Clinical Trials /

AZD6244 Hydrogen Sulfate for Children With Nervous System Tumors

NCT01362803

Description:

Background: - Plexiform neurofibromas are tumors that grow in and around nerves. The only way to treat them is with surgery. Some of these tumors cannot be completely removed. The tumors may be too large, too numerous, or in a bad location for surgery. An experimental drug called AZD6244 hydrogen sulfate may be able to prevent the tumors from growing, slow down their growth, or shrink them. This drug has been tested in adults with cancer and in children with some types of brain cancer. This study will test how well this drug works with these types of tumors. Objectives: - To study the safety and effectiveness of AZD6244 hydrogen sulfate in children and young adults with plexiform neurofibromas that cannot be completely removed by surgery. Eligibility: - Children and young adults between 12 and 18 years of age who have plexiform neurofibromas that cannot be completely removed by surgery. Design: - Patients will be screened with a physical exam, medical history, blood tests, and imaging studies. - They will take the study drug twice a day with 8 ounces of water, every day for 28-day cycles of treatment. During study visits, participants will have blood and urine tests and physical exams. They will also have imaging studies to examine the tumor sizes and locations. They will answer questions about their health. They may have other tests as needed. - Participants will continue to receive the study drug as long as they have no severe side effects and the disease is not getting worse.

Related Conditions:
  • Neurofibroma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

AZD6244 Hydrogen Sulfate for Children With Nervous System Tumors

Title

  • Brief Title: AZD6244 Hydrogen Sulfate for Children With Nervous System Tumors
  • Official Title: A Phase 1/2 Study of the Mitogen Activated Protein Kinase Kinase(MEK) 1 Inhibitor Selumetinib (AZD6244, Hydrogen Sulfate) in Children With Neurofibromatosis Type 1 (NF1) and Inoperable Plexiform Neurofibromas (PN)
  • Clinical Trial IDs

    NCT ID: NCT01362803

    ORG ID: 110161

    NCI ID: 11-C-0161

    Trial Conditions

    Neurofibromatosis 1

    Neurofibromatosis Type 1

    NF 1

    Neurofibroma, Plexiform

    Trial Interventions

    Drug Synonyms Arms
    AZD6244 Arm 1

    Trial Purpose

    Background:

    - Plexiform neurofibromas are tumors that grow in and around nerves. The only way to treat
    them is with surgery. Some of these tumors cannot be completely removed. The tumors may be
    too large, too numerous, or in a bad location for surgery. An experimental drug called
    AZD6244 hydrogen sulfate may be able to prevent the tumors from growing, slow down their
    growth, or shrink them. This drug has been tested in adults with cancer and in children with
    some types of brain cancer. This study will test how well this drug works with these types
    of tumors.

    Objectives:

    - To study the safety and effectiveness of AZD6244 hydrogen sulfate in children and young
    adults with plexiform neurofibromas that cannot be completely removed by surgery.

    Eligibility:

    - Children and young adults between 12 and 18 years of age who have plexiform neurofibromas
    that cannot be completely removed by surgery.

    Design:

    - Patients will be screened with a physical exam, medical history, blood tests, and
    imaging studies.

    - They will take the study drug twice a day with 8 ounces of water, every day for 28-day
    cycles of treatment. During study visits, participants will have blood and urine tests
    and physical exams. They will also have imaging studies to examine the tumor sizes and
    locations. They will answer questions about their health. They may have other tests as
    needed.

    - Participants will continue to receive the study drug as long as they have no severe
    side effects and the disease is not getting worse.

    Detailed Description

    Background

    Patients with Neurofibromatosis 1 (NF1) have an increased risk of developing tumors of the
    central and peripheral nervous system, including plexiform neurofibromas (PN), which are
    benign nerve sheath tumors that are among the most debilitating complications of NF1. PN may
    be congenital and appear to have the fastest growth rate in young children. There are no
    standard treatment options for PN other than surgery, which is often difficult due to the
    encasement of vital structures, and extensive and invasive growth.

    PN are composed of neoplastic Schwann cells that lack NF1 gene expression resulting in
    upregulation of Ras, which initiates several signaling cascades regulating cell
    proliferation.

