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

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

  • ORG STUDY ID: ChildrenHLA
  • NCT ID: NCT02285439

Conditions

  • Low-Grade Gliomas
  • Malignant Neoplasms, Brain
  • Soft Tissue Neoplasms

Interventions

DrugSynonymsArms
MEK162ARRY 438162Phase 1

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 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.

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

NameTypeDescriptionInterventions
Phase 1ExperimentalPatients 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 2ExperimentalChildren 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 ValidationExperimentalPatients 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

        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.
      
Maximum Eligible Age:18 Years
Minimum Eligible Age:1 Year
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Response rate
Time Frame:Study duration (up to 3 years)
Safety Issue:
Description:Phase 2: Response rate (strata 1 and 2)

Secondary Outcome Measures

Measure:Survival
Time Frame:Study duration (up to 3 years)
Safety Issue:
Description:12-month progression-free and overall survival (strata 1 and 2)

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Children's Hospital Los Angeles

Trial Keywords

  • Pediatric Oncology
  • Ras/Raf pathway
  • Low-Grade Glioma
  • MEK inhibitor

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