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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT01340846




Registration number
NCT01340846
Ethics application status
Date submitted
14/04/2011
Date registered
25/04/2011
Date last updated
13/11/2017

Titles & IDs
Public title
A Pharmacokinetics Study of the Effects of GSK2118436 on Warfarin, the Effects of Ketoconazole and Gemfibrozil on GSK2118436, and the Effects of Repeat Doses of GSK2118436 in Subjects With BRAF Mutant Solid Tumors
Scientific title
A Four-Part, Open-Label Study to Evaluate the Effects of Repeat Dose GSK2118436 on the Single Dose Pharmacokinetics of Warfarin, the Effects of Repeat Dose Oral Ketoconazole and Oral Gemfibrozil on the Repeat Dose Pharmacokinetics of GSK2118436, and the Repeat Dose Pharmacokinetics of GSK2118436 in Subjects With BRAF Mutant Solid Tumors
Secondary ID [1] 0 0
113771
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cancer 0 0
Condition category
Condition code

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Warfarin
Treatment: Drugs - Ketoconazole
Treatment: Drugs - Gemfibrozil
Treatment: Drugs - GSK2118436 150mg
Treatment: Drugs - GSK2118436 75mg

Experimental: Part A - Warfarin dosed at 15mg

Experimental: Part B - Ketoconazole dosed at 400mg

Experimental: Part C - Gemfibrozil dosed at 600mg

Experimental: Part D - GSK2118436 dosed alone


Treatment: Drugs: Warfarin
Warfarin dosed at 15mg on Day 1 and Day 22

Treatment: Drugs: Ketoconazole
Ketoconazole dosed at 400mg daily on Days 19 through 22

Treatment: Drugs: Gemfibrozil
Gemfibrozil dosed at 600mg twice daily on Days 19 through 22

