Overview | Neurofibromatosis Type 1 | Neurofibromatosis Type 2 | Schwannomatosis | Multi-type Trials | Clinical Trials Consortium

Neurofibromatosis (NF) refers to a group of three genetically distinct disorders that have a spectrum of clinical manifestations. The disorders, NF1, NF2, and Schwannomatosis, can all lead to tumor growth. Other manifestations include learning deficits and cognitive disorders, skin conditions, visual impairments, nervous system disorders and neurological symptoms, vascular disease, musculoskeletal disorders, malignancies, hearing impairments, and chronic pain. Treatments for NF currently include surgery, radiation, and chemotherapy, but several clinical trials are underway to identify more treatment options.

The Congressionally Directed Medical Research Programs’ Neurofibromatosis Research Program (NFRP) is funding several efforts focused on finding better treatments through two main mechanisms, the Clinical Trial Award and the NF Clinical Trials Consortium. A sSummary of the trials funded to date are found in the tabs on this page.

Neurofibromatosis Type 1 Trials

Updated November 2020

NF190013: Antioxidant Therapy with N-Acetylcysteine for Motor Behavior and Learning in Children with Neurofibromatosis Type 1
Summary: The goal of this Phase II study is to explore efficacy of N-acetylcysteine (NAC), an antioxidant, on motor behavior and attention deficit in children and adolescents with NF1. Safety and tolerability will be evaluated, and potential biomarkers for treatment outcomes will be studied.
Status: Not yet recruiting
ClinicalTrials.gov Identifier: NCT04481048

NF160012: A Phase 1/2 Trial of the MEK inhibitor selumetinib and bromodomain inhibitor AZD5153 with durvalumab (MEDI4736), a PD-L1 antibody for sarcomas including malignant peripheral nerve sheath tumors
Summary: The objective of this trial is to determine safety, tolerability, pharmacokinetics, and optimal doses of the selumetinib, AZD5153, and durvalumab in combination in patients with refractory sarcomas. The study will then assess the clinical benefit of the combination therapy in patients with NF1-associated MPNST.
This trial is being performed by the NF Clinical Trials Consortium.
Status: Not yet recruiting
ClinicalTrials.gov Identifier: TBA

NF160012: Phase II Trial of Poly-ICLC for Progressive, Previously Treated Low-Grade Gliomas in Children and Young Adults with Neurofibromatosis Type 1
Summary: The goal of this trial is evaluate the efficacy of ploy-ICLC in pediatric NF1 patients with progressive low-grad glioma. The study will also evaluate visual outcomes in participants with optic pathway gliomas.
This trial is being performed by the NF Clinical Trials Consortium.
Status: Not yet recruiting
ClinicalTrials.gov Identifier: NCT04544007

NF160012: A Phase II Study of Binimetinib in Children and Adults with NF1 associated Plexiform Neurofibromas
Summary: This Phase II trial will examine the response to binimetinib treatment in children and adults with plexiform neurofibromas, measured by reduction in tumor volume. The study will also evaluate the toxicity of the binimetinib treatment, and assess potential biomarkers to indicate treatment response.
This trial is being performed by the NF Clinical Trials Consortium.
Status: Recruiting
ClinicalTrials.gov Identifier: NCT03231306

NF150092: Accelerated Clinical Development of Rational Therapies for Malignant Peripheral Nerve Sheath Tumors
Summary: The objectives of this multi-institutional, phase 2 clinical trial are to determine the clinical benefit of the MEK inhibitor, selumetinib, in combination with a mTOR inhibitor, in patients with unresectable malignant peripheral nerve sheath tumors, and to explore potential imaging and other biomarkers for use in determining clinical outcomes.
This study is being performed in collaboration with the NF Clinical Trials Consortium.
Status: Recruiting
ClinicalTrials.gov Identifier: NCT03433183

NF140001: Phase 1 Trial of Intratumoral Administration of NIS-Expressing Strain of Measles Virus in Unresectable or Recurrent Malignant Peripheral Nerve Sheath Tumor
Summary: The objective of this phase I trial is to study the safety and optimal dose of an attenuated measles virus administered intratumorally to patients with locally advanced or recurrent MPNST. In addition, the goal is to obtain preliminary evidence for anti-tumor activity of the treatment to guide further studies.
Status: Recruiting
ClinicalTrials.gov Identifier: NCT02700230

