Clinical trial NCT02263898 (phase 2, status: withdrawn)
Conditions: recurrent melanoma, stage iv melanoma
ICD codes: G47.13, J01.41, K11.22, K12.0, N96, F33.8, G03.2, C43.0, C43.31, D03.9, C43.51, C43.9, D03.0, C43.4
Drugs: raf kinase inhibitor lgx818, binimetinib
SMILES: COC(=O)N[C@@H](C)CNC1=NC=CC(=N1)C1=CN(N=C1C1=CC(Cl)=CC(NS(C)(=O)=O)=C1F)C(C)C, CN1C=NC2=C(F)C(NC3=CC=C(Br)C=C3F)=C(C=C12)C(=O)NOCCO
Reason stopped: 
    closed without enrollment
  
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 Gilbertâ€™s 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 (Î²) 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 Gilbertâ€™s 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 Investigatorâ€™s judgment, contraindicate the
             patientâ€™s 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