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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)

NCT02130466

Description:

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).

Related Conditions:
  • Melanoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

A Study of the Safety and Efficacy of <span class="go-doc-concept go-doc-intervention">Pembrolizumab (MK-3475)</span> in Combination With <span class="go-doc-concept go-doc-intervention">Trametinib</span> and <span class="go-doc-concept go-doc-intervention">Dabrafenib</span> in Participants With Advanced <span class="go-doc-concept go-doc-disease">Melanoma</span> (<span class="go-doc-concept go-doc-intervention">MK-3475</span>-022/KEYNOTE-022)

Title

  • Brief 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)
  • 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
  • Clinical Trial IDs

    NCT ID: NCT02130466

    ORG ID: 3475-022

    Trial Conditions

    Melanoma

    Trial Interventions

    Drug Synonyms Arms
    Dabrafenib Pembro+D+T (Parts 1, 2, and 3), Placebo+D+T (Part 3), Pembro+D (Parts 1 and 2)
    Trametinib Pembro+D+T (Parts 1, 2, and 3), Placebo+D+T (Part 3), Pembro+T (Parts 1 and 2)

    Trial Purpose

    This is a 3-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. Parts 1 and 2
    of the study will also explore the MTD/MAD for open-label Pembro+T (for v-raf murine sarcoma
    viral oncogene homolog B1 [BRAF] mutation-negative participants) concurrently with the
    Pembro+D+T arm; Pembro+D (for BRAF mutation-positive participants) may be initiated in Parts
    1 and 2.

    Detailed Description

    Trial Arms

    Name Type Description Interventions
    Pembro+D+T (Parts 1, 2, and 3) Experimental 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 study treatment discontinuation. Dabrafenib, Trametinib
    Placebo+D+T (Part 3) Placebo Comparator 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 study treatment discontinuation. Dabrafenib, Trametinib
    Pembro+T (Parts 1 and 2) Experimental 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 study treatment discontinuation. Trametinib
    Pembro+D (Parts 1 and 2) Experimental 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 study treatment discontinuation. Dabrafenib

    Eligibility Criteria

    Inclusion criteria:

    - Histologically-confirmed diagnosis of advanced (unresectable Stage III) or metastatic
    (Stage IV) melanoma excluding uveal, mucosal, or ocular melanoma

    - At least 1 measurable lesion as defined by Response Evaluation Criteria in Solid
    Tumors Version 1.1 (RECIST 1.1) on imaging studies (computed tomography [CT] or
    magnetic resonance imaging [MRI])

    - BRAF mutation-positive (V600 E or K) tumor, or for Parts 1 and 2 only BRAF
    mutation-negative (wild type) tumor with documented progression of >=1 measurable
    lesion after prior therapy (if prior therapy was received)

    - 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 60 days of Study Day 1) of a tumor lesion not previously irradiated

    - Female participant of non-childbearing potential or 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 the programmed cell death 1(PD-1), PD-1 ligand
    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 therapy with ipilimumab or other
    anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) blocking antibodies

    - 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

    - Known history of a hematologic malignancy or of another primary solid tumor, unless
    the participant has undergone potentially curative therapy with no evidence of that
    disease for 5 years, or underwent successful definitive resection of basal or
    squamous cell carcinoma of the skin, superficial bladder cancer, in situ cervical
    cancer, in situ breast cancer or other in situ cancers

    - Active central nervous system (CNS) metastases and/or carcinomatous meningitis

    - Active infection requiring systemic therapy

    - Active autoimmune disease, or document 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 or evidence of interstitial lung disease or active non-infectious 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

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Number of participants with dose-limiting toxicities (DLTs)

    Progression Free Survival (PFS) (Part 3 only)

    Secondary Outcome Measures

    Objective Response Rate (ORR) (Part 3 only)

    Trial Keywords

    PD1

    PDL1