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Trial of Selumetinib in Patients With Neurofibromatosis Type II Related Tumors (SEL-TH-1601)

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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03095248
Recruitment Status : Recruiting
First Posted : March 29, 2017
Last Update Posted : July 23, 2021
Information provided by (Responsible Party):
Children's Hospital Medical Center, Cincinnati

Brief Summary:

In this research study the researchers want to learn more about the effects (both good and bad) the study drug selumetinib has on participants with neurofibromatosis type II (NF2) related tumor.

The researchers are asking patients with NF2 related tumors to be in the study, because their hearing has decreased and/or their NF2 related tumor has started to grow.

The goals of this study are:

  • Determine if selumetinib will stop NF2 related tumors from growing
  • Measure the changes in hearing after receiving selumetinib for 6 months.
  • Determine if selumetinib improves how participants feel (physically and emotionally) and how participants can perform daily activities.
  • Examine tumor tissue, if available, in a laboratory to see if NF2 related tumors have targets of selumetinib.

Condition or disease Intervention/treatment Phase
Neurofibromatosis 2 Vestibular Schwannoma Meningioma Ependymoma Glioma Drug: Selumetinib Phase 2

Detailed Description:

This is a Phase 2 trial to assess the hearing response rate and radiographic response of VS in children and young adults with NF2 who are treated with selumetinib. Dosing will be based on age: For patients with NF2 who are 3 to < 18 years of age, dosing will be based on BSA. Dosing is based on BSA calculated at the beginning of each course. For patients with NF2 who are ≥ 18 to 45 years of age, dosing will be the standard adult dose of 75 mg BID.

Selumetinib is taken orally twice a day continuously. One course is equivalent to 28 days. Therapy may continue for up to two years (26 courses) in the absence of disease progression or unacceptable toxicity.

There will be two treatment strata. Stratum 1 is for those patients who have a target vestibular schwannoma which is causing hearing loss. Stratum 2 will be reserved for patients who exhibit growth of a tumor(s) besides vestibular schwannoma and are therefore not eligible for stratum 1.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 34 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: All participants with neurofibromatosis type 2 (NF2) will be stratified based upon tumor type. Vestibular schwannomas are assigned and analyzed as Stratum 1 and all other NF2 associated tumor types will be analyzed as Stratum 2.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 2 Trial of Selumetinib in Patients With Neurofibromatosis Type II Related Tumors
Actual Study Start Date : May 8, 2017
Estimated Primary Completion Date : May 2023
Estimated Study Completion Date : May 2024

Arm Intervention/treatment
Experimental: Stratum 1 - NF2 related vestibular schwannomas
Stratum 1 will include patients with NF2 with vestibular schwannomas who exhibit hearing loss. Participants will receive continuous twice daily dosing of selumetinib. Dosing for children (less than 18 is 25 mg/m2/dose) and dosing for adults is fixed 75 mg/dose.
Drug: Selumetinib
Continuous twice daily dosing; oral agent
Other Name: AZD6244

Experimental: Stratum 2: other NF2 related tumors (meningiomas and ependymom
Stratum 2 will include patients who have progressive lesions other than VS (including non-vestibular schwannomas, meningiomas, and spinal cord lesions). Participants will receive continuous twice daily dosing of selumentinib. Dosing for children (less than 18 is 25 mg/m2/dose) and dosing for adults is fixed 75 mg/dose.
Drug: Selumetinib
Continuous twice daily dosing; oral agent
Other Name: AZD6244

Primary Outcome Measures :
  1. Change in hearing response at 24 weeks [ Time Frame: 24 weeks ]
    Word recognition scores

  2. Response rate of other NF2 related tumors [ Time Frame: Through study completion up to 2 years ]
    Radiographic change in tumor measurements

Secondary Outcome Measures :
  1. Response rate of vestibular schwannomas [ Time Frame: Through study completion up to 2 years ]
    Radiographic change in tumor measurements

  2. Change in quality of life [ Time Frame: Through study completion up to 2 years ]
    Neurofibromatosis 2 impact quality of life questionnaire

Information from the National Library of Medicine

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Ages Eligible for Study:   3 Years to 45 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Patients must have a confirmed diagnosis of neurofibromatosis 2 by fulfilling National Institute of Health (NIH) criteria or Manchester criteria, or by detection of a causative mutation in the NF2 gene.

The NIH criteria includes presence of:

  • Bilateral vestibular schwannomas, OR
  • First-degree relative with NF2 and EITHER unilateral eighth nerve mass OR two of the following: neurofibroma, meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacity.

