Clinical Trials /

Dabrafenib and Trametinib in Treating Patients With Stage III-IV BRAF Mutant Melanoma That Cannot Be Removed by Surgery

NCT02196181

Description:

This randomized phase II trial studies how well dabrafenib and trametinib work in treating patients with stage III-IV melanoma that cannot be removed by surgery and contains a B-Raf proto-oncogene, serine/threonine kinase (BRAF) mutation. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Related Conditions:
  • Melanoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

<span class="go-doc-concept go-doc-intervention">Dabrafenib</span> and <span class="go-doc-concept go-doc-intervention">Trametinib</span> in Treating Patients With Stage III-IV <span class="go-doc-concept go-doc-biomarker">BRAF</span> <span class="go-doc-concept go-doc-keyword">Mutant</span> <span class="go-doc-concept go-doc-disease">Melanoma</span> That Cannot Be Removed by Surgery

Title

  • Brief Title: Dabrafenib and Trametinib in Treating Patients With Stage III-IV BRAF Mutant Melanoma That Cannot Be Removed by Surgery
  • Official Title: A Randomized Phase II Trial of Intermittent Versus Continuous Dosing of Dabrafenib (NSC-763760) and Trametinib (NSC-763093) in BRAF V600E/K Mutant Melanoma
  • Clinical Trial IDs

    NCT ID: NCT02196181

    NCT Alias ID: NCT02199730

    ORG ID: NCI-2014-01470

    NCI ID: NCI-2014-01470

    Trial Conditions

    Recurrent Melanoma

    Stage IIIA Skin Melanoma

    Stage IIIB Skin Melanoma

    Stage IIIC Skin Melanoma

    Stage IV Skin Melanoma

    Trial Interventions

    Drug Synonyms Arms
    Dabrafenib BRAF Inhibitor GSK2118436, DABRAFENIB, GSK-2118436A, GSK2118436, Tafinlar Arm I (continuous dosing), Arm II (intermittent dosing)
    Trametinib GSK1120212, JTP-74057, MEK Inhibitor GSK1120212, Mekinist, TRAMETINIB Arm I (continuous dosing), Arm II (intermittent dosing)

    Trial Purpose

    This randomized phase II trial studies how well dabrafenib and trametinib work in treating
    patients with stage III-IV melanoma that cannot be removed by surgery and contains a B-Raf
    proto-oncogene, serine/threonine kinase (BRAF) mutation. Dabrafenib and trametinib may stop
    the growth of tumor cells by blocking some of the enzymes needed for cell growth.

    Detailed Description

    PRIMARY OBJECTIVES:

    I. To compare progression-free survival with intermittent dosing and continuous dosing of
    dabrafenib and trametinib among patients with metastatic BRAF V600E/K mutant melanoma.

    SECONDARY OBJECTIVES:

    I. To estimate the frequency and severity of toxicities of the two dosing schedules.

    II. To compare the frequency and severity of fever >= grade 1 per Common Terminology
    Criteria for Adverse Events (CTCAE) 4.0 of the two dosing schedules.

    III. To compare the response rate (complete and partial response, confirmed and
    unconfirmed), overall survival, and survival after progression between the two dosing
    schedules on step 2.

    TERTIARY OBJECTIVES:

    I. To bank tissue and whole blood in anticipation of future studies to evaluate molecular
    events associated with clinical benefit and disease progression in patients treated with
    continuous versus intermittent dabrafenib and trametinib.

    OUTLINE: Patients are randomized to 1 of 2 treatment arms.

    ARM I (CONTINUOUS DOSING): Patients receive dabrafenib orally (PO) twice daily (BID) and
    trametinib PO once daily (QD) on days 1-56. Courses repeat every 56 days in the absence of
    disease progression or unacceptable toxicity.

    ARM II (INTERMITTENT DOSING): Patients receive dabrafenib PO BID and trametinib PO QD on
    days 1-7 and 29-56. Courses repeat every 56 days in the absence of disease progression or
    unacceptable toxicity.

    After completion of study treatment, patients are followed up every 6 months for 3 years and
    then yearly for 2 years.

