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

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.