A Study of the Safety and Efficacy of Pembrolizumab (MK-3475) in Combination With Trametinib and Dabrafenib in Participants With Advanced Melanoma (MK-3475-022/KEYNOTE-022)

Melanoma Clinical Trial

Official title:

A Phase I/II Study to Assess the Safety and Efficacy of MK-3475 in Combination With Trametinib and Dabrafenib in Subjects With Advanced Melanoma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02130466
• Other study ID #: 3475-022
• Secondary ID: MK-3475-022KEYNO
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: May 29, 2014
• Est. completion date: July 14, 2021

Study information

• Verified date: June 2022
• Source: Merck Sharp & Dohme LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a 5-part dose-finding and preliminary efficacy study of pembrolizumab (Pembro) + dabrafenib (D) + trametinib (T) for participants with advanced melanoma and solid tumors. Parts 1 and 2 are open-label to find and confirm the maximum tolerated dose (MTD)/maximum administered dose (MAD) for Pembro+D+T. The primary hypothesis (Parts 1 and 2) is that Pembro+D+T is sufficiently well-tolerated to permit clinical investigation. Part 3 is a double-blind study of Pembro+D+T versus placebo+D+T. The primary study hypothesis (Part 3 only) is that the Pembro+D+T improves progression-free survival (PFS) compared with placebo+D+T. Part 4 is nonrandomized and open-label and is designed to evaluate the safety and tolerability and identify the MTD or MAD of Pembro+T in participants who have v-raf murine sarcoma viral oncogene homolog B1 [BRAF] mutation-negative (without V600 E or K) melanoma or solid tumors [irrespective of BRAF status]. The primary hypothesis (Part 4) is that Pembro+T is sufficiently well-tolerated to permit clinical investigation. Part 5 will confirm the dose(s) identified in Part 4 in participants BRAF wild type [without V600E or K] melanoma or solid tumors [irrespective of BRAF status] and will further evaluate the safety and preliminary efficacy (Objective Response Rate [ORR]) of Pembro+T in participants who have BRAF wild type [without V600E or K] melanoma or solid tumors [irrespective of BRAF status]. The primary hypotheses (Part 5) are that Pembro+T is sufficiently well-tolerated at the MTD/MAD to permit further clinical investigation and is effective in attaining objective responses based upon Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by Investigator review in participants who have melanoma without BRAF V600 E or K mutations. With Amendment 5 (21-Mar-2019), the Part 5 expansion cohort will not be pursued following the completion of Part 5 dose confirmation. Parts 1 and 2 of the study may also explore, if needed based on tolerability, the backup combinations of open-label Pembro+T (for BRAF mutation-negative participants) or Pembro+D (for BRAF mutation-positive participants). These will run concurrently with the Pembro+D+T arm.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 184
• Est. completion date: July 14, 2021
• Est. primary completion date: July 14, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion criteria:

• Histologically-confirmed diagnosis of advanced (unresectable Stage III) or metastatic (Stage IV) melanoma excluding mucosal, or ocular melanoma (or a histologically or cytologically-documented locally-advanced or metastatic solid malignancy in Parts 4 and 5)
• At least 1 measurable lesion as defined by RECIST 1.1 on imaging studies (computed tomography [CT] or magnetic resonance imaging [MRI])
• For solid tumors other than melanoma, (in Part 4 or 5 [dose confirmation only]), participants must have a malignancy that is incurable and has either: (a) failed prior standard therapy, (b) for which no standard therapy exists, or (c) standard therapy is not considered appropriate by the participants and treating physician. There is no limit to the number of prior treatment regimens, but prior treatment(s) should not include compounds targeting programmed cell death 1 (PD-1), programmed cell death ligand 1 (PD-L1), BRAF, or mitogen-activated protein kinase (MEK). Treatment must end at least 4 weeks prior to randomization
• BRAF mutation-positive (V600 E or K) melanoma for Parts 1, 2 and 3, or for Parts 1, 2, 4 and 5 only BRAF mutation-negative (wild type) melanoma with documented progression of =1 measurable lesion after prior therapy (if prior therapy was received). The inclusion criterion does not apply to participants with solid tumors in Parts 4 and 5 (dose confirmation only)
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
• Anticipated life expectancy of at least 3 months
• Able to swallow and retain oral medication and no clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels
• Adequate organ function
• Provide tissue for biomarker analysis from a newly or recently-obtained biopsy (within 90 days of Study Day 1) of a tumor lesion not previously irradiated
• Female participants of non-childbearing potential must be willing to use highly effective contraceptive measures from the Screening Visit (Visit 1) through 120 days after the last dose of study drug; male participants must agree to use an adequate method of contraception starting with the first dose of study drug through 120 days after the last dose of study drug
• Female participants of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study drug

Exclusion criteria:

• Currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of study drug
• Prior systemic therapy (for participants who are BRAF mutation-positive), or BRAF mutation-negative and has received >1 prior systemic therapy for metastatic melanoma
• Prior therapy with compounds targeting PD-1, PD-L1, BRAF, MEK or other molecules in the mitogen-activated protein kinase (MAPK) pathway
• BRAF mutation-positive and has received prior systemic therapy with ipilimumab or other anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) blocking antibodies. The BRAF exclusion criterion does not apply to participants with solid tumor in Parts 4 and 5 (dose confirmation only)
• Chemotherapy, radioactive, or biological cancer therapy within 4 weeks prior to the first dose of study drug, or not recovered from clinically significant adverse events due to cancer therapeutics administered more than 4 weeks prior to the first dose of study drug
• Expected to require any other form of systemic or localized antineoplastic therapy while in this study
• Has a known additional malignancy that is progressing or requires active treatment. Exceptions include early stage cancers (carcinoma in situ or stage 1) treated with curative intent, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, in situ cervical cancer, or in situ breast cancer that has undergone potentially curative therapy
• Active central nervous system (CNS) metastases and/or carcinomatous meningitis
• Active infection requiring systemic therapy
• Active autoimmune disease, or documented history of autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents
• Previous severe hypersensitivity reaction to treatment with another monoclonal antibody (mAb)
• On chronic systemic steroid therapy (>10 mg/day prednisone or equivalent) within 2 weeks prior to first dose of study drug or on any other form of immunosuppressive medication
• History or evidence of cardiovascular risk
• Uncorrectable electrolyte abnormalities, long QT syndrome or taking medications known to prolong the QT interval
• History of prior or current retinal vein occlusion (RVO)
• Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study drugs, their excipients, and/or dimethyl sulfoxide (DMSO)
• Has had an allogeneic tissue/solid organ transplant, prior stem cell or bone marrow transplant
• History of (non-infectious) pneumonitis that required steroids or current pneumonitis
• Human immunodeficiency virus (HIV)
• Hepatitis B or C
• Received a live vaccine within 30 days prior to first dose of study drug
• Pregnant or breastfeeding or expecting to conceive or father children from the Screening Visit (Visit 1) through 120 days after last dose of study drug

Related Conditions & MeSH terms

• Melanoma
• Solid Tumors

Intervention

Biological:
• Pembrolizumab
IV infusion

Drug:
• Dabrafenib
oral capsule
• Trametinib
oral tablet
• Placebo
IV infusion

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
Merck Sharp & Dohme LLC	Novartis Pharmaceuticals

References & Publications (2)

Ascierto PA, Ferrucci PF, Fisher R, Del Vecchio M, Atkinson V, Schmidt H, Schachter J, Queirolo P, Long GV, Di Giacomo AM, Svane IM, Lotem M, Bar-Sela G, Couture F, Mookerjee B, Ghori R, Ibrahim N, Moreno BH, Ribas A. Dabrafenib, trametinib and pembrolizu — View Citation