    Trial Arms

    Name Type Description Interventions
    Arm I (continuous dosing) Experimental Patients receive dabrafenib PO BID and trametinib PO QD on days 1-56. Courses repeat every 56 days in the absence of disease progression or unacceptable toxicity. Dabrafenib, Trametinib
    Arm II (intermittent dosing) Experimental Patients receive dabrafenib PO BID and trametinib PO QD on days 1-7 and 29-56. Courses repeat every 56 days in the absence of disease progression or unacceptable toxicity. Dabrafenib, Trametinib

    Eligibility Criteria

    Inclusion Criteria:

    - Patients must have histologically or cytologically confirmed stage IV or unresectable
    stage III BRAF^V600E or BRAF^V600K mutant melanoma

    - Patients must have BRAF mutation-positive melanoma (i.e., V600E or V600K) as
    determined via Sanger sequencing or an Food and Drug Administration (FDA)-approved
    BRAF mutation detection assay; BRAFV600 mutant status must be documented by a
    Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory

    - Contrast-enhanced computed tomography (CT) scans of the neck, chest, abdomen and
    pelvis are required; a whole body positron emission tomography (PET)/CT scan with
    diagnostic quality images and intravenous iodinated contrast may be used in lieu of a
    contrast enhanced CT of the neck, chest, abdomen and pelvis; contrast may be omitted
    if the treating investigator believes that exposure to contrast poses an excessive
    risk to the patient; patients must have measurable disease per Response Evaluation
    Criteria in Solid Tumors (RECIST) 1.1; all measurable lesions must be assessed within
    28 days prior to registration; tests to assess non-measurable disease must be
    performed within 42 days prior to registration; all disease must be assessed and
    documented on the Baseline Tumor Assessment Form (RECIST 1.1)

    - Patients must not have received a prior BRAF or mitogen-activated protein kinase
    kinase (MEK) inhibitor

    - Patients must not have brain metastases unless brain metastases have been treated and
    patient is asymptomatic with no residual neurological dysfunction and has not
    received enzyme-reducing anti-epileptic drugs or corticosteroids for at least 7 days
    prior to registration

    - Patients must not have received any anti-cancer drug within 28 days prior to
    registration, and must not have received any nitrosoureas or mitomycin C within 42
    days prior to registration

    - Patients must not have received any major surgery, radiotherapy, or immunotherapy
    within 28 days prior to registration

    - Patients must not have any unresolved toxicity greater than National Cancer Institute
    (NCI)-CTCAE version (v) 4.0 grade 1 from previous anti-cancer therapy except alopecia
    within 7 days prior to registration

    - Absolute neutrophil count (ANC) >= 1,200/ul

    - Platelets >= 100,000/ul

    - Hemoglobin >= 9 g/dL

    - Total bilirubin =< 1.5 x institutional upper limit of normal (IULN) (or =< 2.5 x
    upper limit of normal [ULN] with Gilbert's syndrome)

    - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x IULN (or
    < 5 x IULN for patients with known liver metastases)

    - Serum albumin >= 2.5 g/dL

    - Serum creatinine =< 1.5 x mg/dL OR measured or calculated creatinine clearance >= 50
    mL/min

    - Patients must have lactate dehydrogenase (LDH) obtained within 28 days prior to
    registration in order to obtain baseline stratification information

    - Patients must have a left ventricular ejection fraction (LVEF) >= institutional lower
    limit of normal (ILLN) by echocardiogram (ECHO) or multi gated acquisition scan
    (MUGA) within 28 days prior to registration

    - Patients must have corrected QT interval (QTc) =< 480 msec by electrocardiogram (ECG)
    (corrected using the Bazett's formula) within 28 days prior to registration

    - Patients with known history or current evidence of retinal vein occlusion (RVO) or
    central serous retinopathy (CSR) are not eligible:

    - History of RVO or CSR, or predisposing factors to RVO or CSR (e.g. uncontrolled
    glaucoma or ocular hypertension, uncontrolled systemic disease such as
    hypertension, diabetes mellitus, or history of hyperviscosity or
    hypercoagulability syndromes)

    - Visible retinal pathology as assessed by ophthalmic exam that is considered a
    risk factor for RVO or CSR such as:

    - Evidence of new optic disc cupping

    - Evidence of new visual field defects

    - Intraocular pressure > 21 mmHg

    - NOTE: Ophthalmic exam is required for all patients; exam must be
    obtained within 28 days prior to registration

