A Phase II Study of the Selective BRAF Kinase Inhibitor GSK2118436 in Subjects With Advanced Non-small Cell Lung Cancer and BRAF Mutations

• Progression free survival (PFS) defined as the interval between first dose and the earliest date of disease progression or death due to any cause [ Time Frame: Approximately 2 years ] [ Designated as safety issue: No ]
• Duration of response, defined for the subset of subjects with confirmed CR or PR, as the time from first documented evidence of CR or PR until time of first documented disease progression or death due to any cause [ Time Frame: Approximately 2 years ] [ Designated as safety issue: No ]
• Overall survival defined as the time from first dose until death due to any cause [ Time Frame: Approximately 2 years ] [ Designated as safety issue: No ]
• Number of subjects with adverse events as a measure of safety and tolerability [ Time Frame: Approximately 2 years ] [ Designated as safety issue: Yes ]
• GSK2118436 population pharmacokinetic (PK) parameters such as apparent clearance (CL/F), volume of distribution (V/F) and possible influencing factors such as age, weight or disease-related factors. [ Time Frame: 3, 6, 12 and 20 weeks after onset of dosing ] [ Designated as safety issue: No ]

GSK2118436 is a potent and selective inhibitor of BRAF kinase activity. BRF113928 is a Phase II, non-randomized, open-label study to assess the efficacy, safety, and tolerability of GSK2118436 administered as a single agent to subjects with BRAF mutant advanced non-small cell lung cancer. Subjects will receive GSK2118436 150 mg twice daily (BID) and continue on treatment until disease progression, death, or unacceptable adverse event.

Inclusion Criteria:

• Signed written informed consent;
• Histologically or cytologically confirmed stage IV non-small cell cancer of the lung (NSCLC);
• Documented tumor progression (based on radiological imaging) after receiving at least one prior approved platinum-based chemotherapy regimen for advanced stage/metastatic NSCLC;
• Measurable disease according to Response Evaluation Criteria in Solid Tumors [RECIST 1.1];
• At least 18 years of age;
• Anticipated life expectancy of at least three months;
• Presence of a V600E BRAF mutation in lung cancer tissue confirmed in a CLIA-certified laboratory (or equivalent);
• Able to swallow and retain oral medication;
• Women with child-bearing potential must be willing to practice acceptable methods of birth control during the study;
• Women of childbearing potential must have a menstrual history inconsistent with pregnancy and a negative serum pregnancy test within 14 days before the first dose of study medication and agree to use effective contraception;
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2;
• Must have adequate organ function as defined by the following baseline values:

Absolute neutrophil count (ANC) >/=1.5x109/L Hemoglobin >/=9 g/dL Platelets >/=100x109/L Serum bilirubin </=1.5 x upper limit of normal (ULN) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) </= 2.5xULN Serum creatinine </=1.5 mg/dL (if serum creatinine is >1.5 mg/dL, calculate creatinine clearance using standard Cockcroft and Gault; creatinine clearance must be > 50 mL/min); Prothrombin time /International normalized ratio (INR) and partial thromboplastin time </=1.3xULN Left ventricular ejection fraction >/= institutional lower limit of normal

Exclusion Criteria:

• Previous treatment with a BRAF or MEK inhibitor;
• Anti-cancer therapy including chemotherapy, radiation therapy, immunotherapy, biologic therapy, or major surgery within 14 days prior to start of study therapy;
• Use of any investigational anti-cancer drug within 28 days or 5 half-lives prior to start of study therapy;
• Current use of a prohibited medication or expected to require any of these medications during treatment with GSK2118436;
• Unresolved toxicity of National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI CTCAE v4.0) Grade 2 or higher from previous anti-cancer therapy, except alopecia;
• Presence of active gastrointestinal disease or other condition that will interfere significantly with the absorption of drugs;
• Known human immunodeficiency virus (HIV), Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) infection. Subjects with evidence of hepatitis B virus clearance may be enrolled;
• A history of known glucose-6-phosphate dehydrogenase (G6PD) deficiency;
• History of other malignancy; Exception: (a) Subjects who have been successfully treated and are disease-free for 3 years, (b) a history of completely resected non-melanoma skin cancer, (c) successfully treated in situ carcinoma, (d) CLL in stable remission, or (e) indolent prostate cancer requiring no or only anti-hormonal therapy with histologically confirmed tumor lesions that can be clearly differentiated from lung cancer target and non-target lesions are eligible
• Subjects with brain metastases are excluded if their brain metastases are:

Symptomatic, or Treated (surgery, radiation therapy) but not clinically and radiographically stable 3 weeks after local therapy (as assessed by contrast enhanced MRI), or Asymptomatic and untreated but > 1 cm in the longest dimension

• The following cardiac abnormalities:

Corrected QT (QTc) interval >/= 480 msecs History of acute coronary syndromes (including unstable angina) within the past 24 weeks Coronary angioplasty, or stenting within the past 24 weeks Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system Abnormal cardiac valve morphology (>/= Grade 2) documented by echocardiogram (subjects with Grade 1 abnormalities [ie, mild regurgitation/stenosis] can be entered on study). Subjects with moderate valvular thickening should not be entered on study Known cardiac metastases History of known arrhythmias (except sinus arrhythmia) within the past 24 weeks

• Uncontrolled medical conditions (i.e., diabetes mellitus, hypertension, etc), psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol; or unwillingness or inability to follow the procedures required in the protocol;
• Pregnant, lactating or actively breastfeeding females.