Neoplasms

Nervous System Diseases

Diseases and Abnormalities at or Before Birth

All Conditions

Symptoms and General Pathology

Skin and Connective Tissue Diseases

Rare Diseases

Neurofibromatoses

Neurofibromatosis 1

Neurofibroma

Neurofibroma, Plexiform

Nerve Sheath Neoplasms

Neoplasms, Nerve Tissue

Neoplasms by Histologic Type

Syndrome

Neoplastic Syndromes, Hereditary

Neurocutaneous Syndromes

Heredodegenerative Disorders, Nervous System

Neurodegenerative Diseases

Genetic Diseases, Inborn

Peripheral Nervous System Diseases

Neuromuscular Diseases

Nervous System Neoplasms

Peripheral Nervous System Neoplasms

Neurofibromatosis

Neurofibromatosis Type 1

All Drugs and Chemicals

Amino Acids

Nilotinib

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

Following enrollment each subject will initially receive the drug Tasigna orally at 200 mg twice daily for two weeks. If tolerated, the dose will be increased to 300 mg twice daily after a minimum of two weeks and will be increase to a maximum dose of 400mg twice daily after an additional two weeks if tolerated. Subjects will have his/her dose increased as tolerated dose during the first three months of therapy. The maximum targeted dose is 400mg twice daily.

Following enrollment each subject will initially receive Tasigna orally at 200 mg twice daily for two weeks. If tolerated, the dose will be increased to 300 mg twice daily after a minimum of two weeks and will be increase to a maximum dose of 400mg twice daily after an additional two weeks if tolerated.

Tasigna

Melissa Markel, MD

The purpose of this Pilot Study is to determine if NF1 patients with plexiform neurofibromas treated with Tasgina® respond to therapy.

This is an open-label Pilot Study to determine the efficacy of Tasigna® in adults with neurofibromatosis (NF1) and plexiform neurofibromas with the secondary goals of determining the toxicity, and tumor markers in this genetically defined population. The rationale for this study arises from the response of human and murine NF1 cells to Tasigna® in vitro and the clinical response in NF1 patients with plexiform neurofibromas using the similar drug, Gleevec®. Following enrollment each subject will initially receive Tasigna orally at 200 mg twice daily for two weeks. If tolerated, the dose will be increased to 300 mg twice daily after a minimum of two weeks and will be increase to a maximum dose of 400mg twice daily after an additional two weeks if tolerated. Subjects will have his/her dose increased as tolerated dose during the first three months of therapy. The maximum targeted dose is 400mg twice daily.

Study of Tasigna®/Nilotinib (AMN107) in Neurofibromatosis (NF1) Patients With Plexiform Neurofibromas

Pilot Study of Tasigna®/Nilotinib (AMN107) in Neurofibromatosis (NF1) Patients With Plexiform Neurofibromas

To estimate the disease control rate (PD,SD, PR, CR) with Tasigna® in patients with neurofibromas (NF1) using standard RECIST criteria. Complete Response (CR) is defined as; disappearance of all target lesions. Partial Response (PR) is defined as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as a reference the baseline sum longest diameter. Stable Disease (SD) is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum longest diameter since the treatment started. Disease Progression (PD) is defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions.

Novartis

Indiana University

Age, Categorical

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Dr. Melissa Markel

Disease Response

Overall Study

Cutaneous neurofibromas (cNFs) are the most common tumors in people with neurofibromatosis type 1 (NF1). Despite their benign histology, they can significantly impact patients' quality of life (QoL). In this project, the natural history of cNFs will be prospectively and systematically studied. To accomplish this, the reproducibility and efficiency of using 3D whole-body photography was evaluated in a small cohort of patients. The study is enrolling patients of all ages with cNFs into groups by epochs of life to characterize the baseline tumor burden and the change in number and morphology of cNFs over five years. In addition, the study will perform next generation sequencing to describe the genetic variations in the NF1 gene and evaluate potential relations between genotype and phenotype. Lastly, the study will validate clinician- and patient-reported severity scales of cNFs developed for this patient population.

