Number of Participants With Abnormal Electrocardiograms (ECG) Findings | Up to 3.2 years | 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. |
| Number of Participants With Absolute Change in Left Ventricular Ejection Fraction From Baseline | Baseline and up to 3.2 years | 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. |
| Number of Participants With Change in Clinical Chemistry Parameters From Baseline | Baseline and up to 3.2 years | 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). |
| Number of Participants With Overall Response Rate (ORR) | Up to 3.2 years | 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. |
| Number of Participants With Incidence of Squamous Cell Carcinoma and Keratoacanthoma | Up to 3.2 years | 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. |
| Number of Participants With On-treatment Serious Adverse Events (SAEs) and Non-SAEs | Up to 3.2 years | 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. |
| Plasma Pharmacokinetic Concentration of Trametinib | 4 to 8 hours post-dose at Weeks 2, 8 and 10 | Blood samples were collected for pharmacokinetic analysis of trametinib at indicated time points. Pharmacokinetic analysis was performed using standard non-compartmental method. |
| Plasma Pharmacokinetic Concentration of Dabrafenib | 4 to 8 hours post-dose at Weeks 2, 8 and 10 | Blood samples were collected for pharmacokinetic analysis of Dabrafenib at indicated time points. Pharmacokinetic analysis was performed using standard non-compartmental method. |
| Number of Participants With Change in Hematology Parameters From Baseline | Baseline and up to 3.2 years | 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. |
| Number of Participants With Change in Vital Signs From Baseline | Baseline and up to 3.2 years | 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). |
Countries
France, Spain
Participant flow
Recruitment details
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.
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| Dabrafenib Followed by Combination Therapy Eligible participants received dabrafenib 150 milligrams (mg) twice a day (BID) continuously during 8 weeks of monotherapy treatment followed by the combination of trametinib 2 mg once daily with dabrafenib 150 mg BID until disease progression, death or unacceptable toxicity. | 16 |
| Trametinib Followed by Combination Therapy Eligible participants received trametinib 2 mg per day continuously during 8 weeks of monotherapy treatment followed by the combination of trametinib 2 mg once daily with dabrafenib 150 mg BID until disease progression, death or unacceptable toxicity. | 16 |
| Combination Therapy Eligible participants received trametinib 2 mg per day plus dabrafenib 150 mg BID continuously until disease progression, death or unacceptable toxicity. | 16 |
| Total | 48 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 6 | 4 |
| Overall Study | Other (Study Closed/Terminated) | 5 | 3 | 4 |
| Overall Study | Physician Decision | 2 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | Dabrafenib Followed by Combination Therapy | Trametinib Followed by Combination Therapy | Combination Therapy | Total |
|---|---|---|---|---|
| Age, Continuous | 56.6 Years STANDARD_DEVIATION 16.43 | 56.5 Years STANDARD_DEVIATION 11.77 | 58.9 Years STANDARD_DEVIATION 13.55 | 57.4 Years STANDARD_DEVIATION 13.79 |
| Race/Ethnicity, Customized Asian-South East Asian Heritage | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White - White/Caucasian/European | 16 Participants | 15 Participants | 16 Participants | 47 Participants |
| Sex: Female, Male Female | 7 Participants | 8 Participants | 6 Participants | 21 Participants |
| Sex: Female, Male Male | 9 Participants | 8 Participants | 10 Participants | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 16 | 0 / 16 | 2 / 16 |
| other Total, other adverse events | 16 / 16 | 16 / 16 | 15 / 16 |
| serious Total, serious adverse events | 8 / 16 | 7 / 16 | 4 / 16 |
Outcome results
Primary
Number of Participants With Percentage Change From Baseline in Extracellular Signal-regulated Kinase (ERK) Phosphorylation (p-ERK) H Score From Week 0 to Week 2
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.
Time frame: Baseline (Week 0) and up to 2 weeks
Population: Biomarker Population. Only those participants with data available at specific time point were analyzed.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Combination Therapy | Number of Participants With Percentage Change From Baseline in Extracellular Signal-regulated Kinase (ERK) Phosphorylation (p-ERK) H Score From Week 0 to Week 2 | Any Increase or No Changes | 2 Participants |
| Combination Therapy | Number of Participants With Percentage Change From Baseline in Extracellular Signal-regulated Kinase (ERK) Phosphorylation (p-ERK) H Score From Week 0 to Week 2 | Any Decrease up to 80 percent | 1 Participants |
| Combination Therapy | Number of Participants With Percentage Change From Baseline in Extracellular Signal-regulated Kinase (ERK) Phosphorylation (p-ERK) H Score From Week 0 to Week 2 | Any Decrease > 80 percent | 2 Participants |
Primary
Number of Participants With Percentage Change in p-ERK H Score From Week 8 to Week 10
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.
