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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

Phase 1
18 Years
Open (Enrolling)

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Trial Information

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

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

- 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

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

- 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.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

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

Outcome Description:

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.

Outcome Time Frame:

Screening, Day 1 and Week 6.

Safety Issue:


Principal Investigator

GSK Clinical Trials

Investigator Role:

Study Director

Investigator Affiliation:



European Union: European Medicines Agency

Study ID:




Start Date:

January 2013

Completion Date:

August 2013

Related Keywords:

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



GSK Investigational Site Phoenix, Arizona  85013 - 4496
GSK Investigational Site Germantown, Tennessee  38138
GSK Investigational Site Salt Lake City, Utah  84107