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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)
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
Secondary ID [1] 0 0
MK-3475-022
Secondary ID [2] 0 0
3475-022
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Melanoma 0 0
Solid Tumors 0 0
Condition category
Condition code

Intervention/exposure
Study type
Interventional(has expanded access)
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
Intervention code [1] 0 0
Treatment: Other
Intervention code [2] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Parts 1, 2, 4, and 5: Number of Participants Who Experienced Dose-limiting Toxicities (DLTs)
Timepoint [1] 0 0
Up to approximately 6 weeks
Primary outcome [2] 0 0
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
Timepoint [2] 0 0
Up to approximately 85 months
Primary outcome [3] 0 0
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
Timepoint [3] 0 0
Up to approximately 85 months
Primary outcome [4] 0 0
Part 3: Progression-Free Survival (PFS) Per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations
Timepoint [4] 0 0
Up to approximately 85 months
Primary outcome [5] 0 0
Parts 1, 2, 4, and 5: Number of Participants Who Experienced an Adverse Event (AE)
Timepoint [5] 0 0
Up to approximately 32 months
Primary outcome [6] 0 0
Parts 1, 2, 4, and 5: Number of Participants Who Discontinued Study Treatment Due to an AE
Timepoint [6] 0 0
Up to approximately 29 months
Secondary outcome [1] 0 0
Part 1: ORR Per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations
Timepoint [1] 0 0
Up to approximately 85 months

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
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
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

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
29/05/2014
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
14/07/2021
Sample size
Target
Accrual to date
Final
184
Recruitment in Australia
Recruitment state(s)

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Merck Sharp & Dohme LLC
Address
Country

Ethics approval
Ethics application status

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.
Trial website
https://clinicaltrials.gov/study/NCT02130466
Trial related presentations / publications
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

Contacts
Principal investigator
Name 0 0
Medical Director
Address 0 0
Merck Sharp & Dohme LLC
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT02130466