Phase II Study of Binimetinib in Children and Adults With NF1 Plexiform Neurofibromas

NCT03231306 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: IRB-170616001516027
• Study Type: interventional
• Target: 45
• Locations: 1 country
• Sites: 22

Brief Summary

This is a phase II open label study that will evaluate children ≥ 1 year of age and adults with neurofibromatosis type 1 (NF1) and plexiform neurofibromas treated with the MEK inhibitor, binimetinib. The primary objective is to determine if there is an adequate level of disease responsiveness to binimetinib in children and adults with NF1 and inoperable plexiform neurofibromas. The objective response to binimetinib is defined as ≥ 20% decrease in tumor volume reduction by 12 courses.

Conditions

Neurofibromatosis Type 1; Plexiform Neurofibroma

Keywords

Neurofibroma, Plexiform; Genes, Neurofibromatosis; Peripheral nerve tumors; Neurofibromatosis 1; Neurofibromas

Outcome Measures

Primary Outcomes (1)

• Change From Baseline Target Tumor Volume at 12 Months

  To determine the objective response defined as 20% or greater tumor volume reduction. Patients will undergo volumetric assays of their target PN using MRI.

  Approximately 12 months

Secondary Outcomes (1)

• Incidence of Treatment-Emergent Adverse Events

  Up to 24 months

Study Arms (1)

Open label study of Binimetinib (MEK162)

EXPERIMENTAL

Subjects (≥ 18 years) (Stratum A) will receive a course of binimetinib by mouth twice a day (12 hours apart) of 45 mg/dose. Duration of each course is 4 weeks. After 8 courses, subjects will receive additional courses if MRI results showed at least 15% reduction in volume of the target tumor. Subjects can continue on therapy and will be evaluated at the end of 12 courses. Subjects who have ≥ 20% reduction in volume of the target tumor according to the MRI results can continue therapy up to an additional year (maximum of 24 total courses). Subjects who have not met the tumor reduction at the specified times will be removed from the study therapy. Subjects will be carefully monitored for toxicities associated with binimetinib. Recruitment of subjects 1 - 17 years of age (Stratum B) is currently available. The pediatric maximum tolerated dose (MTD) of binimetinib the pediatric patients (Statum B) was established by a phase 1 study (NCT022).

Drug: Binimetinib

Interventions

Binimetinib DRUG

Adult subjects (18 years and older) will receive binimetinib by mouth twice daily of 45mg/dose. Pediatric subjects (1-17 years of age) are being treated on the pediatric MTD established by a phase I study (NCT02285439).

Also known as: MEK162 or ARRY-438162

Open label study of Binimetinib (MEK162)

Eligibility Criteria

• Age: 1 Year+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Clinical diagnosis of NF1 using the NIH Consensus Conference criteria OR a documented constitutional NF1 mutation
• Plexiform neurofibroma(s) that are progressive or causing significant morbidity
• Presence of new plexiform neurofibroma on MRI or CT (documented by comparison with prior MRI or CT)
• Measurable plexiform neurofibroma(s) amenable to volumetric MRI analysis. Tumors must be at least 3 mL in volume (most PNs 3 cm in longest diameter will meet this criteria)
• Patients must be ≥ 18 years of age at the time of enrollment.
• Performance Level: Karnofsky or Lansky ≥ 50%. If unable to walk due to paralysis, but in a wheelchair, patients will be considered ambulatory for the purpose of assessing the performance level
• Ability to swallow capsules/tablets
• Ability to comply with follow up procedures
• The effects of binimetinib 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, for the duration of study participation, and 3 months after completion of binimetinib administration. 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.
• Negative urine or serum β-HCG test (females of childbearing potential only).
• Prior Therapy:
• Patients are eligible if complete resection of a plexiform neurofibroma with acceptable morbidity is not feasible, or if a subject with surgical option refuses surgery,
• Patients who underwent surgery for a progressive plexiform neurofibroma will be eligible to enter the study after the surgery, provided the plexiform neurofibroma was incompletely resected and is evaluable by volumetric analysis.
• Patients previously treated for a plexiform neurofibroma or other tumor/malignancy, but must have fully recovered from the acute toxic effects of all prior chemotherapy or radiotherapy prior to entering this study.
• Must not have received myelosuppressive chemotherapy within 3 weeks of entry onto this study.

