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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT01978236




Registration number
NCT01978236
Ethics application status
Date submitted
31/10/2013
Date registered
7/11/2013
Date last updated
17/08/2018

Titles & IDs
Public title
Dabrafenib/Trametinib, BRAF or BRAF AND MEK Pre-op With BRAF and MEK Post-op, Phase IIB, Melanoma With Brain Mets,Biomarkers and Metabolites
Scientific title
An Open-Label, Multicentre, Corollary Study of Pre-Operative Therapy With Dabrafenib and the Combination of Dabrafenib With Trametinib in Subjects With BRAF Mutation-Positive Metastatic Melanoma to the Brain
Secondary ID [1] 0 0
116521
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Melanoma and Brain Metastases 0 0
Condition category
Condition code
Cancer 0 0 0 0
Malignant melanoma
Cancer 0 0 0 0
Brain

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Dabrafenib 150 mg
Treatment: Drugs - Trametinib 2.0 mg

Experimental: Cohort A - The first cohort of 15 subjects will receive oral dabrafenib 150 mg twice daily orally for 7 to 14 days prior to surgery in Cohort A; Subjects will be treated for at least 7 days prior to craniotomy, but not more than 14 days. Subjects in either cohort with intracranial and/or extracranial metastases remaining after surgery may resume treatment with the combination of dabrafenib 150 mg BID and trametinib 2 mg once daily no earlier than 72 hours after surgery

Experimental: Cohort B - The second cohort of 15 subjects will receive dabrafenib 150 mg twice daily combined with trametinib 2 mg once daily (Cohort B) orally for 7 to 14 days prior to surgery; Subjects will be treated for at least 7 days prior to craniotomy, but not more than 14 days. Subjects in either cohort with intracranial and/or extracranial metastases remaining after surgery may resume treatment with the combination of dabrafenib 150 mg BID and trametinib 2 mg once daily no earlier than 72 hours after surgery


Treatment: Drugs: Dabrafenib 150 mg
Dabrafenib will be provided for oral administration as 50 mg and 75 mg capsules. Dabrafenib will be dosed orally with approximately 200 mL of water, twice a day. Dabrafenib should be administered under fasting conditions.

Treatment: Drugs: Trametinib 2.0 mg
Trametinib study treatment will be provided as 0.5 mg and 2.0 mg tablets. should be taken orally with approximately 200 mL of water under fasting conditions, either one hour before or two hours after a meal.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Concentrations of Dabrafenib, Its Metabolites Hydroxy-, Carboxy- and Desmethyl-dabrafenib in Peripheral Blood (Plasma)
Timepoint [1] 0 0
Pre-surgery and post-surgery on Day 15
Primary outcome [2] 0 0
Concentrations of Dabrafenib, Its Metabolites Hydroxy-, Carboxy- and Desmethyl-dabrafenib in Parenchymal Brain Metastases
Timepoint [2] 0 0
Day 15
Primary outcome [3] 0 0
Concentrations of Dabrafenib, Its Metabolites Hydroxy-, Carboxy- and Desmethyl-dabrafenib) and Trametinib (Cohort B Only) in CSF Samples.
Timepoint [3] 0 0
Pre-surgery and post-surgery on Day 15
Secondary outcome [1] 0 0
Concentrations of Dabrafenib, Its Metabolites Hydroxy-, Carboxy- and Desmethyl-dabrafenib) in Cerebrospinal Fluid (CSF) Samples
Timepoint [1] 0 0
Day 15
Secondary outcome [2] 0 0
Number of Participants With Changes in Mitogen-activated Protein Kinase (MAPK) Pathway Markers
Timepoint [2] 0 0
Up to Day 15
Secondary outcome [3] 0 0
Number of Participants With Changes in Radiographic Tumors
Timepoint [3] 0 0
Up to 2 years
Secondary outcome [4] 0 0
Percent Change From Baseline to Pre-surgery in the Sum of the Longest Diameters (SLD) of Intracranial Target Lesions
Timepoint [4] 0 0
Up to 2 years
Secondary outcome [5] 0 0
Maximum Percent Change From Baseline in the SLD of Unresected Intracranial Target Lesions
Timepoint [5] 0 0
Up to 2 years
Secondary outcome [6] 0 0
Percentage of Participants With Overall Extracranial Response Rate in Unresected Lesions
Timepoint [6] 0 0
Approximately 2 years or death whichever occurs first
Secondary outcome [7] 0 0
Percentage of Participants With Overall Survival
Timepoint [7] 0 0
Approximately 2 years or death whichever occurs first
Secondary outcome [8] 0 0
Number of Participants With Abnormal Vital Signs
Timepoint [8] 0 0
Up to 2 years
Secondary outcome [9] 0 0
Number of Participants With Abnormal Physical Examinations
Timepoint [9] 0 0
Up to 2 years
Secondary outcome [10] 0 0
Number of Participants With Abnormal 12-lead Electrocardiograms (ECG)
Timepoint [10] 0 0
Screening
Secondary outcome [11] 0 0
Number of Participants With Abnormal Echocardiogram (ECHO)
Timepoint [11] 0 0
Up to 2 years
Secondary outcome [12] 0 0
Number of Participants With Abnormal Clinical Laboratory Assessments
Timepoint [12] 0 0
Up to 2 years
Secondary outcome [13] 0 0
Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)
Timepoint [13] 0 0
Up to 2 years

