NCT02130466

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)

Completed Phase 1, PHASE2 Results posted Last updated 1 August 2022

What this trial tests

Phase 1, PHASE2 trial testing Pembrolizumab in Melanoma in 184 participants. Completed in 14 July 2021.

Timeline

29 May 2014

Primary endpoint
14 July 2021

14 July 2021

Quick facts

Lead sponsor	Merck Sharp & Dohme LLC
Phase	Phase 1, PHASE2
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	double
Primary purpose	treatment
Enrollment	184
Start date	29 May 2014
Primary completion	14 July 2021
Estimated completion	14 July 2021

Drugs / interventions tested

• Pembrolizumab (pembrolizumab) — full drug profile →
• Dabrafenib (dabrafenib) — full drug profile →
• Trametinib (trametinib) — full drug profile →
• Placebo

Conditions studied

• Melanoma — all drugs for Melanoma →
• Solid Tumors — all drugs for Solid Tumors →

Sponsor

Merck Sharp & Dohme LLC — full company profile →

Who can join

18 and older, any sex, with Melanoma or Solid Tumors. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Parts 1, 2, 4, and 5: Number of Participants Who Experienced Dose-limiting Toxicities (DLTs) Primary · Up to approximately 6 weeks

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

Group	Value	95% CI
Part 1:Pembrolizumab 2 mg/kg+dabrafenib150 mg+Trametinib 2 mg	1
Part 1:Pembrolizumab 2 mg/kg+Trametinib 2 mg	1
Part 1:Pembrolizumab 2 mg/kg+Trametinib 1.5 mg	1
Part 2:Pembrolizumab 2 mg/kg+Dabrafenib 150 mg+Trametinib 2 mg	2
Part 2:Pembrolizumab 2 mg/kg+Trametinib 1.5 mg	1
Part 4:4 Weeks Trametinib (Tra) 2mg; Pembrolizumab+Tra 2mg	2
Part 4:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg	0
Part 4:4 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg	0
Part 4:2 Weeks Tra 2mg; Pembrolizumab+Tra 2mg Intermittent	2
Part 4:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg Intermittent	0
Part 5:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg	4
Part 5:2 Weeks Tra 2mg; Pembrolizumab+Tra 2mg Intermittent	2

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 Primary · Up to approximately 85 months

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.

Group	Value	95% CI
Part 2:Pembrolizumab 2 mg/kg+Trametinib 1.5 mg	50.0	1.3 – 98.7

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 Primary · Up to approximately 85 months

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.

Group	Value	95% CI
Part 5:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg	0.0	0.0 – 26.5
Part 5:2 Weeks Tra 2mg; Pembrolizumab+Tra 2mg Intermittent	33.3	7.5 – 70.1

Part 3: Progression-Free Survival (PFS) Per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations Primary · Up to approximately 85 months

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 c

Group	Value	95% CI
Part 3:Pembrolizumab 2 mg/kg+Dabrafenib 150 mg+Trametinib 2 mg	17.0	11.3 – NA
Part 3:Placebo+Dabrafenib 150 mg+Trametinib 2 mg	9.9	6.7 – 15.6

Parts 1, 2, 4, and 5: Number of Participants Who Experienced an Adverse Event (AE) Primary · Up to approximately 32 months

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

Group	Value	95% CI
Part 1:Pembrolizumab 2 mg/kg+dabrafenib150 mg+Trametinib 2 mg	7
Part 1:Pembrolizumab 2 mg/kg+Trametinib 2 mg	3
Part 1:Pembrolizumab 2 mg/kg+Trametinib 1.5 mg	2
Part 2:Pembrolizumab 2 mg/kg+Dabrafenib 150 mg+Trametinib 2 mg	8
Part 2:Pembrolizumab 2 mg/kg+Trametinib 1.5 mg	2
Part 4:4 Weeks Trametinib (Tra) 2mg; Pembrolizumab+Tra 2mg	3
Part 4:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg	4
Part 4:4 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg	5
Part 4:2 Weeks Tra 2mg; Pembrolizumab+Tra 2mg Intermittent	6
Part 4:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg Intermittent	3
Part 5:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg	11
Part 5:2 Weeks Tra 2mg; Pembrolizumab+Tra 2mg Intermittent	9

Parts 1, 2, 4, and 5: Number of Participants Who Discontinued Study Treatment Due to an AE Primary · Up to approximately 29 months