    AZD6244 hyd sulfate, a novel orally bioavailable mitogen activated protein kinase inhibitor,
    is a specific inhibitor of MEK 1, which is currently undergoing evaluation in adult cancers
    and children with brain tumors, and may mediate anti-tumor effects in PN by inhibition of
    downstream signaling of Ras.

    Objectives

    To determine the maximum tolerated dose (MTD) of oral selumetinib administered daily to
    pediatric patients with NF1 and inoperable PN. Based on the results of the dose escalation
    in this study, the current MTD has been determined as 20 mg/m2/dose. To be consistent in
    pedriatric dosing, an additional dose level of 25mg/m2/dose was added, which is the MTD
    recently determined in a study conducted by the Pediatric Brain Tumor Consortium (PBTC).
    Amendment H (November 2014). The MTD has been determined to be 25 mg/m2/dose.

    To determine the effect of selumetinib on the growth rate of PN.

    Eligibility

    Pediatric Patients (3 less than or equal to 18 years) who are able to swallow intact
    capsules, with NF1 and inoperable measurable PN that have the potential to cause significant
    morbidity.

    Design

    AZD6244 hyd sulfate will be administered orally BID on a continuous dosing schedule (28 days
    = 1 treatment cycle). Limited dose escalations will be performed to define the MTD based on
    tolerability of AZD6244 hyd sulfate during the first three treatment cycles.

    Disease status will be evaluated using volumetric MRI analysis at regular intervals.

    The plasma PK and PD of AZD6244 hyd sulfate will be evaluated.

    Trial Arms

    Name Type Description Interventions
    Arm 1 Experimental AZD6244 PO BID AZD6244

    Eligibility Criteria

    -INCLUSION CRITERIA:

    1. Age Phase I: greater than 3 years and less than or equal to 18 years at the time of
    study enrollment, if able to swallow whole capsules. The age limits including young
    children were chosen because early childhood and puberty are considered to be the
    greatest risk for disease progression, and selumetinib may provide the most benefit
    to this young group of patients. In addition, an important objective of this study is
    to characterize the pharmacokinetics of selumetinib in the pediatric population since
    it has been well studied in adults.

    Age PhaseII: geater than 2 years of age and less than or equal to 18 years of age.
    BSA greater than or equal to 0.55 m2, and able to swallow whole capsules.

    2. Diagnosis: Patients with NF1 and inoperable PN, defined as PN that cannot be
    surgically completely removed without risk for substantialmorbidity due to encasement
    of, or close proximity to, vital structures, invasiveness, or high vascularity of the
    PN. The PN has to cause significant morbidity, such as (but not limited to) head and
    neck lesions that could compromise the airway or great vessels, brachial or lumbar
    plexus lesions that could cause nerve compression and loss of function, lesions that
    could result in major deformity (e.g., orbital lesions) or significant cosmetic
    problems, lesions of the extremity that cause limb hypertrophy or loss of function,
    and painful lesions. Patients will be enrolled into stratum 1 or 2 based on PN
    related morbidity.

    Histiologic confirmation of tumor is not necessary in the presence of consistent
    clinical and radiographic findings, but should be considered if malignant
    degeneration of a PN is clinically suspected.

    A PN is defined as a neurofibroma that has grown along the length of a nerve and may
    involve multiple fascicles and branches. A spinal PN involves two or more levels with
    connection between the levels or extending laterally along the nerve. In addition to
    PN, all study subjects must have either positive genetic testing for NF1 or have at
    least one other diagnostic criterion for NF1 listed below:

    - Six or more caf(SqrRoot)(Copyright)-au-lait macules (greater than or equal to 0.5cm
    in prepubertal subjects or greater than or equal to 1.5 cm in post pubertal subjects)

    - Freckling in axilla or groin

    - Optic glioma

    - Two or more Lisch nodules

    - A distinctive bony lesion (dysplasia of the sphenoid bone or dysplasia or thinning
    of long bone cortex)

    - A first-degree relative with NF1

    3. Measurable disease: Patients must have at least one measurable PN, defined as a
    lesion of at least 3 cm measured in one dimension. Patients who underwent surgery for
    resection of a PN are eligible provided the PN was incompletely resected and is
    measurable as per criteria above.

