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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT01738451




Registration number
NCT01738451
Ethics application status
Date submitted
15/11/2012
Date registered
30/11/2012
Date last updated
13/11/2017

Titles & IDs
Public title
A Study to Evaluate the Effect of Repeat Oral Dosing of GSK2118436 on Cardiac Repolarization in Subjects With V600 BRAF Mutation-Positive Tumors
Scientific title
A Two-Part Study to Evaluate the Effect of Repeat Oral Dosing of GSK2118436 on Cardiac Repolarization in Subjects With V600 BRAF Mutation-Positive Tumors: An Open-label, Dose-escalating Safety Lead-in Study Followed by a Single-sequence, Placebo-controlled, Single-blind Study
Secondary ID [1] 0 0
113773
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 - GSK2118436 75 mg
Treatment: Drugs - Placebo

Experimental: Part 1(Cohort 1): GSK2118436 225 mg - GSK2118436 (3 capsules of 75 mg) will be administered orally at the dose of 225 mg BID from Day 1 to 7 (and single dose on Day 8) under fasted conditions, either 1 hour before or 2 hours after a meal.

Experimental: Part 1(Cohort 2): GSK2118436 300 mg - GSK2118436 (4 capsules of 75 mg) will be administered orally at the dose of 300 mg BID from Day 1 to 7 (and single dose on Day 8) under fasted conditions, either 1 hour before or 2 hours after a meal. If 225 mg BID is not tolerated in Part 1 /Cohort 1, then Part 1/Cohort 2 will not be initiated and 150 mg BID will be used in Part 2.

Experimental: Part 2: GSK2118436 300 mg (or highest tolerated dose) - Subjects will receive a single dose of GSK2118436/placebo (4 capsules of 75 mg/highest tolerated dose) orally on the first 2 days of the study followed by 2 doses daily for 6 days and a single dose on the 9th day. There will be 1 day when a placebo will be given. All doses will be administered under fasted conditions, either 1 hour before or 2 hours after a meal.


Treatment: Drugs: GSK2118436 75 mg
Each capsule contains 75 mg of GSK2118436A as the mesylate salt, micronized particles as active equivalents.

Treatment: Drugs: Placebo
Matching placebo capsules will be administered in Part 2 of the study.

