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AZD6244 Hydrogen Sulfate for Children With Nervous System Tumors

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01362803
Recruitment Status : Active, not recruiting
First Posted : May 30, 2011
Last Update Posted : August 4, 2022
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief Summary:


- 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.


- 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.


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


  • 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.

Condition or disease Intervention/treatment Phase
Neurofibromatosis 1 Neurofibromatosis Type 1 NF1 Neurofibroma, Plexiform Drug: AZD6244 Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 99 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II 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)
Actual Study Start Date : September 21, 2011
Estimated Primary Completion Date : January 1, 2025
Estimated Study Completion Date : January 1, 2030

Arm Intervention/treatment
Experimental: Arm 1
Phase 1: AZD6244 PO BID x 28 DAYS
Drug: AZD6244
AZD6244 orally (at recommended Ph2 dose) every 12 hours on continuous daily schedule for cycles of 28 days until unacceptable toxicity, patient withdrawal or PD

Experimental: Arm 2
Phase 2: AZD6244 PO BID x 28 DAYS
Drug: AZD6244
AZD6244 orally (at recommended Ph2 dose) every 12 hours on continuous daily schedule for cycles of 28 days until unacceptable toxicity, patient withdrawal or PD

Primary Outcome Measures :
  1. Ph2: Evaluate the confirmed partial and complete response rate of selumetinib in children and young adults with NF1 and inoperable PN. [ Time Frame: prior to cycles 5,6,13,17,21,25 and then every 6 cycles ]
    Evaluate the confirmed partial and complete response rate of selumetinib in children and young adults with NF1 and inoperable PN.

  2. Ph1: Determine MTD and extended tolerability [ Time Frame: 3 treatment cycles ]
    Determine MTD and extended tolerability

Secondary Outcome Measures :
  1. Study PK [ Time Frame: first course ]
    pharmacokinetics (PK) of selumetinib at baseline and steady state

  2. Ph2: Evaluate effect of selumetinib on bone mineral density, pain, quality of life and physical functioning. [ Time Frame: before cycles 3,5,9,13 and then every 12 cycles ]
    DEXA, survey responses and functional evaluations

  3. Ph2: Evaluate confirmed partial and complete response rate, and duration of response. [ Time Frame: at each response evaluation ]
    Objective response rate

  4. Ph2: determine long term tolerability, and safety [ Time Frame: at each response evaluation ]
    Detailed clinical evaluation and laboratory studies

  5. Measure adherence of chronic dosing [ Time Frame: at each response evaluation ]
    level of adherence to selumetinib

  6. determine effect on growth rate of PN [ Time Frame: at time of PD ]
    Percent PN volume increase per year

  7. Define toxicities [ Time Frame: at each response evaluation ]
    describe and define the toxicities in pediatric patients on chronic dosing of selumetinib

Information from the National Library of Medicine

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Ages Eligible for Study:   2 Years to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No


  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 Phase II: geater than 2 years of age and less than or equal to 18 years of age. BSA greater than or equal to 0.55 m(2), 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 substantial morbidity due to encasement of, or close proximity to, vital structures, invasiveness, or high vascularity of the PN. The PN has to cause (stratum 1) or have the potential to cause (stratum 2) significant morbidity, such as (but not limited to) head and neck lesions that could compromise the airway or great vessels, paraspinal lesions that can cause myelopathy 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 are significantly disfiguring, 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: (NIH Consensus conference):

    • 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.

    Phase II: Measurability and suitability for volumetric MRI analysis of the target PN must be confirmed with the NCI POB prior to enrolling a patient. The target PN will be defined as the clinically most relevant PN, which has to be amenable to volumetric MRI analysis. PN will be classified as typical PN versus nodular PN versus solitary nodular PN prior to enrollment

  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.

    • 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 selumetinib 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, imatinib or other targeted therapies are eligible for enrollment. At least 4 weeks must have elapsed since receiving medical therapy directed at the PN. Patients who received prior medical therapy for their PN must have recovered from the acute toxic effects of all prior therapy to less than or equal to grade 1 before entering this study.
    • Growth factors that support platelet or white cell number or function must not have been administered within 7 days prior to enrollment.
    • At least 6 weeks must have elapsed prior to enrollment since the patient received any prior radiation therapy.
    • At least 4 weeks must have elapsed since any surgeries, with evidence of good wound healing.
  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%. Patients who are wheelchair bound because of paralysis secondary to a plexiform neurofibroma should be considered ambulatory when they are up in their wheelchair. Similarly, patients with limited mobility secondary to need for mechanical support (such as an airway PN requiring tracheostomy or CPAP) will also be considered ambulatory for the purpose of the study.
  6. Hematologic Function: Patients must have an absolute neutrophil count greater than or equal to 1500/(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 AST/ ALT within less than or equal to 3 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 greater than 5 to less than or equal to 10/ Maximum Serum Creatinine 1.0 mg/dL

    Age greater than 10 to 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 or cardiac MRI) greater than or equal to 53% (or the institutional normal; if a range is given then the upper value of the range will be used); QTcF less than or equal to 450 msec.
  10. Adequate Blood Pressure defined as:

    A blood pressure (BP) less than or equal to the 95th percentile for age, height, and gender measured as described in (Appendix IB). Adequate blood pressure can be achieved using medication for treatment of hypertension.

  11. 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.
  12. Willingness to avoid excessive sun exposure and use adequate sunscreen protection if sun exposure is anticipated.
  13. Willingness to avoid the ingestion of grapefruit and Seville oranges (as well as other products containing these fruits, e.g. grapefruit juice or marmalade) during the study, as these may affect selumetinib metabolism.


  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 for all females of childbearing potential as per institutional standards (at NIH subjects 9 years and older or those showing pubertal development). 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. Use of 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.
  11. Evidence of an optic glioma, malignant glioma, malignant peripheral nerve sheath tumor, or other cancer requiring treatment with chemotherapy or radiation therapy.
  12. Supplementation with vitamin E greater than 100% of the daily recommended dose. Any multivitamin containing vitamin E must be stopped prior to initiation of therapy.
  13. Patients not achieving adequate blood pressure in spite of antihypertensive therapy for control of blood pressure.
  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 known glaucoma and increased IOP who do not have meaningful vision (light perception only or no light perception) and are not experiencing pain related to the glaucoma, may be eligible after discussion with the study chair.
    4. Subjects with any other significant abnormality on ophthalmic examination 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01362803

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United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
National Cancer Institute (NCI)
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Principal Investigator: Brigitte C Widemann, M.D. National Cancer Institute (NCI)
Additional Information:
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: National Cancer Institute (NCI) Identifier: NCT01362803    
Other Study ID Numbers: 110161
First Posted: May 30, 2011    Key Record Dates
Last Update Posted: August 4, 2022
Last Verified: June 2, 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: .All IPD recorded in the medical record will be shared with intramural investigators upon request.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Time Frame: Clinical data available during the study and indefinitely.
Access Criteria: Clinical data will be made available via subscription to BTRIS and with the permission of the study PI.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
Maximum Tolerated Dose
Response Rate
pain, quality of life and physical functioning
Additional relevant MeSH terms:
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Neurofibromatosis 1
Neurofibroma, Plexiform
Nerve Sheath Neoplasms
Neoplasms, Nerve Tissue
Neoplasms by Histologic Type
Neoplastic Syndromes, Hereditary
Neurocutaneous Syndromes
Nervous System Diseases
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Genetic Diseases, Inborn
Peripheral Nervous System Diseases
Neuromuscular Diseases
Peripheral Nervous System Neoplasms
Nervous System Neoplasms