    - Patients must be able to take oral medications; patients must not have any impairment
    of gastrointestinal function or gastrointestinal disease that may significantly alter
    the absorption of protocol treatment (e.g. ulcerative disease, uncontrolled nausea,
    vomiting, diarrhea, malabsorption syndrome or small bowel resection)

    - Patients receiving anticoagulation treatment are allowed to participate with
    international normalized ratio (INR) established within the therapeutic range

    - Patients must not have a history of pneumonitis or interstitial lung disease

    - Patients must not have any grade II/III/IV cardiac disease as defined by the New York
    Heart Association criteria (i.e., patients with cardiac disease resulting in marked
    limitation of physical activity or resulting in inability to carry on any physical
    activity without discomfort), unstable angina pectoris, myocardial infarction within
    6 months, or serious uncontrolled cardiac arrhythmia; abnormal cardiac valve
    morphology (>= grade 2) documented by echocardiogram (subjects with grade 1
    abnormalities [i.e., mild regurgitation/stenosis]) can be entered on study; patients
    with a history of atrial fibrillation must have atrial fibrillation controlled for at
    least 30 days prior to registration

    - Patients with known hepatitis B or hepatitis C are not eligible, regardless of
    concomitant antiretroviral therapy or current viral load

    - Patients with known human immunodeficiency virus (HIV) may be eligible providing they
    meet the following additional criteria:

    - Cluster of differentiation (CD)4 cells >= 500/uL

    - Serum HIV viral load of < 25,000 IU/ml

    - No current antiretroviral therapy

    - Tests must be obtained within 28 days prior to registration; patients who
    are HIV positive (+) and do not meet all of these criteria are not eligible
    for this study (HIV/hepatitis testing are not required for patients without
    known infection)

    - Prestudy history and physical must be obtained with 28 days prior to registration

    - Patients must have dermatology exam obtained within 28 days prior to registration to
    obtain baseline measurement; exam to be performed by treating physician or designated
    dermatologist

    - Patients must have Zubrod performance status of 0 or 1

    - No other prior malignancy is allowed except for the following: adequately treated
    basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated
    stage I or II cancer from which the patient is currently in complete remission, or
    any other cancer from which the patient has been disease free for three years;
    exception: patients with known history of colon cancer, cancer of the pancreas, or
    any cancer known to harbor an activating retrovirus-associated deoxyribonucleic acid
    (DNA) sequence (RAS) mutation are ineligible regardless of stage or time since
    diagnosis

    - Patients must not be pregnant or nursing; women/men of reproductive potential must
    have agreed to use an effective contraceptive method; a woman is considered to be of
    "reproductive potential" if she has had menses at any time in the preceding 12
    consecutive months; in addition to routine contraceptive methods, "effective
    contraception" also includes heterosexual celibacy and surgery intended to prevent
    pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy,
    bilateral oophorectomy or bilateral tubal ligation; however, if at any point a
    previously celibate patient chooses to become heterosexually active during the time
    period for use of contraceptive measures outlined in the protocol, he/she is
    responsible for beginning contraceptive measures; hormonal contraception is not
    allowed

    - Patients must be offered the opportunity to participate in specimen banking

    - Patients or their legally authorized representative must be informed of the
    investigational nature of this study and must sign and give written informed consent
    in accordance with institutional and federal guidelines

    - As a part of the Oncology Patient Enrollment Network (OPEN) registration process the
    treating institution's identity is provided in order to ensure that the current
    (within 365 days) date of institutional review board approval for this study has been
    entered in the system

    - STEP 2: RANDOMIZATION

    - After completing one cycle of therapy, patients will be registered for randomization
    between intermittent and continuous dosing, provided that they were eligible for the
    initial step 1 registration and satisfy the following criteria

    - Patients must not have unequivocal disease progression (by RECIST v1.1) during the
    first cycle; patients must have disease assessed using the same method as baseline
    within +/- 5 days of the day 56 scheduled assessment (between days 51-55 of cycle 1,
    or days 1-5 of cycle 2); all disease must be assessed and documented on the follow-up
    tumor assessment form (RECIST 1.1)

    - Patients must be registered to step 2: randomization within 5 days of completing
    cycle 1 of step 1

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Superiority of intermittent dosing of dabrafenib and trametinib compared to continuous dosing with these two same agents based on progression-free survival

    Secondary Outcome Measures

    Overall survival

    Rates of fever

    Response rates

    Trial Keywords