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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/study/NCT02130466
Registration number
NCT02130466
Ethics application status
Date submitted
1/05/2014
Date registered
5/05/2014
Date last updated
1/08/2022
Titles & IDs
Public title
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)
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Scientific 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
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Secondary ID [1]
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MK-3475-022
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Secondary ID [2]
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3475-022
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Melanoma
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Solid Tumors
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Condition category
Condition code
Intervention/exposure
Study type
Interventional(has expanded access)
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Description of intervention(s) / exposure
Treatment: Other - Pembrolizumab
Treatment: Drugs - Dabrafenib
Treatment: Drugs - Trametinib
Treatment: Drugs - Placebo
Experimental: Part 1:pembrolizumab 2 mg/kg+dabrafenib150 mg+trametinib 2 mg - Participants with BRAF mutant melanoma received 2 mg/kg pembrolizumab administered by intravenous (IV) infusion on Days 1 and 22 of each 6-week cycle (Q6W); 150 mg/day total dabrafenib orally, in a divided dose, twice a day (BID) starting on Day 1 and continuing up until study treatment discontinuation; and 2 mg trametinib orally once a day (QD) starting on Day 1 and continuing up until study treatment discontinuation.
Experimental: Part 1:pembrolizumab 2 mg/kg+trametinib 2 mg - Participants with BRAF wild-type melanoma received 2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W and 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.
Experimental: Part 1:pembrolizumab 2 mg/kg+trametinib 1.5 mg - Participants with BRAF wild-type melanoma received 2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W and 1.5 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.
Experimental: Part 2:pembrolizumab 2 mg/kg+dabrafenib 150 mg+trametinib 2 mg - Participants with BRAF mutant melanoma received 2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W; 150 mg/day total dabrafenib orally, in a divided dose, BID starting on Day 1 and continuing up until study treatment discontinuation; and 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.
Experimental: Part 2:pembrolizumab 2 mg/kg+trametinib 1.5 mg - Participants with BRAF wild-type melanoma received 2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W and 1.5 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.
Experimental: Part 3:pembrolizumab 2 mg/kg+dabrafenib 150 mg+trametinib 2 mg - Participants with BRAF mutant melanoma received 2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W; 150 mg/day total dabrafenib orally, in a divided dose, BID starting on Day 1 and continuing up until study treatment discontinuation; and 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.
Placebo comparator: Part 3:placebo+dabrafenib 150 mg+trametinib 2 mg - Participants with BRAF mutant melanoma received saline placebo administered by IV infusion on Days 1 and 22 Q6W; 150 mg/day total dabrafenib orally, in a divided dose, BID starting on Day 1 and continuing up until study treatment discontinuation; and 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.
Experimental: Part 4:trametinib 2 mg for 4 weeks+pembrolizumab 200 mg+trametinib 2 mg concurrent dosing - Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 2 mg trametinib orally QD for 4 weeks. Starting with Week 5, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 of each 3-week cycle (Q3W) and a concurrent dosing schedule of 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.
Experimental: Part 4:trametinib 1.5 mg for 2 weeks+pembrolizumab 200 mg+trametinib 1.5 mg concurrent dosing - Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 1.5 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and a concurrent dosing schedule of 1.5 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.
Experimental: Part 4:trametinib 1.5 mg for 4 weeks+pembrolizumab 200 mg+trametinib 1.5 mg concurrent dosing - Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 1.5 mg trametinib orally QD for 4 weeks. Starting with Week 5, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and a concurrent dosing schedule of 1.5 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.
Experimental: Part 4:trametinib 2 mg for 2 weeks+pembrolizumab 200 mg+trametinib 2 mg intermittent dosing - Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 2 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent dose schedule of 2 mg trametinib orally QD with 1 week OFF trametinib and 2 weeks ON trametinib continuing up until study treatment discontinuation.
Experimental: Part 4:trametinib 1.5 mg for 2 weeks+pembrolizumab 200 mg+trametinib 1.5 mg intermittent dosing - Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 1.5 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent dose schedule of 1.5 mg trametinib orally QD with 1 week OFF trametinib and 2 weeks ON trametinib continuing up until study treatment discontinuation.
Experimental: Part 5:trametinib 1.5 mg for 2 weeks+pembrolizumab 200 mg+trametinib 1.5 mg concurrent dosing - Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 1.5 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and a concurrent dosing schedule of 1.5 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.
Experimental: Part 5:trametinib 2 mg for 2 weeks+pembrolizumab 200 mg+trametinib 2 mg intermittent dosing - Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 2 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent dose schedule of 2 mg trametinib orally QD with 1 week OFF trametinib and 2 weeks ON trametinib continuing up until study treatment discontinuation.
Treatment: Other: Pembrolizumab
IV infusion
Treatment: Drugs: Dabrafenib
oral capsule
Treatment: Drugs: Trametinib
oral tablet
Treatment: Drugs: Placebo
IV infusion
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Intervention code [1]
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Treatment: Other
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Intervention code [2]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Parts 1, 2, 4, and 5: Number of Participants Who Experienced Dose-limiting Toxicities (DLTs)
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Assessment method [1]
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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.
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Timepoint [1]
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Up to approximately 6 weeks
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Primary outcome [2]
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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
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Assessment method [2]
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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.
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Timepoint [2]
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Up to approximately 85 months
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Primary outcome [3]
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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
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Assessment method [3]
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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.
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Timepoint [3]
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Up to approximately 85 months
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Primary outcome [4]
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Part 3: Progression-Free Survival (PFS) Per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations
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Assessment method [4]
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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.
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Timepoint [4]
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Up to approximately 85 months
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Primary outcome [5]
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Parts 1, 2, 4, and 5: Number of Participants Who Experienced an Adverse Event (AE)
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Assessment method [5]
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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.
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Timepoint [5]
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Up to approximately 32 months
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Primary outcome [6]
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Parts 1, 2, 4, and 5: Number of Participants Who Discontinued Study Treatment Due to an AE
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Assessment method [6]
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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.
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Timepoint [6]
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Up to approximately 29 months
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Secondary outcome [1]
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Part 1: ORR Per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations
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Assessment method [1]
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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.
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Timepoint [1]
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Up to approximately 85 months
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Eligibility
Key inclusion criteria
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
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
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
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Blinded (masking used)
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Who is / are masked / blinded?
The people receiving the treatment/s
The people analysing the results/data
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 1
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
29/05/2014
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
14/07/2021
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Sample size
Target
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Accrual to date
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Final
184
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Recruitment in Australia
Recruitment state(s)
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Funding & Sponsors
Primary sponsor type
Commercial sector/industry
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Name
Merck Sharp & Dohme LLC
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Address
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Country
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Ethics approval
Ethics application status
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Summary
Brief 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.
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Trial website
https://clinicaltrials.gov/study/NCT02130466
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Trial related presentations / publications
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Public notes
This record is viewable in the ANZCTR as it had previously listed Australia and/or New Zealand as a recruitment site, however these sites have since been removed
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Contacts
Principal investigator
Name
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Medical Director
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Address
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Merck Sharp & Dohme LLC
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Country
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Phone
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Fax
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Email
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Contact person for public queries
Name
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Address
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Country
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Phone
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Fax
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Email
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Contact person for scientific queries
No information has been provided regarding IPD availability
What supporting documents are/will be available?
No Supporting Document Provided
Results publications and other study-related documents
No documents have been uploaded by study researchers.
Results are available at
https://clinicaltrials.gov/study/NCT02130466
Download to PDF