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Neurofibromatosis (NF) is a neurocutaneous syndrome characterized by the development of tumors of the central or peripheral nervous system including the brain, spinal cord, organs, skin, and bones. There are three types of NF: NF1 accounting for 96% of all cases, NF2 in 3%, and schwannomatosis (SWN) in <1%. The NF1 gene is located on chromosome 17q11.2, which encodes for a tumor suppressor protein, neurofibromin, that functions as a negative regulator of Ras/MAPK and PI3K/mTOR signaling pathways. The NF2 gene is identified on chromosome 22q12, which encodes for merlin, a tumor suppressor protein related to ezrin-radixin-moesin that modulates the activity of PI3K/AKT, Raf/MEK/ERK, and mTOR signaling pathways. In contrast, molecular insights on the different forms of SWN remain unclear. Inactivating mutations in the tumor suppressor genes SMARCB1 and LZTR1 are considered responsible for a majority of cases.
A: The Diagnostic Criteria for NF1 Are Met in an Individual Who Does Not Have a Parent Diagnosed with NF1 if Two or More of the Following Are Present: |
At least six café-au-lait macules (>5 mm diameter in prepubertal individuals and >15 mm in postpubertal individuals) |
Freckling in axillary or inguinal regions #1 |
Optic glioma |
At least two Lisch nodules identified by slit lamp examination or two or more choroidal abnormalities—defined as bright, patchy nodules imaged by optical coherence tomography/near-infrared reflectance imaging |
At least two neurofibromas of any type, or one plexiform neurofibroma |
A distinctive osseous lesion such as sphenoid dysplasia, #2 anterolateral bowing of the tibia, or pseudarthrosis of a long bone |
A heterozygous pathogenic NF1 variant with a variant allele fraction of 50% in apparently normal tissue such as white blood cells |
B: A child of a parent who meets the diagnostic criteria specified in A merits a diagnosis of NF1 if one or more of the criteria in A are present |
ID | Initiation Date | Phase | Nation | N | Disease | Treatment | Primary Outcome |
---|---|---|---|---|---|---|---|
NCT04495127 | 8, 2020 | 1 | Japan | 12 | NF1 | Selumetinib | Toxicity |
NCT01968590 | 8, 2017 | 2 | USA | 320 | NF1 | Cholecalciferol | Bone mineral density |
NCT03962543 | 9, 2019 | 2 | USA | 100 | NF1 Plexiform Neurofibroma |
Mirdametinib (PD-0325901) oral capsule | Complete or partial response rate compared to baseline. |
NCT03231306 | 11, 2017 | 2 | USA | 40 | NF1 Plexiform Neurofibroma |
Binimetinib | Change from Baseline Target Tumor Volume at 12 months |
NCT02839720 | 4, 2017 | 2 | USA | 24 | Cutaneous Neurofibroma NF1 Optic Nerve Glioma |
Selumetinib | Change in the size |
NCT02407405 | 1, 2016 | 2 | USA | 60 | NF1 Plexiform Neurofibromas |
Selumetinib | Determine objective response rate |
NCT04461886 | 7, 2020 | 3 | Japan | 100 | NF | NPC-12G gel | Discontinuation rate associated with adverse events |
NCT03871257 | 10, 2019 | 3 | USA | 290 | Low Grade Glioma NF1 Visual Pathway Glioma |
Carboplatin Selumetinib Sulfate Vincristine Sulfate |
Event-free survival |
NCT02101736 | 6, 2014 | 2 | USA | 48 | NF1 Neurofibromatosis Plexiform Neurofibromas |
Cabozantinib | The change in tumor size based on radiographic assessment |
NCT03326388 | 9, 2019 | 1/2 | USA | 30 | NF1 Plexiform Neurofibroma Optic Nerve Glioma |
Selumetinib | To evaluate the Maximum Tolerated Dose Objective response rate |
