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

This is a 3-part (Part A, Part B, Part C), 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 18 subjects. . The overall goal of this trial is to efficiently establish safe, pharmacologically relevant dose of trametinib in infants, children and adolescents and determine preliminary activity of trametinib monotherapy in selected recurrent, refractory or unresectable childhood tumors.

Conducting Institutions:

Children's Hospital Boston, Dana-Farber Cancer Institute

Overall PI:

Site-responsible Investigators:

Contacts:

Eligibility 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 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 - to be determined after completion of
     enrollment into Part A

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 and Part C only: Previous treatment with dabrafenib or any Rapidly accelerated
     fibrosarcoma 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 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. If clarification is needed as
     to whether a condition will significantly affect absorption of drugs, contact the
     GlaxoSmithKline (GSK) medical monitor for guidance to enrol the subject.

  -  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.