Time frame: Week 8 and up to 10 weeks
Population: Biomarker Population. Only those participants with data available at specific time point were analyzed.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Combination Therapy | Number of Participants With Percentage Change in p-ERK H Score From Week 8 to Week 10 | Any Increase or No Changes | 1 Participants |
| Combination Therapy | Number of Participants With Percentage Change in p-ERK H Score From Week 8 to Week 10 | Any Decrease up to 80 percent | 0 Participants |
| Combination Therapy | Number of Participants With Percentage Change in p-ERK H Score From Week 8 to Week 10 | Any Decrease > 80 percent | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Percentage Change in p-ERK H Score From Week 8 to Week 10 | Any Increase or No Changes | 1 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Percentage Change in p-ERK H Score From Week 8 to Week 10 | Any Decrease up to 80 percent | 1 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Percentage Change in p-ERK H Score From Week 8 to Week 10 | Any Decrease > 80 percent | 1 Participants |
Secondary
Number of Participants With Abnormal Electrocardiograms (ECG) Findings
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.
Time frame: Up to 3.2 years
Population: Safety Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Combination Therapy | Number of Participants With Abnormal Electrocardiograms (ECG) Findings | Abnormal - Not Clinically Significant | 9 Participants |
| Combination Therapy | Number of Participants With Abnormal Electrocardiograms (ECG) Findings | Abnormal - Clinically Significant | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Abnormal Electrocardiograms (ECG) Findings | Abnormal - Not Clinically Significant | 10 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Abnormal Electrocardiograms (ECG) Findings | Abnormal - Clinically Significant | 1 Participants |
| Combination Therapy | Number of Participants With Abnormal Electrocardiograms (ECG) Findings | Abnormal - Not Clinically Significant | 9 Participants |
| Combination Therapy | Number of Participants With Abnormal Electrocardiograms (ECG) Findings | Abnormal - Clinically Significant | 0 Participants |
Secondary
Number of Participants With Absolute Change in Left Ventricular Ejection Fraction From Baseline
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.
Time frame: Baseline and up to 3.2 years
Population: Safety Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Combination Therapy | Number of Participants With Absolute Change in Left Ventricular Ejection Fraction From Baseline | >=10 Decrease And >= Lower limit of Normal (Lln) | 1 Participants |
| Combination Therapy | Number of Participants With Absolute Change in Left Ventricular Ejection Fraction From Baseline | >0-<10 Decrease | 4 Participants |
| Combination Therapy | Number of Participants With Absolute Change in Left Ventricular Ejection Fraction From Baseline | No Change Or Any Increase | 11 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Absolute Change in Left Ventricular Ejection Fraction From Baseline | >=10 Decrease And >= Lower limit of Normal (Lln) | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Absolute Change in Left Ventricular Ejection Fraction From Baseline | No Change Or Any Increase | 14 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Absolute Change in Left Ventricular Ejection Fraction From Baseline | >0-<10 Decrease | 2 Participants |
| Combination Therapy | Number of Participants With Absolute Change in Left Ventricular Ejection Fraction From Baseline | >0-<10 Decrease | 3 Participants |
| Combination Therapy | Number of Participants With Absolute Change in Left Ventricular Ejection Fraction From Baseline | No Change Or Any Increase | 11 Participants |
| Combination Therapy | Number of Participants With Absolute Change in Left Ventricular Ejection Fraction From Baseline | >=10 Decrease And >= Lower limit of Normal (Lln) | 2 Participants |
Secondary
Number of Participants With Change in Clinical Chemistry Parameters From Baseline
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).
Time frame: Baseline and up to 3.2 years
Population: Safety Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | Hyponatremia; n=16,16,16 | 7 Participants |
| Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | Direct bilirubin; n=4,6,3 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | ALT; n=16,16,16 | 3 Participants |
| Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | Hypokalemia; n=16,16,16 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | GCT; n=16,16,16 | 6 Participants |
| Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | AST; n=16,16,16 | 8 Participants |
| Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | Hypocalcemia; n=16,16,16 | 7 Participants |
| Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | Hypercalcemia; n=16,16,16 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | CRTCE; n=5,2,5 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | Hypernatremia; n=16,16,16 | 3 Participants |
| Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | Hyperkalemia; n=16,16,16 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | Protein; n=16,16,16 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | Bilirubin; n=16,16,16 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | Urea; n=15,15,16 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | Phosphate; n=16,16,16 | 10 Participants |
| Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | CRP;n=12,12,13 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | Alkaline phosphatase; n=16,16,16 | 5 Participants |
| Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | LDH; 16,16,15 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | Creatinine; n=16,16,16 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | Albumin; n=16,16,16 | 2 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | Protein; n=16,16,16 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | ALT; n=16,16,16 | 13 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | Albumin; n=16,16,16 | 5 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | Alkaline phosphatase; n=16,16,16 | 10 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | AST; n=16,16,16 | 15 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | Bilirubin; n=16,16,16 | 2 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | CRP;n=12,12,13 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | Creatinine; n=16,16,16 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | Direct bilirubin; n=4,6,3 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | GCT; n=16,16,16 | 12 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | Hypercalcemia; n=16,16,16 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | Hyperkalemia; n=16,16,16 | 4 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | Hypernatremia; n=16,16,16 | 4 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | Hypocalcemia; n=16,16,16 | 7 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | Hypokalemia; n=16,16,16 | 4 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | Hyponatremia; n=16,16,16 | 7 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | LDH; 16,16,15 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | Phosphate; n=16,16,16 | 6 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | Urea; n=15,15,16 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | CRTCE; n=5,2,5 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | Albumin; n=16,16,16 | 2 Participants |
| Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | Hypokalemia; n=16,16,16 | 3 Participants |
| Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | Creatinine; n=16,16,16 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | CRTCE; n=5,2,5 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | Hyponatremia; n=16,16,16 | 5 Participants |
| Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | CRP;n=12,12,13 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | Urea; n=15,15,16 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | LDH; 16,16,15 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | Bilirubin; n=16,16,16 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | ALT; n=16,16,16 | 9 Participants |
| Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | Phosphate; n=16,16,16 | 4 Participants |
| Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | AST; n=16,16,16 | 12 Participants |
| Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | Hyperkalemia; n=16,16,16 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | Hypercalcemia; n=16,16,16 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | Alkaline phosphatase; n=16,16,16 | 4 Participants |
| Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | Hypernatremia; n=16,16,16 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | GCT; n=16,16,16 | 5 Participants |
| Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | Protein; n=16,16,16 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | Hypocalcemia; n=16,16,16 | 4 Participants |
| Combination Therapy | Number of Participants With Change in Clinical Chemistry Parameters From Baseline | Direct bilirubin; n=4,6,3 | 0 Participants |
Secondary
Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline
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.