The Manchester criteria includes presence of:

  • Bilateral vestibular schwannomas, OR
  • First-degree relative with NF2 and EITHER unilateral eighth nerve mass OR two of the following: neurofibroma, meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacity, OR
  • Unilateral vestibular schwannoma AND any two of: neurofibroma, meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacity, OR
  • Multiple meningiomas (two or more) AND unilateral vestibular schwannoma OR any two of: schwannoma, glioma, neurofibroma, cataract.

    - Patients do not need to have a histologic diagnosis in order to start therapy but must have measurable disease (in 2 dimensions) on MRI scan to be eligible.

  • For Stratum 1: Patients must have a target VS with the following qualities:
  • Associated with a word recognition score of < 85% and > 0% AND
  • Documented progression defined as: Either progressive hearing loss or progressive tumor growth in last 18 months defined as ≥ 20% increase in volume.
  • For Stratum 2: Patients must not meet the eligibility criteria as stated for Stratum 1 and have a target lesion that has exhibited progression.
  • Progression is defined as: ≥ 25% increase in sum of the products of perpendicular diameters of lesions in the preceding 18 months; any new lesion; or clinical deterioration related to disease.

    • Patients must be able to swallow capsules
    • Age:
  • Patients must be ≥ 3 years to ≤ 45 years of age at start of treatment

    • Prior Therapy
  • Since there is no standard effective chemotherapy for patients with NF2 and vestibular schwannomas, meningiomas, or ependymomas patients may be treated on this trial without having received prior medical therapy directed at their VS, meningiomas, or ependymomas.
  • Since selumetinib is not expected to cause substantial myelosuppression, there will be no limit to number of prior myelosuppressive regimen for these NF2 patients.
  • Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, biologic therapy or radiotherapy prior to entering this study except for alopecia.
  • Myelosuppressive chemotherapy: Patients must have received their last dose of known myelosuppressive anticancer chemotherapy at least three weeks prior to study registration or at least six weeks if nitrosourea.
  • Biologic agent: Patient must have received their last dose of the biologic agent ≥ 7 days prior to study registration. For biologic agents that have a prolonged half-life, at least three half-lives must have elapsed prior to registration
  • Monoclonal antibody treatment: At least three half-lives must have elapsed prior to registration

    • Corticosteroids:
  • Patients who are receiving dexamethasone or other corticosteroids must be on a stable or decreasing dose for at least 1 week prior to registration. It is recommended that patients be off all steroid therapy or receive the least dose that will control their neurologic symptoms

    • Prior radiotherapy
  • XRT: ≥ 6 months must have elapsed if prior XRT to vestibular schwannoma or other tumor.

    - Stem Cell Transplant or Rescue without TBI:

  • No evidence of active graft vs. host disease and ≥ 3 months must have elapsed since transplant.

    - Performance Status:

  • Karnofsky ≥ 60% for patients > 16 years of age
  • Lansky ≥ 60 for patients ≤ 16 years of age.

    - Organ Function Requirements

  • Adequate Bone Marrow Function Defined as:
  • Peripheral absolute neutrophil count (ANC) ≥ 1000/μL
  • Platelet count ≥ 100,000/μL (transfusion independent, defined as not receiving platelet transfusions within a 7 day period prior to registration)
  • Hemoglobin ≥ 9 g/dL (may receive RBC transfusions)
  • Adequate Renal Function Defined as:
  • Creatinine clearance or radioisotope GFR ≥ 70ml/min/1.73 m2 or
  • A serum creatinine based on age/gender
  • Adequate Liver Function Defined as:
  • Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of normal (ULN) for age
  • AST(SGOT)/ALT(SGPT) <3 X institutional upper limit of normal for age
  • Central Nervous System Function:

    - Patients with seizure disorder may be enrolled if they are receiving non-enzyme inducing anticonvulsants and the seizures are well controlled.

  • Cardiac Function

Adequate cardiac function defined as:

  • LVEF ≥50% by ECHO
  • QTc interval ≤450 msecs by EKG
  • Hypertension
  • Patients, 3 to < 18 years of age must have a blood pressure that is ≤ 95th percentile for age, height and gender at the time of registration.
  • Patients who are ≥18 years of age must have a blood pressure that is <140/90 mm of Hg at the time of registration.

Patients may be on blood pressure medication provided that it is not on the contraindicated list and that the medication has not been adjusted in the previous 3 months.

- Growth factors: All colony forming growth factor(s) have been discontinued for at least one week prior to registration (filgrastim, sargramostim, and erythropoietin). For patients on long acting growth factors, the interval should be two weeks.

  • Inclusion of Women and Minorities Both males and females of all races and ethnic groups are eligible for this study.
  • Informed Consent:

All patients and/or their parents or legal guardians must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines.

