Study to Investigate Safety, Pharmacokinetic (PK), Pharmacodynamic (PD) and Clinical Activity of Trametinib in Subjects With Cancer or Plexiform Neurofibromas and Trametinib in Combination With Dabrafenib in Subjects With Cancers Harboring V600 Mutations

Study Description

Go to 

Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Brief Summary:

This is a 4-part (Part A, Part B, Part C and Part D), Phase I/IIa, multi-center, open label, study in pediatric subjects with refractory or recurrent tumors. Part A is a repeat dose, dose escalation monotherapy study that will identify the recommended phase II dose (RP2D) on the continuous dosing schedule using a 3 + 3 dose- escalation procedure. Part B will evaluate the preliminary activity of trametinib monotherapy in 4 disease-specific cohorts of subjects. Each cohort will enroll at least 10 response-evaluable subjects (evaluable for response is defined as a subject with a pre-dose and at least 1 post-dose disease assessment or clinical assessment of progression of disease). Part C is will be a 3+3 study design to determine the safety, tolerability and preliminary activity of the RP2D of trametinib in combination with a limited dose escalation of dabrafenib. Part C will enroll up to 24 subjects. Part D will evaluate the preliminary activity of trametinib in combination with dabrafenib in 2 disease-specific cohorts of subjects diagnosed with LGG and LCH. LGG cohort will enroll approximately 20 response-evaluable subjects and the LCH cohort will enroll approximately 10 response-evaluable subjects. The overall goal of this trial is to efficiently establish safe, pharmacologically relevant dose of trametinib monotherapy and trametinib in combination with dabrafenib in infants, children and adolescents and determine preliminary activity of trametinib monotherapy and trametinib in combination with dabrafenib in selected recurrent, refractory or unresectable childhood tumors.

Condition or disease	Intervention/treatment	Phase
Cancer	Drug: Trametinib; Drug: Dabrafenib	Phase 1

Study Design

Go to 

Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	142 participants
Allocation:	Randomized
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	An Open-Label, Dose-Escalation, Phase I/II Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of the MEK Inhibitor Trametinib in Children and Adolescents Subjects With Cancer or Plexiform Neurofibromas and Trametinib in Combination With Dabrafenib in Children and Adolescents With Cancers Harboring V600 Mutations
Actual Study Start Date :	January 15, 2015
Estimated Primary Completion Date :	October 15, 2020
Estimated Study Completion Date :	October 15, 2020

Arms and Interventions

Go to 

Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Arm	Intervention/treatment
Experimental: Part A; Trametinib Dose-Escalation: Trametinib is administered orally once daily (OD) under fasting conditions. The starting dose of trametinib (0.0125 milligram per kilogram per dose [mg/kg/dose]) is 50% of the recommended fixed dose in adults (2 mg OD). The second dose level (0.025 mg/kg) is equivalent to the recommended dose in adults (2 mg PO daily). The third dose level (0.040 mg/kg) is equivalent to the maximum tolerated dose [MTD] in adults (3 mg PO daily).	Drug: Trametinib; Trametinib is available in tablet (0.125mg, 0.5mg, 2mg dose) as well as in powder form for Oral Solution (0.05mg/mL dose). It is recommended that subjects drink 4 to 6 mL of water/kg body weight following dosing.
Experimental: Part B; Tumor-Specific Expansion: Trametinib is administered orally once daily under fasting conditions in 4 disease-specific cohorts of subjects Trametinib will be continued until disease progression.	Drug: Trametinib; Trametinib is available in tablet (0.125mg, 0.5mg, 2mg dose) as well as in powder form for Oral Solution (0.05mg/mL dose). It is recommended that subjects drink 4 to 6 mL of water/kg body weight following dosing.
Experimental: Part C; The trametinib dose administered in Part C will be the trametinib monotherapy RP2D from Part A. The monotherapy RP2D of dabrafenib in children will be established on a separate trial (BRF116013). The specifics for Part C will be determined following completion of enrollment into Part A.	Drug: Trametinib; Trametinib is available in tablet (0.125mg, 0.5mg, 2mg dose) as well as in powder form for Oral Solution (0.05mg/mL dose). It is recommended that subjects drink 4 to 6 mL of water/kg body weight following dosing.; Drug: Dabrafenib; Dabrafenib is available in capsules (50mg and 75mg) as well as in powder form for Oral Suspension (10 mg/mL dose) and taken twice a day. It is recommended that subjects drink approximately 1 ounce (30 mL) of water for every 10 pounds of body weight following dosing.
Experimental: Part D; The trametinib and dabrafenib doses administered in Part D will be the combination trametinib and dabrafenib RP2D from Part C.	Drug: Trametinib; Trametinib is available in tablet (0.125mg, 0.5mg, 2mg dose) as well as in powder form for Oral Solution (0.05mg/mL dose). It is recommended that subjects drink 4 to 6 mL of water/kg body weight following dosing.; Drug: Dabrafenib; Dabrafenib is available in capsules (50mg and 75mg) as well as in powder form for Oral Suspension (10 mg/mL dose) and taken twice a day. It is recommended that subjects drink approximately 1 ounce (30 mL) of water for every 10 pounds of body weight following dosing.