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 disco

Group	Value	95% CI
Part 1:Pembrolizumab 2 mg/kg+dabrafenib150 mg+Trametinib 2 mg	2
Part 1:Pembrolizumab 2 mg/kg+Trametinib 2 mg	2
Part 1:Pembrolizumab 2 mg/kg+Trametinib 1.5 mg	1
Part 2:Pembrolizumab 2 mg/kg+Dabrafenib 150 mg+Trametinib 2 mg	5
Part 2:Pembrolizumab 2 mg/kg+Trametinib 1.5 mg	2
Part 4:4 Weeks Trametinib (Tra) 2mg; Pembrolizumab+Tra 2mg	1
Part 4:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg	0
Part 4:4 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg	4
Part 4:2 Weeks Tra 2mg; Pembrolizumab+Tra 2mg Intermittent	2
Part 4:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg Intermittent	1
Part 5:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg	2
Part 5:2 Weeks Tra 2mg; Pembrolizumab+Tra 2mg Intermittent	2

Part 1: ORR Per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations Secondary · Up to approximately 85 months

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.

Group	Value	95% CI
Part 1:Pembrolizumab 2 mg/kg+dabrafenib150 mg+Trametinib 2 mg	57.1	18.4 – 90.1

Part 2: ORR Per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations Secondary · Up to approximately 85 months

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.

Group	Value	95% CI
Part 2:Pembrolizumab 2 mg/kg+Dabrafenib 150 mg+Trametinib 2 mg	75.0	34.9 – 96.8

Part 3: ORR Per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations Secondary · Up to approximately 85 months

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.

Group	Value	95% CI
Part 3:Pembrolizumab 2 mg/kg+Dabrafenib 150 mg+Trametinib 2 mg	65.0	51.6 – 76.9
Part 3:Placebo+Dabrafenib 150 mg+Trametinib 2 mg	71.7	58.6 – 82.5

Part 3: Duration of Response (DOR) Per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations Secondary · Up to approximately 85 months

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

Group	Value	95% CI
Part 3:Pembrolizumab 2 mg/kg+Dabrafenib 150 mg+Trametinib 2 mg	30.2	14.1 – NA
Part 3:Placebo+Dabrafenib 150 mg+Trametinib 2 mg	12.1	6.0 – 15.7

Part 3: Overall Survival (OS) in Participants With BRAF V600 E or K Mutations Secondary · Up to approximately 85 months

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.

Group	Value	95% CI
Part 3:Pembrolizumab 2 mg/kg+Dabrafenib 150 mg+Trametinib 2 mg	46.3	23.9 – NA
Part 3:Placebo+Dabrafenib 150 mg+Trametinib 2 mg	26.3	18.2 – 38.6

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 Secondary · 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.

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.

Group	Value	95% CI
Pooled Parts 1+2:Pembrolizumab+Dabrafenib+1.5/2 mg Trametinib	52.3	± 9.9

Adverse events — posted to ClinicalTrials.gov

Time frame: Up to approximately 85 months. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Part 1:Pembrolizumab 2 mg/kg+Dabrafenib 150 mg+Trametinib 2 mg

Serious: 1/7 (14%)

Deaths: 4/7

Part 1:Pembrolizumab 2 mg/kg+Trametinib 2 mg

Serious: 0/3 (0%)

Deaths: 1/3

Part 1:Pembrolizumab 2 mg/kg+Trametinib 1.5 mg

Serious: 1/2 (50%)

Deaths: 1/2

Part 2:Pembrolizumab 2 mg/kg+Dabrafenib 150 mg+Trametinib 2 mg

Serious: 3/8 (38%)

Deaths: 3/8

Part 2:Pembrolizumab 2 mg/kg+Trametinib 1.5 mg

Serious: 1/2 (50%)

Deaths: 2/2

Part 3:Pembrolizumab 2 mg/kg+Dabrafenib 150 mg+Trametinib 2 mg

Serious: 36/60 (60%)

Deaths: 31/60

Part 3:Placebo+Dabrafenib 150 mg+Trametinib 2 mg

Serious: 20/60 (33%)

Deaths: 45/60

Part 4:4 Weeks Trametinib (Tra) 2mg; Pembrolizumab+Tra 2mg

Serious: 1/3 (33%)

Deaths: 2/3

Part 4:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg

Serious: 1/4 (25%)

Deaths: 3/4

Part 4:4 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg

Serious: 4/5 (80%)

Deaths: 4/5

Part 4:2 Weeks Tra 2mg; Pembrolizumab+Tra 2mg Intermittent

Serious: 4/6 (67%)

Deaths: 5/6

Part 4:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg Intermittent

Serious: 1/3 (33%)

Deaths: 3/3

Part 5:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg

Serious: 4/12 (33%)

Deaths: 11/12

Part 5:2 Weeks Tra 2mg; Pembrolizumab+Tra 2mg Intermittent

Serious: 2/9 (22%)