You may not qualify if:

• Chronic treatment with systemic steroids or another immunosuppressive agent.
• Evidence of an active optic glioma or other low-grade glioma, requiring treatment with chemotherapy or radiation therapy. Patients not requiring treatment are eligible for this protocol.
• Patients with malignant glioma, malignant peripheral nerve sheath tumor, or other malignancy requiring treatment in the last 12 months.
• Patients who have received radiation to the orbit at any time previously.
• Ophthalmologic conditions:
• Current or past history of central serous retinopathy
• Current or past history of retinal vein occlusion
• Known intraocular pressure (IOP) \> 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 review. Patients with orbital plexiform neurofibromas should have IOP measured prior to enrollment.
• Patients with any other significant abnormality on ophthalmic examination will be reviewed for potential eligibility.
• Ophthalmological findings 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
• Uncontrolled arterial hypertension despite medical treatment defined as CTCAE grade 3 or higher.
• Impaired cardiovascular function or clinically significant cardiovascular diseases, including:
• History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting) \< 6 months prior to screening
• Symptomatic chronic heart failure, history or current evidence of clinically significant cardiac arrhythmia and/or conduction abnormality \< 6 months prior to screening except atrial fibrillation and paroxysmal supraventricular tachycardia
• Other concurrent severe and/or uncontrolled medical disease, which could compromise participation in the study (e.g. uncontrolled diabetes, uncontrolled hypertension, severe infection, severe malnutrition, chronic liver or renal disease, active upper GI tract ulceration, congestive heart failure, etc.)

Sponsors & Collaborators

• University of Alabama at Birmingham: lead
• Array BioPharma: collaborator
• Pacific Pediatric Neuro-Oncology Consortium: collaborator

Study Sites (22)

University of Alabama at Birmingham

Birmingham, Alabama, 35294, United States

Location

Children's Hospital of Los Angeles

Los Angeles, California, 90027, United States

Location

University of California at Los Angeles

Los Angeles, California, 90095, United States

Location

UCSF Benioff Children's Hospital Oakland

Oakland, California, 94609, United States

Location

University of California, San Diego - Rady Children's Hospital

San Diego, California, 92123, United States

Location

University of California, San Francisco

San Francisco, California, 94153, United States

Location

Children's National Medical Center

Washington D.C., District of Columbia, 20010, United States

Location

Lurie Children's Hospital of Chicago

Chicago, Illinois, 60611, United States

Location

University of Chicago

Chicago, Illinois, 60637, United States

Location

Indiana University

Indianapolis, Indiana, 46202, United States

Location

Johns Hopkins University

Baltimore, Maryland, 21287, United States

Location

National Institute of Health - National Cancer Institute

Bethesda, Maryland, 20892, United States

Location

Boston Children's Hospital / Dana Farber Cancer Institute / Massachusetts General Hospital

Boston, Massachusetts, 02115, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

New York University Medical Center

New York, New York, 10016, United States

Location

Cinncinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

Nationwide Children's Hospital

Columbus, Ohio, 43205, United States

Location

Ohio State University

Columbus, Ohio, 43210, United States

Location

Oregon Health and Science University Hospital

Portland, Oregon, 97239, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19096, United States

Location

University of Utah

Salt Lake City, Utah, 84132, United States

Location

University of Washington - Seattle Children's Hospital

Seattle, Washington, 98105, United States

Location

Related Publications (24)

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• Citak EC, Oguz A, Karadeniz C, Okur A, Memis L, Boyunaga O. Management of plexiform neurofibroma with interferon alpha. Pediatr Hematol Oncol. 2008 Sep;25(7):673-8. doi: 10.1080/08880010802315983.

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• Widemann BC, Arceci RJ, Jayaprakash N, Fox E, Zannikos P, Goodspeed W, Goodwin A, Wright JJ, Blaney SM, Adamson PC, Balis FM. Phase 1 trial and pharmacokinetic study of the farnesyl transferase inhibitor tipifarnib in children and adolescents with refractory leukemias: a report from the Children's Oncology Group. Pediatr Blood Cancer. 2011 Feb;56(2):226-33. doi: 10.1002/pbc.22775. Epub 2010 Sep 21.

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Related Links

• A phase 1 study of mitogen activated protein kinase (MEK) 1 inhibitor AZD6244 hydrogen sulfate (selumetinib sulfate) in children with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PN)
• Chow, L., et al. "A first in human dose-ranging study to assess the pharmacokinetics, pharmacodynamics, and toxicities of the MEK inhibitor, ARRY-142886 (AZD6244), in patients with advanced solid malignancies." CLINICAL CANCER RESEARCH. Vol. 11. No.24

MeSH Terms

Conditions

Neurofibromatosis 1; Neurofibroma, Plexiform; Neurofibromatoses; Peripheral Nervous System Neoplasms; Neurofibroma

Interventions

binimetinib

Condition Hierarchy (Ancestors)

Nerve Sheath Neoplasms; Neoplasms, Nerve Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplastic Syndromes, Hereditary; Neurocutaneous Syndromes; Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Peripheral Nervous System Diseases; Neuromuscular Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nervous System Neoplasms; Neoplasms by Site

Results Point of Contact

• Title: Coretta Thomas, Scientist & Data Manager for NF Consortium
• Organization: UAB

coretta@uab.edu

2059758629

Study Officials

• Bruce Korf, MD, PhD

  University of Alabama at Birmingham

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: July 21, 2017
• First Posted: July 27, 2017
• Study Start: November 28, 2017
• Primary Completion: April 17, 2024
• Study Completion: April 17, 2024
• Last Updated: May 2, 2025
• Results First Posted: May 2, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (22)