NF140033: Multimodal Intervention Trial for Cognitive Deficits in Neurofibromatosis Type 1: Efficacy of Computerized Cognitive Training and Stimulant Medication
Summary: This phase 2, randomized study compares two interventions on cognitive outcomes in children with neurofibromatosis type 1 (NF1). The study assesses the efficacy of the home-based computerized cognitive training program, Cogmed^RM, on the improvement of working memory with or without methylphenidate, a stimulant medication commonly prescribed to children with NF1. Potential synergistic effects between Cogmed^RM and methylphenidate will also be assessed.
Status: Recruiting
ClinicalTrials.gov Identifier: NCT02944032

NF120087: Phase I/II Trial of an Hsp90 Inhibitor in Combination with an mTOR Inhibitor for Patients with Refractory Malignant Peripheral Nerve Sheath Tumors
Summary: This study was a multi-institutional, phase I/II trial of ganetespib in combination with sirolimus in patients with refractory sarcoma, including MPNST. The study started with determining safety, tolerability, and the recommended dose of the combination, and then determined the benefit in patients with unresectable or metastatic MPNST.
This study was performed in collaboration with the NF Clinical Trials Consortium.
Status: Completed
ClinicalTrials.gov Identifier: NCT02008877
Outcome: While the combination therapy seemed to be tolerable, clinical benefit in patients was not observed.
Publications:
Kim A, Lu Y, Okuno SH, Reinke DK, Maertens O, Perentesis JP, Basu M, Wolters P, DeRaedt T, Chawla S, Chugh R, Van Tine B, Cichowski K, Widemann BC. Targeting Refractory Sarcomas and Malignant Peripheral Nerve Sheath Tumors in a phase I/II study of sirolimus in combination with ganetespib (SARC023). Sarcoma, 2020 Jan 30;2020:5784876. eCollection 2020. PMID: 32089640

NF110052: Cabozantinib (XL184) for NF1-Related Plexiform Neurofibromas
Summary: This Phase II clinical trial will evaluate the response rate of adolescents and adults with NF1 and plexiform neurofibromas treated with cabozantinib. The pediatric dose of cabozantinib has now been identified; the study has been amended to add a separate stratum of 19 evaluable pediatric patients (<16 years of age).
This trial is being performed by the NF Clinical Trials Consortium.
Status: Recruiting
ClinicalTrials.gov Identifier: NCT02101736
Outcome: Cabozantinib had a partial response rate of 42% in the adolescent/adult stratum.

NF110052: PD-0325901 (Mirdametinib) for NF1-Related Plexiform Neurofibromas
Summary: This Phase II clinical trial evaluated the MEK inhibitor mirdametinib for the treatment of NF1-related morbid plexiform neurofibromas in adolescents and adults. The primary endpoint was to determine whether treatment results in objective radiographic responses measured using MRI.
This trial was performed by the NF Clinical Trials Consortium.
Status: Completed
ClinicalTrials.gov Identifier: NCT02096471
Outcome: Mirdametinib had a partial response rate of 42%

NF110052: INFUSE Bone Graft for treatment of NF1-Related Tibial Pseudarthrosis (TPA)
Summary: This Phase II clinical trial was planned to evaluate the utility of adding BMP-2 at the surgical site of TPA repair in children and adolescents with NF1 with regard to improved bone healing. In addition to evaluating the clinical response to, the safety of this drug was to be evaluated in a pediatric NF1 population.
This trial is being performed by the NF Clinical Trials Consortium.
Status: Active, not recruiting
ClinicalTrials.gov Identifier: NCT02718131
Outcome: The study was unable to enroll sufficient participants to meet the objectives of the trial. The research team has provided recommendations for future studies of orthopedic manifestations of NF1.
Publications:
Rios JJ, Richards BS, Stevenson DA, Oberlander B, Viskochil D, Gross AM, Dombi E, Widemann BC, Plotkin SR, May CJ, Ullrich NJ, Goldstein RY, Jain V, Schorry EK; NFCTC Consortium. Are Some Randomized Clinical Trials Impossible? J Pediatr Orthop. 2020 Aug 25. Epub ahead of print. PMID: 32852366.

