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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| ClinicalTrials.gov Identifier: NCT02130466 |
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Recruitment Status :
Recruiting
First Posted : May 5, 2014
Last Update Posted : May 31, 2018
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Sponsor:
Merck Sharp & Dohme Corp.
Collaborator:
Novartis Pharmaceuticals
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.
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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. 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.
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 | Phase 1 Phase 2 |
Expanded Access : An investigational treatment associated with this study is no longer available outside the clinical trial. More info ...
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 219 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 |
| Arm | Intervention/treatment |
|---|---|
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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.
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Biological: Pembrolizumab
IV infusion
Other Names:
Drug: Dabrafenib oral capsule
Other Name: TAFINLAR® Drug: Trametinib oral tablet
Other Name: MEKINIST® |
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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.
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Biological: Pembrolizumab
IV infusion
Other Names:
Drug: Dabrafenib oral capsule
Other Name: TAFINLAR® Drug: Trametinib oral tablet
Other Name: MEKINIST® |
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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.
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Biological: Pembrolizumab
IV infusion
Other Names:
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.
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Biological: Pembrolizumab
IV infusion
Other Names:
Drug: Dabrafenib oral capsule
Other Name: TAFINLAR® |
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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.
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Biological: Pembrolizumab
IV infusion
Other Names:
Drug: Trametinib oral tablet
Other Name: MEKINIST® |
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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.
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Biological: Pembrolizumab
IV infusion
Other Names:
Drug: Trametinib oral tablet
Other Name: MEKINIST® |
Primary Outcome Measures :
- Number of participants with dose-limiting toxicities (DLTs) [ Time Frame: Up to 6 weeks (Cycle 1) ]
- Progression Free Survival (PFS) (Part 3 only) [ Time Frame: Up to 4 years ]
Secondary Outcome Measures :
- Objective Response Rate (ORR) (Part 3 only) [ Time Frame: Up to 4 years ]
Information from the National Library of Medicine
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| 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 adequate 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
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02130466
Contacts
| Contact: Toll Free Number | 1-888-577-8839 |
Locations
| United States, Arizona | |
| Call for Information (Investigational Site 0030) | Recruiting |
| Tucson, Arizona, United States, 85719 | |
| United States, California | |
| Call for Information (Investigational Site 0001) | Recruiting |
| Los Angeles, California, United States, 90025 | |
| Call for Information (Investigational Site 0003) | Recruiting |
| Los Angeles, California, United States, 90095 | |
| Call for Information (Investigational Site 0012) | Recruiting |
| Santa Monica, California, United States, 90404 | |
| United States, Indiana | |
| Call for Information (Investigational Site 0031) | Recruiting |
| Fort Wayne, Indiana, United States, 46845 | |
| United States, Massachusetts | |
| Call for Information (Investigational Site 0002) | Recruiting |
| Boston, Massachusetts, United States, 02215 | |
| United States, Pennsylvania | |
| Call for Information (Investigational Site 0007) | Recruiting |
| Philadelphia, Pennsylvania, United States, 19104 | |
| Australia | |
| Merck Sharp & Dohme | Recruiting |
| North Ryde, Australia | |
| Contact: Australian Medical Information Centre 61 2 8988 8428 | |
| Canada, Quebec | |
| Merck Canada | Recruiting |
| Kirkland, Quebec, Canada, H9H 4M7 | |
| Contact: Medical Information Centre Centre d'information medicale Merck Canada Inc. 514-428-8600 / 1-800-567-2594 | |
| Italy | |
| MSD Italia S.r.l. | Recruiting |
| Rome, Italy | |
| Contact: Paola Chiaretta Fattore 39 0636191739 | |
Sponsors and Collaborators
Merck Sharp & Dohme Corp.
Novartis Pharmaceuticals
Investigators
| Study Director: | Medical Director | Merck Sharp & Dohme Corp. |
| Responsible Party: | Merck Sharp & Dohme Corp. |
| ClinicalTrials.gov Identifier: | NCT02130466 History of Changes |
| Other Study ID Numbers: |
3475-022 2015-000681-55 ( EudraCT Number ) MK-3475-022 ( Other Identifier: Merck Protocol Number ) |
| First Posted: | May 5, 2014 Key Record Dates |
| Last Update Posted: | May 31, 2018 |
| Last Verified: | May 2018 |
| 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.:
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PD1 PD-1 PDL1 PD-L1 |
Additional relevant MeSH terms:
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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 Protein Kinase Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action |