| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | SOC |
| E.1.2 | Classification code | 10029104 |
| E.1.2 | Term | Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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 |
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| E.2.2 | Secondary objectives of the trial |
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. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 <40 kg/m2 (inclusive);
5. Able to swallow and retain oral medication;
6. BRAF V600 mutation-positive tumor as confirmed in a CLIA-approved laboratory or equivalent (the local BRAF testing may be subject to subsequent verification by centralized testing);
7. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 (Appendix 2); NOTE: Subjects with a performance status of 2 can be enrolled if the patient’s confinement to bed and inability to carry our work activities is due solely to cancerrelated
pain, as assessed by the Investigator.
8. Women of child-bearing potential and men with reproductive potential must be willing to practice acceptable methods of birth control (see Section 7.1). Additionally, women of childbearing potential must have a negative serum pregnancy test within 14 days prior to the first dose of study medication;
9. Must have adequate organ function as defined by the following values:
• Absolute neutrophil count (ANC) ≥1.5x109/L
• Hemoglobin ≥9 g/dLPlatelets ≥100 x 109/L
• Serum bilirubin ≤1.5 x ULN
• AST and ALT ≤ 2.5 x ULN; <5 x ULN if liver metastases are present (requires radiographic confirmation of liver metastases)
• Serum Creatinine ≤1.5 mg/dL;
• PT/INR and partial thromboplastin time (PTT) ≤1.3 x ULN
• Left ventricular ejection fraction ≥ institutional lower limit of normal by ECHO
PART A ONLY:10. CYP2C9 genotype of *1/*1 (wildtype), *1/*2 or *1/*3 |
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| E.4 | Principal 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), 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; 17. Subjects with known glucose 6 phosphate dehydrogenase (G6PD) deficiency; 18. Pregnant females as determined by positive hCG test at screening or prior to dosing;
19. Lactating females who are actively breast feeding; 20. Subject is mentally or legally incapacitated; Part A ONLY-
21. Use of warfarin or exogenous Vitamin K (other than from dietary sources) within 30 days prior to treatment with study medication;
22. Subjects with history of GI bleeding, or GI ulceration;
23. Subjects with known history of Protein C and/or Protein S deficiency, or any other type of coagulopathy;
24. Subjects requiring any type of anticoagulation, or taking Aspirin at doses greater than 81 mg/day;
25. Subjects with brain metastases;
26. Any subject who by history regularly consumes a large quantity of foods rich in vitamin K will be excluded unless he/she restricts the vitamin K intake for at least one week prior to the first dose of warfarin. For study purposes, large quantities of vitamin K-containing food will be defined as 10 or more portions per week of the following: kale, spinach, turnip greens, cauliflower, chick peas, brussels sprouts, green tea, liver, soybean oil and soy protein products. |
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| E.5 End points |
| E.5.1 | 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-τ) of GSK2118436 with and without inhibitor. Day 1: tmax, Cmax, AUC(0-τ), AUC(0-24), AUC(0-inf), half-life Day 18: tmax, Cmax, AUC(0-τ), Cτ
Part D Day 1: Pharmacokinetic parameters of tmax, Cmax, AUC(0-τ), AUC(0-24), AUC(0-inf), half-life Day 18: tmax, Cmax, AUC(0-τ), Cτ. Time invariance and accumulation ratio
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| E.5.1.1 | 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
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| E.5.2 | 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 • Cτ (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 Cτ for GSK2118436; AUC(0-τ), Cmax, tmax, Cτ of GSK2285403, GSK2167542 and GSK2298683, and AUC(0-τ) 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
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| E.5.2.1 | 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
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 4 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Switzerland |
| United Kingdom |
| United States |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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After study participation in the current study, subjects will either:
• Transition to rollover study BRF114144, where subjects continue receiving GSK2118436 (follow-up visit required only as described in the Time and Events Table), OR
• Discontinue GSK2118436 (e.g., subject chooses not to enter the roll-over study), where a follow-up visit should be performed (as described in the Time and Events Table). |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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