Neoplasms

Symptoms and General Pathology

All Conditions

Skin and Connective Tissue Diseases

Nervous System Diseases

Rare Diseases

Neoplasm Metastasis

Melanoma

Brain Neoplasms

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

Neoplastic Processes

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

Neuroendocrine Tumor

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Trametinib

Dabrafenib

Protein Kinase Inhibitors

Enzyme Inhibitors

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

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

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.

Dabrafenib 150 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.

Trametinib 2.0 mg

GSK Clinical Trials

This is a global, multi-centre, open-label, study of GSK2118436 conducted in up to 30 evaluable subjects with resectable, BRAF V600E or V600K mutation-positive metastatic melanoma to the brain. All subjects in this study are required to have accessible extracranial metastases and are agreeable to undergo repetitive biopsies. The first cohort of 15 subjects will receive dabrafenib orally 150mg twice daily (BID) for 7 to 14 days prior to surgery (Cohort A); the second cohort of 15 subjects will receive the combination of dabrafenib 150 mg BID and trametinib 2 mg once daily for 7 to 14 days prior to surgery (Cohort B). The primary purpose of this study is to determine levels and distribution of dabrafenib, its metabolites, and trametinib (Cohort B only) in parenchymal brain metastases, extracranial metastases, and peripheral blood (plasma) within two cohorts of subjects with BRAF V600E/K mutation-positive melanoma that has metastasized to the brain. All subjects will be followed for survival and new anti-cancer therapy for a total of two years or until death or the subject wishes to withdraw from further follow-up.

Dabrafenib/Trametinib, BRAF or BRAF AND MEK Pre-op With BRAF and MEK Post-op, Phase IIB, Melanoma With Brain Mets,Biomarkers and Metabolites

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

Blood samples for pharmacokinetic analysis of dabrafenib and its active metabolites, including hydroxy-, carboxy-, and desmethyl-dabrafenib were collected on day of surgical resection of the brain metastasis(es), Two samples were collected before surgery and 2 samples after surgery with one hour gap in between. Upon collection blood was placed on wet ice. Plasma was isolated within 60 minutes of collection and frozen at -20 degree celsius.

Concentrations of dabrafenib, its metabolites, hydroxy-, carboxy, and desmethyl-dabrafenib, and possibly other drug-related species were quantified in the pharmacokinetic tissue sample by an investigative Liquid chromatography- mass spectrometry (LC-MS)/MS method. The spatial distribution of dabrafenib, its metabolites, hydroxy-, carboxy, and desmethyl-dabrafenib and possibly other drug-related species in the tissue samples were determined using an investigative matrix assisted laser desorption ionization (MALDI) analysis method. Parenchymal brain metastases and extracranial metastases using MALDI imaging was not determined for all participants (completed by GSK for the first two participants enrolled)

Blood samples for pharmacokinetic analysis of dabrafenib and its active metabolites, including hydroxy-, carboxy-, and desmethyl-dabrafenib and trametinib (as appropriate), were planned but not collected.

Concentrations of dabrafenib, its metabolites hydroxy-, carboxy- and desmethyl-dabrafenib) and trametinib in CSF (in participants who agree for optional collection of CSF at the time of brain tumor resection). Optional collection of CSF was obtained in the operating room on the day of brain metastasis resection. CSF samples for only one participant were collected and analyzed.

Changes in MAPK pathway markers in paired extracranial biopsies taken pre-treatment, during craniotomy, and at disease progression, and changes in markers between post-operative intracranial and extracranial biopsies was planned but not performed as the study was terminated due to low enrollment.

Changes in the radiographic characteristics of the tumors were planned to be compared to (1) levels of dabrafenib, its metabolites and trametinib (where appropriate) in the brain metastases, plasma, and CSF, and (2) MAPK pathway activation status in tumors at the time of surgery. Results were planned to be compared to the analysis of early clinical responses in extracranial metastases, as determined by the Positron emission tomography (PET-CT) imaging. This analysis was planned but not performed as the study was terminated due to low enrollment

The change from Baseline to the pre-surgery intracranial disease assessment in the SLD of intracranial target lesions was planned to be calculated as a percentage change from the baseline SLD. It was planned to be reported for the V600E and V600K analysis populations for each cohort and also aggregately if appropriate. This analysis was planned but not performed as the study was terminated due to low enrollment.

