Neoplasms

Nervous System Diseases

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Symptoms and General Pathology

Skin and Connective Tissue Diseases

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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

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Peripheral Nervous System Neoplasms

Neurofibromatosis

Neurofibromatosis Type 1

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)

Abemaciclib orally twice daily at escalating doses to determine the MTD/RP2D

Abemaciclib orally twice daily at the RP2D

Abemaciclib is to be administered orally on Days 1 through 28 of each 28-day cycle

Abemaciclib

Amanda M Carbonell

Andrea M Gross, M.D.

For more information at the NIH Clinical Center contact National Cancer Institute Referral Office

Background:

NF1 is a genetic disease that causes tumors called atypical neurofibromas. These tumors, which arise from nerves, can cause serious medical problems. The only treatment is surgery. Researchers want to see if a drug called abemaciclib can help.

Objective:

To find a safe, tolerable dose of abemaciclib for treating atypical neurofibromas.

Eligibility:

People ages 12 and older who have NF1 and have one or more atypical neurofibromas that cannot or will not be removed with surgery

Design:

Participants will be screened with:

Medical history and physical exam

Blood, urine, and heart tests

MRI: Participants will lie in a machine that takes pictures of the body. A padding or coil will be placed around their head. They may have a contrast agent injected into a vein.

Biopsy sample: A small piece of tumor will be removed using a large needle.

Participants will have frequent visits during the study. These will include repeats of the screening tests as well as the following:

PET scan: Participants will lie in a machine that takes pictures of the body. They will have a contrast agent injected into their arm.

Questionnaires about the effects of abemaciclib on pain and quality of life

Possible photographs of tumors

Participants will take abemaciclib capsules orally twice daily in 28-day cycles. They will take the drug for up to 2 years. Some may be able to take it for longer.

Participants will have a follow-up visit about 30 days after their last dose of the study drug. Then they will have visits every 3 months for 1 year.

...

Background:

* Neurofibromatosis type 1 (NF1) is a genetic tumor predisposition syndrome (incidence of 1:3000), which results in the development of progressive tumor and non-tumor manifestations, the majority of which have no effective medical therapies. 25-50% of individuals with neurofibromatosis type 1 (NF1) develop histologically benign plexiform neurofibromas (PN), which can cause substantial morbidity. Recently, the POB identified that MEK inhibitors cause shrinkage of the majority of PN and that PN shrinkage is associated with clinical benefit.
* A natural history study of NF1 at the NCI has gathered comprehensive imaging information using longitudinal whole-body MRI with volumetric measurements. By this approach, distinct nodular lesions (DNL) were identified, many of which are atypical neurofibromas (ANF) based on pathology review.
* The NCI POB and others have described ANF as precursor lesions for aggressive soft tissue sarcomas called malignant peripheral nerve sheath tumors (MPNST), which show poor response to chemotherapy and have poor survival. Of note, ANF appear to be less responsive to treatment with MEK inhibitors indicating a different biology.
* Exome sequencing of 16 ANF resected at the National Cancer Institute, Pediatric Oncology Branch (NCI POB) and Belgium revealed that 90% of the cases had heterozygous loss of CDKN2A/B as the only new somatic change in addition to biallelic NF1 deletion, consistent with prior reports. These results demonstrate that transformation of NF1 nerve tumors may genetically proceed through the premalignant ANF by a common mechanism that might be a point of intervention.
* CDKN2A is the primary inhibitory brake on CDK4/6 driven signaling and is commonly deleted in glioblastoma, pancreas, bladder, breast and prostate cancer. The specific CDK4/6 inhibitor, abemaciclib, has FDA approval for the treatment of metastatic breast cancer.
* ANF is a prototypic premalignant lesion for testing experimental intervention, as these lesions are at risk for transformation, and share a common potentially druggable genomic alteration (CDKN2A/B deletion). We propose a clinical trial of abemaciclib in children and adults with NF1 and unresectable ANF.

Objectives:

* Phase 0: To determine the pharmacodynamic effect of 7-10 days of abemaciclib treatment prior to tumor resection on levels of phosphorylated Retinoblastoma (pRb)
* Phase I: To determine the recommended Phase II dose (RP2D) of abemaciclib in participants with NF1 and a measurable ANF
* Phase II: To determine the objective response rate (ORR) in the target ANF; complete and partial response (CR + PR), response determined by volumetric MRI analysis (\>=20% volume reduction) compared to baseline

Eligibility:

* Participants must be at least 12 years of age with a diagnosis of NF1 with associated agerelated requirements as follows:

  * Willingness of participants \>= 12 years old and \<18 years old to undergo pretreatment percutaneous biopsy of ANF if deemed feasible with minimal morbidity
  * Willingness of participants \>=18 years old to undergo pre-treatment and ontreatment percutaneous biopsy of ANF if deemed feasible with minimal morbidity
* Phase 0 Only:

  * Age \>= 18 years old
  * Presence of \>= 1 measurable ANF (biopsy confirmed) for which surgical removal at the NIH would not likely cause significant morbidity and is clinically indicated
* Phase I/II Only:

  --Presence of \>= 1 measurable ANF (biopsy confirmed) for which surgical removal could cause significant morbidity OR for which participant is unwilling to undergo surgical resection OR the presence of more than one distinct nodular lesion (DNL) including at least 1 biopsy proven ANF
* For participants of all ages with ANF who cannot be safely biopsied with minimal morbidity, biopsy requirement to be performed at NIH Clinical Center will be waived from eligibility criteria. In this case, review of available archival tissue by NIH Pathology will be necessary to confirm diagnosis of ANF, which is mandatory for eligibility.

Design:

* This is a Phase 0/I/II non-randomized, open label, single institution study of the CDK4/6 inhibitor, abemaciclib, in children and adults with NF1 and a measurable ANF or with multiple ANF/DNL.
* The accrual ceiling will be set at 55 eligible participants (to include participants who are screened but found to not be eligible to undergo treatment).
* Phase 0: For participants with a biopsy-proven ANF that can be removed without significant anticipated clinical morbidity and where resection of the ANF is clinically indicated

  * Participants will receive abemaciclib at the same dose level and schedule as the Phase I/II portion at the time of enrollment for at least 7 days and no more than 10 days immediately prior to tumor resection
  * Tumor will be fully resected as per clinical care and participants will discontinue study drug
  * Participants will be followed for 30 days post-treatment or until resolution to \<=grade 1 of any abemaciclib-related adverse events
  * The phase 0 study will have a 2-stage design with 3 participants in the first stage and an expansion to a total of 5 participants if at least one of the initial 3 participants achieves a pharmacodynamic response
* Phase I/II: For participants with a biopsy-proven ANF for which surgical removal could cause significant morbidity OR for which participant is unwilling to undergo surgical resection OR the presence of more than one distinct nodular lesion (DNL)

  * Primarily because the tolerability of investigational agents may differ between the NF1 population and non-NF1 population and secondarily because abemaciclib has not been evaluated in children to date, there will be a limited dose finding phase.
  * During the Phase 1 portion of the trial, the first 6 participants enrolled will be treated at 75% of the adult recommended Phase II dose (ARP2D; 150mg PO BID) of abemaciclib used in participants with malignancies, in a 28-day cycle. For participants \< 18 years of age, dosing will be based on body surface area (BSA).
  * Cohorts of up to 6 participants will be enrolled, with dose adjustment depending on dose-limiting toxicities (DLT) until the maximum tolerated dose (MTD)/ recommended Phase II dose (RP2D) is established.
  * The Phase II trial is a Simon minimax two-stage trial design. An observed response rate of approximately 30% or greater would be considered desirable. The first stage of the Phase II portion of the trial will enroll 15 evaluable participants; if 0 to 2 of the 15 have a PR or CR, then no further participants will be accrued. If 3 or more of the 15 participants have a PR or CR, then accrual would continue until a total of 21 evaluable participants have been enrolled in phase II.
  * All participants will undergo careful toxicity monitoring. Restaging MRI for response will be performed pre-cycles 3 and 5, and then every 4 cycles for remainder of the first year.

Cyclin-Dependent Kinase (CDK)4/6 Inhibitor Abemaciclib for Neurofibromatosis Type I (NF1) Related Atypical Neurofibromas

A Phase 0/I/II Study of the Cyclin-Dependent Kinase(CDK)4/6 Inhibitor Abemaciclib for Neurofibromatosis Type 1 (NF1) Related Atypical Neurofibromas

Duration of treatment and adverse event types and frequency

Proportion of patients that have progressive disease

Changes in non-target ANF/DNL determined by volumetric MRI analysis

Measurement of phosphorylated Retinoblastoma (pRB) in tumor biopsy samples

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
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)
Cyclin-Dependent Kinase (CDK)4/6 Inhibitor Abemaciclib for Neurofibromatosis Type I (NF1) Related Atypical Neurofibromas	NCT04750928	Neurofibromatos...	Abemaciclib	12 Years -	National Institutes of Health Clinical Center (CC)
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)
Cyclin-Dependent Kinase (CDK)4/6 Inhibitor Abemaciclib for Neurofibromatosis Type I (NF1) Related Atypical Neurofibromas	NCT04750928	Neurofibromatos...	Abemaciclib	12 Years -	National Institutes of Health Clinical Center (CC)

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