Evaluation of the natural history of cutaneous neurofibromas

Carlos G Romo, MD

Amanda Johnson

People diagnosed with NF1 may develop cutaneous neurofibromas, also known as cNFs. These benign tumors can cause discomfort and affect a person's quality of life. Researchers at Johns Hopkins are studying how cNF tumors form, grow and change over time. This information may help doctors in the future, provide early interventions and improve quality of life for NF1 patients. Researchers will also explore a new way of monitoring cNF with 3D camera technology. People of all ages with NF1, living in the United States, are invited to participate in this important research study.

The majority of people diagnosed with Neurofibromatosis Type 1 are likely to develop at least one cutaneous neurofibroma-also known as cNF. While benign, these tumors can cause pain, itchiness, disfigurement, and dramatically affect a person's quality of life; and little is known about how it forms and grows. A team of researchers at Johns Hopkins is studying the natural history of cNF to better understand how cNF tumors develop and change over time. This research may help doctors provide early intervention to people at risk of developing cNF, or prevent cNF altogether. And, it will help prioritize future research focused on improving the quality of life for people who have NF1

People of all ages diagnosed with NF1 are invited to participate in this research study. Participants under the age of 18 with parental consent are welcome. Participants will need to provide a saliva sample for genetic testing and NF1 gene identification. Once a year for the next five years, participants will undergo whole-body, 3D imaging. This imaging technology will generate a three-dimensional, digital image with which researchers will monitor changes in cNF over time. It does not use radiation and has no expected side effects.

Participants will need to answer annual health surveys to monitor quality of life, NF1 and cNF symptoms. Participants may also choose to donate blood and tissue samples for future NF research initiatives.

The study is open to anyone with NF1 living in the United States. Annual visits for this study will take place at the Johns Hopkins Outpatient Center in Baltimore, Maryland. There is no cost to the participants, and eligible travel and parking expenses may be reimbursed up to a specified amount. In fact, participants will receive a gift card at the first visit for participating in the study.

Optional donations of blood and cutaneous neurofibroma are accepted

Natural History Study of Cutaneous Neurofibromas in People With NF1

Natural History Study of Cutaneous Neurofibromas in People With Neurofibromatosis Type 1

To characterize the baseline tumor burden of cNFs

Change in number of cNFs once per year over five years.

Using Next Generation Sequencing (NGS) to evaluate pathogenic variants in the NF1 gene and their relation to cNF tumor burden

Neurofibromatosis Therapeutic Acceleration Program

Johns Hopkins University

Participants with clinical or genetic diagnosis of NF1 AND at least one of the eligibility-required high-risk characteristics

Participants with clinical or genetic diagnosis of NF1 AND none of the eligibility-required high-risk characteristic

Parents or guardians of participants 8-17 years old in High-Risk or Low-Risk Cohorts

Jennifer Derise

Brigitte C Widemann, M.D.

National Cancer Institute Referral Office

Background:

Neurofibromatosis type 1 (NF1) is a genetic disease that can cause many symptoms. About half of people with NF1 will develop benign (noncancerous) tumors along nerves in the skin, brain, and other parts of the body. Sometimes, though, these tumors can become cancerous. Researchers do not yet know how to predict which tumors will become cancerous.

Objective:

To test a new method for predicting which benign NF1 tumors will become cancerous.

Eligibility:

People aged 3 years and older with a clinical or genetic diagnosis of NF1.

Design:

* Participants will be screened with a review of their medical history. All participants will have a baseline visit. They will have bood tests and imaging scans. They will have a physical exam. They will answer questions about their family history. Participants aged 8 years and older will take tests of their thinking skills and their emotional health.
* Some participants may be asked to undergo more tests. These may include another type of imaging scan and a biopsy: A small sample of tissue may be removed from the tumor.
* Participants will be divided into two groups: those believed to be at low risk and those believed to be at high risk of developing cancer.
* Participants in the high-risk group will be asked to return for their next visit in 1 month to 3 years.
* Participants in the low-risk group will be asked to return for their next visit in 6 months to 5 years.
* Participants may also have follow-up visits by phone throughout the study. They will be in the study for 10 years.