Outcome Measures

Go to 

Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Primary Outcome Measures :

1. Safety Assessment of trametinib as assessed by Adverse Events (AEs) [ Time Frame: From screening up to 63 months ]
2. Safety Assessment of trametinib as assessed by electrocardiogram (ECG) [ Time Frame: From screening up to 63 months ]
   Single 12-lead ECGs will be obtained to assess safety
3. Safety Assessment of trametinib as assessed by echocardiogram (ECHO) [ Time Frame: From screening up to 63 months ]
   ECHOs will be performed to assess cardiac ejection fraction and cardiac valve morphology
4. Safety Assessment of trametinib as assessed by changes in laboratory values [ Time Frame: From screening up to 63 months ]
   Laboratory assessments will include Hematology, Clinical Chemistry, Routine Urinalysis and Other screening tests
5. Safety Assessment of trametinib assessed by changes in vital signs [ Time Frame: From screening up to 63 months ]
   Vital sign measurements will include systolic and diastolic blood pressure, temperature, respiration rate and pulse rate
6. To determine the dose of trametinib that achieves similar exposures (Ctau) to the recommended adult dose [ Time Frame: Days 15 and 22 ]
   Steady state Ctau of trametinib

Secondary Outcome Measures :

1. PK Assessment of trametinib [ Time Frame: Day 15 and Day 22 ]
   PK parameters including Ctau (trough concentration), area under the concentration-time curve over a period of time (AUC [0-t]), area under the concentration-time curve over the dosing interval (AUC [0-tau]), apparent clearance following oral dosing (CL/F), maximum observed concentration (Cmax), Time of occurrence of Cmax (tmax) (tmax) and half-life (t1/2) of trametinib will be assessed
2. Safety and tolerability assessments for trametinib for AEs [ Time Frame: From screening up to 63 months ]
3. Safety and tolerability assessments for trametinib for ECG [ Time Frame: From screening up to 63 months ]
   12-lead ECGs will be performed to assess safety and tolerability
4. Safety and tolerability assessments for trametinib for changes in laboratory values [ Time Frame: From screening up to 63 months ]
   Laboratory parameter including chemistry and hematology
5. Safety and tolerability assessments for trametinib for vital signs [ Time Frame: From screening up to 63 months ]
   Vital sign measurements will include systolic and diastolic blood pressure, temperature, respiration rate and pulse rate
6. Tumor response for trametinib [ Time Frame: From screening up to 63 months ]
   Disease assessments will be conducted and utilize disease specific response criteria (e.g. RECIST, RANO)
7. Effect of age and weight on the PK of trametinib [ Time Frame: Day 15 and Day 22 ]
   PK parameter will include CL/F, volume of distribution (V/F), absorption rate (ka), and coefficients for significant covariates
8. PK assessment of trametinib and dabrafenib when administered in combination [ Time Frame: Day 1, Day 15 and Day 22 of Part C and Part D ]
   PK parameters include Ctau, AUC (0-t), AUC (0-tau), CL/F, Cmax, tmax, and Cavg
9. Palatability of trametinib and/or dabrafenib in pediatric subjects assessed by palatability questionnaire [ Time Frame: Day 8 ]
   To be completed after the first dose of study drug and no later than Day 8 (+/-3 days). Subjects will complete a form to evaluate the various properties of the suspension (e.g., bitterness, sweetness, appearance, texture and overall taste).
10. Safety Assessment of trametinib and dabrafenib when administered in combination as assessed by Adverse Events (AEs) [ Time Frame: From screening up to 63 months ]
11. Safety Assessment of trametinib and dabrafenib when administered in combination as assessed by ECGs. [ Time Frame: From screening up to 63 months ]
    12-lead ECGs will be performed to assess safety and tolerability
12. Safety Assessment of trametinib and dabrafenib when administered in combination as assessed by Echo. [ Time Frame: From screening up to 63 months ]
13. Safety Assessment of trametinib and dabrafenib when administered in combination as assessed by changes in laboratory values [ Time Frame: From screening up to 63 months ]
    Laboratory parameter including chemistry, hematology and urinalysis.
14. Safety Assessment of trametinib and dabrafenib when administered in combination as assessed by changes in vital sign values [ Time Frame: From screening up to 63 months ]
    Vital sign measurements will include systolic and diastolic blood pressure, temperature, respiration rate and pulse rate
15. Safe and tolerable doses of dabrafenib when administered with trametinib for chronic continuous daily dosing in pediatric subjects as assessed by AEs [ Time Frame: From screening up to 63 months ]
16. Safe and tolerable doses of dabrafenib when administered with trametinib for chronic continuous daily dosing in pediatric subjects as assessed by ECGs [ Time Frame: From screening up to 63 months ]
    12-lead ECGs will be performed to assess safety and tolerability
17. Safe and tolerable doses of dabrafenib when administered with trametinib for chronic continuous daily dosing in pediatric subjects as assessed by Echo [ Time Frame: From screening up to 63 months ]
18. Safe and tolerable doses of dabrafenib when administered with trametinib for chronic continuous daily dosing in pediatric subjects as assessed by changes in lab values [ Time Frame: From screening up to 63 months ]
    Laboratory parameter including chemistry, hematology and urinalysis.
19. Safe and tolerable doses of dabrafenib when administered with trametinib for chronic continuous daily dosing in pediatric subjects as assessed by changes in vital sings [ Time Frame: From screening up to 63 months ]
    Vital sign measurements will include systolic and diastolic blood pressure, temperature, respiration rate and pulse rate.
20. Safe and tolerable doses of dabrafenib when administered with trametinib for chronic continuous daily dosing in pediatric subjects as assessed by steady state Ctau of trametinib and by steady state AUC (0-12) of dabrafenib [ Time Frame: Day 15 and Day 22 of Part C and Part D ]
21. Tumor response for trametinib in combination with dabrafenib [ Time Frame: From screening up to 63 months ]
    Disease assessments will be conducted and utilize disease specific response criteria (e.g. RECIST, RANO)