Time frame: Baseline and up to 3.2 years
Population: Safety Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 0 to 3 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 3 to 1 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 1 to 4-5 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 4-5 to 4-5 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 0 to 0 | 5 Participants |
| Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 2 to 0 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 4-5 to 1 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 3 to 0 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 2 to 1 | 2 Participants |
| Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 0 to 4-5 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 2 to 4-5 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 2 to 2 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 4-5 to 3 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 2 to 3 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 4-5 to 0 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 1 to 0 | 6 Participants |
| Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 0 to 2 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 3 to 4-5 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 1 to 1 | 3 Participants |
| Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 0 to 1 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 3 to 3 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 1 to 2 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 4-5 to 2 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 3 to 2 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 1 to 3 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 3 to 0 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 0 to 0 | 5 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 0 to 1 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 0 to 2 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 0 to 3 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 0 to 4-5 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 1 to 0 | 10 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 1 to 1 | 1 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 1 to 2 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 1 to 3 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 1 to 4-5 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 2 to 0 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 2 to 1 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 2 to 2 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 2 to 3 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 2 to 4-5 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 3 to 1 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 3 to 2 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 3 to 3 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 3 to 4-5 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 4-5 to 0 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 4-5 to 1 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 4-5 to 2 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 4-5 to 3 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 4-5 to 4-5 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 3 to 1 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 1 to 2 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 0 to 0 | 6 Participants |
| Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 3 to 2 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 1 to 1 | 2 Participants |
| Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 4-5 to 2 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 3 to 3 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 1 to 0 | 5 Participants |
| Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 0 to 1 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 3 to 4-5 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 0 to 4-5 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 4-5 to 4-5 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 4-5 to 0 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 0 to 3 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 2 to 2 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 4-5 to 3 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 2 to 3 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 2 to 1 | 2 Participants |
| Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 4-5 to 1 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 2 to 4-5 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 2 to 0 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 1 to 4-5 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 3 to 0 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 1 to 3 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline | 0 to 2 | 0 Participants |
Secondary
Number of Participants With Change in Hematology Parameters From Baseline
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.
Time frame: Baseline and up to 3.2 years
Population: Safety Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Combination Therapy | Number of Participants With Change in Hematology Parameters From Baseline | Leukocytes | 5 Participants |
| Combination Therapy | Number of Participants With Change in Hematology Parameters From Baseline | Lymphocytosis | 2 Participants |
| Combination Therapy | Number of Participants With Change in Hematology Parameters From Baseline | Neutrophils | 6 Participants |
| Combination Therapy | Number of Participants With Change in Hematology Parameters From Baseline | Monocytes | 0 Participants |
| Combination Therapy | Number of Participants With Change in Hematology Parameters From Baseline | Basophils | 0 Participants |
| Combination Therapy | Number of Participants With Change in Hematology Parameters From Baseline | Lymphocytopenia | 8 Participants |
| Combination Therapy | Number of Participants With Change in Hematology Parameters From Baseline | Hemoglobin | 4 Participants |
| Combination Therapy | Number of Participants With Change in Hematology Parameters From Baseline | Eosinophils | 0 Participants |
| Combination Therapy | Number of Participants With Change in Hematology Parameters From Baseline | Platelets | 2 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Hematology Parameters From Baseline | Monocytes | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Hematology Parameters From Baseline | Basophils | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Hematology Parameters From Baseline | Eosinophils | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Hematology Parameters From Baseline | Hemoglobin | 6 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Hematology Parameters From Baseline | Leukocytes | 9 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Hematology Parameters From Baseline | Neutrophils | 9 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Hematology Parameters From Baseline | Platelets | 5 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Hematology Parameters From Baseline | Lymphocytopenia | 6 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Hematology Parameters From Baseline | Lymphocytosis | 0 Participants |
| Combination Therapy | Number of Participants With Change in Hematology Parameters From Baseline | Hemoglobin | 4 Participants |
| Combination Therapy | Number of Participants With Change in Hematology Parameters From Baseline | Basophils | 0 Participants |
| Combination Therapy | Number of Participants With Change in Hematology Parameters From Baseline | Platelets | 3 Participants |
| Combination Therapy | Number of Participants With Change in Hematology Parameters From Baseline | Eosinophils | 0 Participants |
| Combination Therapy | Number of Participants With Change in Hematology Parameters From Baseline | Lymphocytosis | 0 Participants |
| Combination Therapy | Number of Participants With Change in Hematology Parameters From Baseline | Monocytes | 0 Participants |
| Combination Therapy | Number of Participants With Change in Hematology Parameters From Baseline | Leukocytes | 10 Participants |
| Combination Therapy | Number of Participants With Change in Hematology Parameters From Baseline | Lymphocytopenia | 6 Participants |
| Combination Therapy | Number of Participants With Change in Hematology Parameters From Baseline | Neutrophils | 9 Participants |
Secondary
Number of Participants With Change in Vital Signs From Baseline
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).