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Part 1: Safety and tolerability of GSK2118436 as assessed by changes in physical examination findings
Timepoint [1] 0 0
Screening, Day 1 and Week 6.
Primary outcome [2] 0 0
Part 1: Safety and tolerability of GSK2118436 as assessed by changes in vital signs measurements
Timepoint [2] 0 0
Screening, pre-dose and 8 hours post-dose on Study Day 1, 8, 15, and Week 6.
Primary outcome [3] 0 0
Part 1: Safety and tolerability of GSK2118436 as assessed by changes in ECG readings
Timepoint [3] 0 0
Screening, Day 1, 8 Day 15 and Week 6. On study days 1 and 8, ECG will be obtained at 30 minutes pre-dose and 2-hours (hrs) post-dose administration.
Primary outcome [4] 0 0
Part 1: Safety and tolerability of GSK2118436 as assessed by changes in clinical laboratory assessments
Timepoint [4] 0 0
Day 1, 8, 15 and and Week 6.
Primary outcome [5] 0 0
Part 2: Change from Baseline in QTcF interval at each time point for GSK2118436
Timepoint [5] 0 0
Baseline (Study Day -1)/pre-dose (Study Days 1 and 8) (within 30 minutes prior to administration of study treatment) and 1, 1.5, 2, 3, 4, 6, 8, 10 and 24-hrs post-dose. Day 2 and 9, 24 hr post dose Holter ECG.
Secondary outcome [1] 0 0
Part 1: Plasma concentration of GSK2118436 and its metabolites
Timepoint [1] 0 0
On Day 1 and Day 8 at pre-dose (30 minutes (mins) prior to the administration of study treatment) and 1, 1.5, 2, 3, 4, 6, 8, and 10-hours post-dose.
Secondary outcome [2] 0 0
Part 1: The AUC(0-t)) of GSK2118436 and its metabolites
Timepoint [2] 0 0
On Day 1 and Day 8 at pre-dose (30 mins prior to the administration of study treatment) and 1, 1.5, 2, 3, 4, 6, 8, and 10-hours post-dose.
Secondary outcome [3] 0 0
Part 1: The Cmax of GSK2118436 and its metabolites
Timepoint [3] 0 0
Part 1: Day 1 and Day 8 pre-dose (30 mins prior to the administration of study treatment) and 1, 1.5, 2, 3, 4, 6, 8, and 10-hours post-dose.
Secondary outcome [4] 0 0
The Ctrough of GSK2118436 and its metabolites
Timepoint [4] 0 0
Part 1: Day 8 pre-dose (30 mins prior to the administration of study treatment) and 1, 1.5, 2, 3, 4, 6, 8, and 10-hours post-dose.
Secondary outcome [5] 0 0
The tmax of GSK2118436 and its metabolites
Timepoint [5] 0 0
Part 1: Day 1 and Day 8 pre-dose (30 mins prior to the administration of study treatment) and 1, 1.5, 2, 3, 4, 6, 8, and 10-hours post-dose.
Secondary outcome [6] 0 0
Part 2: Change from Baseline in slope of the relationships between the baseline-adjusted, placebo-corrected change in QTc interval and the plasma concentrations of GSK2118436 or its metabolites and predicted change in QTc
Timepoint [6] 0 0
Part 2: Baseline (pre-dose study Days 1 and 8 within 30 minutes prior to administration of study treatment) and 1, 1.5, 2, 3, 4, 6, 8, 10 and 24-hrs post-dose (Day 1 and 8). On Day 2 and 9, 24-hr post-dose PK sample and Holter ECG.
Secondary outcome [7] 0 0
Part 2: ECG parameters: and morphology assessments
Timepoint [7] 0 0
Part 2: Baseline (pre-dose study Days 1 and 8 within 30 minutes prior to administration of study treatment) and 1, 1.5, 2, 3, 4, 6, 8, 10 and 24-hrs post-dose (Day 1 and 8). On Day 2 and 9, 24-hr post dose Holter ECG.
Secondary outcome [8] 0 0
Part 2: Plasma concentrations of GSK2118436 and its metabolites
Timepoint [8] 0 0
On Days -1, 1 and 8 at pre-dose (within 30 minutes prior to administration of study treatment) and 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hrs post-dose (Day 1 and 8). On Days 2 and 9 at 24-hr post dose PK sample.
Secondary outcome [9] 0 0
The AUC(0-10) and AUC(0 t) of GSK2118436 and its metabolites (GSK2285403, GSK2298683 and GSK2167542)
Timepoint [9] 0 0
Part 2: Days -1, 1 and 8: pre-dose (within 30 minutes prior to administration of study treatment) and 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hrs post-dose (Day 1 and 8). On Day 2 and 9, 24-hr post dose PK sample.
Secondary outcome [10] 0 0
The AUC(0-infinity) of GSK2118436 and its metabolites (GSK2285403, GSK2298683 and GSK2167542)
Timepoint [10] 0 0
Part 2: Day 1: pre-dose (within 30 minutes prior to administration of study treatment) and 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hrs post-dose (Day 1).
Secondary outcome [11] 0 0
The t½ of GSK2167542 and its metabolites
Timepoint [11] 0 0
Part 2: Study Day 1 pre-dose (within 30 minutes prior to administration of study treatment) and 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hrs post-dose.
Secondary outcome [12] 0 0
Part 2: The Ctrough of GSK2167542 and its metabolites
Timepoint [12] 0 0
Part 2: Study Day 8 pre-dose (within 30 minutes prior to administration of study treatment) and 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hrs post-dose.
Secondary outcome [13] 0 0
Part 2: The Cmax, of GSK2167542 and its metabolites
Timepoint [13] 0 0
Days -1, 1 and 8: pre-dose (within 30 minutes prior to administration of study treatment) and 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hrs post-dose (Day 1 and 8). On Day 2 and 9, 24-hr post dose PK sample.
Secondary outcome [14] 0 0
Part 2: The tmax, of GSK2167542 and its metabolites
Timepoint [14] 0 0
Days -1, 1 and 8: pre-dose (within 30 minutes prior to administration of study treatment) and 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hrs post-dose (Day 1 and 8). On Day 2 and 9, 24-hr post dose PK sample.
Secondary outcome [15] 0 0
Part 2: Safety of GSK2118436 as assessed by number of subjects with adverse events (AE)s
Timepoint [15] 0 0
Continuous throughout the study.
Secondary outcome [16] 0 0
Part 2: Safety of GSK2118436 as assessed by changes in vital signs measurements
Timepoint [16] 0 0
Screening, Day -1, Day 1, Day 8, Day 9 and Week 5.
Secondary outcome [17] 0 0
Part 2: Safety of GSK2118436 as assessed by changes in ECG readings
Timepoint [17] 0 0
Screening, Day -1, Day 1, Day 2, Day 8, Day 9 and Week 5.
Secondary outcome [18] 0 0
Part 2: Safety of GSK2118436 as assessed by changes in clinical laboratory assessments
Timepoint [18] 0 0
Screening, Day -1, Day 1, Day 8, Day 9 and Week 5.