Ribas A, Lawrence D, Atkinson V, Agarwal S, Miller WH Jr, Carlino MS, Fisher R, Long GV, Hodi FS, Tsoi J, Grasso CS, Mookerjee B, Zhao Q, Ghori R, Moreno BH, Ibrahim N, Hamid O. Combined BRAF and MEK inhibition with PD-1 blockade immunotherapy in BRAF-mut — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Parts 1, 2, 4, and 5: Number of Participants Who Experienced Dose-limiting Toxicities (DLTs)	DLTs were graded using National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. Events were considered a DLT if occurred during the DLT evaluation period and met =1 of the following: significant hematologic toxicity; significant Grade =3 non-hematologic toxicity not previously identified or known to occur and cannot be controlled with routine supportive measures; drug-related toxicity that results in an interruption of any component of study therapy for >21 consecutive days and cannot be controlled =2 weeks from onset; any other Grade =2 non-hematological toxicity that is dose limiting with some exceptions; and liver chemistries meeting study stopping guidelines. The DLT evaluable population included all participants in Parts 1, 2, 4, and 5 who received =66% of planned treatments during the DLT observation period or discontinued treatment due to a DLT. Per protocol, DLT outcome analysis did not include Part 3.	Up to approximately 6 weeks
Primary	Part 2: Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Investigator in Participants Without BRAF V600 E or K Mutations	ORR was defined as the percentage of participants without BRAF V600 E or K mutation who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: divided into very good partial response [VGPR; >60% tumor reduction] and moderate partial response [MPR; >30-=60% tumor reduction]) per RECIST 1.1 as assessed by investigator. The percentage of participants who experienced a CR or PR based on RECIST 1.1 as assessed by investigator were reported.	Up to approximately 85 months
Primary	Part 5: ORR Per RECIST 1.1 as Assessed by Investigator in Participants Without BRAF V600 E or K Mutations or With Solid Tumors Irrespective of BRAF Status	ORR was defined as the percentage of participants without BRAF V600 E or K mutation who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: divided into very good partial response [VGPR; >60% tumor reduction] and moderate partial response [MPR; >30-=60% tumor reduction]) per RECIST 1.1 as assessed by investigator. The percentage of participants who experienced a CR or PR based on RECIST 1.1 as assessed by investigator were reported.	Up to approximately 85 months
Primary	Part 3: Progression-Free Survival (PFS) Per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations	PFS was defined as the time from randomization to the first documented disease progression (PD) or death due to any cause, whichever occurred first, based on RECIST 1.1 by investigator review. Per RECIST 1.1, PD is defined as =20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of =5 mm. The appearance of one or more new lesions was also considered PD. PFS was analyzed using the Kaplan-Meier method and was reported in months. Statistical analysis used a Cox regression model with treatment as a covariate and stratified by Eastern Cooperative Oncology Group performance status and Lactate Dehydrogenase.	Up to approximately 85 months
Primary	Parts 1, 2, 4, and 5: Number of Participants Who Experienced an Adverse Event (AE)	An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have a causal relationship with this treatment. An AE was any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the study drug, was also an AE. The number of participants who experienced an AE was reported. Per protocol, AE outcome analysis did not include Part 3.	Up to approximately 32 months
Primary	Parts 1, 2, 4, and 5: Number of Participants Who Discontinued Study Treatment Due to an AE	An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily had to have a causal relationship with this treatment. An AE was any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the study drug, was also an AE. The number of participants who discontinued study treatment due to an AE was reported. Per protocol, discontinuation outcome analysis did not include Part 3.	Up to approximately 29 months
Secondary	Part 1: ORR Per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations	ORR was defined as the percentage of participants who had a CR (Disappearance of all target lesions) or a PR (divided into very good partial response [VGPR; >60% tumor reduction] and moderate partial response [MPR; >30-=60% tumor reduction]) per RECIST 1.1 as assessed by investigator. The percentage of participants who experienced a CR or PR as assessed by the investigator was presented.	Up to approximately 85 months
Secondary	Part 2: ORR Per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations	ORR was defined as the percentage of participants who had a CR (Disappearance of all target lesions) or a PR (divided into very good partial response [VGPR; >60% tumor reduction] and moderate partial response [MPR; >30-=60% tumor reduction]) per RECIST 1.1 as assessed by investigator. The percentage of participants who experienced a CR or PR as assessed by the investigator was presented.	Up to approximately 85 months
Secondary	Part 3: ORR Per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations	ORR was defined as the percentage of participants who had a CR (Disappearance of all target lesions) or a PR (divided into very good partial response [VGPR; >60% tumor reduction] and moderate partial response [MPR; >30-=60% tumor reduction]) per RECIST 1.1 as assessed by investigator. The percentage of participants who experienced a CR or PR as assessed by the investigator was presented.	Up to approximately 85 months
Secondary	Part 3: Duration of Response (DOR) Per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations	For participants who demonstrated a confirmed CR (Disappearance of all target lesions) or a confirmed PR (divided by VGPR [>60% tumor reduction] and MPR [>30-=60% tumor reduction]) per RECIST 1.1 as assessed by the investigator, DOR was defined as the time from first documented evidence of CR or PR until progressive disease (PD). Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD. The DOR as assessed by the investigator was analyzed using Kaplan-Meier method and reported in months.	Up to approximately 85 months
Secondary	Part 3: Overall Survival (OS) in Participants With BRAF V600 E or K Mutations	OS was defined as the time from randomization to death due to any cause. OS was analyzed using the Kaplan-Meier method and was reported in months. Statistical analysis used a Cox regression model with treatment as a covariate and stratified by Eastern Cooperative Oncology Group performance status and Lactate Dehydrogenase.	Up to approximately 85 months