Time frame: Baseline and up to 3.2 years
Population: Safety Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 64; Increase to >100; n=3,3,3 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 16; Any grade increase; n=14,16,13 | 4 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 80; Any grade increase; n=3, 1, 2 | 2 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 68; Decrease to <60; n=4,2,2 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 68; Any grade increase; n=4,2, 2 | 2 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 76; Any grade increase; n=4, 1, 2 | 2 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 68; Increase to >100; n=4,2,2 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 72; Decrease to <60; n=3,2,2 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 12; Increase to >100; n=16,16,13 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 72; Any grade increase; n=3,2, 2 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 72; Increase to >100; n=3,2,2 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 112; Any grade increase; n=2,0,0 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 68; Any grade increase; n=4,2, 2 | 2 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 76; Decrease to <60; n=4,1,2 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 64; Any grade increase; n=3,3, 3 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 64; Any grade increase; n=3, 3, 3 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 76; Increase to >100; n=4,1,2 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 16; Decrease to <60; n=14,16,13 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 96; Any grade increase; n=3, 1,1 | 2 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 80; Decrease to <60; n=3,1,2 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 32; Any grade increase; n=7,11, 8 | 2 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 44; Any grade increase; n=5, 5, 4 | 2 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 80; Increase to >100; n=3,1,2 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 60; Any grade increase; n=3,2,4 | 2 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 40; Any grade increase; n=6,11, 7 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 84; Decrease to <60; n=3,1,1 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 16; Increase to >100; n=14,16,13 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 12; Any grade increase; n=16,16,13 | 3 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 84; Increase to >100; n=3,1,1 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 36; Any grade increase; n=5, 11, 8 | 3 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 8; Any grade increase; n=16,16,14 | 3 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 88; Decrease to <60; n=3,1,1 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 56; Any grade increase; n=4,3,4 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 4; Any grade increase; n=15,16,16 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 88; Increase to >100; n=3,1,1 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 20; Decrease to <60; n=11,15,13 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 124; Increase to >100; n=1, 0,0 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 92; Decrease to <60; n=3,1,1 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 52; Increase to >100; n=4,3,4 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 124; Decrease to <60; n=1, 0,0 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 92; Increase to >100; n=3,1,1 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 124; Any grade increase; n=1,0,0 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 120; Increase to >100; n=1, 0,0 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 96; Decrease to <60; n=3,1,1 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 52; Any grade increase; n=4,3,4 | 2 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 120; Decrease to <60; n=1, 0,0 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 96; Increase to >100; n=3,1,1 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 48; Any grade increase; n=5, 4,4 | 2 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 116; Increase to >100; n=1, 0,0 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 100; Decrease to <60; n=3,1,1 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 108; Any grade increase; n=2,0,1 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 116; Decrease to <60; n=1, 0,0 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 100; Increase to >100; n=3,1,1 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 44; Any grade increase; n=5, 5,4 | 4 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 112; Increase to >100; n=2, 0,0 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 104; Decrease to <60; n=3,1,1 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 20; Increase to >100; n=11,15,13 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 112; Decrease to <60; n=2,0,0 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 104; Increase to >100; n=3,1,1 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 48; Any grade increase; n=5,4, 4 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 108; Increase to >100; n=2,0,1 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 108; Decrease to <60; n=2,0,1 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 40; Any grade increase; n=6, 11,7 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 24; Decrease to <60; n=12,14,13 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 20; Any grade increase; n=11,15, 13 | 2 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 36; Any grade increase; n=5, 11,8 | 2 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 24; Increase to >100; n=12,14,13 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 104; Any grade increase; n=3,1,1 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 32; Any grade increase; n=7, 11,8 | 2 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 28; Decrease to <60; n=8,12,7 | 2 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 52; Any grade increase; n=4,3, 4 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 28; Any grade increase; n=8, 12,7 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 28; Increase to >100; n=8,12,7 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 100; Any grade increase; n=3,1,1 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 24; Any grade increase; n=12, 14,13 | 3 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 32; Decrease to <60; n=7,11,8 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 92; Any grade increase; n=3, 1,1 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 20; Any grade increase; n=11, 15,13 | 4 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 32; Increase to >100; n=7,11,8 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 60; Any grade increase; n=3, 2, 4 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 36; Decrease to <60; n=5,11,8 | 2 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 120; Any grade increase; n=1,0,0 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 16; Any grade increase; n=14, 16,13 | 5 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 36; Increase to >100; n=5,11,8 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 88; Any grade increase; n=3,1,1 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 12; Any grade increase; n=16, 16, 13 | 4 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 40; Decrease to <60; n=6,11,7 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 4; Decrease to <60; n=15,16,16 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 8; Any grade increase; n=16, 16,14 | 4 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 40; Increase to >100; n=6,11,7 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 24; Any grade increase; n=12, 14,13 | 2 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 4; Any grade increase; n=15, 16, 16 | 