Background

* Patients with NF1 are at risk for the development of both benign and malignant peripheral nerve sheath tumors (MPNST). Some factors that increase risk for malignant tumors are known, such as large benign plexiform neurofibroma (PN) tumor burden, germline NF1 microdeletion, and history of radiation therapy. However, there is not currently a consensus in the field about the most appropriate clinical surveillance or management strategy for these patients at increased risk of malignancy.
* In the past decade, data from the existing NCI POB NF1 Natural History study (08-C-0079, NCT00924196) and others have identified atypical neurofibromas (AN) and atypical neurofibromatous neoplasms of uncertainly biologic potential (ANNUBP) as premalignant lesions characterized by heterozygous loss of CDKN2A/B in addition to the homozygous loss of NF1 found in all PN.
* On Magnetic Resonance Imaging (MRI), distinct nodular lesions (DNL) have been identified as having unique characteristics, including increased fluorodeoxyglucose (FDG)-positron emission tomography (PET) avidity and growth rate compared to surrounding PN, and are often, though not always, found to be AN on histologic evaluation.

Objective

- To assess the feasibility of the study algorithm in identifying ANs, ANNUBPs, CDKN2A/B mutated lesions, and/or MPNST.

Eligibility

* Participants aged \>= 3 years old with a clinical or genetic diagnosis of NF1.
* Participants will be enrolled in one of the following cohorts:

  * For the High-Risk Cohort one of the following criteria: microdeletion or 844-848 missense variants or other variants associated with increased risk of MPNST, family history of MPNST/ANNUBP/AN, personal history of MPNST/ANNUBP/AN or neurofibroma with CDKN2A/B loss, prior radiation therapy at any site, large PN burden (\>= 350 mL), or presence \>= 1 DNL at baseline.
  * For the Low-Risk Cohort: none of the criteria noted for the high-risk cohort beyond NF1 diagnosis.

Design

* This is a Natural History Study to identify risk factors associated with severe disease in NF1 and to assess the feasibility of a novel NF1 Increased MPNST Risk Surveillance and Management Algorithm to aid in the surveillance and management of participants with NF1.
* 225 participants will be enrolled in this study.

Surveillance for Malignant Transformation of Neurofibromatosis Type 1 (NF1) Related Peripheral Nerve Sheath Tumors (PNST)

.All IPD recorded in the medical record will be shared with intramural investigators upon request. In addition, all large scale genomic sequencing data will be shared with subscribers to dbGaP.

Proportion of lesions that undergo surgical intervention (biopsy or resection) that are ANs, ANNUBPs, CDKN2A mutated lesions and/or MPNST

Number of participants complying with recommendations for imaging/surgical interventionsNumber of resections recommended vs successfully completedProportion of subjects from the low-risk cohort that transition to the high- risk algorithm during the study observation periodThe number of subjects who develop high grade MPNST during the observation periodNumber of subjects who develop high grade MPNST outside of a pre-existing DNL or PN during the observation periodData from the Tumor Specific Risk Factor and Participant Specific Risk Factor Checklists

National Cancer Institute (NCI)

Neuroma

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).

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).

Binimetinib

Bruce Korf, MD, PhD

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.

Patients ≥ 1 year with progressive NF1 and PN(s) by serial imaging or causing significant morbidity and that can be analyzed by volumetric MRI are eligible for this study. Initially, the study will open to adult patients,18 years and older, (Stratum A). The pediatric patients (Statum B) will be receive the pediatric maximum tolerated dose (MTD) of binimetinib that is currently being established in an ongoing phase 1 study (NCT02285439). For adult subjects, binimetinib (established adult RP2D) is taken orally twice a day. Dosing will be continuous, with 28 days defined as a course and will continue for a total of 24 courses or until one of the Off Treatment or Off Study criteria are met. Subjects will undergo volumetric assays of their targeted PN using MRI after every 4 courses for the first year and then every 6 courses. MRI review of the volumetric assays will occur centrally under the guidance of Dr. Dombi at NCI. Subjects may receive additional courses beyond course 8 only if there is at least a 15% reduction in volume of the target tumor, as measured from baseline. Treatment beyond course 12 will be only be given to those subjects who achieve a response of ≥ 20% tumor shrinkage by volumetric analysis and can continue on therapy up to an additional year for a maximum of 24 total courses. For those who respond to binimetinib after 12 courses, an MRI scan of the target lesion must be performed at 4 and 12 months after stopping drug in order to determine whether response is maintained post-therapy. Subjects will be carefully monitored for development of binimetinib associated toxicities. Subjects will be removed from the study for significant toxicity, treatment delay of ≥ 21 days, or objective progression of tumor growth by ≥ 20% by volumetric analysis at any time.

