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

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.