Deaths: 7/9

Serious adverse events (87 terms)

Reaction	System	Part 1:Pembrolizumab 2 mg/…	Part 1:Pembrolizumab 2 mg/…	Part 1:Pembrolizumab 2 mg/…	Part 2:Pembrolizumab 2 mg/…	Part 2:Pembrolizumab 2 mg/…	Part 3:Pembrolizumab 2 mg/…	Part 3:Placebo+Dabrafenib …	Part 4:4 Weeks Trametinib …	Part 4:2 Weeks Tra 1.5mg; …	Part 4:4 Weeks Tra 1.5mg; …	Part 4:2 Weeks Tra 2mg; Pe…	Part 4:2 Weeks Tra 1.5mg; …	Part 5:2 Weeks Tra 1.5mg; …	Part 5:2 Weeks Tra 2mg; Pe…
Pyrexia	General disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Pneumonitis	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Chills	General disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Pneumonia	Infections and infestations	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Sepsis	Infections and infestations	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Basal cell carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Tubulointerstitial nephritis	Renal and urinary disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Deep vein thrombosis	Vascular disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Anaemia	Blood and lymphatic system disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Febrile neutropenia	Blood and lymphatic system disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Neutropenia	Blood and lymphatic system disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Thrombocytopenia	Blood and lymphatic system disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Atrial fibrillation	Cardiac disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Mitral valve incompetence	Cardiac disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Myocardial infarction	Cardiac disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Tachycardia	Cardiac disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Hypophysitis	Endocrine disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Detachment of retinal pigment epithelium	Eye disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Retinal detachment	Eye disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Uveitis	Eye disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Colitis	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Discoloured vomit	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Dysphagia	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Faeces discoloured	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—

Other adverse events (328 terms — click to expand)

Reaction	System	Part 1:Pembrolizumab 2 mg/…	Part 1:Pembrolizumab 2 mg/…	Part 1:Pembrolizumab 2 mg/…	Part 2:Pembrolizumab 2 mg/…	Part 2:Pembrolizumab 2 mg/…	Part 3:Pembrolizumab 2 mg/…	Part 3:Placebo+Dabrafenib …	Part 4:4 Weeks Trametinib …	Part 4:2 Weeks Tra 1.5mg; …	Part 4:4 Weeks Tra 1.5mg; …	Part 4:2 Weeks Tra 2mg; Pe…	Part 4:2 Weeks Tra 1.5mg; …	Part 5:2 Weeks Tra 1.5mg; …	Part 5:2 Weeks Tra 2mg; Pe…
Pyrexia	General disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Nausea	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Rash	Skin and subcutaneous tissue disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Fatigue	General disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Chills	General disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Asthenia	General disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Headache	Nervous system disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Myalgia	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Decreased appetite	Metabolism and nutrition disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Aspartate aminotransferase increased	Investigations	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Blood alkaline phosphatase increased	Investigations	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Vitiligo	Skin and subcutaneous tissue disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Alanine aminotransferase increased	Investigations	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Oedema peripheral	General disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Gamma-glutamyltransferase increased	Investigations	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Pruritus	Skin and subcutaneous tissue disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Hypotension	Vascular disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Abdominal pain upper	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Dermatitis acneiform	Skin and subcutaneous tissue disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Anaemia	Blood and lymphatic system disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Dry mouth	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Influenza like illness	General disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Accidental overdose	Injury, poisoning and procedural complications	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Dizziness	Nervous system disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Oropharyngeal pain	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Constipation	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Weight decreased	Investigations	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Pain in extremity	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Dry skin	Skin and subcutaneous tissue disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Erythema	Skin and subcutaneous tissue disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Neutropenia	Blood and lymphatic system disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Nasopharyngitis	Infections and infestations	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Urinary tract infection	Infections and infestations	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Blood creatine phosphokinase increased	Investigations	—	—	—	—	—	—	—	—	—	—	—	—	—	—

Most-reported serious reactions: Pyrexia, Pneumonitis, Diarrhoea, Chills, Pneumonia, Sepsis, Basal cell carcinoma, Tubulointerstitial nephritis.

Data from ClinicalTrials.gov NCT02130466 adverse events section.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. PD-1 and PD-L1 Checkpoint Signaling Inhibition for Cancer Immunotherapy: Mechanism, Combinations, and Clinical Outcome.
   Alsaab HO, Sau S, Alzhrani R, Tatiparti K, et al · · 2017 · cited 1206× · PMID 28878676 · DOI 10.3389/fphar.2017.00561
2. Exploring treatment options in cancer: Tumor treatment strategies.
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