Eligibility Criteria

Go to 

Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Ages Eligible for Study:	1 Month to 17 Years (Child)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• General Eligibility Criteria (All Parts)
• Written informed consent - a signed informed consent and/or assent (as age appropriate) for study participation including PK sampling will be obtained according to institutional guidelines.
• Male or female between one month and <18 years of age (inclusive) at the time of signing the informed consent form (Part C and Part D between 12 months and <18 years of age, inclusive).
• Must have a disease that is relapsed/refractory to all potentially curative standard treatment regimens or must have a current disease for which there is no known curative therapy, or therapy proven to prolong survival with an acceptable quality of life.
• Prior therapy: The subject's disease (i.e. cancer, neurofibromatosis type 1 [NF-1] with plexiform neurofibroma [PN], or Langerhans cell histocytosis [LCH]) must have relapsed after or failed to respond to frontline curative therapy or there must not be other potentially curative treatment options available. Curative therapy may include surgery, radiation therapy, chemotherapy, or any combination of these modalities. All subjects must have recovered to grade <=1 from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to enrollment. Prior therapy includes; myelosuppressive chemotherapy, differentiating agents/ biologic response modifiers (small molecules, antibodies, viral therapies) (anti-cancer agent), non-myelosuppressive anticancer agents, investigational agent, radiation therapy, stem cell transplantation or infusion, number of prior treatment regimens, colony stimulating factors, corticosteroids.
• Performance score of >=50% according to the Karnofsky/Lansky performance status scale.
• Females of child-bearing potential must be willing to practice acceptable methods of birth control. Additionally, females of childbearing potential must have a negative serum pregnancy test within 7 days prior to start of study drugs, throughout treatment period and for 4 months after last dose of study drugs.
• Must have adequate organ function as defined by the following values: renal function - 24 hr creatinine clearance (revised Schwartz formula), or radioisotope glomerular filtration rate (GFR) >=60 milliliter (mL) per minute per 1.73 meter square (mL/min/1.73m^2); or a serum creatinine <=upper limit of normal (ULN) for age and gender; liver functions as bilirubin (sum of conjugated + unconjugated) <=1.5 x ULN for age, alanine aminotransferase (ALT) <=2.5 x ULN; for the purposes of enrollment and toxicity monitoring the ULN for ALT will be 45 unit per liter (U/L); cardiac function - corrected QT (QTcB) interval <480 milliseconds (msec), left ventricular ejection fraction (LVEF) >=lower limit of normal (LLN) by ECHO.
• Able to swallow and retain enterally (per oral [PO] or nasogastric or gastric tube) administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels.
• Adequate Blood Pressure Control defined as: Blood pressure <= the 95th percentile for age, height, and gender.
• French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.
• Specific Eligibility Criteria, Part A
• Subjects must meet general eligibility criteria.
• For the initial dose escalation to identify the maximum tolerable or PK target dose, age between 2 years and <18 years (inclusive) at the time of signing the informed consent form. Children < 2 years of age will be enrolled once the age specific expansion cohorts are open.
• Histologically confirmed solid tumors, which may include but are not limited to rhabdomyosarcoma and other soft tissue sarcomas, Ewing sarcoma family of tumors, osteosarcoma, neuroblastoma, Wilms' tumor, hepatic tumors, germ cell tumors, primary brain tumors, NF-1 associated PF and LCH. In subjects with brain stem gliomas the requirement for histological confirmation can be waived if a biopsy was not performed. For plexiform neurofibromas, histologic confirmation of tumor is not necessary in the presence of consistent clinical and radiological findings, but should be considered if malignant degeneration of a PN is clinically suspected.
• Measurable or evaluable tumors. Subjects with neuroblastoma that is only detectable by Meta-iodobenzylguanidine (MIBG) scan are eligible. Subjects with neuroblastoma that is only detected by bone marrow aspirate/biopsy or elevated homovanillic acid / vanillylmandelic acid (HVA/VMA) are not eligible.
• Adequate bone marrow function defined as absolute neutrophil count (ANC) >=1000/microliter, hemoglobin >=8.0 gram per deciliter (g/dL) (may receive red blood cell transfusions), platelets >=75,000/ microliter (transfusion independent, defined as not receiving platelet transfusions within a 7 day period prior to enrollment).
• Specific Eligibility Criteria, Part B
• Subjects must meet general eligibility criteria. The specific eligibility criteria listed here will apply to subjects enrolling to different cohorts of Part B.
