Trial of Selumetinib in Patients With Neurofibromatosis Type II Related Tumors

NCT03095248 | Terminated Phase 2 Results DMC FDA Drug

• 2 other identifiers: SEL-TH-16012016-8833
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

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.

Conditions

Neurofibromatosis 2; Vestibular Schwannoma; Meningioma; Ependymoma; Glioma

Outcome Measures

Primary Outcomes (2)

• Stratum 1- Number of Patients With Hearing Response at 24 Weeks as Measured by Word Recognition

  The primary endpoint for the Stratum 1 is hearing response at 24 weeks, defined as an improvement in word recognition score above the 95% critical difference, taking as reference the baseline word recognition score. Audiology will include measurement of pure tone thresholds and determination of word recognition scores. Word recognition scores measure the ability to recognize (as opposed to detect) auditory information. Patients are presented a list of 50 words at a fully audible level and the percentage identified correctly is the score. This study will use full 50-item monosyllable lists and standardized recordings. This Outcome Measure was pre-specified to be assessed only within the Stratum 1 Arm/Group.

  24 weeks

• Radiographic Tumor Response

  To determine the radiographic response rate for Stratum 1 and Stratum 2. Specifics for each stratum are defined in the Arms/ Groups.

  Through study completion up to 2 years

Study Arms (2)

Stratum 1 - NF2 related vestibular schwannomas

EXPERIMENTAL

Stratum 1 included patients with NF2 with vestibular schwannomas who exhibit hearing loss. Participants received continuous twice daily dosing of selumetinib. Dosing was based on BSA calculated at the beginning of each course. One course is equivalent to 28 days. Therapy continued for up to two years (26 courses) in the absence of disease progression or unacceptable toxicity.

Drug: Selumetinib

Stratum 2: other NF2 related tumors (meningiomas and ependymoma)

EXPERIMENTAL

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 is based on BSA calculated at the beginning of each course. 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.

Drug: Selumetinib

Interventions

Selumetinib DRUG

Continuous twice daily dosing; oral agent

Also known as: AZD6244

Stratum 1 - NF2 related vestibular schwannomas; Stratum 2: other NF2 related tumors (meningiomas and ependymoma)

Eligibility Criteria

• Age: 3 Years - 45 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• Male patients with sexual partners who are pregnant or who could become pregnant (i.e. women of child-bearing potential) must use acceptable, effective and reliable methods of contraception during the study and for at least 12 weeks after the last dose of selumetinib or for longer if required, depending on the prescribing information of the combination or concomitantly administered medications.
• 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:

Sponsors & Collaborators

• Children's Hospital Medical Center, Cincinnati: lead
• AstraZeneca: collaborator

Study Sites (1)

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

Related Links

• Cincinnati Children's Hospital Medical Center home page

MeSH Terms

Conditions

Neurofibromatosis 2; Neuroma, Acoustic; Meningioma; Ependymoma; Glioma

Interventions

AZD 6244

Condition Hierarchy (Ancestors)

Neurilemmoma; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neurofibromatoses; Neurofibroma; Nerve Sheath Neoplasms; Neoplasms, Nerve Tissue; Neuroma; Neoplastic Syndromes, Hereditary; Vestibulocochlear Nerve Diseases; Retrocochlear Diseases; Ear Diseases; Otorhinolaryngologic Diseases; Otorhinolaryngologic Neoplasms; Cranial Nerve Neoplasms; Cranial Nerve Diseases; Nervous System Diseases; Neurocutaneous Syndromes; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nervous System Neoplasms; Neoplasms by Site; Peripheral Nervous System Neoplasms; Neoplasms, Vascular Tissue; Meningeal Neoplasms; Central Nervous System Neoplasms; Neoplasms, Neuroepithelial; Neoplasms, Glandular and Epithelial

Limitations and Caveats

Early termination due to not meeting study endpoints as defined per protocol.

Results Point of Contact

• Title: Senior Regulatory Specialist
• Organization: Cincinnati Children's Hospital Medical Center

andrea.bidwell@cchmc.org

15135350640

Study Officials

• Trent Hummel, MD

  Children's Hospital Medical Center, Cincinnati

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: March 8, 2017
• First Posted: March 29, 2017
• Study Start: May 8, 2017
• Primary Completion: May 21, 2024
• Study Completion: May 21, 2024
• Last Updated: April 22, 2025
• Results First Posted: April 22, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)