Eligibility
Key inclusion criteria
* Has provided signed, written informed consent for this study.
* Male or female, age >=18 years of age at the time of signing the informed consent form
* Has confirmed diagnosis of a V600 BRAF-mutation positive tumor as determined by appropriate genetic testing.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
* Has adequate baseline organ function as defined by: Absolute neutrophil count>=1.2 × 10^9/liter (L), hemoglobin>=9 gram (g)/deciliter (dL), platelets>= 75 × 10^9/L, prothrombin time (PT), international normalization ratio (INR) and partial thromboplastin time (PTT)<=1.3 times upper limit of normal (ULN), total bilirubin<=1.5 times ULN, alanine aminotransferase (ALT)<=2.5 times ULN; <5 times ULN if liver metastases are present, creatinine or<=1.5 times ULN, calculated creatinine clearance or 24-hour urine creatinine clearance>=60 mL/min and left ventricular ejection fraction (LVEF)>= institutional lower limit of normal (LLN) by echocardiogram (ECHO).
* For Part 2 subjects only: Have serum potassium, serum magnesium, and total serum calcium levels within normal limits.
* Able to swallow and retain orally administered medication and does not have any clinically significant GI abnormalities that may alter the absorption such as malabsorption syndrome or major resection of the stomach or bowels.
* If a female subject of childbearing potential, must have a negative serum pregnancy test within 14 days of first dose of study treatment and agree to use effective contraception, during the study and for 4 weeks following the last dose of study treatment.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
* Known immediate or delayed hypersensitivity reaction to dabrafenib or excipients;
* Any of the following ECG findings: QT duration corrected using Fridericia's formula (QTcF) interval >450 milliseconds (msec), PR interval >220 msec or <=110 msec, bradycardia defined as sinus rate <50 beats per minute (bpm)
* Cardiac conduction abnormalities denoted by any of the following: evidence of second-degree (type II) or third-degree atrioventricular block, evidence of ventricular pre-excitation, electrocardiographic evidence of complete left bundle branch block (LBBB), intraventricular conduction delay with QRS duration >120 msec, evidence of atrial fibrillation or history of atrial fibrillation within the past 6 months or presence of cardiac pacemaker
* History of any one of the following cardiovascular conditions within the past 6 months: Class II, III, IV heart failure as defined by the New York Heart Association (NYHA), cardiac angioplasty or stenting, myocardial infarction, unstable angina or symptomatic peripheral vascular disease or other clinically significant cardiac disease
* LVEF, as measured by ECHO, below the institutional LLN, or if a LLN does not exist at an institution, <50%.
* Abnormal cardiac valve morphology (>=grade 2) documented by echocardiogram (subjects with minimal abnormalities [ie, mild regurgitation/stenosis] can be entered)
* Moderate valvular thickening
* Personal or immediate family history of long-QT syndrome.
* Anti-cancer therapy (e.g., chemotherapy with delayed toxicity, extensive radiation therapy, immunotherapy, biologic therapy, or major surgery) within 21 days prior to enrolment; chemotherapy regimens without delayed toxicity within 14 days prior to enrollment; or use of an investigational anti-cancer drug within 28 days preceding the first dose of study treatment.
* Current use of a prohibited medication(s) or requires any of these medications during treatment with study treatment
* Current use of therapeutic warfarin.
* Unresolved toxicity of Grade 2 or higher from previous anticancer therapy, except alopecia or hemoglobin.
* A history of known Human Immunodeficiency Virus, Hepatitis B Virus (HBV), or Hepatitis C Virus infection. Subjects with documented laboratory evidence of HBV clearance may be enrolled.
* A history of known glucose-6-phosphate dehydrogenase (G6PD) deficiency.
* Brain metastases that are: symptomatic, or treated (surgery, radiation therapy) but not clinically and radiographically stable 1 month after local therapy, or asymptomatic and untreated but >1 centimeter (cm) in the longest dimension
* Uncontrolled medical conditions (i.e., diabetes mellitus, hypertension), 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.
* History of another malignancy; Only (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 (definition: clinical stage T1 or T2a, Gleason score <=6, and PSA < 10 nanogram (ng)/mL) requiring no or only anti-hormonal therapy with histologically confirmed tumour lesions that can be clearly differentiated from lung cancer target and non-target lesions are eligible
* Pregnant or lactating/actively breastfeeding female.

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
Single group
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
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 0 0
GSK Investigational Site - Heidelberg
Recruitment hospital [2] 0 0
GSK Investigational Site - Melbourne
Recruitment postcode(s) [1] 0 0
3084 - Heidelberg
Recruitment postcode(s) [2] 0 0
3004 - Melbourne
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
Tennessee
Country [3] 0 0
United States of America
State/province [3] 0 0
Texas
Country [4] 0 0
United States of America
State/province [4] 0 0
Utah
Country [5] 0 0
United Kingdom
State/province [5] 0 0
London

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

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
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

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

No documents have been uploaded by study researchers.