2 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 44; Decrease to <60; n=5,5,4 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 84; Any grade increase; n=3,1,1 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 124; Any grade increase; n=1, 0, 0 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 44; Increase to >100; n=5,5,4 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 4; Increase to >100; n=15,16,16 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 120; Any grade increase; n=1, 0, 0 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 48; Decrease to <60; n=5,4,4 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 56; Any grade increase; n=4, 3, 4 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 116; Any grade increase; n=1, 0, 0 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 48; Increase to >100; n=5,4,4 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 80; Any grade increase; n=3,1,2 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 112; Any grade increase; n=2, 0, 0 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 52; Decrease to <60; n=4,3,4 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 8; Decrease to <60; n=16,16,14 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 108; Any grade increase; n=2,0, 1 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 116; Any grade increase; n=1,0,0 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 104; Any grade increase; n=3, 1, 1 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 56; Decrease to <60; n=4,3,4 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 76; Any grade increase; n=4,1,2 | 2 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 100; Any grade increase; n=3, 1, 1 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 56; Increase to >100; n=4,3,4 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 8; Increase to >100; n=16,16,14 | 2 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 96; Any grade increase; n=3,1, 1 | 2 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 60; Decrease to <60; n=3,3,4 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 28; Any grade increase; n=8, 12,7 | 2 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 92; Any grade increase; n=3, 1, 1 | 2 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 60; Increase to >100; n=3,3,4 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 72; Any grade increase; n=3,2,2 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 88; Any grade increase; n=3, 1,1 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 64; Decrease to <60; n=3,3,3 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 12; Decrease to <60; n=16,16,13 | 2 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 84; Any grade increase; n=3, 1,1 | 2 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 52; Any grade increase; n=4,3,4 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 16; Any grade increase; n=14,16,13 | 3 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 20; Any grade increase; n=11,15, 13 | 3 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 24; Any grade increase; n=12, 14,13 | 3 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 28; Any grade increase; n=8, 12,7 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 32; Any grade increase; n=7,11, 8 | 3 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 44; Any grade increase; n=5, 5, 4 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 48; Any grade increase; n=5,4, 4 | 1 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 92; Any grade increase; n=3, 1,1 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 52; Any grade increase; n=4,3, 4 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 4; Decrease to <60; n=15,16,16 | 3 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 4; Increase to >100; n=15,16,16 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 8; Decrease to <60; n=16,16,14 | 2 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 8; Increase to >100; n=16,16,14 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 12; Decrease to <60; n=16,16,13 | 1 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 12; Increase to >100; n=16,16,13 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 16; Decrease to <60; n=14,16,13 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 16; Increase to >100; n=14,16,13 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 68; Increase to >100; n=4,2,2 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 20; Decrease to <60; n=11,15,13 | 1 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 20; Increase to >100; n=11,15,13 | 1 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 24; Decrease to <60; n=12,14,13 | 2 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 24; Increase to >100; n=12,14,13 | 2 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 28; Decrease to <60; n=8,12,7 | 2 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 28; Increase to >100; n=8,12,7 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 32; Decrease to <60; n=7,11,8 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 32; Increase to >100; n=7,11,8 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 36; Decrease to <60; n=5,11,8 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 36; Increase to >100; n=5,11,8 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 40; Decrease to <60; n=6,11,7 | 1 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 40; Increase to >100; n=6,11,7 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 44; Decrease to <60; n=5,5,4 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 44; Increase to >100; n=5,5,4 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 48; Decrease to <60; n=5,4,4 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 48; Increase to >100; n=5,4,4 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 52; Decrease to <60; n=4,3,4 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 52; Increase to >100; n=4,3,4 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 56; Decrease to <60; n=4,3,4 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 56; Increase to >100; n=4,3,4 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 60; Decrease to <60; n=3,3,4 | 1 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 60; Increase to >100; n=3,3,4 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 64; Decrease to <60; n=3,3,3 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 64; Increase to >100; n=3,3,3 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 68; Decrease to <60; n=4,2,2 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 72; Decrease to <60; n=3,2,2 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 72; Increase to >100; n=3,2,2 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 76; Decrease to <60; n=4,1,2 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 76; Increase to >100; n=4,1,2 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 80; Decrease to <60; n=3,1,2 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 80; Increase to >100; n=3,1,2 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 84; Decrease to <60; n=3,1,1 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 84; Increase to >100; n=3,1,1 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 88; Decrease to <60; n=3,1,1 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 88; Increase to >100; n=3,1,1 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 92; Decrease to <60; n=3,1,1 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 92; Increase to >100; n=3,1,1 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 96; Decrease to <60; n=3,1,1 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 96; Increase to >100; n=3,1,1 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 100; Decrease to <60; n=3,1,1 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 100; Increase to >100; n=3,1,1 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 104; Decrease to <60; n=3,1,1 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 104; Increase