• Tumor tissue (archived or fresh) is required and must be available to be shipped to GSK or site specific laboratory.
• Solid tumor cohort (B1) specific criteria
• B1: Refractory or relapsed neuroblastoma
• B2: Recurrent or unresectable low grade gliomas with BRAF tandem duplication with fusion
• B3: Neurofibromatosis Type -1 associated plexiform neurofibromas (NF-1 with PN) that are unresectable and medically significant.
• B4: BRAF V600 mutant tumors.
• Specific Eligibility Criteria, Part C - Subjects must meet general eligibility criteria.
• Tumors that have been documented by CLIA or equivalent certified laboratory test to harbor BRAF V600 mutation at diagnosis or relapse
• Measurable or evaluable disease
• Adequate bone marrow function
• Specific Eligibility Criteria, Part D - Subjects must meet general eligibility criteria
• Measurable or evaluable disease
• Recurrent or refractory BRAFV600 mutant LGG or LCH tumors
• Adequate bone marrow function

Exclusion Criteria:

• Lactating or pregnant female.
• History of another malignancy including resected non-melanomatous skin cancer.
• Subjects with NF-1 associated optic pathway tumors are excluded if they are actively receiving therapy for the optic pathway tumor or do not meet criteria for PN or malignant solid tumor.
• Subjects with a history of NF-1 related cerebral vascular anomaly (such as Moyamoya).
• Subjects with NF-1 actively receiving therapy for the optic pathway tumor.
• Subjects with NF-1 and only PN lesions that cannot be evaluated by volumetric analysis (only applicable to Part B).
• 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.
• Any prohibited medication(s), currently used or expected to be required.
• Any medications for treatment of left ventricular systolic dysfunction.
• Part B, Part C and Part D only: Previous treatment with dabrafenib or any BRAF inhibitor, trametinib or another MEK inhibitor, or and Extracellular signal-regulated kinase inhibitor (exception: prior treatment with sorafenib is permitted). Patients who have received prior dabrafenib or another BRAF inhibitor may enrol into Part B4. Patients who have had prior dabrafenib or BRAF inhibitor therapy may enroll in Part C or Part D if they have had prior benefit to dabrafenib or BRAF inhibitor monotherapy, as determined by the investigator.
• Administration of an investigational study treatment within 30 days preceding the first dose of study treatment(s) in this study.
• Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to study treatment or excipients that contraindicate their participation.
• Current active liver or biliary disease (with the exception of Gilbert's syndrome or asymptomatic gallstones, or liver metastases).
• History of hepatic sinusoid obstructive syndrome (venoocculsive disease) within the prior 3 months.
• History of heparin-induced thrombocytopenia.
• History of interstitial lung disease or pneumonitis.
• History of or current evidence of retinal vein occlusion (RVO).
• For subjects with solid tumors that are not primary central nervous system (CNS) tumors or NF-1 associated plexiform neurofibromas subjects with symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression are excluded. NOTE: Subjects previously treated for these conditions that have had stable CNS disease (verified with consecutive imaging studies) for >3 months, are asymptomatic and are not currently taking corticosteroids, or are on stable dose or decreasing of corticosteroids for at least 7 days prior to enrolment are permitted.
• A history of known Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection. Subjects with laboratory evidence of cleared HBV and HCV infection may be enrolled.
• Unresolved toxicity of National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI CTCAE v4.0) Grade 2 or higher from previous anti-cancer therapy, except alopecia.
• Presence of active gastrointestinal (GI) disease or other condition that will interfere significantly with the absorption of drugs.
• A history or evidence of cardiovascular risk including: a QT interval corrected for heart rate using the Bazett's formula (QTcB) >=480 msec; a history or evidence of current clinically significant uncontrolled arrhythmias (clarification: Subjects with atrial fibrillation controlled for >30 days prior to dosing are eligible); a history of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization; a history or evidence of current >=Class II congestive heart failure as defined by the New York Heart Association (NYHA) guidelines; subjects with intra-cardiac defibrillators; abnormal cardiac valve morphology (>=grade 2) documented by echocardiogram (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study). Subjects with moderate valvular thickening should not be entered on study. Subjects with prosthetic valves can be considered eligible provided they meet the criteria as stated above; Treatment refractory hypertension defined as a blood pressure of systolic >140 millimeter of mercury (mmHg) and/or diastolic >90 mmHg (or above 95th age-specific percentile listed in protocol), which cannot be controlled by anti-hypertensive therapy.

