A Phase II study of the BRAF inhibitor dabrafenib as a single agent and in combination with the MEK inhibitor trametinib in subjects with BRAF V600E mutation positive metastatic (stage IV) non-small cell lung cancer.
Description: 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 orally twice daily (BID) and continue on treatment until disease progression, or unacceptable adverse event.
Subjects eligible for enrollment in the study must meet all of the following criteria: 1. Signed written informed consent; 2. Histologically or cytologically confirmed stage IV non-small cell cancer of the lung AJCC staging system, 7th edition) [Greene, 2009]. The subjects need to have received one or more prior cytotoxic chemotherapy regimen for advanced NSCLC. Chemotherapy administered as neoadjuvant, adjuvant, or with combined modality treatment (chemotherapy plus chest radiotherapy) more than 6 months prior to study enrollment is not considered a prior line of therapy for the purpose of the study; 3. Measurable disease according to RECIST 1.1 [Eisenhauer, 2009]; 4. Age ï¿½18 years of age; 5. Anticipated life expectancy of at least three months; 6. Presence of a V600E BRAF mutation in lung cancer tissue confirmed in a CLIA certified laboratory (or equivalent); 7. Able to swallow and retain oral medication; 8. Women with child-bearing potential and men with reproductive potential must be willing to practice acceptable methods of birth control during the study NOTE: Oral contraceptives are not reliable due to potential drug-drug interaction with GSK2118436 9. 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, (as defined in Section 7.4), during the study; 10. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2 [Oken, 1982] ; 11. Thorough dermatologic examination and documentation of baseline skin lesions with appropriate evaluation by a dermatologist as deemed necessary by the treating physician; 12. Must have adequate organ function as defined by the following baseline values: ï¿½ Absolute neutrophil count (ANC) ï¿½1.5x109/L ï¿½ Hemoglobin ï¿½9 g/dL ï¿½ Platelets ï¿½75x109/L ï¿½ Serum bilirubin ï¿½1.5 x upper limit of normal (ULN) ï¿½ Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ï¿½ 2.5xULN ï¿½ Serum creatinine ï¿½1.5 mg/dL (if serum creatinine is greater than 1.5 mg/dL, calculate creatinine clearance using standard Cockcroft and Gault; creatinine clearance must be greater than 50 mL/min); ï¿½ Prothrombin time /International normalized ratio (INR) and partial thromboplastin time ï¿½1.3xULN ï¿½ Left ventricular ejection fraction ï¿½ institutional lower limit of normal Subjects meeting any of the following criteria must not be enrolled in the study.Deviations from the exclusion criteria are not allowed because they can potentiallyjeopardize the scientific integrity of the study, regulatory acceptability or subject safety. 1. Previous treatment with a BRAF or MEK inhibitor; 2. Cancer therapy (chemotherapy with delayed toxicity, immunotherapy, biologic therapy, or major surgery) within the last three weeks; chemotherapy regimens without delayed toxicity within the last two weeks; or use of any nvestigational drug within 28 days or five half-lives, whichever is longer, preceding the first dose of GSK2118436; 3. Current use of a prohibited medication or expected to require any of these medications during treatment with GSK2118436 (Per protocol); 4. Current use of therapeutic warfarin NOTE: Low molecular weight heparin and prophylactic low-dose warfarin are permitted; 5. Unresolved toxicity of National Cancer Institute Common Terminology Criteria for Adverse Events, (NCI CTCAE v4.0) [NCI, 2009] Grade 2 or higher from previous anti-cancer therapy, except alopecia; 6. Presence of active gastrointestinal disease or other condition that will interfere significantly with the absorption of drugs. 7. A history of known human immunodeficiency virus (HIV) infection (subjects with laboratory evidence of hepatitis B virus clearance may be enrolled with notification of the GSK medical monitor); 8. A history of known glucose-6-phosphate dehydrogenase (G6PD) deficiency; 9. History of other malignancy within the past 3 years; Note: Subjects who have been successfully treated and cancer-free for three years,or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible; 10. Symptomatic central nervous system (CNS) metastases or newly diagnosed CNS metastases that have not yet been definitively treated with radiation and/or surgery. Subjects with previously diagnosed brain metastases are eligible if they have completed treatment with clinically stable disease for one month. Subjects must have discontinued corticosteroid treatment for at least 2 weeks before the first dose of study medication; 11. The following cardiac abnormalities: ï¿½ Corrected QT (QTc) interval 480 msecs ï¿½ History of acute coronary syndromes (including unstable angina) within the past 24 weeks ï¿½ Coronary angioplasty, or stenting within the past 24 weeks ï¿½ Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system ï¿½ Abnormal cardiac valve morphology (ï¿½ 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 ï¿½ Known cardiac metastases 12. 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; 13. Pregnant females; 14. Lactating females that are actively breastfeeding. Prohibited Medications: PROHIBITED ï¿½ strong inducers/inhibitors of CYP3A, CYP2C8, Pgp and Bcrp since concentrations of GSK2118436 may be decreased/increased: Strong CYP2C8/3A/Pgp/Bcrp Inhibitor/Inducer Therapeutic Area clarithromycin, telithromycin, rifamycin class agents (e.g. rifampin, rifabutin, rifapentine), troleandomycin-Antibiotics itraconazole, ketoconazole, posaconazole, voriconazole-Antifungals nefazodone-Antidepressants gemfibrozil-Hyperlipidemia carbamazepine, phenobarbital, amiodarone, , phenytoin, smephenytoin, bosentan, mibefranil, conivaptan-Miscellaneous Cyclosporine-Immunosuppressive agents
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 orally 150 mg twice daily (BID) and continue on treatment until disease progression,or unacceptable adverse event. Following screening, cycle visits are every 3 weeks. Scans are done every 2 cycles.
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