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)

• ClinicalTrials.gov Identifier: NCT02130466
• Recruitment Status: Active, not recruiting
• First Posted: May 5, 2014
• Last Update Posted: March 23, 2021
• Sponsor: Merck Sharp & Dohme Corp.
• Collaborator: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Merck Sharp & Dohme Corp.

Study Description

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 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).

Condition or disease	Intervention/treatment	Phase
Melanoma; Solid Tumors	Biological: Pembrolizumab; Drug: Dabrafenib; Drug: Trametinib; Drug: Placebo	Phase 1; Phase 2

Expanded Access : An investigational treatment associated with this study is no longer available outside the clinical trial.   More info ...

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 190 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: May 29, 2014
• Estimated Primary Completion Date: July 10, 2021
• Estimated Study Completion Date: July 10, 2021

Arms and Interventions

Arm	Intervention/treatment
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.	Biological: Pembrolizumab; IV infusion; Other Names: MK-3475; KEYTRUDA®; Drug: Dabrafenib; oral capsule; Other Name: TAFINLAR®; Drug: Trametinib; oral tablet; Other Name: MEKINIST®
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.	Drug: Dabrafenib; oral capsule; Other Name: TAFINLAR®; Drug: Trametinib; oral tablet; Other Name: MEKINIST®; Drug: Placebo; IV infusion
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.	Biological: Pembrolizumab; IV infusion; Other Names: MK-3475; KEYTRUDA®; Drug: Trametinib; oral tablet; Other Name: MEKINIST®
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.	Biological: Pembrolizumab; IV infusion; Other Names: MK-3475; KEYTRUDA®; Drug: Dabrafenib; oral capsule; Other Name: TAFINLAR®
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.	Biological: Pembrolizumab; IV infusion; Other Names: MK-3475; KEYTRUDA®; Drug: Trametinib; oral tablet; Other Name: MEKINIST®
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.	Biological: Pembrolizumab; IV infusion; Other Names: MK-3475; KEYTRUDA®; Drug: Trametinib; oral tablet; Other Name: MEKINIST®

Outcome Measures

Primary Outcome Measures :

1. Parts 1, 2, 4 and 5: Number of Participants with Dose-limiting Toxicities (DLTs) [ Time Frame: Up to 6 weeks (Cycle 1) ]
2. Part 2: Objective Response Rate (ORR) in Participants Without BRAF V600 E or K Mutations [ Time Frame: Up to approximately 4 years ]
3. Part 5: Objective Response Rate (ORR) in Participants Without BRAF V600 E or K Mutations or With Solid Tumors Irrespective of BRAF Status [ Time Frame: Up to approximately 4 years ]
4. Part 3: Progression-Free Survival (PFS) in Participants With BRAF V600 E or K Mutations [ Time Frame: Up to approximately 4 years ]

Secondary Outcome Measures :

1. Part 1: Objective Response Rate (ORR) in Participants With BRAF V600 E or K Mutations [ Time Frame: Up to approximately 4 years ]
2. Part 2: Objective Response Rate (ORR) in Participants With BRAF V600 E or K Mutations [ Time Frame: Up to approximately 4 years ]
3. Part 3: Objective Response Rate (ORR) in Participants With BRAF V600 E or K Mutations [ Time Frame: Up to approximately 4 years ]
4. Part 3: Duration of Response (DOR) in Participants With BRAF V600 E or K Mutations [ Time Frame: Up to approximately 4 years ]
5. Part 3: Overall Survival (OS) in Participants With BRAF V600 E or K Mutations [ Time Frame: Up to approximately 4 years ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

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

Contacts and Locations

Sponsors and Collaborators

Merck Sharp & Dohme Corp.

Novartis Pharmaceuticals

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme Corp.

More Information

Additional Information:

Merck Oncology Clinical Trials Information 

Publications of Results:

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-mutant melanoma. Nat Med. 2019 Jun;25(6):936-940. doi: 10.1038/s41591-019-0476-5. Epub 2019 Jun 6. Erratum in: Nat Med. 2019 Aug;25(8):1319.

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 pembrolizumab or placebo in BRAF-mutant melanoma. Nat Med. 2019 Jun;25(6):941-946. doi: 10.1038/s41591-019-0448-9. Epub 2019 Jun 6.

• Responsible Party: Merck Sharp & Dohme Corp.
• ClinicalTrials.gov Identifier: NCT02130466
• Other Study ID Numbers: 3475-022; 2015-000681-55 ( EudraCT Number ); MK-3475-022 ( Other Identifier: Merck ); KEYNOTE-022 ( Other Identifier: Merck )
• First Posted: May 5, 2014
• Last Update Posted: March 23, 2021
• Last Verified: March 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
• URL: http://engagezone.msd.com/ds_documentation.php

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Merck Sharp & Dohme Corp.:

PD1; PD-1; PDL1; PD-L1

Additional relevant MeSH terms:

Melanoma; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Pembrolizumab; Trametinib; Dabrafenib; Antineoplastic Agents, Immunological; Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action