NCT03741101 | 6, 2019 | 2 | Sweden | 15 | NF1 Plexiform Neurofibromas |
Trametinib | Remission of tumor volume ≥20% |
NCT02728388 | 8, 2016 | 2 | USA | 30 | NF1 | aminolevulinic acid | Time to disease progression |
NCT04435665 | 8, 2020 | 2 | USA | 48 | NF1 Cutaneous Neurofibroma |
NFX-179 Gel | Phospho-erk (p-ERK) levels of Target cNF Tumors Toxicity |
NCT02390752 | 4, 2015 | 1/2 | USA | 81 | Neurofibroma, Plexiform | PLX3397 | Toxicity Objective response rate |
NCT03688568 | 9, 2018 | 2 | USA | 20 | Neurofibroma, Plexiform | Imatinib Mesylate | Quantitative Functional Airway Response |
NCT03433183 | 10, 2019 | 2 | USA | 21 | Malignant Peripheral Nerve Sheath Tumors NF1 |
Selumetinib Sirolimus | Clinical benefit rate of selumetinib in combination with sirolimus |
NCT04085159 | 9, 2019 | 1/2 | China | 100 | Neurofibromatosis Schwannomatosis | Antigen-specific T cells CART/CTL and DCvac | Percentage of adverse effects |
Bilateral vestibular schwannomas or |
First-degree relative with neurofibromatosis type 2 plus |
1. Unilateral vestibular schwannomas or |
2. Any two of the following: Meningioma, glioma, schwannoma, or juvenile PLO |
ID | Initiation Date | Phase | Nation | N | Disease | Treatment | Primary Outcome |
---|---|---|---|---|---|---|---|
NCT02934256 | 7, 2016 | 2 | China | 20 | NF2 | Icotinib | Change from Baseline in volume of tumor |
NCT02129647 | 4, 2014 | 2 | USA | 12 | NF2 Progressive VS |
Axitinib | volumetric response rates |
NCT01345136 | 7, 2015 | 2 | USA | 4 | NF2 | RAD001, everolimus | Vestibular schwannoma volume |
NCT01767792 | 5, 2013 | 2 | USA | 22 | NF2 Progressive VS |
Bevacizumab | Hearing |
NCT04283669 | 2, 2020 | 2 | USA | 19 | NF2 Progressive VS |
Crizotinib | Volumetric response rate |
NCT02831257 | 8, 2016 | 2 | USA | 18 | NF2 Meningioma |
AZD2014 | Volumetric response rate |
NCT04374305 | 6, 2020 | 2 | USA | 80 | NF2 Vestibular Schwannoma Non-vestibular Schwannoma Meningioma Ependymoma |
Brigatinib | Volumetric response rate |
NCT03095248 | 5, 2017 | 2 | USA | 34 | NF2 Vestibular Schwannoma Meningioma Ependymoma Glioma |
Selumetinib | Hearing response Volumetric response rate |
NCT03079999 | 6, 2018 | 2 | USA | 300 | NF2 Vestibular schwannoma |
Aspirin | Progression-free survival |
Definite Schwannomatosis |
A. Age >30 years and two or more schwannomas (not intradermal), at least one with histologic confirmation with no evidence of vestibular tumor on brain MRI scan and no known NF mutation |
B. Vestibular schwannoma (pathologically confirmed) plus first-degree relative who meets the criteria of schwannomatosis |
Possible schwannomatosis |
A. Age <30 years plus two or more schwannomas (not intradermal), at least one with histologic confirmation with no evidence of vestibular tumor on brain MRI scan and no known NF mutation |
B. Age >45 years plus two or more schwannomas (not dermal), at least one with histologic confirmation and no symptoms of 8th nerve dysfunction and NF type 2 |
C. Evidence of a non-vestibular schwannoma and first-degree relative meeting criteria for definite schwannomatosis |
ID | Initiation Date | Phase | Nation | N | Disease | Treatment | Primary Outcome |
---|---|---|---|---|---|---|---|
NCT04163419 | 4, 2020 | 2 | USA | 46 | Schwannomatosis | Tanezumab | Change in pain level |
NCT04085159 | 9, 2019 | 1/2 | China | 100 | Neurofibromatosis Schwannomatosis | Antigen-specific T cells CART/CTL and DCvac | Percentage of adverse effects |