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Phase II Study of Binimetinib in Children and Adults With NF1 Plexiform Neurofibromas (NF108-BINI)

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ClinicalTrials.gov Identifier: NCT03231306
Recruitment Status : Recruiting
First Posted : July 27, 2017
Last Update Posted : January 15, 2019
Sponsor:
Collaborators:
Array BioPharma
Pacific Pediatric Neuro-Oncology Consortium
Information provided by (Responsible Party):
Bruce Korf, MD, University of Alabama at Birmingham

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.

Condition or disease Intervention/treatment Phase
Neurofibromatosis Type 1 Plexiform Neurofibroma Drug: Binimetinib Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study of Binimetinib in Children and Adults With NF1 Associated Plexiform Neurofibromas (PNOC010)
Actual Study Start Date : November 28, 2017
Estimated Primary Completion Date : October 2019
Estimated Study Completion Date : December 2023


Arm Intervention/treatment
Experimental: Open label study of Binimetinib (MEK162)

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
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).




Primary Outcome Measures :
  1. Change from Baseline Target Tumor Volume at 12 months [ Time Frame: Approximately 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.


Secondary Outcome Measures :
  1. Incidence of Treatment-Emergent Adverse Events [ Time Frame: Up to 24 months ]
    To evaluate the toxicity of protracted binimetinib administration in this patient population. Subjects will be monitored continuously for adverse events and serious adverse events throughout the study.



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Ages Eligible for Study:   1 Year and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

  • 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.
  • At least 7 days since the completion of therapy with a hematopoietic growth factor that supports platelet, red or white cell number or function.
  • At least 4 weeks since the completion of therapy with a biologic anti-neoplastic agent. For agents that have known adverse events occurring beyond 14 days after administration, this period must be extended beyond the time during which adverse events are known to occur.
  • Patients must not have received an investigational drug within 4 weeks.
  • Patients with endocrine deficiencies are allowed to receive physiologic or stress doses of steroids, if necessary.
  • Radiation ≥ 6 months from involved field radiation to index plexiform neurofibroma(s), ≥ 6 weeks must have elapsed if patient has received radiation to areas outside index plexiform neurofibroma(s). Patients who have received radiation to the orbit at any time are excluded.
  • At least 3 weeks since undergoing any major surgery and must be recovered from effects of surgery.

Organ Function Requirements:

  • Adequate bone marrow function defined as:

    • Peripheral absolute neutrophil count (ANC) ≥ 1500/µL
    • Platelet count ≥ 100,000/µL (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
    • Hemoglobin ≥ 10.0 gm/dL without transfusions.
  • Adequate renal function defined as:

    • Maximum serum creatinine based on age/gender or a creatinine clearance or radioisotope GFR ≥ 70 ml/min/1.73 m²
  • Adequate liver function defined as:

    • Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of normal (ULN) for age
    • SGPT (ALT) ≤ 2.5 x upper limit of normal (ULN) for age
    • Serum albumin ≥ 2 g/dL
  • Adequate cardiac function defined as:

    • Left ventricular fractions (LVEF) ≥ 50% as determined by a multigated acquisition (MUGA) scan or echocardiogram
    • QTc interval ≤ 480 ms.

Exclusion Criteria

  • 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.)
  • Subjects who have an uncontrolled infection.
  • Known positive serology for HIV (human immunodeficiency virus), active hepatitis B, and/or active hepatitis C infection.
  • Impairment of gastrointestinal function or gastrointestinal disease (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection).
  • History of Gilbert's syndrome or patients who are known to be homozygous for UGT1A1 (7/7).
  • Patients who have neuromuscular disorders that are associated with elevated CK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy)
  • Patients who are planning to embark on a new strenuous exercise regimen after first dose of study treatment. NB: muscular activities, such as strenuous exercise, that can result in significant increases in plasma CK levels should be avoided while on binimetinib treatment.
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to binimetinib.
  • Women who are pregnant or breastfeeding.
  • Any other condition that would contraindicate, in the Investigator's judgement, the patient's participation in the clinical study due to safety concerns or compliance with clinical study procedures, e.g. infection/inflammation, intestinal obstruction, unable to swallow medication, social/ psychological issues, etc.
  • History of noncompliance to medical regimens.
  • Patients unwilling to or unable to comply with the protocol, or who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study.
  • Prior treatment with a MEK inhibitor of any kind.