Secondary	Maximum Concentration (Cmax) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination With Dabrafenib and/or Trametinib in Participants Pooled From Parts 1 and 2	Cmax was defined as the maximum concentration of pembrolizumab observed after administration of 2 mg/kg pembrolizumab in combination with dabrafenib and/or trametinib. Blood samples were collected at multiple time points to estimate the Cmax of pembrolizumab. All participants who received pembrolizumab from Parts 1 and 2 were handled as a single arm and analyzed as a single study population for this outcome measure since Part 2 was the dose confirmation phase of Part 1. The Cmax of pembrolizumab is presented.	Cycle 1 Day 1: predose, postdose, 24 - 96 hours (hrs) postdose; Cycle 1 Day 22: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.
Secondary	Maximum Concentration (Cmax) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination With Dabrafenib and Trametinib in Participants From Part 3	Cmax was defined as the maximum concentration of pembrolizumab observed after administration of 2 mg/kg pembrolizumab in combination with dabrafenib and trametinib. Blood samples were collected at multiple time points to estimate the Cmax of pembrolizumab. The Cmax of pembrolizumab is presented.	Cycle 1 Day 1: predose, postdose, 24 - 96 hours (hrs) postdose; Cycle 1 Day 22: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.
Secondary	Maximum Concentration (Cmax) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination With Trametinib in Participants From Part 4	Cmax was defined as the maximum concentration of pembrolizumab observed after administration of 200 mg pembrolizumab in combination with trametinib. Blood samples were collected at multiple time points to estimate the Cmax of pembrolizumab. The Cmax of pembrolizumab is presented.	Cycle 1 Day 15: predose, postdose, 24 - 96 hrs postdose; Cycle 1 Day 36: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.
Secondary	Maximum Concentration (Cmax) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination With Trametinib in Participants From Part 5	Cmax was defined as the maximum concentration of pembrolizumab observed after administration of 200 mg pembrolizumab in combination with trametinib. Blood samples were collected at multiple time points to estimate the Cmax of pembrolizumab. The Cmax of pembrolizumab is presented.	Cycle 1 Day 15: predose, postdose, 24 - 96 hrs postdose; Cycle 1 Day 36: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.
Secondary	Trough Concentration (Ctrough) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination With Dabrafenib and/or Trametinib in Participants Pooled From Parts 1 and 2	Ctrough was defined as the lowest concentration of pembrolizumab that occurred immediately prior to the next dose of 2 mg/kg pembrolizumab administered in combination with dabrafenib and/or trametinib. Blood samples were collected at multiple time points to estimate the Ctrough of pembrolizumab. All participants who received pembrolizumab from Parts 1 and 2 were handled as a single arm and analyzed as a single study population for this outcome measure since Part 2 was the dose confirmation phase of Part 1. The Ctrough of pembrolizumab is presented.	Cycle 1 Day 1: predose, postdose, 24 - 96 hours (hrs) postdose; Cycle 1 Day 22: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.
Secondary	Trough Concentration (Ctrough) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination With Dabrafenib and Trametinib in Participants From Part 3	Ctrough was defined as the lowest concentration of pembrolizumab that occurred immediately prior to the next dose of 2 mg/kg pembrolizumab administered in combination with dabrafenib and trametinib. Blood samples were collected at multiple time points to estimate the Ctrough of pembrolizumab. The Ctrough of pembrolizumab is presented.	Cycle 1 Day 1: predose, postdose, 24 - 96 hours (hrs) postdose; Cycle 1 Day 22: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.
Secondary	Trough Concentration (Ctrough) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination With Trametinib in Participants From Part 4	Ctrough was defined as the lowest concentration of pembrolizumab that occurred immediately prior to the next dose of 200 mg pembrolizumab administered in combination with trametinib. Blood samples were collected at multiple time points to estimate the Ctrough of pembrolizumab. The Ctrough of pembrolizumab is presented.	Cycle 1 Day 15: predose, postdose, 24 - 96 hrs postdose; Cycle 1 Day 36: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.
Secondary	Trough Concentration (Ctrough) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination With Trametinib in Participants From Part 5	Ctrough was defined as the lowest concentration of pembrolizumab that occurred immediately prior to the next dose of 200 mg pembrolizumab administered in combination with trametinib. Blood samples were collected at multiple time points to estimate the Ctrough of pembrolizumab. The Ctrough of pembrolizumab is presented.	Cycle 1 Day 15: predose, postdose, 24 - 96 hrs postdose; Cycle 1 Day 36: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.
Secondary	Maximum Concentration (Cmax) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants Pooled From Parts 1 and 2	Cmax was defined as the maximum concentration of dabrafenib observed after administration of 150 mg dabrafenib in combination with 2 mg/kg pembrolizumab and 2 mg trametinib. Blood samples were collected at multiple time points to estimate the Cmax of dabrafenib. All participants who received dabrafenib from Parts 1 and 2 were handled as a single arm and analyzed as a single study population for this outcome measure since Part 2 was the dose confirmation phase of Part 1. The Cmax of dabrafenib is presented.	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Secondary	Maximum Concentration (Cmax) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants From Part 3	Cmax was defined as the maximum concentration of dabrafenib observed after administration of 150 mg dabrafenib in combination with 2 mg/kg pembrolizumab and 2 mg trametinib. Blood samples were collected at multiple time points to estimate the Cmax of dabrafenib. The Cmax of dabrafenib is presented.	