ClinicalTrials.gg
Sign In
CompletedNCT01738451Updated Nov 13, 2017

A Study to Evaluate the Effect of Repeat Oral Dosing of GSK2118436 on Cardiac Repolarization in Subjects With V600 BRAF Mutation-Positive Tumors

A Phase 1 interventional study of GSK2118436 75 mg and Placebo in Cancer, sponsored by GlaxoSmithKline. Completed at 8 sites in 3 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2017-11-13.

Sponsored by GlaxoSmithKline · Phase 1, Interventional, and Treatment

Phase
Phase 1
Study type
Interventional
Enrollment
50
Allocation
Non-randomized
Ages
18 Years and older
Sex
All
01

Study summary

This is a Phase I, multicenter, 2-part study with Part 1 designed as a safety lead-in and Part 2 designed to evaluate the effect of GSK2118436 on cardiac repolarization (corrected QT interval [QTc] duration) as compared with placebo in subjects with V600 BRAF mutation-positive tumors.

Each part of the study will consist of screening (14 days prior to the start of the study treatment), treatment and follow-up period (14 days).

In Part 1 in Cohort 1 six subjects will receive GSK2118436 225 mg twice a day (BID) on study days 1 to 7 and a single 225 milligram (mg) dose on morning of Day 8. Based on the safety data of subjects in Cohort 1 subjects will be enrolled in Cohort 2 and the dose of GSK2118436 will be escalated to 300 mg BID. If the 225 mg dose of GSK2118436 is not well tolerated in Cohort 1 (i.e., 2 or more dose-limiting toxicities [DLTs]), then Cohort 2 of Part 1 will not be initiated and a dose of 150 mg BID of GSK2118436 will be administered in Part 2 of the study. In Cohort 2 six subjects will receive GSK2118436 300 mg BID on Study Days 1 to 7 and a single 300 mg dose on the morning of Day 8. Based on the safety data of subjects in Cohort 2 subjects will be enrolled in Part 2. If the 300 mg BID dose level of GSK2118436 is not well tolerated, then the highest tolerated dose will be selected for Part 2 of the study.

In Part 1 of the study the decision to proceed to the next cohort or Part 2 of the study will be based on the safety data of at least 6 evaluable subjects (\<=1 DLTs during the 14 days following the first dose of GSK2118436).

In Part 2 of the study eligible 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.

In both the parts of the study serial blood samples for pharmacokinetic (PK) analysis for GSK2118436 and its metabolites (GSK2285403, GSK2298683 and GSK2167542) will be obtained at the same time points on the first and last day of dosing (2nd day of dosing also included for Part 2). Safety electrocardiogram (ECG)s will be performed at several timepoints during the study. In Part 2 Holter ECG monitoring will be performed for 24 hours on the 1st, 2nd and 9th days of dosing.

02

Conditions studied

  • Cancer

Browse trials for

Keywords

  • ECG intervals and morphology
  • BRAF-mutation positive tumor
  • Holter monitor
  • BRAF inhibitor
  • GSK2118436
  • safety
  • cancer
  • QTc
  • pharmacokinetics
03

In context

Neoplasms

9,610 studies on the registry are indexed under Neoplasms; 2,508 are open to participants now.

This study's enrollment of 50 is close to the median of 50 across 7,429 interventional studies indexed under Neoplasms.

Browse Neoplasms studies →

Lead sponsor

GlaxoSmithKline is the lead sponsor of 3,647 studies on the registry; 118 are open to participants now.

Of its 264 completed or terminated interventional studies of FDA-regulated products, 239 (91%) have results posted.

Browse GlaxoSmithKline studies →

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
18 Years and older
Sexes eligible
All
Accepts healthy volunteers
No

Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.

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.

Exclusion criteria

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.
05

Study design

Phase
Phase 1
Primary purpose
Treatment
Allocation
Non-randomized
Intervention model
Single group
Masking
None (open label)
Enrollment
50 participants (actual)

Study arms

  • 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.

    Drug: GSK2118436 75 mg

  • 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.

    Drug: GSK2118436 75 mg

  • 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.

    Drug: GSK2118436 75 mg · Drug: Placebo

Interventions

  • DrugGSK2118436 75 mg

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

  • DrugPlacebo

    Matching placebo capsules will be administered in Part 2 of the study.

06

What researchers measure

Primary outcomes

  1. Part 1: Safety and tolerability of GSK2118436 as assessed by changes in physical examination findings

    Safety and tolerability parameter will include a complete (head, eyes, ears, nose, throat, skin, thyroid, neurological, lungs, cardiovascular, abdomen \[liver and spleen\], lymph nodes, extremities, height and weight) and brief (skin, lungs, cardiovascular system, abdomen \[liver and spleen\] and weight) physical examination at Baseline and at the end of Part 1 of the study.

