Phase I/II Study of MEK162 for Children With Ras/Raf Pathway Activated Tumors
Phase I/II Study of MEK162 for Children With Ras/Raf Pathway Activated Tumors
The main purpose of phase I studies in general is to determine the best dose ("maximum
 tolerated dose") of a drug, and to find out the most common side effects. The main purpose of
 the phase I component of this study specifically is to determine the best dose of the
 experimental drug MEK162 and to find out whether the drug is safe in children and adolescents
 with tumors that have grown or come back despite standard therapy.

 Another purpose of this study is to measure the concentration of drug in the blood to help
 understand how much drug gets into the body and how quickly the drug is removed from the
 body. Another purpose of this study is to determine whether MEK162 turns off the Ras/Raf/MAP
 pathway as expected by measuring this pathway in blood cells. Finally, in this study, the
 investigators hope to start finding out whether or not MEK162 causes different types of
 tumors in children to shrink or stop growing.

 The main purpose of the phase II component of the study is to determine whether MEK162 causes
 specific types of tumors in children and adolescents to shrink or stop growing. These
 specific types of tumors include low-grade gliomas, tumors in patients with a genetic
 condition called neurofibromatosis type 1, and other tumors thought to be caused by abnormal
 activation of the Ras/Raf/MEK molecular pathway.

 Another purpose of this study is for researchers to learn whether specific abnormalities in
 the DNA of tumors can help predict whether tumors will respond to MEK162.
PROTOCOL SUMMARY:

 Phase 1: Patients with non-hematologic malignancies that are recurrent, progressive, or
 refractory after standard up-front therapy receiving MEK162 will define the maximum tolerated
 dose (MTD), dose-limiting toxicities (DLT), and toxicity profile.

 Phase 2: Patients with recurrent or progressive tumors signaling through the ras/raf pathway
 after standard up-front therapy will be treated in three strata to define the activity of
 MEK162.

 Stratum 1: Pediatric patients with recurrent or progressive low-grade glioma (LGG)
 characterized by a BRAF truncated fusion (KIAA1549 and similar translocations).

 Stratum 2: Pediatric patients with neurofibromatosis type 1 (NF1) and recurrent or
 progressive LGG.

 Stratum 3: Pediatric patients with recurrent or progressive tumors thought to involve the
 ras/raf/MAP pathway but not included in strata 1 or 2. This includes any LGG not included in
 strata 1 or 2 (i.e., any LGG without a BRAF truncated fusion in a patient without NF1), any
 tumor other than LGG in a patient with NF1, and any other tumor with a known activating BRAF,
 NRAS or KRAS mutation.

 Target validation phase: Patient enrolled on the phase 2 component (any stratum) for whom
 tumor biopsy or resection is clinically indicated. Patients will receive MEK162 for 7 to 21
 days prior to their surgery. Samples will be analyzed for concentration of drug and target
 inhibition.

 Length of therapy:

 Protocol treatment will last approximately 48 weeks from the start of MEK162 in the absence
 of significant toxicity. Treatment will be administered based on the dose escalation schema
 for phase 1. Patients in the phase 2 component of the trial will also receive a planned 48
 weeks of therapy. Those undergoing planned tumor resection based on clinical criteria will be
 eligible to receive 7-21 days of treatment with MEK162 prior to the surgical procedure.

 Imaging to assess response will be obtained at the end of cycle 1 (+/- 1 week), at the end of
 cycle 3 (+/- 2 weeks) and after every three cycles thereafter (+/- 2 weeks). A cycle will
 consist of 28 days (+/- 3 days) and MEK162 will be given continuously. Patients deriving
 benefit may continue therapy beyond study completion but all protocol specific evaluations
 (other than survival or progression) will conclude after one year. All patients will be
 followed with progression as the end point.
Patients with recurrent or progressive disease, as defined in the following three strata
 below, will be eligible. For eligibility determination, tumor imaging from at least two
 time-points must be available to document radiographic progression or recurrence. Patients
 with non-progressive refractory tumors will not be eligible.

 -  Stratum 1: patients with LGG with a BRAF truncated fusion that is measurable in at
 least two dimensions on imaging.

 -  Stratum 2: patients with NF1 and LGG that is measurable in at least two dimensions on
 imaging.