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Secondary	Maximum Concentration (Cmax) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With Placebo and 2 mg Trametinib in Participants From Part 3	Cmax was defined as the maximum concentration of dabrafenib observed after administration of 150 mg dabrafenib in combination with saline placebo and 2 mg trametinib. Blood samples were collected at multiple time points to estimate the Cmax of dabrafenib. The Cmax of dabrafenib is presented.	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Secondary	Trough Concentration (Ctrough) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants Pooled From Parts 1 and 2	Ctrough was defined as the lowest concentration of dabrafenib that occurred immediately prior to the next dose of 150 mg dabrafenib administered in combination with 2 mg/kg pembrolizumab and 2 mg trametinib. Blood samples were collected at multiple time points to estimate the Ctrough of dabrafenib. All participants who received dabrafenib from Parts 1 and 2 were handled as a single arm and analyzed as a single study population for this outcome measure since Part 2 was the dose confirmation phase of Part 1. The Ctrough of dabrafenib is presented.	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Secondary	Trough Concentration (Ctrough) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants From Part 3	Ctrough was defined as the lowest concentration of dabrafenib that occurred immediately prior to the next dose of 150 mg dabrafenib administered in combination with 2 mg/kg pembrolizumab and 2 mg trametinib. Blood samples were collected at multiple time points to estimate the Ctrough of dabrafenib. The Ctrough of dabrafenib is presented.	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Secondary	Trough Concentration (Ctrough) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With Placebo and 2 mg Trametinib in Participants From Part 3	Ctrough was defined as the lowest concentration of dabrafenib that occurred immediately prior to the next dose of 150 mg dabrafenib administered in combination with saline placebo and 2 mg trametinib. Blood samples were collected at multiple time points to estimate the Ctrough of dabrafenib. The Ctrough of dabrafenib is presented.	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Secondary	Maximum Concentration (Cmax) of Trametinib Following Administration of 2 mg Trametinib in Combination With 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants Pooled From Parts 1 and 2	Cmax was defined as the maximum concentration of trametinib observed after administration of 2 mg trametinib in combination with 2 mg/kg pembrolizumab and 150 mg dabrafenib. Blood samples were collected at multiple time points to estimate the Cmax of trametinib. All participants who received 2 mg trametinib from Parts 1 and 2 were treated as a single arm and analyzed as a single study population for this outcome measure since Part 2 was the dose confirmation phase of Part 1. The Cmax of trametinib is presented.	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Secondary	Maximum Concentration (Cmax) of Trametinib Following Administration of 1.5 mg Trametinib in Combination With 2 mg/kg Pembrolizumab in Participants Pooled From Parts 1 and 2	Cmax was defined as the maximum concentration of trametinib observed after administration of 1.5 mg trametinib in combination with 2 mg/kg pembrolizumab. Blood samples were collected at multiple time points to estimate the Cmax of trametinib. All participants who received 1.5 mg trametinib from Parts 1 and 2 were treated as a single arm and analyzed as a single study population for this outcome measure since Part 2 was the dose confirmation phase of Part 1. The Cmax of trametinib is presented.	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Secondary	Maximum Concentration (Cmax) of Trametinib Following Administration of 2 mg Trametinib in Combination With 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants From Part 3	Cmax was defined as the maximum concentration of trametinib observed after administration of 2 mg trametinib in combination with 2 mg/kg pembrolizumab and 150 mg dabrafenib. Blood samples were collected at multiple time points to estimate the Cmax of trametinib. The Cmax of trametinib is presented.	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Secondary	Maximum Concentration (Cmax) of Trametinib Following Administration of 2 mg Trametinib in Combination With Placebo and 150 mg Dabrafenib in Participants From Part 3	Cmax was defined as the maximum concentration of trametinib observed after administration of 2 mg trametinib in combination with saline placebo and 150 mg dabrafenib. Blood samples were collected at multiple time points to estimate the Cmax of trametinib. The Cmax of trametinib is presented.	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Secondary	Maximum Concentration (Cmax) of Trametinib Following Administration of 2 mg Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 4	Cmax was defined as the maximum concentration of trametinib observed after administration of 2 mg trametinib in combination with 200 mg pembrolizumab. Blood samples were collected at multiple time points to estimate the Cmax of trametinib. The Cmax of trametinib is presented.	Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Secondary	Maximum Concentration (Cmax) of Trametinib Following Administration of 1.5 mg Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 4	Cmax was defined as the maximum concentration of trametinib observed after administration of 1.5 mg trametinib in combination with 200 mg pembrolizumab. Blood samples were collected at multiple time points to estimate the Cmax of trametinib. The Cmax of trametinib is presented.	Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Secondary	Maximum Concentration (Cmax) of Trametinib Following Administration of 2 mg of Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 5	Cmax was defined as the maximum concentration of trametinib observed after administration of 2 mg trametinib in combination with 200 mg pembrolizumab. Blood samples were collected at multiple time points to estimate the Cmax of trametinib. The Cmax of trametinib is presented.	Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Secondary	Maximum Concentration (Cmax) of Trametinib Following Administration of 1.5 mg of Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 5	Cmax was defined as the maximum concentration of trametinib observed after administration of 1.5 mg trametinib in combination with 200 mg pembrolizumab. Blood samples were collected at multiple time points to estimate the Cmax of trametinib. The Cmax of trametinib is presented.	Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Secondary	Trough Concentration (Ctrough) of Trametinib Following Administration of 2 mg Trametinib in Combination With 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants Pooled From Parts 1 and 2	Ctrough was defined as the lowest concentration of trametinib that occurred immediately prior to the next dose of 2 mg trametinib administered in combination with 2 mg/kg pembrolizumab and 150 mg dabrafenib. Blood samples were collected at multiple time points to estimate the Ctrough of trametinib. All participants who received 2 mg trametinib from Parts 1 and 2 were treated as a single arm and analyzed as a single study population for this outcome measure since Part 2 was the dose confirmation phase of Part 1. The Ctrough of trametinib is presented.	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Secondary	Trough Concentration (Ctrough) of Trametinib Following Administration of 1.5 mg Trametinib in Combination With 2 mg/kg Pembrolizumab in Participants Pooled From Parts 1 and 2	Ctrough was defined as the lowest concentration of trametinib that occurred immediately prior to the next dose of 1.5 mg trametinib administered in combination with 2 mg/kg pembrolizumab. Blood samples were collected at multiple time points to estimate the Ctrough of trametinib. All participants who received 1.5 mg trametinib from Parts 1 and 2 were treated as a single arm and analyzed as a single study population for this outcome measure since Part 2 was the dose confirmation phase of Part 1. The Ctrough of trametinib is presented.	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Secondary	Trough Concentration (Ctrough) of Trametinib Following Administration of 2 mg Trametinib in Combination With 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants From Part 3	Ctrough was defined as the lowest concentration of trametinib that occurred immediately prior to the next dose of 2 mg trametinib administered in combination with 2 mg/kg pembrolizumab and 150 mg dabrafenib. Blood samples were collected at multiple time points to estimate the Ctrough of trametinib. The Ctrough of trametinib is presented.	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Secondary	Trough Concentration (Ctrough) of Trametinib Following Administration of 2 mg Trametinib in Combination With Placebo and 150 mg Dabrafenib in Participants From Part 3	Ctrough was defined as the lowest concentration of trametinib that occurred immediately prior to the next dose of 2 mg trametinib administered in combination with saline placebo and 150 mg dabrafenib. Blood samples were collected at multiple time points to estimate the Ctrough of trametinib. The Ctrough of trametinib is presented.	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Secondary	Trough Concentration (Ctrough) of Trametinib Following Administration of 2 mg Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 4	Ctrough was defined as the lowest concentration of trametinib that occurred immediately prior to the next dose of 2 mg trametinib administered in combination with 200 mg pembrolizumab. Blood samples were collected at multiple time points to estimate the Ctrough of trametinib. The Ctrough of trametinib is presented.	Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Secondary	Trough Concentration (Ctrough) of Trametinib Following Administration of 1.5 mg Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 4	Ctrough was defined as the lowest concentration of trametinib that occurred immediately prior to the next dose of 1.5 mg trametinib administered in combination with 200 mg pembrolizumab. Blood samples were collected at multiple time points to estimate the Ctrough of trametinib. The Ctrough of trametinib is presented.	Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Secondary	Trough Concentration (Ctrough) of Trametinib Following Administration of 2 mg of Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 5	Ctrough was defined as the lowest concentration of trametinib that occurred immediately prior to the next dose of 2 mg trametinib administered in combination with 200 mg pembrolizumab. Blood samples were collected at multiple time points to estimate the Ctrough of trametinib. The Ctrough of trametinib is presented.	Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Secondary	Trough Concentration (Ctrough) of Trametinib Following Administration of 1.5 mg of Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 5	Ctrough was defined as the lowest concentration of trametinib that occurred immediately prior to the next dose of 1.5 mg trametinib administered in combination with 200 mg pembrolizumab. Blood samples were collected at multiple time points to estimate the Ctrough of trametinib. The Ctrough of trametinib is presented.	Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Secondary	Clearance (Cl) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination With Dabrafenib and/or Trametinib in Participants Pooled From Parts 1 and 2	Blood samples were to be collected at pre-specified time points for analysis of the Cl of pembrolizumab, defined as the volume of plasma from which pembrolizumab is eliminated per unit time following pembrolizumab administration. This analysis was not performed.	Cycle 1 Day 1: predose, postdose, 24 - 96 hours (hrs) postdose; Cycle 1 Day 22: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.
Secondary	Clearance (Cl) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination With Dabrafenib and Trametinib in Participants From Part 3	Blood samples were to be collected at pre-specified time points for analysis of the Cl of pembrolizumab, defined as the volume of plasma from which pembrolizumab is eliminated per unit time following pembrolizumab administration. This analysis was not performed.	Cycle 1 Day 1: predose, postdose, 24 - 96 hours (hrs) postdose; Cycle 1 Day 22: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.
Secondary	Clearance (Cl) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination With Trametinib in Participants From Part 4	Blood samples were to be collected at pre-specified time points for analysis of the Cl of pembrolizumab, defined as the volume of plasma from which pembrolizumab is eliminated per unit time following pembrolizumab administration. This analysis was not performed.	Cycle 1 Day 15: predose, postdose, 24 - 96 hrs postdose; Cycle 1 Day 36: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.
Secondary	Clearance (Cl) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination With Trametinib in Participants From Part 5	Blood samples were to be collected at pre-specified time points for analysis of the Cl of pembrolizumab, defined as the volume of plasma from which pembrolizumab is eliminated per unit time following pembrolizumab administration. This analysis was not performed.	Cycle 1 Day 15: predose, postdose, 24 - 96 hrs postdose; Cycle 1 Day 36: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.
