Trial of Selumetinib in Patients With Neurofibromatosis Type II Related Tumors

  • STATUS
    Recruiting
  • End date
    May 28, 2024
  • participants needed
    34
  • sponsor
    Children's Hospital Medical Center, Cincinnati
Updated on 28 July 2021
platelet count
renal function
corticosteroids
medical therapy
filgrastim
absolute neutrophil count
monoclonal antibodies
biologic agent
nitrosoureas
schwannoma
deafness
neurofibromatosis type 2
measurable disease
cataract
meningioma
sargramostim
anticonvulsants
ependymoma
multiple meningiomas
tumor growth
growth factor
MRI
biological factors
erythropoietin
dexamethasone
seizures
epilepsy
MRI Scan
neutrophil count
blood transfusion
seizure
alopecia
myelosuppressive chemotherapy
growth factors
selumetinib
hematopoietic stem cell transplantation
acoustic neuroma
nf2 gene

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.

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.

Details
Condition Neurofibromatosis, Acoustic Neuroma, Ependymoma, Meningioma, Glioma, Bilateral acoustic neurofibromatosis, Gliomas, Meningiomas, neurofibromatosis type 2, neurofibromatosis type ii, type 2 neurofibromatosis, vestibular schwannoma, glial tumor
Treatment Selumetinib
Clinical Study IdentifierNCT03095248
SponsorChildren's Hospital Medical Center, Cincinnati
Last Modified on28 July 2021

Eligibility

Yes No Not Sure

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/L
Platelet count 100,000/L (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
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
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
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
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
Current or past history of retinal pigment epithelial detachment (RPED)/central serous retinopathy (CSR) or retinal vein occlusion
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
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