    Time frame: Screening, Day 1 and Week 6.

  2. Part 1: Safety and tolerability of GSK2118436 as assessed by changes in vital signs measurements

    Safety and tolerability parameter will include measurement of vital signs (recording of systolic and diastolic blood pressure, temperature, and pulse rate) at Baseline and at the end of Part 1 of the study.

    Time frame: Screening, pre-dose and 8 hours post-dose on Study Day 1, 8, 15, and Week 6.

  3. Part 1: Safety and tolerability of GSK2118436 as assessed by changes in ECG readings

    Safety and tolerability parameter will include ECGs readings (heart rate and measurement of RR, PR, QRS, QT, and QTc intervals) at Baseline and at the end of Part 1 of the study.

    Time frame: 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.

  4. Part 1: Safety and tolerability of GSK2118436 as assessed by changes in clinical laboratory assessments

    Safety and tolerability parameter will include laboratory values (hematology, clinical chemistry, coagulation, liver function tests, cardiac enzyme and beta-hCG/serum or urine pregnancy test for female subjects of childbearing potential only) at Baseline and at end of Part 1 of the study.

    Time frame: Day 1, 8, 15 and and Week 6.

  5. Part 2: Change from Baseline in QTcF interval at each time point for GSK2118436

    Change from Baseline in QTcF interval at each time point for GSK2118436 will be calculated as average of 3 Holter ECG replicates per time point minus the value at Baseline.

    Time frame: 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 outcomes

  1. Part 1: Plasma concentration of GSK2118436 and its metabolites

    Plasma concentrations of GSK2118436 and its metabolites GSK2285403, GSK2298683 and GSK2167542 will be recorded.

    Time frame: 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.

  2. Part 1: The AUC(0-t)) of GSK2118436 and its metabolites

    Pharmacokinetic data will include area under the time-concentration curve from time zero (pre-dose) to last time of quantifiable concentration (AUC(0-t)) of GSK2118436 and its metabolites GSK2285403, GSK2298683 and GSK2167542.

    Time frame: 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.

  3. Part 1: The Cmax of GSK2118436 and its metabolites

    Pharmacokinetic data will include maximum plasma concentration (Cmax) of GSK2118436 and its metabolites GSK2285403, GSK2298683 and GSK2167542.

    Time frame: 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.

  4. The Ctrough of GSK2118436 and its metabolites

    Pharmacokinetic data will include predose concentration (Ctrough) of GSK2118436 and its metabolites GSK2285403, GSK2298683 and GSK2167542.

    Time frame: 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.

  5. The tmax of GSK2118436 and its metabolites

    Pharmacokinetic data will include time of occurrence of Cmax (tmax) of GSK2118436 and its metabolites GSK2285403, GSK2298683 and GSK2167542.

    Time frame: 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.

  6. 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

    The relationship between plasma concentrations of GSK2118436 and its metabolites (GSK2285403, GSK2298683 and GSK2167542) and the baseline-adjusted, placebo-corrected, time-matched change from Baseline in QTc intervals will be assessed.

    Time frame: 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.

  7. Part 2: ECG parameters: and morphology assessments

    ECG parameters: QT, QTcB, QTci, HR, RR interval, PR interval, QRS interval and morphology will be assessed in subjects receiving GSK2118436.

    Time frame: 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.

  8. Part 2: Plasma concentrations of GSK2118436 and its metabolites

    The plasma concentration of GSK2118436 and its metabolites GSK2285403, GSK2298683 and GSK2167542 will be measured.

    Time frame: 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.

  9. The AUC(0-10) and AUC(0 t) of GSK2118436 and its metabolites (GSK2285403, GSK2298683 and GSK2167542)

    Pharmacokinetic data will include AUC from time zero (pre-dose) to 10 hours after the last dose of study treatment (AUC(0-10)) and AUC(0 t) of GSK2118436 and its metabolites GSK2285403, GSK2298683 and GSK2167542.

    Time frame: 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.

  10. The AUC(0-infinity) of GSK2118436 and its metabolites (GSK2285403, GSK2298683 and GSK2167542)

    Pharmacokinetic data will include AUC from time zero to infinity AUC(0-infinity) of GSK2118436 and its metabolites GSK2285403, GSK2298683 and GSK2167542 on Study Day 1, if data permit).

    Time frame: 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).

  11. The t½ of GSK2167542 and its metabolites

    Pharmacokinetic data will include elimination half life (t1/2) of GSK2118436 and its metabolites GSK2285403, GSK2298683 and GSK2167542 if data permits.