Secondary	Clearance (Cl) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants Pooled From Parts 1 and 2	Blood samples were to be collected at pre-specified time points for analysis of the Cl of dabrafenib, defined as the volume of plasma from which dabrafenib is eliminated per unit time following dabrafenib administration. This analysis was not performed.	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Secondary	Clearance (Cl) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants From Part 3	Blood samples were to be collected at pre-specified time points for analysis of the Cl of dabrafenib, defined as the volume of plasma from which dabrafenib is eliminated per unit time following dabrafenib administration. This analysis was not performed.	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Secondary	Clearance (Cl) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With Placebo and 2 mg Trametinib in Participants From Part 3	Blood samples were to be collected at pre-specified time points for analysis of the Cl of dabrafenib, defined as the volume of plasma from which dabrafenib is eliminated per unit time following dabrafenib administration. This analysis was not performed.	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Secondary	Clearance (Cl) of Trametinib Following Administration of 2 mg Trametinib in Combination With 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants Pooled From Parts 1 and 2	Blood samples were to be collected at pre-specified time points for analysis of the Cl of trametinib, defined as the volume of plasma from which trametinib is eliminated per unit time following trametinib administration. This analysis was not performed.	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Secondary	Clearance (Cl) of Trametinib Following Administration of 1.5 mg Trametinib in Combination With 2 mg/kg Pembrolizumab in Participants Pooled From Parts 1 and 2	Blood samples were to be collected at pre-specified time points for analysis of the Cl of trametinib, defined as the volume of plasma from which trametinib is eliminated per unit time following trametinib administration. This analysis was not performed.	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Secondary	Clearance (Cl) of Trametinib Following Administration of 2 mg Trametinib in Combination With 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants From Part 3	Blood samples were to be collected at pre-specified time points for analysis of the Cl of trametinib, defined as the volume of plasma from which trametinib is eliminated per unit time following trametinib administration. This analysis was not performed.	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Secondary	Clearance (Cl) of Trametinib Following Administration of 2 mg Trametinib in Combination With Placebo and 150 mg Dabrafenib in Participants From Part 3	Blood samples were to be collected at pre-specified time points for analysis of the Cl of trametinib, defined as the volume of plasma from which trametinib is eliminated per unit time following trametinib administration. This analysis was not performed.	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Secondary	Clearance (Cl) of Trametinib Following Administration of 2 mg Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 4	Blood samples were to be collected at pre-specified time points for analysis of the Cl of trametinib, defined as the volume of plasma from which trametinib is eliminated per unit time following trametinib administration. This analysis was not performed.	Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Secondary	Clearance (Cl) of Trametinib Following Administration of 1.5 mg Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 4	Blood samples were to be collected at pre-specified time points for analysis of the Cl of trametinib, defined as the volume of plasma from which trametinib is eliminated per unit time following trametinib administration. This analysis was not performed.	Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Secondary	Clearance (Cl) of Trametinib Following Administration of 2 mg of Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 5	Blood samples were to be collected at pre-specified time points for analysis of the Cl of trametinib, defined as the volume of plasma from which trametinib is eliminated per unit time following trametinib administration. This analysis was not performed.	Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Secondary	Clearance (Cl) of Trametinib Following Administration of 1.5 mg of Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 5	Blood samples were to be collected at pre-specified time points for analysis of the Cl of trametinib, defined as the volume of plasma from which trametinib is eliminated per unit time following trametinib administration. This analysis was not performed.	Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Secondary	Volume of Distribution (Vc) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination With Dabrafenib and/or Trametinib in Participants Pooled From Parts 1 and 2	Blood samples were to be collected at pre-specified time points for analysis of the Vc of pembrolizumab, defined as the theoretical volume that would be necessary to contain the total amount of administered pembrolizumab at the same concentration that it is observed in the blood plasma. This analysis was not performed.	Cycle 1 Day 1: predose, postdose, 24 - 96 hours (hrs) postdose; Cycle 1 Day 22: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.
Secondary	Volume of Distribution (Vc) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination With Dabrafenib and Trametinib in Participants From Part 3	Blood samples were to be collected at pre-specified time points for analysis of the Vc of pembrolizumab, defined as the theoretical volume that would be necessary to contain the total amount of administered pembrolizumab at the same concentration that it is observed in the blood plasma. This analysis was not performed.	Cycle 1 Day 1: predose, postdose, 24 - 96 hours (hrs) postdose; Cycle 1 Day 22: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.
Secondary	Volume of Distribution (Vc) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination With Trametinib in Participants From Part 4	Blood samples were to be collected at pre-specified time points for analysis of the Vc of pembrolizumab, defined as the theoretical volume that would be necessary to contain the total amount of administered pembrolizumab at the same concentration that it is observed in the blood plasma. This analysis was not performed.	Cycle 1 Day 15: predose, postdose, 24 - 96 hrs postdose; Cycle 1 Day 36: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.