Treatment: Drugs: GSK2118436 150mg
GSK2118436 dosed at 150mg twice daily

Treatment: Drugs: GSK2118436 75mg
GSK2118436 dosed at 75mg twice daily
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Maximum plasma concentration (Cmax) of S-warfarin with and without GSK2118436
Timepoint [1] 0 0
Up to 168 hours after dosing on Day 1 (warfarin alone) and Day 22 (warfarin in combination with GSK2118436)
Primary outcome [2] 0 0
Area under the concentration time curve (AUC) of S-warfarin with and without GSK2118436
Timepoint [2] 0 0
Up to 168 hours after dosing on Day 1 (warfarin alone) and Day 22 (warfarin in combination with GSK2118436)
Primary outcome [3] 0 0
Maximum plasma concentration (Cmax) of GSK2118436 with and without an inhibitor
Timepoint [3] 0 0
Up to 12 hours after dosing on Day 18 (GSK2118436 alone) and Day 22 (GSK2118436 in combination with inhibitor)
Primary outcome [4] 0 0
Area under the concentration time curve (AUC) of GSK2118436 with and without an inhibitor
Timepoint [4] 0 0
Up to12 hours after dosing on Day 18 (GSK2118436 alone) and Day 22 (GSK2118436 in combination with inhibitor)
Primary outcome [5] 0 0
Cmax of GSK2118436 and metabolites after single and multiple 75mg HPMC dose
Timepoint [5] 0 0
Up to 24 hours after dosing on Day 1 and up to 12 hours after dosing on Day 18
Primary outcome [6] 0 0
AUC of GSK2118436 and metabolites after single and multiple 75mg HPMC dose
Timepoint [6] 0 0
Up to 24 hours after dosing on Day 1 and up to 12 hours after dosing on Day 18
Primary outcome [7] 0 0
Time to Cmax (Tmax) of GSK2118436 and metabolites after single and multiple 75mg HPMC dose
Timepoint [7] 0 0
Up to 24 hours after dosing on Day 1 and up to 12 hours after dosing on Day 18
Primary outcome [8] 0 0
Half-life of GSK2118436 and metabolites after single 75mg HPMC dose
Timepoint [8] 0 0
Up to 24 hours after dosing on Day 1
Primary outcome [9] 0 0
Cmax of GSK2118436 and metabolites after single and multiple 150mg HPMC dose
Timepoint [9] 0 0
Up to 24 hours after dosing on Day 1 and up to 12 hours after dosing on Day 18
Primary outcome [10] 0 0
AUC of GSK2118436 and metabolites after single and multiple 150mg HPMC dose
Timepoint [10] 0 0
Up to 24 hours after dosing on Day 1 and up to 12 hours after dosing on Day 18
Primary outcome [11] 0 0
Tmax of GSK2118436 and metabolites after single and multiple 150mg HPMC dose
Timepoint [11] 0 0
Up to 24 hours after dosing on Day 1 and up to 12 hours after dosing on Day 18
Primary outcome [12] 0 0
Half-life of GSK2118436 and metabolites after single 150mg HPMC dose
Timepoint [12] 0 0
Up to 24 hours after dosing on Day 1
Secondary outcome [1] 0 0
Cmax of R-warfarin with and without GSK2118436
Timepoint [1] 0 0
Up to 168 hours after dosing on Day 1 (warfarin alone) and Day 22 (warfarin in combination with GSK2118436)
Secondary outcome [2] 0 0
Time to Cmax (Tmax) of R-warfarin
Timepoint [2] 0 0
Up to 168 hours after dosing on Day 1 (warfarin alone) and Day 22 (warfarin in combination with GSK2118436)
Secondary outcome [3] 0 0
Trough concentration of GSK2118436
Timepoint [3] 0 0
Up to168 hours after dosing on Day 22
Secondary outcome [4] 0 0
Number of subjects with adverse events as a measure of safety and tolerability
Timepoint [4] 0 0
From date of first dose to transition to Rollover protocol BRF114144 (22 - 29 days) or study follow up visit if subject does not transition to BRF114144 (approximately 29 - 39 days)
Secondary outcome [5] 0 0
Tmax for GSK2118436 with and without an inhibitor
Timepoint [5] 0 0
Up to 12 hours after dosing on Day 18 (GSK2118436 alone) and Day 22 (GSK2118436 in combination with inhibitor)
Secondary outcome [6] 0 0
AUC, Cmax, Tmax and trough concentration of GSK2118436 metabolites with and without an inhibitor, and AUC ratio of metabolites to parent
Timepoint [6] 0 0
Up to 12 hours after dosing on Day 18 (GSK2118436 alone) and Day 22 (GSK2118436 in combination with inhibitor)
Secondary outcome [7] 0 0
Inhibitor concentrations in combination with GSK2118436
Timepoint [7] 0 0
Up to12 hours after dosing on Day 22 (GSK2118436 in combination with inhibitor)
Secondary outcome [8] 0 0
AUC of R-warfarin with and without GSK2118436
Timepoint [8] 0 0
Up to 168 hours after dosing on Day 1 (warfarin alone) and Day 22 (warfarin in combination with GSK2118436)
Secondary outcome [9] 0 0
Terminal half-life (t1/2) of R-warfarin
Timepoint [9] 0 0
Up to 168 hours after dosing on Day 1 (warfarin alone) and Day 22 (warfarin in combination with GSK2118436)
Secondary outcome [10] 0 0
Cmax of GSK2118436
Timepoint [10] 0 0
Up to168 hours after dosing on Day 22
Secondary outcome [11] 0 0
Trough concentration for GSK2118436 with and without an inhibitor
Timepoint [11] 0 0
Up to 12 hours after dosing on Day 18 (GSK2118436 alone) and Day 22 (GSK2118436 in combination with inhibitor)
Secondary outcome [12] 0 0
Cmax of GSK2118436 metabolites with and without an inhibitor
Timepoint [12] 0 0
Up to 12 hours after dosing on Day 18 (GSK2118436 alone) and Day 22 (GSK2118436 in combination with inhibitor)
Secondary outcome [13] 0 0
Tmax of GSK2118436 metabolites with and without an inhibitor
Timepoint [13] 0 0
Up to 12 hours after dosing on Day 18 (GSK2118436 alone) and Day 22 (GSK2118436 in combination with inhibitor)
Secondary outcome [14] 0 0
Trough concentration of GSK2118436 metabolites with and without an inhibitor
Timepoint [14] 0 0
Up to 12 hours after dosing on Day 18 (GSK2118436 alone) and Day 22 (GSK2118436 in combination with inhibitor)
Secondary outcome [15] 0 0
AUC ratio of metabolites to parent with and without an inhibitor
Timepoint [15] 0 0
Up to 12 hours after dosing on Day 18 (GSK2118436 alone) and Day 22 (GSK2118436 in combination with inhibitor)

Eligibility
Key inclusion criteria
- Male or female at least 18 years of age at the time of signing the informed consent
form;

- Capable of giving written informed consent, which includes compliance with the
requirements and restrictions listed in the consent form;

- Body weight >/= 45 kg and a body mass index >/= 19 kg/m2 and </= 35 kg/m2 (inclusive);

- Able to swallow and retain oral medication;

- BRAF V600 mutation-positive tumor as determined in a CLIA-approved laboratory or
equivalent (the local BRAF testing may be subject to subsequent verification by
centralized testing);

- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1; NOTE: Subjects
with a performance status of 2 can be enrolled if the patient's confinement to bed and
inability to carry out work activities is due solely to cancer-related pain, as
assessed by the Investigator;

- Women of child-bearing potential and men with reproductive potential must be willing
to practice acceptable methods of birth control. Additionally, women of childbearing
potential must have a negative serum pregnancy test within 14 days prior to the first
dose of study medication;