NF110052: Phase I/II Study of Binimetinib (MEK162) for Children with Low-Grade Gliomas and Other Ras/Raf/MAP Pathway Activated Tumors
Summary: This Phase I/II trial will evaluate the use of binimetinib (MEK162) in patients with low-grade gliomas, NF1 associated tumors, and other tumors thought to be caused by abnormal activation of the Ras/Raf/MEK molecular pathway. The primary goals of this trial are to determine the dose and evaluate the safety and tolerability of the treatment, as well as determine the clinical benefit in patients.
This trial is being performed by the NF Clinical Trials Consortium.
Status: Recruiting
ClinicalTrials.gov Identifier: NCT02285439

NF110055: A Phase II Trial on the Effect of Low-Dose versus High-Dose Vitamin D Supplementation on Bone Mass in Adults with Neurofibromatosis 1 (NF1)
Summary: This phase II clinical trial aims to determine whether a therapeutic dose of oral vitamin D (4,000 versus 600 International Units) for patients with insufficient levels of the vitamin in serum will lead to the preservation of bone mineral density in adults with neurofibromatosis type 1.  Additional measured outcomes are history of bone fractures, quality of life, and laboratory samples.  
Status: Recruiting
ClinicalTrials.gov Identifier: NCT01968590

NF100031: A Phase II Study of Sutent Sunitinib, an Oral Multitargeted Tyrosine Kinase Inhibitor in Subjects with NF-1 Plexiform Neurofibromas
Summary: This phase II study sought to evaluate the efficacy of Sutent Sunitinib, an oral multi-targeted tyrosine kinase inhibitor, in individuals with clinically significant plexiform tumors. Multiple measurements, including imaging, cellular activity, molecular signaling, and quality of life, were incorporated into the study to provide a more complete measure of response.
Status: Terminated, due to patient death of uncertain cause, possibly related to drug
ClinicalTrials.gov Identifier: NCT01402817

NF093105: Phase 2 Study: RAD001 with and without Bevacizumab in Sporadic and Neurofibromatosis Type 1-Related Refractory Malignant Peripheral Nerve Sheath Tumors
Summary: This phase 2 study aimed to determine the clinical response rate of everolimus in combination with bevacizumab for patients with chemotherapy refractory sporadic or neurofibromatosis type 1 associated MPNST. In addition, the study evaluated the safety and toxicity of everolimus in combination with bevacizumab in individuals with MPNST. Other outcomes included the analysis of correlations of response with changes in pharmacodynamic parameters in peripheral blood and urine samples.
This study was performed in collaboration with the NF Clinical Trials Consortium.
Status: Completed
ClinicalTrials.gov Identifier: NCT01661283
Outcome: The combination of everolimus and bevacizumab did not reach the study's target response rate and is not considered active in refractory malignant peripheral nerve sheath tumors.
Publications: Widemann BC, Lu Y, Reinke D, et al. Targeting Sporadic and Neurofibromatosis Type 1 (NF1) Related Refractory Malignant Peripheral Nerve Sheath Tumors (MPNST) in a Phase II Study of Everolimus in Combination with Bevacizumab (SARC016). Sarcoma. 2019 Jul 24;2019:7656747.

NF080099: Pilot Study of Gleevec® /Imatinib Mesylate (STI-571, NSC 716051) in Neurofibromatosis (NF1) Patients with Plexiform Neurofibromas
Summary: A previous trial had shown limitations with the established methods of determining response to treatment, so the goal of this pilot study was to trial and develop multiple techniques for determining the response of NF1 patients with plexiform neurofibromas to Gleevec® therapy for use in subsequent clinical trials.
Status: Completed
ClinicalTrials.gov Identifier: NCT01140360
Outcome: This trial provided data that will inform a future phase 2 study of imatinib for the treatment of airway tumors in children with NF1 supported by the NIH.

NF073119: Phase I Study of Intratumoral Photodynamic Therapy in Children with NF1 and Plexiform Neurofibromas
Summary: The goal of this study was to determine the safety and tolerability of photodynamic therapy for the treatment of PN in children combined with talaporfin sodium (LS11). Upon identification of the maximum tolerated dose, the therapy was to be evaluated for feasibility in preparation for a phase 2 trial.
Status: Terminated due to expiration of study materials.
ClinicalTrials.gov Identifier: NCT00716469

