ANZCTR - Registration

Technical difficulties have been reported by some users of the search function and is being investigated by technical staff. Thank you for your patience and apologies for any inconvenience caused.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers

Trial details imported from ClinicalTrials.gov

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

113773

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Cancer

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]

Treatment: Drugs

Comparator / control treatment

Control group

Outcomes

Primary outcome [1]

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

Timepoint [1]

Screening, Day 1 and Week 6.

Primary outcome [2]

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

Timepoint [2]

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

Primary outcome [3]

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

Timepoint [3]

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]

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

Timepoint [4]

Day 1, 8, 15 and and Week 6.

Primary outcome [5]

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

Timepoint [5]

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]

Part 1: Plasma concentration of GSK2118436 and its metabolites

Timepoint [1]

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]

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

Timepoint [2]

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]

Part 1: The Cmax of GSK2118436 and its metabolites

Timepoint [3]

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]

The Ctrough of GSK2118436 and its metabolites

Timepoint [4]

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]

The tmax of GSK2118436 and its metabolites

Timepoint [5]

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]

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]

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]

Part 2: ECG parameters: and morphology assessments

Timepoint [7]

Secondary outcome [8]

Part 2: Plasma concentrations of GSK2118436 and its metabolites

Timepoint [8]

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]

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

Timepoint [9]

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]

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

Timepoint [10]

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]

The t½ of GSK2167542 and its metabolites

Timepoint [11]

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]

Part 2: The Ctrough of GSK2167542 and its metabolites

Timepoint [12]

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]

Part 2: The Cmax, of GSK2167542 and its metabolites

Timepoint [13]

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]

Part 2: The tmax, of GSK2167542 and its metabolites

Timepoint [14]

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]

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

Timepoint [15]

Continuous throughout the study.

Secondary outcome [16]

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

Timepoint [16]

Screening, Day -1, Day 1, Day 8, Day 9 and Week 5.

Secondary outcome [17]

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

Timepoint [17]

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

Secondary outcome [18]

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

Timepoint [18]

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?

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

22/01/2013

Date of last participant enrolment

Anticipated

Actual

Date of last data collection

Anticipated

Actual

28/11/2014

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

VIC

Recruitment hospital [1]

GSK Investigational Site - Heidelberg

Recruitment hospital [2]

GSK Investigational Site - Melbourne

Recruitment postcode(s) [1]

3084 - Heidelberg

Recruitment postcode(s) [2]

3004 - Melbourne

Recruitment outside Australia

Country [1]

United States of America

State/province [1]

Arizona

Country [2]

United States of America

State/province [2]

Tennessee

Country [3]

United States of America

State/province [3]

Texas

Country [4]

United States of America

State/province [4]

Utah

Country [5]

United Kingdom

State/province [5]

London

Funding & Sponsors

Primary sponsor type

Commercial sector/Industry

Name

GlaxoSmithKline

Address

Country

Ethics approval

Ethics application status

Summary

Brief 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.

Trial website

https://clinicaltrials.gov/ct2/show/NCT01738451

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

GSK Clinical Trials

Address

GlaxoSmithKline

Country

Phone

Fax

Contact person for public queries

Name

Address

Country

Phone

Fax

Contact person for scientific queries

Trial Review

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT01738451