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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT02130466




Registration number
NCT02130466
Ethics application status
Date submitted
1/05/2014
Date registered
1/05/2014
Date last updated
5/04/2019

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
2015-000681-55
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
Melanoma 0 0
Solid Tumors 0 0
Condition category
Condition code
Cancer 0 0 0 0
Malignant melanoma

Intervention/exposure
Study type
Interventional(has expanded access)
Description of intervention(s) / exposure
Other interventions - Pembrolizumab
Treatment: Drugs - Dabrafenib
Treatment: Drugs - Trametinib
Other interventions - Pembrolizumab
Treatment: Drugs - Dabrafenib
Treatment: Drugs - Trametinib

Experimental: Pembro+D+T (Parts 1, 2 & 3) - Participants receive pembrolizumab intravenously (IV) on Days 1 and 22 of each 6-week cycle; dabrafenib capsules, 150 mg/day total, orally, in a divided dose (twice per day, or BID) starting on Day 1, through study treatment discontinuation; and trametinib tablets, 2 mg, orally, once daily (QD) starting on Day 1, through completion of 2 years of treatment or through study treatment discontinuation.

Placebo Comparator: Placebo+D+T (Part 3) - Participants receive placebo IV on Days 1 and 22 of each 6-week cycle; dabrafenib capsules, 150 mg/day total, orally, in a divided dose BID starting on Day 1, through study treatment discontinuation; and trametinib tablets, 2 mg, orally, QD starting on Day 1, through completion of 2 years of treatment or through study treatment discontinuation.

Experimental: Pembro+T (Parts 1 & 2) - Participants receive pembrolizumab IV on Days 1 and 22 of each 6-week cycle and trametinib tablets, 2 mg, orally, QD starting on Day 1, through completion of 2 years of treatment or through study treatment discontinuation.

Experimental: Pembro+D (Parts 1 & 2) - Participants receive pembrolizumab IV on Days 1 and 22 of each 6-week cycle and dabrafenib capsules, 150 mg/day total, orally, in a divided dose BID starting on Day 1, through completion of 2 years of treatment or through study treatment discontinuation.

Experimental: Pembro+T Concurrent Dosing (Parts 4 & 5) - Participants receive trametinib tablets, 1.5 mg monotherapy, orally, QD for 4 weeks. Starting with Week 5, participants receive pembrolizumab IV on Day 1 of each 3-week cycle and a concurrent dosing schedule for trametinib tablets, 1.5 mg, orally, QD starting on Day 1, through completion of 2 years of treatment or through study treatment discontinuation.

Experimental: Pembro+T Intermittent Dosing (Parts 4 & 5) - Participants receive trametinib 1.5 mg monotherapy, orally QD for 2 weeks. Starting with Week 3, participants receive pembrolizumab 200 mg IV on Day 1 of each 3-week cycle and an intermittent dose schedule for trametinib tablets, 1.5 mg, orally, QD with 1 week OFF trametinib and 2 weeks ON trametinib through completion of 2 years of treatment or through study treatment discontinuation.

Experimental: Pembro+D+T (Parts 1, 2 & 3) - Participants receive pembrolizumab intravenously (IV) on Days 1 and 22 of each 6-week cycle; dabrafenib capsules, 150 mg/day total, orally, in a divided dose (twice per day, or BID) starting on Day 1, through study treatment discontinuation; and trametinib tablets, 2 mg, orally, once daily (QD) starting on Day 1, through completion of 2 years of treatment or through study treatment discontinuation.

Placebo Comparator: Placebo+D+T (Part 3) - Participants receive placebo IV on Days 1 and 22 of each 6-week cycle; dabrafenib capsules, 150 mg/day total, orally, in a divided dose BID starting on Day 1, through study treatment discontinuation; and trametinib tablets, 2 mg, orally, QD starting on Day 1, through completion of 2 years of treatment or through study treatment discontinuation.

Experimental: Pembro+T (Parts 1 & 2) - Participants receive pembrolizumab IV on Days 1 and 22 of each 6-week cycle and trametinib tablets, 2 mg, orally, QD starting on Day 1, through completion of 2 years of treatment or through study treatment discontinuation.

Experimental: Pembro+D (Parts 1 & 2) - Participants receive pembrolizumab IV on Days 1 and 22 of each 6-week cycle and dabrafenib capsules, 150 mg/day total, orally, in a divided dose BID starting on Day 1, through completion of 2 years of treatment or through study treatment discontinuation.

Experimental: Pembro+T Concurrent Dosing (Parts 4 & 5) - Participants receive trametinib tablets, 1.5 mg monotherapy, orally, QD for 4 weeks. Starting with Week 5, participants receive pembrolizumab IV on Day 1 of each 3-week cycle and a concurrent dosing schedule for trametinib tablets, 1.5 mg, orally, QD starting on Day 1, through completion of 2 years of treatment or through study treatment discontinuation.