    4. Prior Therapy: Patients with NF1 will only be eligible if complete tumor resection is
    not considered to be feasible without substantial risk or morbidity, or if a patient
    with a surgical option refuses surgery.

    - Since there is no standard effective chemotherapy for patients with NF1 and PN,
    patients may be treated on this trial without having received prior medical therapy
    directed at their PN.

    - Since AZD6244 hyd sulfate is not expected to cause substantial myelosuppression,
    there will be no limit to number of prior myelosuppressive regimen for PN or other
    tumor manifestations associated with NF1 such as optic glioma.

    - Patients who have received previous investigational agents or biologic therapy,
    such as tipifarnib, pirfenidone, Peg-Intron, sorafenib, or other VEGFR
    inhibitors are eligible for enrollment.

    - Growth factors that support platelet or white cell number or function must not
    have been administered within the past 7 days.

    - Patients who received prior medical therapy for their PN must have recovered
    from the toxic effects of all prior therapy before entering this study.

    - At least 6 weeks must have elapsed prior to enrollment since the patient
    received any prior radiation therapy.

    5. Performance status: Patients greater than or equal to 16 years of age must have a
    Karnofsky performance level of greater than or equal to70%, and children < 16 years
    old must have a Lansky performance of greater than or equal to 70%.

    6. Hematologic Function: Patients must have an absolute neutrophil count greater than or
    equal to 1000/(micro)l, hemoglobin greater than or equal to 9g/dl, and platelet
    greater than or equal to 100,000/(micro)l.

    7. Hepatic Function: Patients must have bilirubin within 1.5 times the upper limit of
    normal for age, with the exception of Gilbert syndrome, and ALT within less than or
    equal to 1.5 times the upper limit of normal.

    8. Renal Function: Patients must have a creatinine clearance or radioisotope GFR greater
    than or equal to 60ml/min/1.73 m(2) or a normal serum creatinine based on age
    described below.

    Age (years)/Maximum Serum Creatinine(mg/dL):

    Age less than or equal to 5/Maximum Serum Creatinine 0.8 mg/dL

    Age 5 and/or less than or equal to 10/ Maximum Serum Creatinine 1.0 mg/dL

    Age 10 and/or less than or equal to 15/ Maximum Serum Creatinine 1.2 mg/dL

    Age greater than 15/ Maximum Serum Creatinine 1.5 mg/dL

    9. Cardiac Function: Normal ejection fraction (ECHO) greater than or equal to 55% (if a
    range is given then the upper limit of the range will be used)

    10. Informed Consent: Diagnostic or laboratory studies performed exclusively to determine
    eligibility for this trial must only be done after obtaining written informed consent
    from all patients or their legal guardians (if the patient is < 18 years old). When
    appropriate, pediatric patients will be included in all discussions. This can be
    accomplished through one of the following mechanisms: a) the NCI, POB screening
    protocol, b) an IRB-approved institutional screening protocol or c) the
    study-specific protocol.

    Documentation of the informed consent for screening will be maintained in the patient
    s research chart. Studies or procedures that were performed for clinical indications
    (not exclusively to determine eligibility) may be used for baseline values even if
    the studies were done before informed consent was obtained.

    11. Durable Power of Attorney (DPA): All patients greater than or equal to 18 years of
    age will be offered the opportunity to assign DPA so that another person can make
    decisions about their medical care if they become incapacitated or cognitively
    impaired.

    EXCLUSION CRITERIA:

    1. Pregnant or breast-feeding females are excluded due to potential risks of fetal and
    teratogenic adverse events of an investigational agent. Pregnancy tests must be
    obtained prior to enrollment on this study in girls, age 9 or older. Males or females
    of reproductive potential may not participate unless they have agreed to use an
    effective contraceptive method. Abstinence is an acceptable method of birth control.

    2. Phase I: Patients who anticipate the need for surgical intervention within the first
    three cycles (3 months), as surgical intervention during the period of DLT evaluation
    may affect analysis of adherence and/or make the subject inevaluable.