to >100; n=3,1,1 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 4; Any grade increase; n=15,16,16 | 8 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 8; Any grade increase; n=16,16,14 | 5 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 12; Any grade increase; n=16,16,13 | 5 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 36; Any grade increase; n=5, 11, 8 | 3 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 40; Any grade increase; n=6,11, 7 | 4 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 96; Any grade increase; n=3, 1,1 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 60; Any grade increase; n=3, 2, 4 | 1 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 64; Any grade increase; n=3, 3, 3 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 104; Any grade increase; n=3, 1, 1 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 68; Any grade increase; n=4,2, 2 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 72; Any grade increase; n=3,2, 2 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 76; Any grade increase; n=4, 1, 2 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 80; Any grade increase; n=3, 1, 2 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 84; Any grade increase; n=3, 1,1 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 88; Any grade increase; n=3, 1,1 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 92; Any grade increase; n=3, 1, 1 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 96; Any grade increase; n=3,1, 1 | 1 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 100; Any grade increase; n=3, 1, 1 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 4; Any grade increase; n=15, 16, 16 | 10 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 8; Any grade increase; n=16, 16,14 | 8 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 12; Any grade increase; n=16, 16, 13 | 4 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 16; Any grade increase; n=14, 16,13 | 5 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 20; Any grade increase; n=11, 15,13 | 5 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 24; Any grade increase; n=12, 14,13 | 3 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 28; Any grade increase; n=8, 12,7 | 2 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 32; Any grade increase; n=7, 11,8 | 3 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 36; Any grade increase; n=5, 11,8 | 1 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 40; Any grade increase; n=6, 11,7 | 1 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 44; Any grade increase; n=5, 5,4 | 1 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 48; Any grade increase; n=5, 4,4 | 1 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 88; Any grade increase; n=3,1,1 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 56; Any grade increase; n=4,3,4 | 1 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 60; Any grade increase; n=3,2,4 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 76; Any grade increase; n=4,1,2 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 64; Any grade increase; n=3,3, 3 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 68; Any grade increase; n=4,2, 2 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 72; Any grade increase; n=3,2,2 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 80; Any grade increase; n=3,1,2 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 84; Any grade increase; n=3,1,1 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 100; Any grade increase; n=3,1,1 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 104; Any grade increase; n=3,1,1 | 0 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 56; Any grade increase; n=4, 3, 4 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 12; Decrease to <60; n=16,16,13 | 2 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 76; Any grade increase; n=4, 1, 2 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 64; Increase to >100; n=3,3,3 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 24; Any grade increase; n=12, 14,13 | 2 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 80; Any grade increase; n=3, 1, 2 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 64; Decrease to <60; n=3,3,3 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 68; Any grade increase; n=4,2, 2 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 84; Any grade increase; n=3, 1,1 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 60; Increase to >100; n=3,3,4 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 8; Increase to >100; n=16,16,14 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 88; Any grade increase; n=3, 1,1 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 60; Decrease to <60; n=3,3,4 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 20; Any grade increase; n=11,15, 13 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 92; Any grade increase; n=3, 1, 1 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 56; Increase to >100; n=4,3,4 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 72; Any grade increase; n=3,2,2 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 96; Any grade increase; n=3,1, 1 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 56; Decrease to <60; n=4,3,4 | 3 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 8; Decrease to <60; n=16,16,14 | 2 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 100; Any grade increase; n=3, 1, 1 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 52; Increase to >100; n=4,3,4 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 104; Any grade increase; n=3, 1, 1 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 52; Decrease to <60; n=4,3,4 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 108; Any grade increase; n=2,0, 1 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 48; Increase to >100; n=5,4,4 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 48; Decrease to <60; n=5,4,4 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 44; Increase to >100; n=5,5,4 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 44; Decrease to <60; n=5,5,4 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 40; Increase to >100; n=6,11,7 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 76; Any grade increase; n=4,1,2 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 4; Any grade increase; n=15, 16, 16 | 5 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 40; Decrease to <60; n=6,11,7 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 4; Increase to >100; n=15,16,16 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 8; Any grade increase; n=16, 16,14 | 3 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 36; Increase to >100; n=5,11,8 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 16; Any grade increase; n=14,16,13 | 2 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 12; Any grade increase; n=16, 16, 13 | 2 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 36; Decrease to <60; n=5,11,8 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 80; Any grade increase; n=3,1,2 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 16; Any grade increase; n=14, 16,13 | 3 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 32; Decrease to <60; n=7,11,8 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 4; Decrease to <60; n=15,16,16 | 3 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 20; Any grade increase; n=11, 15,13 | 2 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 28; Increase to >100; n=8,12,7 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 32; Any grade increase; n=7,11, 8 | 2 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 24; Any grade increase; n=12, 14,13 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 28; Decrease to <60; n=8,12,7 | 2 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 84; Any grade increase; n=3,1,1 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 28; Any grade increase; n=8, 12,7 