Eligibility
Key inclusion criteria
* Signed written informed consent
* Histologically-confirmed metastatic melanoma (Stage IV), carrying BRAF V600E or V600K mutation as determined by testing certified for clinical diagnostic purposes. Previously performed certified BRAF testing is acceptable. If no prior BRAF mutation testing results are available, testing of a distant metastasis is preferred, but testing of a regional metastasis or primary tumor is also acceptable
* At least one intracranial lesion >=1.0 cm but <=4.0 cm that can be treated with surgical resection in the opinion of the treating physicians, and for which immediate local therapy is not clinically indicated
* At least two extracranial lesions that are easily accessible for biopsy, in the judgment of the treating physician. Easily accessible tumors may include cutaneous, subcutaneous, and superficial lymph node metastases.
* Age >18 years of age.
* Able to swallow and retain oral medication
* Women with child-bearing potential must be willing to practice acceptable methods of birth control during the study
* Women of childbearing potential must have a negative serum pregnancy test within 14 days of first dose of study treatment.
* Must be able to understand and comply with protocol requirements and instructions
* Eastern Co-operative Oncology Group (ECOG) performance status of 0-2
* Must have adequate organ function as defined by the following screening values (Retesting of borderline screening organ function and treatment with blood transfusions, growth factors etc. will be allowed):
* Absolute neutrophil count (ANC) >=1.2x10^9/L
* Hemoglobin >=9 g/dL
* Platelets >=100x10^9/L
* Serum bilirubin <=1.5 x upper limit of normal (ULN)
* Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <=2.5xULN
* Serum creatinine <=1.5 mg/dL (If serum creatinine is >1.5 mg/dL, calculate creatinine clearance using standard Cockcroft and Gault Method Creatinine clearance must be >50 mL/min)
* Prothrombin time (PT)/International normalized ratio (INR) and partial thromboplastin time (PTT) <=1.3xULN
* Left ventricular ejection fraction (LVEF) >= institutional lower limit of normal (LLN)
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
* Neurological symptoms related to brain metastasis that are not controlled with a stable or decreasing dose of oral steroids for at least 7 days prior to starting GSK2118436
* Prior Central Nervous System (CNS)-directed local therapies, including surgical resection, whole brain radiation (WBRT), Stereotactic radiosurgery (SRS), or gamma knife (GK)
* Previous treatment with a BRAF or MEK inhibitor
* Cancer therapy (chemotherapy with delayed toxicity, extensive radiation therapy, immunotherapy, biologic therapy, or major surgery) or investigational anti-cancer drugs within the last 3 weeks, or chemotherapy without delayed toxicity within the last 2 weeks, preceding the first dose of study treatment.
* Current or expected use of a prohibited medication, including enzyme-inducing antiepileptic drugs (EIAEDs) during treatment with GSK2118436.
* Presence of leptomeningeal disease or dural metastases.
* History of another active malignancy within the past 5 years, or any malignancy with a confirmed activating RAS mutation. The prospective RAS mutation testing is not required, however, if results of previous RAS testing are known, they must be used in assessing eligibility. Subjects with a history of completely resected non-melanoma skin cancer are eligible.
* Known allergies against contrast agents required for magnetic resonance imaging (MRI) of intracranial lesions, or other contraindications for MRI, i.e., pacemaker
* Current use of therapeutic warfarin. Low-molecular-weight heparin and prophylactic low-dose warfarin are permitted
* Unresolved toxicity of National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (CTCAE v4.0) Grade 2 or higher from previous anti-cancer therapy, except alopecia
* Presence of active gastrointestinal disease or other condition that will interfere significantly with the absorption of drugs.
* History of a prior symptomatic stroke, dementia, or other significant central neurologic condition (i.e. multiple sclerosis)
* A history of known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection
* Current acute infection requiring intravenous antibiotics
* A history of known glucose-6-phosphate dehydrogenase (G6PD) deficiency
* The history or evidence of following cardiac abnormalities:
* Corrected QT (QTc) interval using Bazett's Formula; (QTcB) >= 480 msecs
* A history of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization
* Coronary angioplasty or stenting within the past 12 weeks
* Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system
* Abnormal cardiac valve morphology (>= Grade 2) documented by echocardiogram (ECHO)
* History of or evidence of clinically significant uncontrolled cardiac arrhythmias
* Treatment refractory hypertension defined as a blood pressure of systolic >140 mmHg and/or diastolic >90 mm Hg which cannot be controlled by anti-hypertensive therapy
* Subjects with intra-cardiac defibrillators or permanent pacemakers
* Pregnant, lactating or breastfeeding females
* Any serious and/or unstable pre-existing medical, psychiatric disorder or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures
* Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to GSK2118436 or excipients that contraindicate their participation

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled 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 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Stopped early
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
8/04/2014
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
26/04/2017
Sample size
Target
Accrual to date
Final
6
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 0 0
GSK Investigational Site - North Sydney
Recruitment postcode(s) [1] 0 0
2060 - North Sydney
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Pennsylvania
Country [2] 0 0
United States of America
State/province [2] 0 0
Texas

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?




Results publications and other study-related documents

No documents have been uploaded by study researchers.

Results are available at https://clinicaltrials.gov/study/NCT01978236