The investigational nature and objectives of this trial, the procedures and treatment involved, the risks, discomforts, and benefits, and potential alternatives therapies will be carefully explained to the subject and/or subject's parent(s) or guardian by the site Principal Investigator or designated associate investigator. A signed informed consent document will be obtained prior to determining eligibility and entry criteria to this trial. Subjects entered on this trial will be treated with therapeutic intent and response to therapy will be closely monitored. This protocol involves greater than minimal risk but presents the potential for direct benefit to individual subjects.

Schedule of study evaluations are summarized below:

Pre-Study (Eligibility Screening):

* Physical assessment, vital signs and neurological exam
* Complete medical history including past and current medical conditions, treatments, and surgeries.
* Karnofsky/Lansky performance status to assess of your ability to perform everyday tasks
* Review of current medications
* Blood draw (about two tablespoons) for routine safety tests
* Serum or urine pregnancy test for females of childbearing age
* Eye exam
* Electrocardiogram (ECG) and echocardiogram (ECHO) or multigated acquisition (MUGA) scan of your heart
* MRI of neurofibroma tumors
* Functional evaluation: Depending on the location of your plexiform neurofibroma, specific functional assessments will be performed. The functional assessments may include a 6-Minute Walk-Test if you have a plexiform neurofibroma affecting your legs or airway, evaluation of muscle strength and range of motion if you have plexiform neurofibroma affecting your arms or legs, and/or grooved pegboard test if you have plexiform neurofibroma affecting your hands. The study team will review all evaluations that apply to you in detail
* Completion of health-related questionnaires on quality of life, pain assessment, bowel and bladder dysfunction, and PN symptom checklist (upon study entry)
* Photography of visible PN (optional)

End of course 1, 2, 3, 4, 6, 8, 10, 12, 15, 18, 21, and 24:

* Medical history update and hospitalization since last study visit
* Physical assessment, vital signs, and neurological exam
* Karnofsky/Lansky performance status to assess your ability to perform everyday tasks
* Review of your medication diary and any side effects you may be experiencing
* Review of current medications
* Blood draw (about two tablespoons) for routine safety tests
* Serum or urine pregnancy test for females of childbearing age

End of course 4, 8, 12, 18, and 24:

* Eye exam
* MRI of neurofibromas
* ECHO and ECG
* Functional evaluation: (see description above)
* Completion of health-related questionnaires on quality of life, pain assessment, bowel and bladder dysfunction, and PN symptom checklist
* Photography of visible PN (optional): If you agree to take part, photographs of visible PN will be taken. Photos will be taken before treatment and then after cycles 4, 8, 12, 18, and 24.

End of course 1 and 4:

• Blood draw (about one tablespoon) for cytokine studies (optional)

End of Treatment Visit (this is an additional visit if the visit is not within the specified times mentioned above):

* Physical assessment, vital signs and neurological exam
* Medical history update and hospitalization since last study visit
* Karnofsky/Lansky performance status to assess of your ability to perform everyday tasks
* Review of your medication diary and any side effects you may be experiencing
* Review of current medications
* Blood draw (about two tablespoons) for routine safety tests
* Serum or urine pregnancy test for females of childbearing age
* Eye exam
* Electrocardiogram (ECG) and ECHO or multigated acquisition (MUGA) scan of your heart
* MRI of neurofibroma tumors (for those who respond to binimetinib after 12 courses, an MRI at 4 and 12 months after stopping drug)
* Functional evaluation: (see description above)
* Completion of health-related questionnaires on quality of life, pain assessment, bowel and bladder dysfunction, and PN symptom checklist
* Photography of visible PN (optional)