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 24; Increase to >100; n=12,14,13 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 52; Any grade increase; n=4,3, 4 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 32; Any grade increase; n=7, 11,8 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 24; Decrease to <60; n=12,14,13 | 2 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 88; Any grade increase; n=3,1,1 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 36; Any grade increase; n=5, 11,8 | 2 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 20; Increase to >100; n=11,15,13 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 12; Any grade increase; n=16,16,13 | 2 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 40; Any grade increase; n=6, 11,7 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 20; Decrease to <60; n=11,15,13 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 100; Any grade increase; n=3,1,1 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 44; Any grade increase; n=5, 5,4 | 2 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 32; Increase to >100; n=7,11,8 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 48; Any grade increase; n=5,4, 4 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 48; Any grade increase; n=5, 4,4 | 2 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 68; Increase to >100; n=4,2,2 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 56; Any grade increase; n=4, 3, 4 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 108; Decrease to <60; n=2,0,1 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 104; Increase to >100; n=3,1,1 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 108; Increase to >100; n=2,0,1 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 104; Decrease to <60; n=3,1,1 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 100; Increase to >100; n=3,1,1 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 100; Decrease to <60; n=3,1,1 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 96; Increase to >100; n=3,1,1 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 96; Decrease to <60; n=3,1,1 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 92; Increase to >100; n=3,1,1 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 92; Decrease to <60; n=3,1,1 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 88; Increase to >100; n=3,1,1 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 88; Decrease to <60; n=3,1,1 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 52; Any grade increase; n=4,3,4 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 4; Any grade increase; n=15,16,16 | 4 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 84; Increase to >100; n=3,1,1 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 16; Increase to >100; n=14,16,13 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 8; Any grade increase; n=16,16,14 | 4 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 84; Decrease to <60; n=3,1,1 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 104; Any grade increase; n=3,1,1 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 56; Any grade increase; n=4,3,4 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 36; Any grade increase; n=5, 11, 8 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 80; Increase to >100; n=3,1,2 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 16; Decrease to <60; n=14,16,13 | 2 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 40; Any grade increase; n=6,11, 7 | 2 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 80; Decrease to <60; n=3,1,2 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 92; Any grade increase; n=3, 1,1 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 76; Increase to >100; n=4,1,2 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 44; Any grade increase; n=5, 5, 4 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 96; Any grade increase; n=3, 1,1 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 60; Any grade increase; n=3,2,4 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 60; Any grade increase; n=3, 2, 4 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 76; Decrease to <60; n=4,1,2 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 12; Increase to >100; n=16,16,13 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 64; Any grade increase; n=3, 3, 3 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 108; Any grade increase; n=2,0,1 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 72; Increase to >100; n=3,2,2 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 28; Any grade increase; n=8, 12,7 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 68; Any grade increase; n=4,2, 2 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 72; Decrease to <60; n=3,2,2 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | DBP; Week 64; Any grade increase; n=3,3, 3 | 1 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | SBP; Week 72; Any grade increase; n=3,2, 2 | 0 Participants |
| Combination Therapy | Number of Participants With Change in Vital Signs From Baseline | HR; Week 68; Decrease to <60; n=4,2,2 | 2 Participants |
Secondary
Number of Participants With Clinically Significant Abnormal Findings Undergoing Physical Examinations
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.
Time frame: Up to 3.2 years
Population: Safety Population. This analysis was planned but data was not captured in the database.
Secondary
Number of Participants With Incidence of Squamous Cell Carcinoma and Keratoacanthoma
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.
Time frame: Up to 3.2 years
Population: Safety Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Combination Therapy | Number of Participants With Incidence of Squamous Cell Carcinoma and Keratoacanthoma | 1 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Incidence of Squamous Cell Carcinoma and Keratoacanthoma | 0 Participants |
| Combination Therapy | Number of Participants With Incidence of Squamous Cell Carcinoma and Keratoacanthoma | 0 Participants |
Secondary
Number of Participants With On-treatment Serious Adverse Events (SAEs) and Non-SAEs
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.
Time frame: Up to 3.2 years
Population: Safety Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Combination Therapy | Number of Participants With On-treatment Serious Adverse Events (SAEs) and Non-SAEs | Any Non-SAE | 16 Participants |
| Combination Therapy | Number of Participants With On-treatment Serious Adverse Events (SAEs) and Non-SAEs | Any SAE | 8 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With On-treatment Serious Adverse Events (SAEs) and Non-SAEs | Any Non-SAE | 16 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With On-treatment Serious Adverse Events (SAEs) and Non-SAEs | Any SAE | 7 Participants |
| Combination Therapy | Number of Participants With On-treatment Serious Adverse Events (SAEs) and Non-SAEs | Any Non-SAE | 15 Participants |
| Combination Therapy | Number of Participants With On-treatment Serious Adverse Events (SAEs) and Non-SAEs | Any SAE | 4 Participants |
Secondary
Number of Participants With Overall Response Rate (ORR)
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.
Time frame: Up to 3.2 years
Population: Intent-to-Treat Population (ITT)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Combination Therapy | Number of Participants With Overall Response Rate (ORR) | 11 Participants |
| Trametinib Followed by Combination Therapy | Number of Participants With Overall Response Rate (ORR) | 13 Participants |
| Combination Therapy | Number of Participants With Overall Response Rate (ORR) | 11 Participants |
p-value: 195% CI: [0.224, 4.459]Cochran-Mantel-Haenszel
p-value: 0.421695% CI: [0.382, 10.166]Cochran-Mantel-Haenszel
Secondary
Plasma Pharmacokinetic Concentration of Dabrafenib
Blood samples were collected for pharmacokinetic analysis of Dabrafenib at indicated time points. Pharmacokinetic analysis was performed using standard non-compartmental method.