The maximum change from Baseline in the SLD of unresected intracranial target lesions was planned to be calculated as a percentage change from the baseline SLD. It was planned to be reported for the V600E and V600K analysis populations for each cohort and also aggregately if appropriate. This analysis was planned but not performed as the study was terminated due to low enrollment.

Overall Extracranial Response Rate was defined as the percentage of participants with Complete response (CR) or Partial response (PR) at anytime as per modified Response Evaluation Criteria in Solid Tumors (RECIST). The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence and is determined programmatically based on the investigator's assessment of response at each time point. Overall Extracranial Response Rate was planned but not analyzed as the study was terminated due to low enrollment.

Overall survival, defined as the time from first dose of study treatment to death for any reason, was planned to summarize using Kaplan-Meier quartile estimates along with two sided 95% confidence intervals. But were not performed as the study was terminated due to low enrollment.

Vital sign measurements including temperature, respiratory rate, systolic and diastolic blood pressure, and pulse rate were planned to be performed but were neither summarized nor listed as the study was terminated.

A complete physical examination was planned which included assessments of the head, eyes, ears, nose, throat, skin, thyroid, lungs, cardiovascular, abdomen (liver and spleen), lymph nodes, and extremities. Height and weight was also planned to be measured and recorded. A complete physical exam including a thorough genitourinary examination for female participants, inspection of the head and neck region, and digital rectal examination for both male and female participants was planned to be performed at Screening, and Month 12 or at discontinuation if discontinuation occurs prior to Month 12. If the participants had a genitourinary and rectal exam within 6 months of screening, these assessments need not to be repeated at screening. But data for physical examinations were not summarized and listed as the study was terminated.

112-lead ECGs were planned to be obtained at screening during the study using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and corrected QT (QTc) intervals. At each assessment a 12-lead ECG was planned to be performed by qualified personnel at the site after at least a five-minute rest with the participants in a semi-recumbent or supine position. But data for 12-lead ECGs were not summarized and listed as the study was terminated.

ECHO include an evaluation for Left ventricular ejection fraction (LVEF) and both right- and left-sided valvular lesions. ECHO was planned to be performed at screening, Week 8 and every 16 weeks till discontinuation. data for ECHO was not summarized and listed as the study was terminated.

Laboratory assessments included parameters like Hematology, Standard Chemistry, Coagulation, Serum Pregnancy. Assessment of these parameters were planned to be performed by the central laboratory on screening, Day prior to surgery, Every 4 weeks after restart and Discontinuation, but were not analyzed as the study was terminated due to low enrollment.

AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. AE were collected from the time the first dose of study treatment is administered until 30 days following discontinuation of study treatment regardless of initiation of a new cancer therapy using Medical Dictionary for Regulatory Activities (MedDRA)

GlaxoSmithKline

AEs and SAEs were collected in Safety Set Population which comprised of all participants who received at least one dose of study treatment.

Participants in Cohort A received dabrafenib orally 150 milligram twice daily for 7 to 14 days prior to surgery.