The sample size is 20 subjects for each adult and children cohorts with a minimum target of 17 evaluable subjects per cohort. Evaluable is defined as: any subjects who received ≥ one dose of binimetinib and had a ≥ Grade 3 binimetinib associated toxicity, or in absence of a ≥ Grade 3 toxicity, any subjects who completed one full course of therapy; subjects who have completed at least two courses of therapy and had their first follow-up MRI evaluation except for discovery of a target tumor other than a PN; and any subjects who has at least two samples drawn for plasma cytokines/growth factors, one at baseline and at least one other after starting therapy.

Data Safety Monitoring Board (DSMB) and a Medical Monitor have been established for this study for the purpose of ensuring data compliance and regular monitoring. An early stopping rules have been defined within the protocol. The early stopping rule will invoked for both Strata separately to potentially prevent accrual subjects onto the study in the event that binimetinib is associated with a higher than acceptable rate of dose-limiting toxicity (DLT) requiring removal from study (10% or higher) during the first 2 courses. Toxicity will be continuously monitored. If at any time \>2 of the first 10 subjects or 4 or more of the first 15 total subjects are removed for toxicity, then accrual will be stopped until the DSMB reviews the safety and efficacy data for the study. Based on the review, the DSMB can either recommend termination of the study or reopen recruitment. The Medical Monitor is a qualified physician who is not associated with this protocol and is a member of the DSMB. The Medical Monitor may perform oversight functions duties: may discuss the research protocol with the investigators, interview human subjects, and consult with others outside of the study about the research; shall have the authority to stop the research protocol in progress, remove individual subjects from protocol, and take whatever steps are necessary to protect the safety and well being of human subjects until the Institutional Review Board (IRB) can assess the monitor's report; and shall have the responsibility to promptly report the observation and findings to the IRB or other designated official/organization. The Medical Monitor is specifically required to review and provide written report of all unanticipated problems involving risk to subjects or others and serious adverse events.

In addition, as part of the Data Safety Monitoring Plan, the Study Chairs and the NF Consortium Clinical Research Nurse Manager will review subject eligibility, study progress, safety issues, protocol deviations and adverse events. Monthly reports will be generated by the NF Consortium Data Management Center to assess completeness of data. Monthly phone conferences will take place between NF Consortium Operations Center and the Protocol Team to address data issues.

The sample size for this trial is based on safety and feasibility factors. The data needed for safety is based on risk versus benefit, and for feasibility, we expect at least efficacy of 25% response rate. For safety reasons, subjects who do not achieve at least 15% reduction in volume of target tumor after 8 courses will be discontinued from the trial, as the likelihood of achieving a 20% reduction in tumor volume by 12 months is minimal. Safety analysis set will be described and summarized based on information regarding study treatment administrations, drug dosing and course compliance, and safety variables (e.g. adverse events/serious adverse events). All analyses for outcome results will be based on evaluable subjects. Given the difference in the clinical behavior of PN in the adults and pediatric subjects, the adult and children stratum will be analyzed independently.

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

A Phase II Study of Binimetinib in Children and Adults With NF1 Associated Plexiform Neurofibromas (PNOC010)

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

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.

Array BioPharma

Pacific Pediatric Neuro-Oncology Consortium

University of Alabama at Birmingham

Principal Investigator

Carolyn Raski, MS

Jenny Garzon, MD

Carolyn Serbinski, MS

Carlos Prada, MD

The purpose of this study is to identify tumor biomarkers in individuals with Neurofibromatosis type 1 (NF1). Biomarkers are signals that the investigator can measure that tell us about a process such as progress of a disease or treatment. Individuals with this diagnosis are at an elevated risk of developing a type of tumor called a plexiform neurofibroma. Currently, detecting the risk factors of these tumors in children is difficult and requires whole body imaging. The NF1 team at Lurie Children's established a way of using blood plasma in mice with neurofibromatosis type 1 to identify biomarkers that might signal the presence of tumors in people with NF1.