Time frame: 4 to 8 hours post-dose at Weeks 2, 8 and 10
Population: Biomarker Population. Only those participants with data available at specific time point were analyzed (represented by n=x in category titles).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Combination Therapy | Plasma Pharmacokinetic Concentration of Dabrafenib | WEEK 8 ; 4 to 8 HOURS POST-DOSE; n=12, 12, 10 | 259.1 Nanograms per milliliter | Standard Deviation 669.6 |
| Combination Therapy | Plasma Pharmacokinetic Concentration of Dabrafenib | WEEK 2 ; 4 to 8 HOURS POST-DOSE; n= 12, 14,13 | 219.7 Nanograms per milliliter | Standard Deviation 545.46 |
| Combination Therapy | Plasma Pharmacokinetic Concentration of Dabrafenib | WEEK 10 ; 4 to 8 HOURS POST-DOSE; n=13, 13, 11 | 92.6 Nanograms per milliliter | Standard Deviation 169.45 |
| Trametinib Followed by Combination Therapy | Plasma Pharmacokinetic Concentration of Dabrafenib | WEEK 8 ; 4 to 8 HOURS POST-DOSE; n=12, 12, 10 | 0.0 Nanograms per milliliter | Standard Deviation 0 |
| Trametinib Followed by Combination Therapy | Plasma Pharmacokinetic Concentration of Dabrafenib | WEEK 2 ; 4 to 8 HOURS POST-DOSE; n= 12, 14,13 | 0.0 Nanograms per milliliter | Standard Deviation 0 |
| Trametinib Followed by Combination Therapy | Plasma Pharmacokinetic Concentration of Dabrafenib | WEEK 10 ; 4 to 8 HOURS POST-DOSE; n=13, 13, 11 | 81.8 Nanograms per milliliter | Standard Deviation 168.16 |
| Combination Therapy | Plasma Pharmacokinetic Concentration of Dabrafenib | WEEK 2 ; 4 to 8 HOURS POST-DOSE; n= 12, 14,13 | 438.1 Nanograms per milliliter | Standard Deviation 487.26 |
| Combination Therapy | Plasma Pharmacokinetic Concentration of Dabrafenib | WEEK 10 ; 4 to 8 HOURS POST-DOSE; n=13, 13, 11 | 429.2 Nanograms per milliliter | Standard Deviation 735.69 |
| Combination Therapy | Plasma Pharmacokinetic Concentration of Dabrafenib | WEEK 8 ; 4 to 8 HOURS POST-DOSE; n=12, 12, 10 | 226.5 Nanograms per milliliter | Standard Deviation 236.37 |
Secondary
Plasma Pharmacokinetic Concentration of Trametinib
Blood samples were collected for pharmacokinetic analysis of trametinib at indicated time points. Pharmacokinetic analysis was performed using standard non-compartmental method.
Time frame: 4 to 8 hours post-dose at Weeks 2, 8 and 10
Population: Biomarker Population. Only those participants with data available at specific time point were analyzed (represented by n=x in category titles).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Combination Therapy | Plasma Pharmacokinetic Concentration of Trametinib | WEEK 8 ; 4 to 8 HOURS POST-DOSE; n=12, 12, 10 | 0.6 Nanograms per milliliter | Standard Deviation 2.06 |
| Combination Therapy | Plasma Pharmacokinetic Concentration of Trametinib | WEEK 2 ; 4 to 8 HOURS POST-DOSE; n= 12, 14,13 | 1.4 Nanograms per milliliter | Standard Deviation 4.99 |
| Combination Therapy | Plasma Pharmacokinetic Concentration of Trametinib | WEEK 10 ; 4 to 8 HOURS POST-DOSE; n=13, 13, 11 | 10.5 Nanograms per milliliter | Standard Deviation 5.33 |
| Trametinib Followed by Combination Therapy | Plasma Pharmacokinetic Concentration of Trametinib | WEEK 8 ; 4 to 8 HOURS POST-DOSE; n=12, 12, 10 | 12.9 Nanograms per milliliter | Standard Deviation 8.82 |
| Trametinib Followed by Combination Therapy | Plasma Pharmacokinetic Concentration of Trametinib | WEEK 2 ; 4 to 8 HOURS POST-DOSE; n= 12, 14,13 | 14.6 Nanograms per milliliter | Standard Deviation 5.15 |
| Trametinib Followed by Combination Therapy | Plasma Pharmacokinetic Concentration of Trametinib | WEEK 10 ; 4 to 8 HOURS POST-DOSE; n=13, 13, 11 | 8.8 Nanograms per milliliter | Standard Deviation 7.5 |
| Combination Therapy | Plasma Pharmacokinetic Concentration of Trametinib | WEEK 2 ; 4 to 8 HOURS POST-DOSE; n= 12, 14,13 | 16.3 Nanograms per milliliter | Standard Deviation 5.73 |
| Combination Therapy | Plasma Pharmacokinetic Concentration of Trametinib | WEEK 10 ; 4 to 8 HOURS POST-DOSE; n=13, 13, 11 | 14.7 Nanograms per milliliter | Standard Deviation 6.66 |
| Combination Therapy | Plasma Pharmacokinetic Concentration of Trametinib | WEEK 8 ; 4 to 8 HOURS POST-DOSE; n=12, 12, 10 | 13.8 Nanograms per milliliter | Standard Deviation 6.46 |