Contacts and Locations

Go to 

Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Contacts

Contact: Novartis Pharmaceuticals	1-888-669-6682	Novartis.email@novartis.com
Contact: Novartis Pharmaceuticals

Locations

United States, Arizona
Novartis Investigative Site	Recruiting
Phoenix, Arizona, United States, 85016-7710
United States, California
Novartis Investigative Site	Recruiting
San Francisco, California, United States
United States, Maryland
Novartis Investigative Site	Recruiting
Baltimore, Maryland, United States, 21287
United States, Massachusetts
Novartis Investigative Site	Recruiting
Boston, Massachusetts, United States, 02115
United States, Minnesota
Novartis Investigative Site	Recruiting
Minneapolis, Minnesota, United States, 55455
United States, New York
Novartis Investigative Site	Recruiting
New York, New York, United States, 10065
United States, Ohio
Novartis Investigative Site	Recruiting
Cincinnati, Ohio, United States, 45229
United States, Pennsylvania
Novartis Investigative Site	Recruiting
Philadelphia, Pennsylvania, United States, 19104
United States, Tennessee
Novartis Investigative Site	Recruiting
Memphis, Tennessee, United States, 38105-3678
United States, Washington
Novartis Investigative Site	Recruiting
DC, Washington, United States, DC 20010
Australia, New South Wales
Novartis Investigative Site	Recruiting
Westmead, New South Wales, Australia, 2145
Canada, Ontario
Novartis Investigative Site	Recruiting
Toronto, Ontario, Canada, M5G 1X8
France
Novartis Investigative Site	Recruiting
Paris Cedex 05, France, 75248
Novartis Investigative Site	Recruiting
Villejuif Cedex, France, 94805
United Kingdom
Novartis Investigative Site	Recruiting
Sutton, Surrey, United Kingdom, SM2 5PT
Novartis Investigative Site	Recruiting
London, United Kingdom, WC1N 3JH

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

Study Director:	Novartis Pharmaceuticals	Novartis Pharmaceuticals

More Information

Go to 

Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	Novartis Pharmaceuticals
ClinicalTrials.gov Identifier:	NCT02124772 History of Changes
Other Study ID Numbers:	116540
First Posted:	April 28, 2014
Last Update Posted:	October 11, 2018
Last Verified:	October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

v600-mutation; neuroblastoma; Trametinib	pediatrics; Langerhans Cell Histiocytosis; low grade glioma plexiform neurofibromas

Additional relevant MeSH terms:

Neurofibroma; Neurofibromatoses; Neurofibroma, Plexiform; Nerve Sheath Neoplasms; Neoplasms, Nerve Tissue; Neoplasms by Histologic Type; Neoplasms; Peripheral Nervous System Neoplasms; Nervous System Neoplasms; Nervous System Diseases; Peripheral Nervous System Diseases; Neuromuscular Diseases	Neoplastic Syndromes, Hereditary; Neurocutaneous Syndromes; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Genetic Diseases, Inborn; Trametinib; Dabrafenib; Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action