This study is an effort to create biomarker profiles of patients with NF1 with known tumors. The study team will utilize whole-body MRI and mass spectrometry (a method for identifying unknown compounds and the properties of molecules). The ultimate goal of this study is to better understand the tumor biomarkers in patients with NF1.

Neurofibromatosis type 1 (NF1) is a common inherited human disorder, with a frequency of approximately 1:2500 worldwide. A hallmark of NF1 is development of plexiform neurofibromas (PNFs) in 30 to 50% of NF1 patients. Currently, there are no biomarkers of tumor burden and whole-body magnetic resonance imaging (MRI) is expensive and limited to few centers. The investigator established an unbiased pipeline to identify candidate biomarker signals of tumor burden using plasma from neurofibroma-bearing DhhCre;Nf1fl/fl mice using untargeted metabolomics. Our preliminary data show that glucosylceramide (GC) is the most significantly deregulated compound in plasma from neurofibroma-bearing DhhCre;Nf1fl/fl mice. The investigator developed a novel targeted mass spectrometry method to accurately quantify multiple elevated GC and lactosylceramide (LC) species. In this proposal, the investigator will combine the clinical infrastructure of the NF1 comprehensive program and advance imaging at Ann \& Robert H. Lurie Children's Hospital of Chicago with the mass spectrometry capabilities at Cincinnati Children's Hospital Medical Center.

Taking advantage of our large, well-characterized, Lurie Children's NF1 population, the investigator propose to perform analytical validation studies of candidate GC/LC biomarker signature of tumor burden in plasma from NF1 patients with defined numbers of PNF (tumor burden) by whole body MRI. The potential outcomes of our study are identification of candidate biomarker of tumor burden that contribute to patient risk stratification, and analytical validation of GC/LC biomarker signature (context of use). Collectively, this work represents a synergistic approach for discovery and validation of biomarkers of tumor burden in NF1.

Developing Biomarkers of Plexiform Tumor Burden in Patients With Neurofibromatosis-Type 1

Developing Novel Biomarkers of Plexiform Neurofibroma Tumor Burden

The investigator and team will collect blood samples from individuals with NF1 stratified plexiform tumor (PNF) burden (none, small, intermediate, and large) versus age and sex matched healthy control.

The investigator and team will enroll 20 individuals with NF1 and inoperable PNFs in treatment with MEK inhibitors to correlate biomarker with tumor burden changes with therapy.

Whole-body MRI at baseline and at time of annual visit (9-to-18-month intervals) will be used to deeply phenotype individuals based on tumor burden and tumor volume. Individuals will undergo plasma collection and clinical history assessment (medications, diet log, supplements, and anthropometric measurements) at each visit. For patients undergoing treatment with MEK inhibitors, a sample prior to treatment will be collected during this study.

The investigator and team will test GC/LC levels using validated mass spectrometry target method for quantification of these biomarkers.

GC/LC biomarker thresholds (cut-off) will be refined to evaluate predictive ability to identify individuals with large tumor burden. Tumor burden will be measured from whole-body MRI analysis with post-imaging processing software.

National Institute of Neurological Disorders and Stroke (NINDS)

Children's Hospital Medical Center, Cincinnati

Ann & Robert H Lurie Children's Hospital of Chicago

Antineoplastic Agents

Imatinib Mesylate

Gleevec will be dosed orally with a starting dose of 100 mg twice daily for patients with a BSA \> 1.8 m2 or 55 mg/m2 twice daily for patients with BSA \< 1.8 m2. For patients with a BSA \> 1.8 m2 the dose will increase by increments of 100 mg bid every two weeks as tolerated up to a maximum dose of 400 mg bid. For patients with a BSA \< 1.8 m2 the dose will increase by increments of 55 mg/m2 bid every two weeks as tolerated up to a maximum dose of 220 mg/m2 bid.Treatment will continue for 6 months with an option to continue for 24 months if the patient is deriving a clinical benefit.