NF060016: STOPN: Sirolimus for the Treatment of NF1-Related Plexiform Neurofibromas
Summary: STOPN was a Phase II clinical trial to evaluate the mTOR inhibitor sirolimus in the treatment of plexiform neurofibromas in children and adults with NF1. The goals of this trial were to find out if sirolimus could stop or slow the growth of and/or shrink plexiform neurofibromas, evaluate the feasibility and toxicity of chronic sirolimus administration, and characterize the active pharmacokinetic profile of sirolimus when administered to this patient population.
This trial was performed by the NF Clinical Trials Consortium.
Status: Completed.
ClinicalTrials.gov Identifier: NCT00634270
Outcome: In the progressive disease stratum, the data indicated that sirolimus can increase time to progression in NF1 patients with progressive plexiform neurofibromas. In the non-progressive disease stratum, the researchers observed that sirolimus treatment did not lead to decreased tumor volume.
Publications:
Scott JR, Courter JD, Saldaña SN, et al. 2013. Population pharmacokinetics of sirolimus in pediatric patients with neurofibromatosis type 1. Therapeutic Drug Monitoring 35(3):332-337.
Weiss B, Widemann BC, Wolters P, et al. 2014. Sirolimus for non-progressive NF1-associated plexiform neurofibromas: An NF Clinical Trials Consortium Phase II study. Pediatr Blood Cancer. 2014 Jun;61(6):982-6.
Weiss B, Widemann BC, Wolters P, et al. 2015. Sirolimus for Progressive Neurofibromatosis Type 1-Associated Plexiform Neurofibromas: A Neurofibromatosis Clinical Trials Consortium Phase II Study. Neuro-Oncology, 2015 17(4):596-603.
Emoto C, Fukuda T, Mizuno T, et al. 2015. Age Dependent Changes in Sirolimus Metabolite Formation in Patients with Neurofibromatosis Type 1. Therapeutic Drug Monitoring, 2015 37(3):395-399.

NF060016: STARS: Lovastatin for the Treatment of Learning Disabilities in Children with NF1
Summary: STARS was a placebo-controlled, double-blind Phase II clinical trial to evaluate the effectiveness of lovastatin in the treatment of learning disabilities in children with NF1. The goals of this study were to determine whether lovastatin significantly improves visual spatial learning and/or sustained attention in children with NF1, affects measures of executive function, behavior, and quality of life in children with NF1 and cognitive deficits, and is safe and tolerable in this population.  
This trial was performed by the NF Clinical Trials Consortium.
Status: Completed.
ClinicalTrials.gov Identifier: NCT00853580
Outcome: No improvement in the primary outcome measures was observed. The research team examined the data from this trial further in an effort to help inform future trials. They found that single observed endpoints are not appropriate for use in efficacy studies due to variable test-retest reliability. The team also evaluated the relationships between functional outcomes and cognition and ADHD symptoms; they found that ADHD symptoms (irrespective of cognitive deficits) negatively impact functioning in children with NF1.
Publications:
Payne JM, Barton B, Ullrich NJ, et al. 2016. Randomized placebo-controlled study of lovastatin in children with neurofibromatosis type 1. Neurology. 2016 Dec 13;87(24):2575-2584.
Payne JM, Hearps SJC, Walsh KS, et al. Reproducibility of cognitive endpoints in clinical trials: lessons from neurofibromatosis type 1. Ann Clin Transl Neurol. 2019;6(12):2555-2565. doi:10.1002/acn3.50952
Payne JM, Haebich KM, MacKenzie R, et al. Cognition, ADHD Symptoms, and Functional Impairment in Children and Adolescents With Neurofibromatosis Type 1. J Atten Disord. 2019;1087054719894384. doi:10.1177/1087054719894384
Ullrich NJ, Payne JM, Walsh KS, et al. Visual spatial learning outcomes for clinical trials in neurofibromatosis type 1. Ann Clin Transl Neurol. 2020;7(2):245-249. doi:10.1002/acn3.50976

NF060016: RAD001: RAD001 for Children with NF1 and Chemotherapy-Refractory Radiographic Progressive Low-Grade Gliomas
Summary: This trial was a single-arm Phase II trial to evaluate the effectiveness of RAD001 (everolimus) in the treatment of pediatric patients with NF1 and low-grade gliomas (brain tumors and optic gliomas) that have not responded to standard therapies. In addition to evaluating the clinical response to RAD001, the safety of this drug was evaluated in this patient population.
This trial was performed by the NF Clinical Trials Consortium.
Status: Completed.
ClinicalTrials.gov Identifier: NCT01158651
Outcome: Everolimus was well-tolerated by the participants in the study. Fifteen of the 22 participants in the study experienced tumor shrinkage or no tumor growth, with 10 of those remaining free of progression during follow-up. The study indicates that everolimus should be considered for therapy in this patient population. In addition, amongst those with an optic pathway glioma, the majority had stable visual acuity after treatment with everolimus.   
Publications:
Ullrich NJ, Prabhu SP, Reddy AT, et al. A Phase II Study of Continuous Oral mTOR Inhibitor Everolimus for Recurrent, Radiographic-Progressive Neurofibromatosis Type 1-Associated Pediatric Low-Grade Glioma: A Neurofibromatosis Clinical Trials Consortium Study. Neuro Oncol. 2020;noaa071. doi:10.1093/neuonc/noaa071 PMID:32236425 Ullrich NJ, Prabhu SP, Packer RJ, et al. Visual Outcomes following everolimus targeted therapy for neurofibromatosis type 1-associated optic pathway gliomas in children. Pediatric Blood & Cancer, In Press.