Exclusion Criteria:

  • Pregnant or breast-feeding women will not be entered on this study due to risks of fetal and teratogenic adverse events as seen in animal/human studies. The effects of selumetinib on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation, and for four weeks after dosing with selumetinib ceases. The selumetinib manufacturer recommends that adequate contraception for male patients should be used for 16 weeks post-last dose due to sperm life cycle. Women of child-bearing potential must have a negative pregnancy test prior to study registration. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.

Note: Female subjects are considered "of child-bearing potential" if they are anatomically and physiologically capable of becoming pregnant. For girls of normal reproductive potential, the possibility of becoming pregnant requires ovulatory menstrual cycles and heterosexual intercourse. Although the timing of ovulation relative to menarche is variable, there is consistent evidence that some girls may have ovulatory cycles prior to menarche, and that, in healthy populations, regular ovulation may begin within a few months of menarche. Therefore, menarche is the most feasible clinical indicator of the biological potential for pregnancy.

  • Patients with any clinically significant unrelated systemic illness (serious infections or significant cardiac, pulmonary, hepatic or other organ dysfunction) that is likely to interfere with the study procedures or results
  • Patients who are currently receiving another investigational drug within 4 weeks prior to the first dose of study treatment, or within a period during which the investigational drug or systemic anticancer treatment has not been cleared from the body (e.g. a period of 5 'half-lives'), whichever is the most appropriate and as judged by the investigator are not eligible.
  • Patients who have taken another BRAF inhibitor such as Vemurafenib or Dabrafenib prior to study registration are not eligible. Prior treatment with selumetinib or another MEK inhibitor is not allowed.
  • Patients with QTc interval of > 450 msec
  • Patients who require enzyme inducing anti-convulsants to control seizures.
  • Anticoagulation: Patients receiving coumadin are eligible but must have their PT and INR monitored prior to each 4 week course.
  • Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible.
  • The following cardiac conditions:

    a. Uncontrolled hypertension in adults (BP ≥ 140/90 mmHg despite medical therapy) b. Acute coronary syndrome within 6 months prior to starting treatment c. Uncontrolled Angina - Canadian Cardiovascular Society grade II-IV despite medical therapy (Appendix H) d. Symptomatic heart failure NYHA Class II-IV, prior or current cardiomyopathy, or severe valvular heart disease (Appendix I) e. Prior or current cardiomyopathy including but not limited to the following: i. Known hypertrophic cardiomyopathy ii. Known arrhythmogenic right ventricular cardiomyopathy

    f. Previous moderate or severe impairment of left ventricular systolic function (LVEF <45% on echocardiography or equivalent on MuGA) if known even if full recovery has occurred.

    g. Severe valvular heart disease h. Baseline Left ventricular ejection fraction (LVEF) below the LLN or <50% measured by echocardiography or institution's LLN for MUGA i. Atrial fibrillation with a ventricular rate >100 bpm on ECG at rest

  • Ophthalmological conditions as follows:

    1. Current or past history of retinal pigment epithelial detachment (RPED)/central serous retinopathy (CSR) or retinal vein occlusion
    2. Intraocular pressure (IOP) > 21 mmHg or uncontrolled glaucoma (irrespective of IOP)
  • No major surgery within 4 weeks of starting selumetinib. Portacath insertion, G Tube placement, and insertion of ventriculoperitoneal shunt are not considered major surgeries.
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to selumetinib
  • History of a medical or psychiatric illness, that in the investigator's judgment renders the patient incapable of further therapy on this protocol
  • Patients with progressive disease associated with significant or disabling clinical symptoms requiring immediate intervention with surgery or radiation therapy are not eligible.

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): NCT03095248

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Contact: Site Primary Contact 513-636-2799

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United States, Ohio
Cincinnati Children's Hospital Medical Center Recruiting
Cincinnati, Ohio, United States, 45229
Contact: Laura Fossett    513-636-2799   
Sponsors and Collaborators
Children's Hospital Medical Center, Cincinnati
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Study Chair: Trent Hummel, MD Children's Hospital Medical Center, Cincinnati
Additional Information:
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Responsible Party: Children's Hospital Medical Center, Cincinnati Identifier: NCT03095248    
Other Study ID Numbers: SEL-TH-1601
2016-8833 ( Other Identifier: Institutional review board )
First Posted: March 29, 2017    Key Record Dates
Last Update Posted: July 23, 2021
Last Verified: July 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Neurofibromatosis 1
Neuroma, Acoustic
Neurofibromatosis 2
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplasms, Vascular Tissue
Meningeal Neoplasms
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Nervous System Diseases
Nerve Sheath Neoplasms
Neoplastic Syndromes, Hereditary
Neurocutaneous Syndromes
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Genetic Diseases, Inborn
Peripheral Nervous System Diseases
Neuromuscular Diseases