DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Overview | Consortium History | Management and Oversight | Research Site Details | Approved Trial Details | NFRP Clinical Trials

The Neurofibromatosis Clinical Trials Consortium (NFCTC, http://www.uab.edu/nfconsortium) was established by the Department of Defense Neurofibromatosis Research Program (NFRP) to develop and perform clinical trials for the treatment of neurofibromatosis (NF) complications in children and adults. The Consortium is composed of fifteen clinical sites, ten collaborating affiliate sites, and an Operations Center at the University of Alabama at Birmingham under the direction of Dr. Bruce Korf. The purpose of the Operations Center is to provide administrative, data management, and statistical support to the NFCTC. Each of the clinical and collaborating sites has expertise in the treatment and management of NF and an established patient population available for clinical trials.


Updated November 2020

 

Approved NFCTC Clinical Trials (FY06 NFRP Award)

(1) STOPN: Sirolimus for the Treatment of NF1-Related Plexiform Neurofibromas
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.

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.

(2) STARS: Lovastatin for the Treatment of Learning Disabilities in Children with NF1
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.  

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


(3) RAD001: RAD001 for Children with NF1 and Chemotherapy-Refractory Radiographic Progressive Low-Grade Gliomas
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. 

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.

(4) RAD001 in Combination with Bevacizumab for Patients with Sporadic and NF1-Related Refractory MPNST
This Phase II clinical trial evaluated the use of RAD001 (everolimus) in combination with bevacizumab for patients with sporadic and NF1-related refractory MPNST. The primary goals of this trial were to evaluate the clinical benefit of treatment of chemotherapy refractory MPNST with RAD001 in combination with bevacizumab, and assess the toxicity and safety of this drug combination. This study was performed in collaboration with the Sarcoma Alliance for Research through Collaboration (SARC) and was funded by award NF093105.

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.

 

Approved NFCTC Clinical Trials (FY11 NFRP Award)

(1) Bevacizumab for NF2-Related Progressive Vestibular Schwannomas
This study is an open-label, Phase II clinical trial to evaluate bevacizumab in children and young adults with NF2 and progressive vestibular schwannomas that are poor candidates for standard treatment with surgery or radiation. The primary objective of this study is to determine the hearing response rate after beginning treatment with bevacizumab for symptomatic vestibular schwannomas in children and young adults with NF2.

Status: Active, not recruiting

ClinicalTrials.gov Identifier: NCT01767792

Outcome: High-dose and standard-dose bevacizumab seem to be similarly effective for treatment of patients with NF2 with hearing loss. Unlike adults, pediatric participants did not experience tumor shrinkage. However, adult and pediatric cohorts reported similar improvement in QOL. Treatments incorporating bevacizumab should be considered for children with NF2.

Publications:

Plotkin SR, Duda DG, Muzikansky A, Karajannis MA, Allen J, Blakeley J, Rosser T, Campian JL, Clapp DW, Fisher MJ, Tonsgard J, Ullrich NJ, Thomas C, Cutter G, Korf B, Packer R.  Multicenter prospective phase II and biomarker study of high dose bevacizumab as induction therapy in NF 2 patients with progressive vestibular schwannoma: differential response in pediatric versus adult patients. J Clin Oncol, 37(35):3446-3454, 2019.  PMID:31626572

(2) Cabozantinib (XL184) for NF1-Related Plexiform Neurofibromas
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 being amended to add a separate stratum of 19 evaluable pediatric patients (3-15 years of age).

Status: Recruiting pediatric arm

ClinicalTrials.gov Identifier: NCT02101736

Outcome: Cabozantinib had a partial response rate of 42% in the adolescent/adult stratum.


(3) PD-0325901 (Mirdametinib) for NF1-Related Plexiform Neurofibromas
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. 

Status: Completed

ClinicalTrials.gov Identifier: NCT02096471

Outcome: Mirdametinib had a partial response rate of 42%

 

(4) INFUSE Bone Graft for Treatment of NF1-Related Tibial Pseudarthrosis (TPA)

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. 

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.

(5) Phase I/II Trial of Ganetespib in Combination with Sirolimus for Patients with Refractory MPNST

This Phase I/II trial evaluated the use of the combination of ganetespib and sirolimus in patients with unresectable or metastatic sporadic or NF1 associated MPNST. The primary goals of this trial were to determine the dose and evaluate the safety and tolerability of the drug combination, as well as determine the clinical benefit in patients. This study was performed in collaboration with SARC and was funded under award NF120087.

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

(6) Phase I/II Study of Binimetinib (MEK162) for Children with Low-Grade Gliomas and Other Ras/Raf/MAP Pathway Activated Tumors

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. The NFCTC sites are collaborating with non-consortium sites for the NF1-specific cohort in Phase II of the study.

Status: Recruiting

ClinicalTrials.gov Identifier: NCT02285439

(7) Phase II Trial of Selumetinib in Combination with Sirolimus for Patients with Refractory MPNST

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, sirolimus, 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 was performed in collaboration with the Sarcoma Alliance for Research through Collaboration (SARC) and was funded by award NF150092.

Status:  Recruiting

ClinicalTrials.gov Identifier: NCT03433183

 

Approved NFCTC Clinical Trials (FY16 NFRP Award)

 (1) A Phase II Study of Binimetinib in Children and Adults with NF1 associated Plexiform Neurofibromas

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 functional outcomes of treatment.  This study is being performed in collaboration with PNOC.

Status: Recruiting

ClinicalTrials.gov Identifier: NCT03231306

(2) Open-label, Phase 2 Clinical Trial of Crizotinib for Children and Adults with Neurofibromatosis Type 2 and Progressive Vestibular Schwannomas

This Phase 2 trial will determine the response rate to crizotinib in children and adult NF2 patients with vestibular schwannomas, and determine safety and tolerability of treatment in these cohorts.

Status: Recruiting

ClinicalTrials.gov Identifier: NCT04283669

(3) Phase II Trial of Poly-ICLC for Progressive, Previously Treated Low-Grade Gliomas in Children and Young Adults with Neurofibromatosis Type 1

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.

Status: Not yet recruiting

ClinicalTrials.gov Identifier: NCT04544007

(4) 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

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.

Status: Not yet recruiting

ClinicalTrials.gov Identifier: TBA

Last updated Monday, January 3, 2022