Skin Cancer MedDRA version: 14.1 Level: SOC Classification code 10029104 Term: Neoplasms benign, malignant and unspecified (incl cysts and polyps) System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Name: GSK2118436
Product Code: GSK2118436
Pharmaceutical Form: Capsule
Current Sponsor code: GSK2118436
Other descriptive name: GSK2118436
Concentration unit: mg milligram(s)
Concentration typ
Sponsors
GlaxoSmithKline Research and Development Limited
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: PART A,B,C,D 1. Has signed informed consent; 2. Male or female at least 18 years of age at the time of signing the informed consent form; 3. Capable of compliance with the requirements and restrictions listed in the consent form; 4. Body weight = 45 kg and a body mass index = 19 kg/m2 and =65 years) yes F.1.3.1 Number of subjects for this age range 8
Exclusion criteria
Exclusion criteria: Parts A, B, C & D: 1. Currently receiving cancer therapy (e.g., chemotherapy with delayed toxicity, extensive radiation therapy, immunotherapy, biologic therapy) within the last 3 weeks; chemotherapy regimens without delayed toxicity within the last 2 weeks; 2. The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 28 days or 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is warranted by the data); 3. Current use of a prohibited medication or herbal preparation (Section 7.2) or requires any of these medications during the study; 4. Consumption of red wine, Seville oranges, grapefruit or grapefruit juice from 7 days prior to the first dose of study medication; 5. History of sensitivity to heparin or heparin-induced thrombocytopenia; 6. Any major surgery within the last 4 weeks; 7. Unresolved toxicity greater than National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI CTCAE v4.0) [NCI, 2009] Grade 2 from previous anti-cancer therapy except alopecia; 8. Presence of active GI disease or other condition (e.g., small bowel or large bowel resection) that will interfere significantly with the absorption of drugs. If clarification is needed as to whether a condition will significantly affect absorption of drugs, contact the GSK medical monitor; 9. A history of known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection (subjects with laboratory evidence of HBV clearance may be enrolled); 10. Presence of invasive malignancy, other than the primary diagnosis;11. Parts B and C and D: Subjects with brain metastases are excluded if their brain metastases are: • Symptomatic • Treated (surgery, radiation therapy) but not clinically and radiographically stable one month after local therapy, OR • Asymptomatic and untreated but > 1 cm in the longest dimension Patients with small (= 1 cm in the longest dimension), asymptomatic brain metastases that do not need immediate local therapy can be enrolled. Subjects on a stable dose of corticosteroids for more than one month, or those who have been off corticosteroids for at least 2 weeks can be enrolled. Subjects must also be off of enzyme-inducing anticonvulsants for more than 4 weeks; PART A : Any brain metastases (must be excluded by prior imaging); 12. Corrected QT (QTcB) interval = 480 msecs; 13. History of acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting within the past 24 weeks; 14. Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system (Appendix 3); abnormal cardiac valve morphology documented by ECHO (subjects with minimal abnormalities [i.e., mild regurgitation/stenosis] can be entered on study - if clarification is needed as to whether an ECHO abnormality is minimal, please contact the GSK medical monitor); or history of known cardiac arrhythmias (except sinus arrythmias) within the past 24 weeks; 15. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study drugs, or excipients (note: to date there are no known drugs chemically related to GSK2118436 which are approved by the FDA) 16. Uncontrolled medical conditions (e.g., diabetes mellitus, hypertension, liver disease), p
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: PART A-To evaluate the effect of repeat doses of GSK2118436 on the single dose PK of S-warfarin in subjects with BRAF mutant solid tumors. PART B & C-To evaluate the effect of repeat oral doses of an inhibitor, ketoconazole (Part B) or gemfibrozil (Part C) on the repeat dose PK of GSK2118436 in subjects with BRAF mutant solid tumors • To evaluate the single- and repeat-dose PK of GSK2118436 and its metabolites (GSK2285403, GSK2167542, GSK2298683) following administration of GSK2118436 75 mg HPMC capsules(or lower dose, based on emerging PK data) PART D (REPEAT DOSING WITH GSK2118436) To evaluate the single- and repeat dose PK of GSK2118436 and its metabolites (GSK2285403, GSK2167542, GSK2298683) following administration of GSK2118436 150 mg BID HPMC capsules. PART B & D (REPEAT DOSING WITH GSK2118436) SEE PROTOCOL P25;Secondary Objective: PART A-• To evaluate the effect of repeat doses of GSK2118436 on the single dose PK of R-warfarin • To confirm exposure to GSK2118436 • To assess the short term safety and tolerability of warfarin and GSK2118436. PART B&C-To assess the PK of GSK2118436 and its metabolites, GSK2285403, GSK2167542, GSK2298683 with ketoconazole (Part B) and gemfibrozil (Part C). • To assess the short term safety and tolerability of ketoconazole (Part B), gemfibrozil (Part C) in combination with GSK2118436 • To confirm exposure to inhibitors [ketoconazole (Part B) or gemfibrozil (Part C)]. PART D (REPEAT DOSING WITH GSK2118436)-To assess the short term safety and tolerability of repeat doses of GSK2118436.;Primary end point(s): Part A—Pharmacokinetic parameters of Cmax, AUC(0-t) and AUC(0-inf) of S-warfarin with and without GSK2118436. Parts B (ketoconazole) and C (Gemfibrozol)- Pharmacokinetic parameters of Cmax, and AUC(0-t) of GSK2118436 with and without inhibitor. Day 1: tmax, Cmax, AUC(0-t), AUC(0-24), AUC(0-inf), half-life Day 18: tmax, Cmax, AUC(0-t), Ct Part D Day 1: Pharmacokinetic parameters of tmax, Cmax, AUC(0-t), AUC(0-2 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Part A- Pharmacokinetic parameters of Cmax, AUC(0-t) and AUC(0-inf) of R-warfarin with and without GSK2118436 • tmax, t½ for R- and S-warfarin • Ct (trough) and Cmax concentrations of GSK2118436 • AEs; electrocardiogram (ECG); changes in laboratory values and vital signs; international normalized ratio (INR) Parts B (ketoconazole) and C (Gemfibrozol)-Pharmacokinetic parameters of Day 22: tmax, and Ct for GSK2118436; AUC(0-t), Cmax, tmax, Ct of GSK2285403, GSK2167542 and GSK2298683, and AUC(0-t) ratio of metabolite to parent (GSK2118436) • Safety and tolerability data including vital signs, ECG data, clinical laboratory tests, and AEs. • Ketoconazole and gemfibrozil concentrations on Day 22 Part D-- AEs; ECGs; changes in laboratory values and vital signs ;Timepoint(s) of evaluation of this end point: Part A Day 1 (along with blood sample on Days 2, 3, 4, 6 and 8) and Day 22 (along with blood samples on Days 23, 24, 25, 27, and 29) Parts B and C- Day 1, Day 18 and Day 22 Part D-Day 1 and Day 18 | — |
Countries
Australia, Switzerland, United Kingdom, United States
Contacts
Public ContactClinical Trials Helpdesk
GlaxoSmithKline
Outcome results
None listed