Cohort A

Age, Continuous

Sex: Female, Male

White - Arabic/North African Heritage

White/Caucasian/European Heritage

Race/Ethnicity, Customized

GSK Response Center

Participant 1, Dabrafenib, Pre-Surgery 1

Participant 1, Dabrafenib, Pre-Surgery 2

Participant 1, Dabrafenib, Post-Surgery 1

Participant 1, Dabrafenib, Post-Surgery 2

Participant 1, Desmethyl-dabrafenib,Pre-Surgery 1

Participant 1, Desmethyl-dabrafenib,Pre-Surgery 2

Participant 1, Desmethyl-dabrafenib,Post-Surgery 1

Participant 1, Desmethyl-dabrafenib,Post-Surgery 2

Participant 1,Hydroxy-dabrafenib,Pre-Surgery 1

Participant 1,Hydroxy-dabrafenib,Pre-Surgery 2

Participant 1,Hydroxy-dabrafenib,Post-Surgery 1

Participant 1,Hydroxy-dabrafenib,Post-Surgery 2

Participant 1,carboxy-dabrafenib,Pre-Surgery 1

Participant 1,carboxy-dabrafenib,Pre-Surgery 2

Participant 1,carboxy-dabrafenib,Post-Surgery 1

Participant 1,carboxy-dabrafenib,Post-Surgery 2

Participant 2, Dabrafenib, Pre-Surgery 1

Participant 2, Dabrafenib, Pre-Surgery 2

Participant 2, Dabrafenib, Post-Surgery 1

Participant 2, Dabrafenib, Post-Surgery 2

Participant 2, Desmethyl-dabrafenib,Pre-Surgery 1

Participant 2, Desmethyl-dabrafenib,Pre-Surgery 2

Participant 2, Desmethyl-dabrafenib,Post-Surgery 1

Participant 2, Desmethyl-dabrafenib,Post-Surgery 2

Participant 2,Hydroxy-dabrafenib,Pre-Surgery 1

Participant 2,Hydroxy-dabrafenib,Pre-Surgery 2

Participant 2,Hydroxy-dabrafenib,Post-Surgery 1

Participant 2,Hydroxy-dabrafenib,Post-Surgery 2

Participant 2,carboxy-dabrafenib,Pre-Surgery 1

Participant 2,carboxy-dabrafenib,Pre-Surgery 2

Participant 2,carboxy-dabrafenib,Post-Surgery 1

Participant 2,carboxy-dabrafenib,Post-Surgery 2

Participant 3, Dabrafenib, Pre-Surgery 1

Participant 3, Dabrafenib, Pre-Surgery 2

Participant 3, Dabrafenib, Post-Surgery 1

Participant 3, Dabrafenib, Post-Surgery 2

Participant 3, Desmethyl-dabrafenib,Pre-Surgery 1

Participant 3, Desmethyl-dabrafenib,Pre-Surgery 2

Participant 3, Desmethyl-dabrafenib,Post-Surgery 1

Participant 3, Desmethyl-dabrafenib,Post-Surgery 2

Participant 3,Hydroxy-dabrafenib,Pre-Surgery 1

Participant 3,Hydroxy-dabrafenib,Pre-Surgery 2

Participant 3,Hydroxy-dabrafenib,Post-Surgery 1

Participant 3,Hydroxy-dabrafenib,Post-Surgery 2

Participant 3,carboxy-dabrafenib,Pre-Surgery 1

Participant 3,carboxy-dabrafenib,Pre-Surgery 2

Participant 3,carboxy-dabrafenib,Post-Surgery 1

Participant 3,carboxy-dabrafenib,Post-Surgery 2

Participant 4, Dabrafenib, Pre-Surgery 1

Participant 4, Dabrafenib, Pre-Surgery 2

Participant 4, Dabrafenib, Post-Surgery 1

Participant 4, Dabrafenib, Post-Surgery 2

Participant 4, Desmethyl-dabrafenib,Pre-Surgery 1

Participant 4, Desmethyl-dabrafenib,Pre-Surgery 2

Participant 4, Desmethyl-dabrafenib,Post-Surgery 1

Participant 4, Desmethyl-dabrafenib,Post-Surgery 2

Participant 4,Hydroxy-dabrafenib,Pre-Surgery 1

Participant 4,Hydroxy-dabrafenib,Pre-Surgery 2

Participant 4,Hydroxy-dabrafenib,Post-Surgery 1

Participant 4,Hydroxy-dabrafenib,Post-Surgery 2

Participant 4,carboxy-dabrafenib,Pre-Surgery 1

Participant 4,carboxy-dabrafenib,Pre-Surgery 2

Participant 4,carboxy-dabrafenib,Post-Surgery 1

Participant 4,carboxy-dabrafenib,Post-Surgery 2

Participant 5, Dabrafenib, Pre-Surgery 1

Participant 5, Dabrafenib, Pre-Surgery 2

Participant 5, Dabrafenib, Post-Surgery 1

Participant 5, Dabrafenib, Post-Surgery 2

Participant 5, Desmethyl-dabrafenib,Pre-Surgery 1

Participant 5, Desmethyl-dabrafenib,Pre-Surgery 2

Participant 5, Desmethyl-dabrafenib,Post-Surgery 1

Participant 5, Desmethyl-dabrafenib,Post-Surgery 2

Participant 5,Hydroxy-dabrafenib,Pre-Surgery 1