Gleevec

Kent Robertson, MD PhD

This is a second Pilot Study to determine the efficacy of Gleevec® in neurofibromatosis (NF1) patients with plexiform neurofibromas using new response assessment modalities with the secondary goals of assessing Gleevec toxicity, and characterizing markers of response. The rationale for this study arises from the response of human and murine NF1 cells to Gleevec® in vitro, the response of a NF1 patient treated with Gleevec® for airway compression by a plexiform neurofibroma with a dramatic response not previously seen in NF1 therapy, and the experience in 37 NF1 patients treated with Gleevec® in the initial pilot study. Gleevec will be dosed orally with a starting dose of 100 mg twice daily for patients with a BSA \> 1.8 m2 or 55 mg/m2 twice daily for patients with BSA \< 1.8 m2. For patients with a BSA \> 1.8 m2 the dose will increase by increments of 100 mg bid every two weeks as tolerated up to a maximum dose of 400 mg bid. For patients with a BSA \< 1.8 m2 the dose will increase by increments of 55 mg/m2 bid every two weeks as tolerated up to a maximum dose of 220 mg/m2 bid. Treatment will continue for 6 months with an option to continue for 24 months if the patient is deriving a clinical benefit.

Pilot Study of Gleevec/Imatinib Mesylate (STI-571, NSC 716051) in Neurofibromatosis (NF1) Patient With Plexiform Neurofibromas

To estimate the disease control rate (SD, PR, CR) with Gleevec/Imatinib Mesylate in patients with neurofibromas (NF1). The sum of the longest diameter (LD) for all target lesions will be calculated and reported as the disease measurement. Complete Response (CR) disappearance of target lesions. Partial Response (PR) at least a 30% decrease in the disease measurement, taking as reference the disease measurement done to confirm measurable disease at study entry. Progressive Disease (PD) at least a 20% increase in the disease measurement, taking as reference the smallest disease measurement recorded since the start of treatment. Stable Disease (SD) neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest disease measurement since the treatment started.

Kent Robertson

Associate Professor of Pediatrics

Dr. Kent Robertson

13 participants reached the 1 year evaluation time-point. 6 participants withdrew prior to the 1 year evaluation time-point.

Anti-Inflammatory Agents

Antirheumatic Agents

Analgesics

Anti-Infective Agents

Temozolomide

Vincristine

Celecoxib

Interferons

Peginterferon alfa-2b

Interferon-alpha

Interferon alpha-2

Antiviral Agents

Tubulin Modulators

Antimitotic Agents

Antineoplastic Agents, Alkylating

Alkylating Agents

Immunologic Factors

Anti-Inflammatory Agents, Non-Steroidal

Analgesics, Non-Narcotic

Cyclooxygenase 2 Inhibitors

Cyclooxygenase Inhibitors

This is a phase II single arm study with sequential treatments available by response where all participants begin therapy with a combination of celecoxib and interferon alpha-2b (CI, treatment-1). Response to CI therapy will be assessed at six months by clinical and radiographic evaluations. Those patients who have achieved a partial response (improvement in pain, improvement in functioning, or ≥50% reduction in tumor size) or complete response (resolution of pain, and normalization of functioning with a ≥ 90% reduction in tumor size) will continue with the same CI therapy for up-to two years on study.

Peg-Interferon alpha-2b

Celecoxib (Celebrex)

Temozolomide (temodar)

Vincristine Sulfate (Oncovin)

Albert S Cornelius, MD

Patients with neurofibromatosis type 1 (NF1) commonly develop non-cancerous tumors called plexiform neurofibromas. These tumors can be defined as "high-risk" when they result in severe pain, physical disability, organ dysfunction and/or become life-threatening. Presently, there is no effective medical therapy to offer patients with "high-risk" plexiform neurofibromas, and surgery does not provide lasting help. This study will evaluate the effectiveness of two treatment combinations in patients with "high-risk" plexiform neurofibromas.

The study's design involves treating eligible patients with a combination of celecoxib and pegylated interferon alpha-2b. If the patients have at least a partial response after six months, they may continue on the same treatment for up to two years. If the patient experiences less than a partial response, or has progressive disease after six months of therapy, then vincristine and temozolomide will be added to the celecoxib and interferon alpha-2b backbone. Response to treatment will be assessed after a minimum of six months, presuming the patient has not experienced progressive disease. Total duration of therapy on study is two years for any individual treatment plan.