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 ClinicalTrials.gov identifier (NCT number): NCT03231306


Contacts
Contact: Sabine Mueller, MD, PhD 415-476-3831 sabine.mueller@ucsf.edu
Contact: Karen C Plourde, BS 205-934-5140 kcole@uab.edu

Locations
United States, Alabama
University of Alabama at Birmingham Recruiting
Birmingham, Alabama, United States, 35294
Contact: Bruce Korf, MD, PhD    205-934-9411    bkorf@uabmc.edu   
Principal Investigator: Bruce Korf, MD, PhD         
Sub-Investigator: Alyssa Reddy, MD         
United States, California
Children's Hospital of Los Angeles Recruiting
Los Angeles, California, United States, 90027
Contact: Tena Rosser, MD    323-361-2471    trosser@chla.usc.edu   
Contact: Patricia Diaz    323-361-7319    padiaz@chla.usc.edu   
Principal Investigator: Tena Rosser, MD         
University of California at Los Angeles Not yet recruiting
Los Angeles, California, United States, 90095
Contact: Alcino Silva, PhD       silvaa@mednet.ucla.edu   
UCSF Benioff Children's Hospital Oakland Not yet recruiting
Oakland, California, United States, 94609
Contact: Joseph Charles Torkildson, MD         
University of California, San Diego - Rady Children's Hospital Not yet recruiting
San Diego, California, United States, 92123
Contact: John Ross Crawford, MD, MS         
University of California, San Francisco Recruiting
San Francisco, California, United States, 94153
Contact: Sabine Mueller, MD, PhD    415-476-3831    sabine.mueller@ucsf.edu   
Principal Investigator: Sabine Mueller, MD, PhD         
United States, District of Columbia
Children's National Medical Center Recruiting
Washington, District of Columbia, United States, 20010
Contact: Miriam Bornhorst, MD    202-476-5068    mbornhorst@childrensnational.org   
Contact: Erica Keafer    202-476-5299    ekeafer@childrensnational.org   
Principal Investigator: Roger Packer, MD         
United States, Illinois
Lurie Children's Hospital of Chicago Not yet recruiting
Chicago, Illinois, United States, 60611
Contact: Robert Listernick, MD       rlisternick@luriechildrens.org   
Principal Investigator: Robert Listernick, MD         
Sub-Investigator: Stewart Goldman, MD         
University of Chicago Recruiting
Chicago, Illinois, United States, 60637
Contact: James Tonsgard, MD    773-702-6488    jtonsgar@peds.bsd.uchicago.edu   
Contact: Cynthia MacKenzie, RN    773-203-2344    cmackenzie@peds.bsd.uchicago.edu   
Principal Investigator: James Tonsgard, MD         
United States, Indiana
Indiana University Recruiting
Indianapolis, Indiana, United States, 46202
Contact: Michael J Ferguson, MD    317-367-9091    micjferg@iu.edu   
Contact: Leah Engelstad, RN    317-944-2832    leovermy@iu.edu   
Principal Investigator: Wade Clapp, MD         
United States, Maryland
Johns Hopkins University Recruiting
Baltimore, Maryland, United States, 21287
Contact: Jaishri Blakely, MD    410-502-6732    jblakel3@jhmi.edu   
Contact: Bronwyn Slobogean, PA-C    410-955-8000    bslobog1@jhmi.edu   
National Institute of Health - National Cancer Institute Not yet recruiting
Bethesda, Maryland, United States, 20892
Contact: Bridgette Widemann, MD    301-496-7387    widemanb@mail.nih.gov   
United States, Massachusetts
Boston Children's Hospital / Dana Farber Cancer Institute / Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02115
Contact: Nicole Ullrich, MD, PhD    617-355-3193    nicole.ullrich@childrens.harvard.edu   