    3. An investigational agent within the past 30 days.

    4. Ongoing radiation therapy, chemotherapy, hormonal therapy directed at the tumor,
    immunotherapy, or biologic therapy.

    5. Any evidence of severe or uncontrolled systemic disease, active infection, active
    bleeding diatheses, or renal transplant, including any patient known to have
    hepatitis C, or human immunodeficiency virus (HIV) will be excluded. Patients with
    HIV who have adequate CD4 count, not requiring antiretroviral medication, may be
    enrolled.

    6. Patients who in the opinion of the investigator may not be able to comply with the
    safety monitoring requirements of the study.

    7. Inability to swallow capsules, since capsules cannot be crushed or broken.

    8. Inability to undergo MRI and/or contraindication for MRI examinations following the
    MRI protocol. Prosthesis or orthopedic or dental braces that would interfere with
    volumetric analysis of target PN on MRI.

    9. Refractory nausea and vomiting, chronic grastointestinal disease (e.g., inflammatory
    bowel disease), or significant bowel resection that would preclude adequate
    absorption.

    10. Prior treatment with selumetinib or another specific MEK1/2 inhibitor (unless the
    subject meets criteria for re-treatment.

    12. Evidence of an optic glioma, malignant glioma, malignant peripheral nerve sheath
    tumor, or other cancer requiring treatment with chemotherapy or radiation therapy.

    13. Supplementation with vitamin E greater than 100% of the daily recommended dose.

    14. Cardiac Function: a) known inherited coronary disease, b) Symptomatic heart failure
    (NYHA Class II-IV prior or current cardiomyopathy, or severe valvular heart disease), c)
    Prior or current cardiomyopathy, d) Sever valvular heart disease, 3) History of atrial
    fibrillation

    15. Ophthalmologic conditions:

    1. Current or past history of central serous retinopathy

    2. Current or past history of retinal vein occlusion

    3. Known intraocular pression (IOP) greater than 21 mmHg (or ULN adjusted by age) or
    uncontrolled glaucoma (irrespective of IOP); patients with controlled glaucoma and
    increased IOP who do not have meaningful vision (light perception only or no light
    perception) may be eligible after discussion with the study chair.

    4. Subjects with any other significant abnormality on ophthalmic examination (performed
    by an ophthalmologist) should be discussed with the Study Chair for potential
    eligibility

    5. Ophthalmological f ndings secondary to long-standing optic pathway glioma (such as
    visual loss, optic nerve pallor or strabismus) or long-standing orbito-temporal PN
    (such as visual loss, strabismus) will NOT be considered a significant abnormality
    for the purposes of the study

    16. Known severe hypersensitivity to selumetinib or any excipient of selumetinib or
    history of allergic reactions attributed to compounds of similar chemical or biologic
    composition to selumetinib.

    17. Recent major surgery within a minimum of 4 weeks prior to starting study
    treatment, with the exception of surgical placement for vascular access.

    18. Any unresolved chronic toxicity with CTC AE grade greater than or equal to 2 from
    anti-NF1 therapy, except for alopecia.

    19. Clinical judgement by the investigator that the patient should not participate in
    the study.

    20. While not an exclusion criterion, unless considered clinically indicated,
    patients should avoid taking other additional non-study medications that may
    interfere with the study medications. In particular, patients should avoid
    medications that are known to either induce or inhibit the activity of hepatic
    mircrosomal isoenzymes CYP1A2, CYP2C19 and CYP3A4, as this may interfere with the
    metabolism of selumetinib.

    Minimum Eligible Age: 2 Years

    Maximum Eligible Age: 18 Years

    Eligible Gender: Both

    Primary Outcome Measures

    Determine MTD and extended tolerability

    Secondary Outcome Measures

    Determine effect on growth rate of PN

    Study PK

    Measure adherence of chronic dosing

    Define toxicities

    Trial Keywords

    Maximum Tolerated Dose

    Pharmacokinetics

    Pharmacodynamics

    Response Rate

    pain, quality of life and physical functioning

    Neurofibromatosis Type 1

    NF1

    Plexiform Neurofibroma