Secondary	Volume of Distribution (Vc) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination With Trametinib in Participants From Part 5	Blood samples were to be collected at pre-specified time points for analysis of the Vc of pembrolizumab, defined as the theoretical volume that would be necessary to contain the total amount of administered pembrolizumab at the same concentration that it is observed in the blood plasma. This analysis was not performed.	Cycle 1 Day 15: predose, postdose, 24 - 96 hrs postdose; Cycle 1 Day 36: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.
Secondary	Volume of Distribution (Vc) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants Pooled From Parts 1 and 2	Blood samples were to be collected at pre-specified time points for analysis of the Vc of dabrafenib, defined as the theoretical volume that would be necessary to contain the total amount of administered dabrafenib at the same concentration that it is observed in the blood plasma. This analysis was not performed.	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Secondary	Volume of Distribution (Vc) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants From Part 3	Blood samples were to be collected at pre-specified time points for analysis of the Vc of dabrafenib, defined as the theoretical volume that would be necessary to contain the total amount of administered dabrafenib at the same concentration that it is observed in the blood plasma. This analysis was not performed.	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Secondary	Volume of Distribution (Vc) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With Placebo and 2 mg Trametinib in Participants From Part 3	Blood samples were to be collected at pre-specified time points for analysis of the Vc of dabrafenib, defined as the theoretical volume that would be necessary to contain the total amount of administered dabrafenib at the same concentration that it is observed in the blood plasma. This analysis was not performed.	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Secondary	Volume of Distribution (Vc) of Trametinib Following Administration of 2 mg Trametinib in Combination With 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants Pooled From Parts 1 and 2	Blood samples were to be collected at pre-specified time points for analysis of the Vc of trametinib, defined as the theoretical volume that would be necessary to contain the total amount of administered trametinib at the same concentration that it is observed in the blood plasma. This analysis was not performed.	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Secondary	Volume of Distribution (Vc) of Trametinib Following Administration of 1.5 mg Trametinib in Combination With 2 mg/kg Pembrolizumab in Participants Pooled From Parts 1 and 2	Blood samples were to be collected at pre-specified time points for analysis of the Vc of trametinib, defined as the theoretical volume that would be necessary to contain the total amount of administered trametinib at the same concentration that it is observed in the blood plasma. This analysis was not performed.	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Secondary	Volume of Distribution (Vc) of Trametinib Following Administration of 2 mg Trametinib in Combination With 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants From Part 3	Blood samples were to be collected at pre-specified time points for analysis of the Vc of trametinib, defined as the theoretical volume that would be necessary to contain the total amount of administered trametinib at the same concentration that it is observed in the blood plasma. This analysis was not performed.	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Secondary	Volume of Distribution (Vc) of Trametinib Following Administration of 2 mg Trametinib in Combination With Placebo and 150 mg Dabrafenib in Participants From Part 3	Blood samples were to be collected at pre-specified time points for analysis of the Vc of trametinib, defined as the theoretical volume that would be necessary to contain the total amount of administered trametinib at the same concentration that it is observed in the blood plasma. This analysis was not performed.	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Secondary	Volume of Distribution (Vc) of Trametinib Following Administration of 2 mg Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 4	Blood samples were to be collected at pre-specified time points for analysis of the Vc of trametinib, defined as the theoretical volume that would be necessary to contain the total amount of administered trametinib at the same concentration that it is observed in the blood plasma. This analysis was not performed.	Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Secondary	Volume of Distribution (Vc) of Trametinib Following Administration of 1.5 mg Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 4	Blood samples were to be collected at pre-specified time points for analysis of the Vc of trametinib, defined as the theoretical volume that would be necessary to contain the total amount of administered trametinib at the same concentration that it is observed in the blood plasma. This analysis was not performed.	Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Secondary	Volume of Distribution (Vc) of Trametinib Following Administration of 2 mg of Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 5	Blood samples were to be collected at pre-specified time points for analysis of the Vc of trametinib, defined as the theoretical volume that would be necessary to contain the total amount of administered trametinib at the same concentration that it is observed in the blood plasma. This analysis was not performed.	Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Secondary	Volume of Distribution (Vc) of Trametinib Following Administration of 1.5 mg of Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 5	Blood samples were to be collected at pre-specified time points for analysis of the Vc of trametinib, defined as the theoretical volume that would be necessary to contain the total amount of administered trametinib at the same concentration that it is observed in the blood plasma. This analysis was not performed.	Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

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