Clinical Trials /

Intermittent LGX818 and MEK162 in Treating Patients With Metastatic Melanoma Who Have BRAFV600 Mutations

NCT02263898

Description:

This phase II trial studies intermittent dosing of BRAF inhibitor LGX818 (encorafenib) and MEK inhibitor MEK 162 (binimetinib) in treating patients with melanoma that has spread to other parts of the body (metastatic) and have a BRAF V600 mutation. LGX818 and MEK162 may stop the growth of tumor cells by blocking different enzymes needed for cell growth. Giving LGX818 and MEK162 with breaks between each course (intermittently) may help delay the time when tumors become resistant to the drugs.

Related Conditions:
  • Melanoma
Recruiting Status:

Withdrawn

Phase:

Phase 2

Trial Eligibility

Document

Intermittent <span class="go-doc-concept go-doc-intervention">LGX818</span> and MEK162 in Treating Patients With Metastatic <span class="go-doc-concept go-doc-disease">Melanoma</span> Who Have BRAFV600 <span class="go-doc-concept go-doc-keyword">Mutations</span>

Title

  • Brief Title: Intermittent LGX818 and MEK162 in Treating Patients With Metastatic Melanoma Who Have BRAFV600 Mutations
  • Official Title: Biomarkers of Durable Response With Intermittent Therapy With LGX818 and MEK162 Combined Therapy in Patients With BRAF Mutant Metastatic Melanoma
  • Clinical Trial IDs

    NCT ID: NCT02263898

    ORG ID: 14-000616

    NCI ID: NCI-2014-01971

    Trial Conditions

    Recurrent Melanoma

    Stage IV Melanoma

    Trial Interventions

    Drug Synonyms Arms
    Raf kinase inhibitor LGX818 LGX818 Treatment (LGX818, MEK162)
    binimetinib ARRY-162, ARRY-438162, MEK inhibitor ARRY-438162, MEK162 Treatment (LGX818, MEK162)

    Trial Purpose

    This phase II trial studies intermittent dosing of BRAF inhibitor LGX818 (encorafenib) and
    MEK inhibitor MEK 162 (binimetinib) in treating patients with melanoma that has spread to
    other parts of the body (metastatic) and have a BRAF V600 mutation. LGX818 and MEK162 may
    stop the growth of tumor cells by blocking different enzymes needed for cell growth. Giving
    LGX818 and MEK162 with breaks between each course (intermittently) may help delay the time
    when tumors become resistant to the drugs.

    Detailed Description

    PRIMARY OBJECTIVES:

    I. One year progression free survival (PFS) rate.

    SECONDARY OBJECTIVES:

    I. Obtain biopsy samples from patients treated with an intermittent schedule of LGX818 and
    MEK162 to study adaptive and acquired resistance as well as melanoma evolutionary patterns.

    II. Study molecular changes of adaptive resistance and acquired resistance to LGX818 and
    MEK162 in circulating melanoma cells.

    III. Study plasma samples for circulating deoxyribonucleic acid (DNA), microribonucleic acid
    (microRNA) and protein signatures of adaptive resistance and acquired resistance.

    IV. Explore the median progression free survival and overall survival of patients receiving
    an intermittent schedule of LGX818 and MEK162.

    OUTLINE:

    Patients receive LGX818 orally (PO) once daily (QD) and MEK162 PO twice daily (BID)
    continuously for 8 weeks, followed by intermittent dosing in subsequent cycles (3 weeks off
    therapy, 5 weeks on therapy). Cycles repeat every 8 weeks in the absence of disease
    progression or unacceptable toxicity.

    After completion of study treatment, patients are followed up at 30 days and then every 6
    months thereafter.

    Trial Arms

    Name Type Description Interventions
    Treatment (LGX818, MEK162) Experimental Patients receive LGX818 PO QD and MEK162 PO BID continuously for 8 weeks followed by intermittent dosing in subsequent cycles (3 weeks off therapy, 5 weeks on therapy). Cycles repeat every 8 weeks in the absence of disease progression or unacceptable toxicity. Raf kinase inhibitor LGX818, binimetinib

    Eligibility Criteria

    Inclusion Criteria:

    - Signed written informed consent

    - Histologically confirmed diagnosis of metastatic melanoma with the presence of the
    B-Raf proto-oncogene, serine/threonine kinase (BRAFV600) mutation

    - Eastern Cooperative Oncology Group (ECOG) performance status < 3

    - Absolute neutrophil count (ANC) >= 1.0 x 10^9/L

    - Hemoglobin (Hgb) >= 9 g/dL without transfusions

    - Platelets (PLT) >= 90 x 10^9/L without transfusions

    - Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) =< 2.5 x upper
    limit of normal (ULN); patient with liver metastases =< 5 x ULN

    - Total bilirubin =< 2 x ULN, or < 5 ULN if Gilberts disease

    - Creatinine =< 1.5 mg/dL, or calculated creatinine clearance (determined as per
    Cockcroft-Gault) >= 50 mL/min

    - Left ventricular ejection fraction (LVEF) >= 50% as determined by a multigated
    acquisition (MUGA) scan or echocardiogram (ECHO)

    - Corrected QT (QTc) interval =< 480 ms

    - Able to take oral medications

    - Patient is deemed by the Investigator to have the initiative and means to be
    compliant with the protocol (treatment and follow-up)

