BKM120 Combined With Vemurafenib (PLX4032) in BRAFV600E/K Mutant Advanced Melanoma

Inclusion Criteria

• Histologically or cytologically confirmed diagnosis of unresectable stage III and stage IV melanoma
• BRAFV600E or BRAFV600K mutation-positive
• Age >= 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status = 1.5 x 109/L, Platelets >= 100 x 109/L, Hb >9 g/dL
• Total calcium (corrected for serum albumin) within normal limits (biphosphonate use for malignant hypercalcemia control is not allowed)
• Magnesium ≥ the lower limit of normal
• Potassium within normal limits for the institution
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) within normal range (or = 50 mL/min
• Serum amylase 4 weeks from therapy completion (incl. radiation and/or surgery) and clinically stable at the time of study entry
• Patients with acute or chronic liver, renal disease or pancreatitis
• Patients with the following mood disorders as judged by the Investigator or a psychiatrist, or as a result of patient's mood assessment questionnaire:
• Medically documented history of or active major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, history of suicidal attempt or ideation, or homicidal ideation
• >= CTCAE grade 3 anxiety
• Meets the cut-off score of >= 10 in the Patient Health Questionnaire-9 (PHQ-9) or a cut-off of >= 15 in the General Anxiety Disorder-7 (GAD-7) mood scale, respectively, or selects a positive response of "1, 2, or 3" to question number 9 regarding potential for suicidal thoughts in the PHQ-9 (independent of the total score of the PHQ-9) will be excluded from the study unless overruled by the psychiatric assessment
• Patients with diarrhea >= CTCAE grade 2
• Patient has active cardiac disease including any of the following:
• Left ventricular ejection fraction (LVEF) 480 msec on screening ECG (using the QTcF formula)
• Personal or family history of prolonged QT syndrome
• Angina pectoris that requires the use of anti-anginal medication
• Ventricular arrhythmias except for benign premature ventricular contractions
• Supraventricular and nodal arrythmias requiring a pacemaker or not controlled with medication
• Conduction abnormality requiring a pacemaker
• Symptomatic pericarditis
• Patient has a history of cardiac dysfunction including any of the following:
• Myocardial infarction within the last 6 months, documented by persistent elevated cardiac enzymes or persistent regional wall abnormalities on assessment of left ventricular ejection fraction (LVEF) function
• History of documented congestive heart failure (New York Heart Association functional classification III-IV)
• Documented cardiomyopathy
• Poorly controlled diabetes mellitus (HbA1c > 8 %)
• Other concurrent severe and/or uncontrolled concomitant medical conditions that could cause unacceptable safety risks or compromise compliance with the protocol
• Significant symptomatic deterioration of lung function; if clinically indicated, pulmonary function tests including measures of predicted lung volumes, Diffusing capacity of the lungs for carbon monoxide (DLCO), oxygen (O2) saturation at rest on room air should be considered to exclude pneumonitis or pulmonary infiltrates
• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of BKM120 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
• Patients who have been treated with any hematopoietic colony-stimulating growth factors (e.g., Granulocyte colony-stimulating factor (G-CSF), Granulocyte-macrophage colony-stimulating factor (GM-CSF)) 40 milli-international units per millilitre (mIU/mL) [for US only: and estradiol < 20 pg/mL] or have had surgical bilateral oophorectomy (with or without hysterectomy) 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