Contact: Kristen Lawler    617-632-5727    kristend_lawler@dfci.harvard.edu   
Principal Investigator: Nicole Ullrich, MD, PhD         
Sub-Investigator: Scott Plotkin, MD         
Sub-Investigator: Mark Kieran, MD, PhD         
United States, Missouri
Washington University School of Medicine Not yet recruiting
Saint Louis, Missouri, United States, 63110
Contact: David Gutmann, MD, PhD    314-362-7379    gutmannd@neuro.wustl.edu   
Contact: Bruna Lluka    314-286-1728    lluka_b@kids.wustl.edu   
Principal Investigator: David Gutman, MD, PhD         
United States, New York
New York University Medical Center Recruiting
New York, New York, United States, 10016
Contact: Jeffrey Allen, MD    212-263-9907    jeffrey.allen@nyumc.org   
Contact: Anna Yaffe    212-263-9945    anna.yaffe@nyumc.org   
Principal Investigator: Jeffrey Allen, MD         
United States, Ohio
Cinncinnati Children's Hospital Medical Center Not yet recruiting
Cincinnati, Ohio, United States, 45229
Contact: Elizabeth Schorry, MD    523-636-4760    elizabeth.schorry@cchmc.org   
Contact: Julie McDonald    513-636-8240    julie.mcdonald@cchmc.org   
Principal Investigator: Elizabeth Schorry, MD         
Nationwide Children's Hospital Not yet recruiting
Columbus, Ohio, United States, 43205
Contact: Mohamed S AbdelBaki, MD         
Ohio State University Not yet recruiting
Columbus, Ohio, United States, 43210
Contact: Elizabeth Schorry, MD         
United States, Oregon
Oregon Health and Science University Hospital Not yet recruiting
Portland, Oregon, United States, 97239
Contact: Kellie J Nazemi, MD         
United States, Pennsylvania
Children's Hospital of Philadelphia Recruiting
Philadelphia, Pennsylvania, United States, 19096
Contact: Michael Fisher, MD    215-590-5188    fisherm@email.chop.edu   
Contact: Ratnakar Patti    267-426-5503    pattir@email.chop.edu   
Principal Investigator: Michael Fisher, MD         
United States, Utah
University of Utah Not yet recruiting
Salt Lake City, Utah, United States, 84132
Contact: David Viskochil, MD, PhD    801-581-8943    dave.viskochil@hsc.utah.edu   
Contact: Carrie Bailey, BS    801-587-3605    carrie.bailey@hsc.utah.edu   
Principal Investigator: David Viskochil, MD, PhD         
United States, Washington
University of Washington - Seattle Children's Hospital Not yet recruiting
Seattle, Washington, United States, 98105
Contact: Sarah Leary, MD         
Sponsors and Collaborators
University of Alabama at Birmingham
Array BioPharma
Pacific Pediatric Neuro-Oncology Consortium
Investigators
Study Chair: Bruce Korf, MD, PhD University of Alabama at Birmingham

Additional Information:
Publications:

Responsible Party: Bruce Korf, MD, Principal Investigator, University of Alabama at Birmingham
ClinicalTrials.gov Identifier: NCT03231306     History of Changes
Other Study ID Numbers: IRB-170616001
First Posted: July 27, 2017    Key Record Dates
Last Update Posted: January 15, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Bruce Korf, MD, University of Alabama at Birmingham:
Neurofibroma, Plexiform
Genes, Neurofibromatosis
Peripheral nerve tumors
Neurofibromatosis 1
Neurofibromas

Additional relevant MeSH terms:
Neurofibromatoses
Neurofibromatosis 1
Neurofibroma
Neurofibroma, Plexiform
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
Genetic Diseases, Inborn
Peripheral Nervous System Diseases
Neuromuscular Diseases
Peripheral Nervous System Neoplasms
Nervous System Neoplasms