    - Negative serum beta () human chorionic gonadotropin (HCG) test (female patient of
    childbearing potential only) within 72 hours prior to first dose

    Exclusion Criteria:

    - Prior exposure to BRAF or MEK inhibitors

    - Any active central nervous system (CNS) lesion (i.e., those with radiographically
    unstable, symptomatic lesions) and/or leptomeningeal metastases; however, patient
    treated with stereotactic radiotherapy, whole brain radiation or surgery are eligible
    if patient remained without evidence of CNS disease progression >= 4 weeks; patients
    must be off corticosteroid therapy for >= 2 weeks

    - History or current evidence of retinal vein occlusion (RVO) or predisposing factors
    to RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity
    or hypercoagulability syndromes)

    - History of retinal degenerative disease

    - History of Gilberts syndrome

    - Previous or concurrent malignancy is not an exclusion provided that the other
    malignancy is considered under control and target lesions from melanoma are clearly
    defined for response assessment

    - Impaired cardiovascular function or clinically significant cardiovascular diseases,
    including any of the following:

    - History of acute coronary syndromes (including myocardial infarction, unstable
    angina, coronary artery bypass grafting, coronary angioplasty, or stenting) < 6
    months prior to screening,

    - Symptomatic chronic heart failure, history or current evidence of clinically
    significant cardiac arrhythmia and/or conduction abnormality < 6 months prior to
    screening except atrial fibrillation and paroxysmal supraventricular tachycardia

    - Uncontrolled arterial hypertension despite medical treatment

    - Known positive serology for HIV (human immunodeficiency virus), active hepatitis B,
    and/or active hepatitis C infection

    - Patients who have neuromuscular disorders that are associated with elevated creatine
    kinase (CK) (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral
    sclerosis, spinal muscular atrophy)

    - Patients who are planning on embarking on a new strenuous exercise regimen after
    first dose of study treatment; muscular activities, such as strenuous exercise, that
    can result in significant increases in plasma CK levels should be avoided while on
    MEK162 treatment

    - Impairment of gastrointestinal function or gastrointestinal disease (e.g., ulcerative
    disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel
    resection)

    - Patients taking non-topical medication known to be a strong inhibitor of cytochrome
    P450, family 3, subfamily A, polypeptide 4 (CYP3A4); however patients who either
    discontinue their treatment or switch to another medication at least three days prior
    to randomization are eligible

    - Any other condition that would, in the Investigators judgment, contraindicate the
    patients participation in the clinical study due to safety concerns or compliance
    with clinical study procedures, e.g., infection/inflammation, intestinal obstruction,
    unable to swallow medication, social/psychological issues, etc.

    - Patients who have undergone major surgery =< 3 weeks prior to starting study drug or
    who have not recovered from side effects of such procedure

    - Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a
    female after conception and until the termination of gestation, confirmed by a
    positive hCG laboratory test

    - Women of child-bearing potential, defined as all women physiologically capable of
    becoming pregnant, unless they are using highly effective methods of contraception
    throughout the study and for 8 weeks after study drug discontinuation; highly
    effective contraception methods include:

    - Total abstinence when this is in line with the preferred and usual lifestyle of
    the patient; periodic abstinence (e.g., calendar, ovulation, symptothermal,
    post-ovulation methods) and withdrawal are not acceptable methods of
    contraception

    - Female sterilization (have had surgical bilateral oophorectomy with or without
    hysterectomy) or tubal ligation at least six weeks before taking study
    treatment; in case of oophorectomy alone, only when the reproductive status of
    the woman has been confirmed by follow up hormone level assessment

    - Male sterilization (at least 6 months prior to screening); for female patients
    on the study, the vasectomized male partner should be the sole partner for that
    patient

    - Combination of any of the two following (a+b or a+c or b+c)

    - a. Use of oral, injected or implanted hormonal methods of contraception or
    other forms of hormonal contraception that have comparable efficacy
    (failure rate < 1%), for example hormone vaginal ring or transdermal
    hormone contraception

    - b. Placement of an intrauterine device (IUD) or intrauterine system (IUS)

    - c. Barrier methods of contraception: Condom or occlusive cap (diaphragm or
    cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal
    suppository

    - In case of use of oral contraception, women should have been stable on the same
    pill before taking study treatment

    - Note: Oral contraceptives are allowed but should be used in conjunction with a
    barrier method of contraception

    - Women are considered post-menopausal and not of child bearing potential if they
    have had 12 months of natural (spontaneous) amenorrhea with an appropriate
    clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have
    had surgical bilateral oophorectomy (with or without hysterectomy) or tubal
    ligation at least six weeks ago; in the case of oophorectomy alone, only when
    the reproductive status of the woman has been confirmed by follow up hormone
    level assessment is she considered not of child bearing potential

    - Sexually active males unless they use a condom during intercourse while taking the
    drug and for 8 weeks after stopping treatment and should not father a child in this
    period; a condom is required to be used also by vasectomized men

    - Medical, psychiatric, cognitive or other conditions that may compromise the patient's
    ability to understand the patient information, give informed consent, comply with the
    study protocol or complete the study

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    PFS rate

    Secondary Outcome Measures

    Trial Keywords