    Time frame: 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.

  12. Part 2: The Ctrough of GSK2167542 and its metabolites

    Pharmacokinetic data will include C trough of GSK2118436 and its metabolites GSK2285403, GSK2298683 and GSK2167542.

    Time frame: 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.

  13. Part 2: The Cmax, of GSK2167542 and its metabolites

    Pharmacokinetic data will include Cmax of GSK2118436 and its metabolites GSK2285403, GSK2298683 and GSK2167542.

    Time frame: 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.

  14. Part 2: The tmax, of GSK2167542 and its metabolites

    Pharmacokinetic data will include tmax of GSK2118436 and its metabolites GSK2285403, GSK2298683 and GSK2167542.

    Time frame: 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.

  15. Part 2: Safety of GSK2118436 as assessed by number of subjects with adverse events (AE)s

    Safety parameters will include recording of AEs, in Part 2 of the study.

    Time frame: Continuous throughout the study.

  16. Part 2: Safety of GSK2118436 as assessed by changes in vital signs measurements

    Safety parameters will include measurement of vital signs (recording of systolic and diastolic blood pressure, temperature, and pulse rate) at Baseline and at the end of Part 2 of the study.

    Time frame: Screening, Day -1, Day 1, Day 8, Day 9 and Week 5.

  17. Part 2: Safety of GSK2118436 as assessed by changes in ECG readings

    Safety parameters will include ECGs readings (heart rate and measurement of RR, PR, QRS, QT, and QTc intervals) at Baseline and at the end of Part 2 of the study.

    Time frame: Screening, Day -1, Day 1, Day 2, Day 8, Day 9 and Week 5.

  18. Part 2: Safety of GSK2118436 as assessed by changes in clinical laboratory assessments

    Safety parameters will include laboratory values (hematology, clinical chemistry, coagulation, liver function tests, cardiac enzyme and beta-hCG/serum or urine pregnancy test for female subjects of childbearing potential only) at Baseline and at end of Part 2 of the study.

    Time frame: Screening, Day -1, Day 1, Day 8, Day 9 and Week 5.

07

Study locations

8 sites
  • GSK Investigational Site
    Scottsdale, Arizona 85259, United States
  • GSK Investigational Site
    Memphis, Tennessee 38120, United States
  • GSK Investigational Site
    Nashville, Tennessee 37203, United States
  • GSK Investigational Site
    San Antonio, Texas 78229, United States
  • GSK Investigational Site
    Salt Lake City, Utah 84112-5550, United States
  • GSK Investigational Site
    Heidelberg, Victoria 3084, Australia
  • GSK Investigational Site
    Melbourne, Victoria 3004, Australia
  • GSK Investigational Site
    London, W1G 6AD, United Kingdom
08

References and documents

Publications

  • Nebot N, Arkenau HT, Infante JR, Chandler JC, Weickhardt A, Lickliter JD, Sarantopoulos J, Gordon MS, Mak G, St-Pierre A, Tang L, Mookerjee B, Carson SW, Hayes S, Grossmann KF. Evaluation of the effect of dabrafenib and metabolites on QTc interval in patients with BRAF V600-mutant tumours. Br J Clin Pharmacol. 2018 Apr;84(4):764-775. doi: 10.1111/bcp.13488. Epub 2018 Jan 23. PubMed 29243287 ↗
09

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Nov 13, 2017, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
10

Registry details

Key details

Study ID
NCT01738451
Lead sponsor
GlaxoSmithKline
Responsible party
Sponsor
First posted
Nov 30, 2012
Start date
Jan 22, 2013
Primary completion
Nov 28, 2014
Completion
Nov 28, 2014
Last update
Nov 13, 2017

Study contacts

GSK Clinical Trials
study director · GlaxoSmithKline

Oversight

Data monitoring committee
No
View the source record on ClinicalTrials.gov ↗

Not currently enrolling

This study is completed, as verified in Nov 2017. You cannot join it, but the record below documents what was studied.

Follow this study

Get an email when the registry record changes — status, dates, results — or when someone posts here.

Sign in to follow

Discussion

Questions and observations about this study, from anyone following it. Not medical advice, and not a channel to the study team — their contact details are on the registry record.

Sign in to join the discussion. Reading takes no account; posting does. You choose a display name, and a pseudonym is the default.

Nothing here yet. If you are running this trial, taking part in it, or weighing whether to, this is the place to say so.

Studies of the drug tested here: Dabrafenib

Other studies in this condition

Neoplasms →

Other studies from this sponsor

GlaxoSmithKline →

Start the discussion