Participant 5,Hydroxy-dabrafenib,Pre-Surgery 2

Participant 5,Hydroxy-dabrafenib,Post-Surgery 1

Participant 5,Hydroxy-dabrafenib,Post-Surgery 2

Participant 5,carboxy-dabrafenib,Pre-Surgery 1

Participant 5,carboxy-dabrafenib,Pre-Surgery 2

Participant 5,carboxy-dabrafenib,Post-Surgery 1

Participant 5,carboxy-dabrafenib,Post-Surgery 2

Participant 6, Dabrafenib, Pre-Surgery 1

Participant 6, Dabrafenib, Pre-Surgery 2

Participant 6, Dabrafenib, Post-Surgery 1

Participant 6, Dabrafenib, Post-Surgery 2

Participant 6, Desmethyl-dabrafenib,Pre-Surgery 1

Participant 6, Desmethyl-dabrafenib,Pre-Surgery 2

Participant 6, Desmethyl-dabrafenib,Post-Surgery 1

Participant 6, Desmethyl-dabrafenib,Post-Surgery 2

Participant 6,Hydroxy-dabrafenib,Pre-Surgery 1

Participant 6,Hydroxy-dabrafenib,Pre-Surgery 2

Participant 6,Hydroxy-dabrafenib,Post-Surgery 1

Participant 6,Hydroxy-dabrafenib,Post-Surgery 2

Participant 6,carboxy-dabrafenib,Pre-Surgery 1

Participant 6,carboxy-dabrafenib,Pre-Surgery 2

Participant 6,carboxy-dabrafenib,Post-Surgery 1

Participant 6,carboxy-dabrafenib,Post-Surgery 2

The Pharmacokinetic analysis set included all participants who provided at least one evaluable Pharmacokinetic concentration.

Concentrations of Dabrafenib, Its Metabolites Hydroxy-, Carboxy- and Desmethyl-dabrafenib in Peripheral Blood (Plasma)

Participant 1,Dabrafenib

: Participant 1, Hydroxy-dabrafenib

Participant 1, Carboxy-dabrafenib

Participant 1, Desmethyl-dabrafenib

Participant 2,Dabrafenib

Participant 2, Hydroxy-dabrafenib

Participant 2, Carboxy-dabrafenib

Participant 2, Desmethyl-dabrafenib

Participant 3,Dabrafenib

Participant 3, Hydroxy-dabrafenib

Participant 3, Carboxy-dabrafenib

Participant 3, Desmethyl-dabrafenib

Participant 4,Dabrafenib

Participant 4, Hydroxy-dabrafenib

Participant 4, Carboxy-dabrafenib

Participant 4, Desmethyl-dabrafenib

Participant 5,Dabrafenib

Participant 5, Hydroxy-dabrafenib

Participant 5, Carboxy-dabrafenib

Participant 5, Desmethyl-dabrafenib

Participant 6,Dabrafenib

Participant 6, Hydroxy-dabrafenib

Participant 6, Carboxy-dabrafenib

Participant 6, Desmethyl-dabrafenib

Concentrations of Dabrafenib, Its Metabolites Hydroxy-, Carboxy- and Desmethyl-dabrafenib in Parenchymal Brain Metastases

Concentrations of Dabrafenib, Its Metabolites Hydroxy-, Carboxy- and Desmethyl-dabrafenib) and Trametinib (Cohort B Only) in CSF Samples.

Desmethyl-dabrafenib

Hydroxy-dabrafenib

Carboxy-dabrafenib

Concentrations of Dabrafenib, Its Metabolites Hydroxy-, Carboxy- and Desmethyl-dabrafenib) in Cerebrospinal Fluid (CSF) Samples

Full Analysis Set. Analysis was planned but not performed as the study was terminated due to low enrollment.

Number of Participants With Changes in Mitogen-activated Protein Kinase (MAPK) Pathway Markers

Number of Participants With Changes in Radiographic Tumors

Full Analysis Set. This analysis was planned but not performed as the study was terminated due to low enrollment.

Percent Change From Baseline to Pre-surgery in the Sum of the Longest Diameters (SLD) of Intracranial Target Lesions

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Dabrafenib/Trametinib, BRAF or BRAF AND MEK Pre-op With BRAF and MEK Post-op, Phase IIB, Melanoma With Brain Mets,Biomarkers and Metabolites	NCT01978236	Melanoma and Br...	Dabrafenib 150 ... Trametinib 2.0 ...	18 Years -	GlaxoSmithKline
Dabrafenib/Trametinib, BRAF or BRAF AND MEK Pre-op With BRAF and MEK Post-op, Phase IIB, Melanoma With Brain Mets,Biomarkers and Metabolites	NCT01978236	Melanoma and Br...	Dabrafenib 150 ... Trametinib 2.0 ...	18 Years -	GlaxoSmithKline

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