Clinical Trials /

Phase I/II Study of MEK162 for Children With Ras/Raf Pathway Activated Tumors

NCT02285439

Description:

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.

Related Conditions:
  • Glioma
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Phase I/II Study of MEK162 for Children With Ras/Raf Pathway Activated Tumors

Title

  • Brief Title: Phase I/II Study of MEK162 for Children With Ras/Raf Pathway Activated Tumors
  • Official Title: Phase I Study of MEK162 for Children With Progressive or Recurrent Cancer and a Phase II Study for Children With Low-Grade Gliomas and Other Ras/Raf/MAP Pathway Activated Tumors
  • Clinical Trial IDs

    NCT ID: NCT02285439

    ORG ID: ChildrenHLA

    Trial Conditions

    Low-Grade Gliomas

    Malignant Neoplasms, Brain

    Soft Tissue Neoplasms

    Trial Interventions

    Drug Synonyms Arms
    MEK162 ARRY 438162 Phase 1, Phase 2, Target Validation

    Trial Purpose

    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 causes by abnormal
    activation of the Ras/Raf/MAP 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.

    Detailed Description

    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.

    Trial Arms

    Name Type Description Interventions
    Phase 1 Experimental Patients with non-hematologic malignancies that are recurrent, progressive, or refractory after standard up-front therapy receiving MEK162 will define the MTD, DLT, and toxicity profile. MEK162
    Phase 2 Experimental Children with recurrent tumors signaling through the Ras/Raf pathway will be treated in 3 strata to define the activity of MEK162. S1: Children with LGG characterized by a BRAF truncated fusion (KIAA1549 and similar translocations). S2: Children with NF1 and LGG. S 3: Children with tumors involving the Ras/Raf pathway not included in strata 1 or 2. MEK162
    Target Validation Experimental Patients eligible for phase 2 (any stratum) for whom tumor biopsy or resection is clinically indicated may be enrolled on the target validation arm. Patients will receive MEK162 for 7 to 21 days prior to their surgery. Tumor sample will be analyzed for drug concentration and target inhibition. MEK162

    Eligibility Criteria

    Inclusion Criteria:

    - Patients with recurrent, refractory, or progressive non-hematologic malignancies (CNS
    or solid tumors) characterized by known or presumed Ras-Raf pathway activation will
    be eligible.

    - Age >1 year and <18 years.

    - Karnofsky Performance Scale (patients > 12 years old) or Lansky Play - Performance
    Scale (patients 12 years old) > 60.

    - Normal organ and marrow function as defined below:

    - Absolute neutrophil count > 1,000/mcL

    - Platelets > 75,000/mcL and > 7 days since last platelet transfusion. Hemoglobin
    > 9gm/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 < 1.5 times the upper limit of institutional normal for
    age or GFR > 70 ml/min/1.73m2.

    - QTc interval < 450ms.

    - Left ventricular ejection fraction (LVEF) > 50%.

    - 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.

    - 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 must not have 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 5 x t1/2 (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).

    Minimum Eligible Age: 1 Year

    Maximum Eligible Age: 18 Years

    Eligible Gender: Both

    Primary Outcome Measures

    Response rate

    Secondary Outcome Measures

    Survival

    Trial Keywords

    Pediatric Oncology

    Ras/Raf pathway

    Low-Grade Glioma

    MEK inhibitor