Experimental: Pembro+T Intermittent Dosing (Parts 4 & 5) - Participants receive trametinib 1.5 mg monotherapy, orally QD for 2 weeks. Starting with Week 3, participants receive pembrolizumab 200 mg IV on Day 1 of each 3-week cycle and an intermittent dose schedule for trametinib tablets, 1.5 mg, orally, QD with 1 week OFF trametinib and 2 weeks ON trametinib through completion of 2 years of treatment or through study treatment discontinuation.


Other interventions: Pembrolizumab
IV infusion

Treatment: Drugs: Dabrafenib
oral capsule

Treatment: Drugs: Trametinib
oral tablet

Other interventions: Pembrolizumab
IV infusion

Treatment: Drugs: Dabrafenib
oral capsule

Treatment: Drugs: Trametinib
oral tablet

Intervention code [1] 0 0
Other interventions
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 with Dose-limiting Toxicities (DLTs)
Timepoint [1] 0 0
Up to 6 weeks (Cycle 1)
Primary outcome [2] 0 0
Part 2: Objective Response Rate (ORR) in Participants Without BRAF V600 E or K Mutations
Timepoint [2] 0 0
Up to approximately 4 years
Primary outcome [3] 0 0
Part 3: Progression-Free Survival (PFS) in Participants With BRAF V600 E or K Mutations
Timepoint [3] 0 0
Up to approximately 4 years
Primary outcome [4] 0 0
Parts 1, 2, 4 and 5: Number of Participants with Dose-limiting Toxicities (DLTs)
Timepoint [4] 0 0
Up to 6 weeks (Cycle 1)
Primary outcome [5] 0 0
Part 2: Objective Response Rate (ORR) in Participants Without BRAF V600 E or K Mutations
Timepoint [5] 0 0
Up to approximately 4 years
Primary outcome [6] 0 0
Part 3: Progression-Free Survival (PFS) in Participants With BRAF V600 E or K Mutations
Timepoint [6] 0 0
Up to approximately 4 years
Secondary outcome [1] 0 0
Part 1: Objective Response Rate (ORR) in Participants With BRAF V600 E or K Mutations
Timepoint [1] 0 0
Up to approximately 4 years
Secondary outcome [2] 0 0
Part 2: Objective Response Rate (ORR) in Participants With BRAF V600 E or K Mutations
Timepoint [2] 0 0
Up to approximately 4 years
Secondary outcome [3] 0 0
Part 3: Objective Response Rate (ORR) in Participants With BRAF V600 E or K Mutations
Timepoint [3] 0 0
Up to approximately 4 years
Secondary outcome [4] 0 0
Part 3: Duration of Response (DOR) in Participants With BRAF V600 E or K Mutations
Timepoint [4] 0 0
Up to approximately 4 years
Secondary outcome [5] 0 0
Part 3: Overall Survival (OS) in Participants With BRAF V600 E or K Mutations
Timepoint [5] 0 0
Up to approximately 4 years
Secondary outcome [6] 0 0
Part 1: Objective Response Rate (ORR) in Participants With BRAF V600 E or K Mutations
Timepoint [6] 0 0
Up to approximately 4 years
Secondary outcome [7] 0 0
Part 2: Objective Response Rate (ORR) in Participants With BRAF V600 E or K Mutations
Timepoint [7] 0 0
Up to approximately 4 years
Secondary outcome [8] 0 0
Part 3: Objective Response Rate (ORR) in Participants With BRAF V600 E or K Mutations
Timepoint [8] 0 0
Up to approximately 4 years
Secondary outcome [9] 0 0
Part 3: Duration of Response (DOR) in Participants With BRAF V600 E or K Mutations
Timepoint [9] 0 0
Up to approximately 4 years
Secondary outcome [10] 0 0
Part 3: Overall Survival (OS) in Participants With BRAF V600 E or K Mutations
Timepoint [10] 0 0
Up to approximately 4 years

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), PD-1 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
Gender
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, mitogen-activated protein
kinase (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/Phase 2
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment hospital [1] 0 0
Merck Sharp & Dohme - North Ryde
Recruitment postcode(s) [1] 0 0
- North Ryde
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Massachusetts
Country [3] 0 0
Canada
State/province [3] 0 0
Quebec

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Merck Sharp & Dohme Corp.
Address
Country
Other collaborator category [1] 0 0
Commercial sector/Industry
Name [1] 0 0
Novartis Pharmaceuticals
Address [1] 0 0
Country [1] 0 0
Other collaborator category [2] 0 0
Commercial sector/Industry
Name [2] 0 0
Novartis Pharmaceuticals
Address [2] 0 0
Country [2] 0 0

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 only. 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 will also explore the MTD/MAD for open-label Pembro+T (for BRAF
mutation-negative participants) concurrently with the Pembro+D+T arm; Pembro+D (for BRAF
mutation-positive participants).
Trial website
https://clinicaltrials.gov/show/NCT02130466
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Medical Director
Address 0 0
Merck Sharp & Dohme Corp.
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Toll Free Number
Address 0 0
Country 0 0
Phone 0 0
1-888-577-8839
Fax 0 0
Email 0 0
Contact person for scientific queries

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