NF050022: Phase II Trial of Neoadjuvant Chemotherapy in High-Grade Unresectable Malignant Peripheral Nerve Sheath Tumors.
Summary: This phase 2 clinical trial examined how well combination chemotherapy worked in treating patients with malignant peripheral nerve sheath tumors. The study assessed the clinical response rate of patients with sporadic or neurofibromatosis type 1-associated high-grade MPNST after treatment with chemotherapy. The drugs evaluated in the study were ifosfamide, doxorubicin, and etoposide.
Status: Completed
ClinicalTrials.gov Identifier: NCT00304083
Outcome: Almost 18% of the NF1 patients and 44% of the sporadic MPNST patients had a partial response; however, only 1 additional partial response was observed in the NF1 patients in the next stage. While the objective response rate was lower in the NF1 patients, the qualitative responses observed were similar. Disease stabilization was observed in most patients, regardless of NF1 sStatus.
Publications: Higham, C. S., Steinberg, S. M., Dombi, E., Perry, A., Helman, L. J., Schuetze, S. M., ... & Jones, R. L. (2017). SARC006: Phase II Trial of Chemotherapy in Sporadic and Neurofibromatosis Type 1 Associated Chemotherapy-Naive Malignant Peripheral Nerve Sheath Tumors. Sarcoma, 2017. 2017:8685638. doi: 10.1155/2017/8685638.

NF010042: Phase I and Phase II Studies of Pirfenidone in Children with Neurofibromatosis Type 1 and Progressive Plexiform Neurofibromas
Summary: This project encompassed two studies. The first was a phase 1 study to determine the pediatric dose and evaluate toxicity of pirfenidone, a novel antifibrotic agent. The second study was a phase 2 study to assess the effects of pirfenidone in children and young adults with neurofibromatosis type 1 and plexiform neurofibromas. 
Status: Completed
ClinicalTrials.gov Identifier: NCT00076102 (NCT00754780, NCT00053937)
Outcome: While pirfenidone was found to be tolerated well, no objective responses were observed, and it was determined to not be effective for treatment of plexiform neurofibromas in NF1 patients.
Publications:
Babovic-Vuksanovic, D., Widemann, B. C., Dombi, E., et al. (2007). Phase I trial of pirfenidone in children with neurofibromatosis 1 and plexiform neurofibromas. Pediatric neurology, 36(5), 293-300.
Widemann, B. C., Babovic‐Vuksanovic, D., Dombi, E., et al. (2014). Phase II trial of pirfenidone in children and young adults with neurofibromatosis type 1 and progressive plexiform neurofibromas. Pediatric Blood Cancer, 61(9), 1598-1602.

NF000027: A Phase ll Trial of the Farnesyltransferase Inhibitor R115777 in Pediatric Patients with Neurofibromatosis Type 1
Summary: This phase II clinical trial examined whether the experimental drug Tipifarnib (R115777), a farnesyltransferase inhibitor, was capable of shrinking or slowing down the growth of plexiform neurofibromas in children and young adults with neurofibromatosis type 1. Toxicities were also examined.
Status: Completed
ClinicalTrials.gov Identifier: NCT00021541
Outcome: While tipifarnib was found to be well-tolerated, time to progression was not significantly affected by treatment.
Publications:
Widemann, B. C., Dombi, E., Gillespie, A., et al. (2014). Phase 2 randomized, flexible crossover, double-blinded, placebo-controlled trial of the farnesyltransferase inhibitor tipifarnib in children and young adults with neurofibromatosis type 1 and progressive plexiform neurofibromas. Neuro-oncology, 16(5), 707-718.
Dombi E, Solomon J, Gillespie AJ, et al. 2007. NF1 plexiform neurofibroma growth rate by volumetric MRI: relationship to age and body weight. Neurology 68(9):643-647.