- Must have adequate organ function as defined by the following values:

Absolute neutrophil count (ANC) >/=1.2 x 109/L Hemoglobin >/= 9 g/dL Platelets >/= 100 x
109/L Serum bilirubin >/= 1.5 x Upper Limit of Normal (ULN) AST and ALT >/= 2.5 x ULN; <5 x
ULN if liver metastases are present (with approval of GSK medical monitor) Serum creatinine
>/= ULN or calculated creatinine clearance >/= 60 mL/min PT/INR and partial thromboplastin
time (PTT) >/= 1.3 x ULN Left ventricular ejection fraction >/= institutional lower limit
of normal by ECHO

- CYP2C9 genotype of *1/*1 (wildtype), *1/*2 or *1/*3 (Part A only)
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Currently receiving cancer therapy (e.g., chemotherapy with delayed toxicity,
extensive radiation therapy, immunotherapy, biologic therapy) within the last three
weeks; chemotherapy regimens without delayed toxicity within the last 2 weeks;

- 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, 5 half-lives or twice the duration of the biological effect of the
investigational product (whichever is warranted by the data);

- Current use of a prohibited medication or herbal preparation or requires any of these
medications during the study;

- Consumption of red wine, Seville oranges, grapefruit or grapefruit juice from 7 days
prior to the first dose of study medication;

- History of sensitivity to heparin or heparin-induced thrombocytopenia;

- Any major surgery within the last 4 weeks;

- 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;

- 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;

- 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);

- Presence of invasive malignancy, other than the primary diagnosis;

- Parts B and C: Subjects with brain metastases are excluded if their brain metastases
are either:

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 with the approval of
the GSK medical monitor. Subjects on a stable dose of corticosteroids for more than one
month, or those who have been off corticosteroids for at least two weeks can be enrolled.
Subjects must also be off of enzyme-inducing anticonvulsants for more than four weeks;
Note: Any brain metastases is exclusionary for Part A (must be excluded by prior imaging);

- Corrected QT (QTcB) interval >/= 480 msecs;

- History of acute coronary syndromes (including unstable angina), 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 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;

- 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);

- 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;

- Subjects with known glucose 6 phosphate dehydrogenase (G6PD) deficiency;

- Pregnant females as determined by positive hCG test at screening or prior to dosing;

- Lactating females who are actively breast feeding;

- Subject is mentally or legally incapacitated;

- Part A only: Use of warfarin or exogenous Vitamin K (other than from dietary sources)
within 30 days prior to treatment with study medication;

- Part A only: Subjects with history of GI bleeding, or GI ulceration;

- Part A only: Subjects with known history of Protein C and/or Protein S deficiency, or
any other type of coagulopathy;

- Part A only: Subjects requiring any type of anticoagulation, or taking Aspirin at
doses greater than 81 mg/day;

- Part A only: Subjects with brain metastases;

- Part A only: 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
3/09/2012
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
14/11/2012
Sample size
Target
Accrual to date
Final
48
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 0 0
GSK Investigational Site - Nedlands
Recruitment postcode(s) [1] 0 0
6009 - Nedlands
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Arizona
Country [2] 0 0
United States of America
State/province [2] 0 0
Florida
Country [3] 0 0
United States of America
State/province [3] 0 0
Michigan
Country [4] 0 0
United States of America
State/province [4] 0 0
Ohio
Country [5] 0 0
United States of America
State/province [5] 0 0
Oklahoma
Country [6] 0 0
United States of America
State/province [6] 0 0
South Carolina
Country [7] 0 0
United States of America
State/province [7] 0 0
Tennessee
Country [8] 0 0
United States of America
State/province [8] 0 0
Utah
Country [9] 0 0
United Kingdom
State/province [9] 0 0
Headington
Country [10] 0 0
United Kingdom
State/province [10] 0 0
London

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
GlaxoSmithKline
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
GSK2118436 is an orally administered, potent and selective small molecule BRAF inhibitor that
is being developed for the treatment of BRAF mutation-positive tumors. This is a 4-part study
(in 4 separate cohorts of subjects) designed to examine the interaction potential of
GSK2118436, either as a perpetrator (i.e., effect of GSK2118436 on warfarin; Part A) or
victim (i.e., effect of other drugs on GSK2118436; Part B: ketoconazole and Part C:
gemfibrozil), as well as to evaluate the single and repeat dose pharmacokinetic parameters of
GSK2118436 (Part D). A sufficient number of subjects will be screened to obtain approximately
12 evaluable subjects each for Part A, Part B, Part C and Part D. Following completion of
this study, subjects may continue dosing with GSK2118436 in the roll-over study, Protocol
BRF114144.
Trial website
https://clinicaltrials.gov/ct2/show/NCT01340846
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
GSK Clinical Trials
Address 0 0
GlaxoSmithKline
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT01340846