 -  Stratum 3: Pediatric patients with a recurrent or progressive tumor thought to involve
 the Ras/Raf/ERK pathway but not included in strata 1 or 2 that is measurable in at
 least two dimensions on imaging. This includes any LGG not included in strata 1 or 2
 (i.e., any LGG without a BRAF truncated fusion in a patient without NF1), any tumor
 other than LGG in a patient with NF1, and any other tumor with a documented activating
 BRAF, NRAS, or KRAS mutation.

 -  Stratum 4 (surgical arm, target validation): Patients who meet criteria for stratum 1,
 2, or 3 for whom tumor biopsy and/or resection is clinically indicated.

 -  Tumor tissue for correlative studies must be available for all patients except those
 with NF1 and LGG (stratum 2) or any patient with optic pathway glioma (stratum 2 or
 3), for whom tumor tissue is optional.

 -  Patients must have received at least one prior chemotherapy or radiation regimen prior
 to progression.

 -  At the time of enrollment, at least 6 weeks must have elapsed since the last dose of
 any nitrosourea, and the longer of 2 weeks or 3 half-lives must have elapsed since the
 last dose of any other tumor-directed medication. or biologic therapy.

 -  At least 3 months must have elapsed since the last dose of irradiation to the target
 tumor(s) at the time of enrollment.

 -  Patients must be >1 year and <18 years old.

 -  Performance Score using the Karnofsky Performance Scale (patients > 12 years old) or
 Lansky Play - Performance Scale (patients ≤ 12 years old) must be ≥ 60 assessed within
 two weeks prior to enrollment.

 -  Participants must have normal organ and marrow function as defined below within two
 weeks prior to enrollment:

 -  Absolute neutrophil count > 1,000/mcL

 -  Platelets > 75,000/mcL and > 7 days since last platelet transfusion. Hemoglobin >
 9 gm/dL and > 7 days since last red blood cell transfusion

 -  Not refractory to red cell or platelet transfusions

 -  Hepatic: Total bilirubin ≤ 1.5 times the upper limit of normal; SGPT (ALT) and
 SGOT (AST) < 3 times the institutional upper limit of normal

 -  Renal: Serum creatinine which is less than 1.5 time the upper limit of
 institutional normal for age or GFR > 70 ml/min/1.73m2

 -  QTc interval < 450ms

 -  Left ventricular ejection fraction (LVEF) > 50% as determined by an
 echocardiogram

 -  Female patients of childbearing potential must have negative serum or urine pregnancy
 test within 72 hours of the first dose of MEK162. Patient must not be pregnant or
 breast-feeding. Patients of childbearing or child-fathering potential must be willing
 to use a medically acceptable form of birth control, which includes abstinence, while
 being treated on this study and for 30 days following cessation of treatment.

 -  Patient must be able to take oral/enteral medication.

 -  Patient, parent, or legal guardian must be able to understand and willing to provide
 informed consent.

 -  Patients must have recovered from the effects of prior therapy.

 Exclusion Criteria

 Patients with any of the following characteristics will not be eligible:

 -  Patients for whom other curative or established standard-of-care therapeutic options
 with acceptable morbidity exist.

 -  Patients with any significant medical illnesses that in the investigator's opinion
 cannot be adequately controlled with appropriate therapy or would compromise the
 patient's ability to tolerate this therapy.

 -  History of Gilbert's syndrome

 -  Patients receiving any other anticancer or experimental drug therapy.

 -  Use of hematopoietic growth factors within 2 weeks prior to initiation of therapy.

 -  Any other investigational agents within 2 weeks or ≤ 3 half-lives (whichever is
 longer) before start of study therapy.

 -  Patients who have undergone surgery ≤ 3 weeks or who have not recovered from side
 effects of this procedure prior to receiving study drug.

 -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
 infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
 arrhythmia, impaired gastrointestinal function, or psychiatric illness/social
 situations that would limit compliance with study requirements.

 -  History or current evidence of retinal vein occlusion (RVO) or predisposing factors to
 RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or
 hypercoagulability syndromes).

 -  History of retinal degenerative disease

 -  Prior therapy with a MEK inhibitor

 -  Impairment of gastrointestinal function (e.g., active ulcerative disease, uncontrolled
 nausea, vomiting, diarrhea, malabsorption syndrome)

 -  Patients who have a neuromuscular disorder that is associated with elevated CK (e.g.,
 inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal
 muscular atrophy).

 -  Patients with uncontrolled hypertension

 Inclusion of Women, Minorities, and Other Underrepresented Populations This protocol is
 open to males and females of all races. See Inclusion Criteria above regarding specific
 eligibility requirements for female and male patients of child-bearing or child-fathering
 potential, respectively.