Medical Treatment of "High-Risk" Neurofibromas

Medical Treatment of "High-Risk" Neurofibromas in Patients With Type 1 Neurofibromatosis: A Clinical Trial of Sequential Medical Therapies

Subjects will be evaluated for pain and Quality of Life scores

partial response by RICST criteria is defined as \>50% tumor shrinkage

Psychological toxicity defined as suicidal ideation

Spectrum Health Hospitals

adverse events collected during provider appointments

This is a phase II single arm study with sequential treatments available by response where all participants begin therapy with a combination of celecoxib and interferon alpha-2b (CI, treatment-1). Response to CI therapy will be assessed at six months by clinical and radiographic evaluations. Those patients who have achieved a partial response (improvement in pain, improvement in functioning, or ≥50% reduction in tumor size) or complete response (resolution of pain, and normalization of functioning with a ≥ 90% reduction in tumor size) will continue with the same CI therapy for up-to two years on study.

Peg-Interferon alpha-2b: age and weight dependant

Celecoxib (Celebrex): age and weight dependant

Temozolomide (temodar): age and weight dependant

Vincristine Sulfate (Oncovin): age and weight dependant

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Study of Tasigna®/Nilotinib (AMN107) in Neurofibromatosis (NF1) Patients With Plexiform Neurofibromas	NCT01275586	Neurofibromatos... NF1 Neurofibromas	Tasigna	18 Years -	Indiana University
Natural History Study of Cutaneous Neurofibromas in People With NF1	NCT05581511	Neurofibromatos... Neurofibromatos... Neurofibromatos... Cutaneous Neuro...	Evaluation of t...	1 Year - 100 Years	Johns Hopkins University
Surveillance for Malignant Transformation of Neurofibromatosis Type 1 (NF1) Related Peripheral Nerve Sheath Tumors (PNST)	NCT06222203	Neurofibromatos... Nerve Sheath Ne...		3 Years - 120 Years	National Institutes of Health Clinical Center (CC)
Phase II Study of Binimetinib in Children and Adults With NF1 Plexiform Neurofibromas	NCT03231306	Neurofibromatos... Plexiform Neuro...	Binimetinib	1 Year -	University of Alabama at Birmingham
Developing Biomarkers of Plexiform Tumor Burden in Patients With Neurofibromatosis-Type 1	NCT05238909	Neurofibromatos... NF1 Neurofibromatos...		-	Ann & Robert H Lurie Children's Hospital of Chicago
Surveillance for Malignant Transformation of Neurofibromatosis Type 1 (NF1) Related Peripheral Nerve Sheath Tumors (PNST)	NCT06222203	Neurofibromatos... Nerve Sheath Ne...		3 Years - 120 Years	National Institutes of Health Clinical Center (CC)
Pilot Study of Gleevec/Imatinib Mesylate (STI-571, NSC 716051) in Neurofibromatosis (NF1) Patient With Plexiform Neurofibromas	NCT01140360	Neurofibromatos... Neurofibromas	Gleevec	3 Years - 65 Years	Indiana University
Study of Tasigna®/Nilotinib (AMN107) in Neurofibromatosis (NF1) Patients With Plexiform Neurofibromas	NCT01275586	Neurofibromatos... NF1 Neurofibromas	Tasigna	18 Years -	Indiana University
Medical Treatment of "High-Risk" Neurofibromas	NCT00846430	Neurofibromatos...	Peg-Interferon ... Celecoxib (Cele... Temozolomide (t... Vincristine Sul...	2 Years - 30 Years	Spectrum Health Hospitals
Medical Treatment of "High-Risk" Neurofibromas	NCT00846430	Neurofibromatos...	Peg-Interferon ... Celecoxib (Cele... Temozolomide (t... Vincristine Sul...	2 Years - 30 Years	Spectrum Health Hospitals
Phase II Study of Binimetinib in Children and Adults With NF1 Plexiform Neurofibromas	NCT03231306	Neurofibromatos... Plexiform Neuro...	Binimetinib	1 Year -	University of Alabama at Birmingham

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