Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT05677594 |
| Other study ID # |
IRB00268132 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
July 1, 2021 |
| Est. completion date |
June 30, 2026 |
Study information
| Verified date |
December 2023 |
| Source |
Johns Hopkins University |
| Contact |
Shivani Ahlawat, PhD |
| Phone |
(443)287-2917 |
| Email |
sahlawa1[@]jhmi.edu |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
The goal of this prospective observational study is to learn about the utility of imaging and
clinical features in patients with Neurofibromatosis type 1 categorized as high risk for the
development of malignant peripheral nerve sheath tumors.
The main objectives are:
- To evaluate the prevalence, multi-parametric imaging features of distinct nodular
lesions ("DNLs") and natural history in people with NF1 with clinical and genetic
features deemed "high-risk" for malignancy.
- To assess the relationship between individual clinical, genetic and imaging factors that
have been suggested to be risk factors for malignant peripheral nerve sheath tumors
(MPNST) and the confirmation of atypical neurofibromas (aNF)/ atypical neurofibromatous
neoplasm of unknown biologic potential (ANNUBP) or MPNST on pathology.
In this research study, the participants will be asked to undergo whole body MRI, provide
blood sample and clinical evaluation annually.
Description:
Patients with the autosomal dominant genetic tumor predisposition syndrome neurofibromatosis
type 1 (NF1) have an increased risk of developing both benign and malignant neoplasms
throughout life. The most common tumors are peripheral nerve sheath tumors (PNSTs) such as
plexiform neurofibromas (pNFs). pNFs are multicellular primary tumors of the peripheral nerve
that are histologically benign but often cause significant neurologic morbidity due to
involvement of critical nerves. However, the greatest fear is the development of malignant
peripheral nerve sheath tumors (MPNSTs). MPNST is an aggressive, treatment resistant sarcoma
with a 5-year survival rate of only 15-50% and is the leading cause of death in NF1 patients,
especially in those under 50 years of age. An estimated 50% of NF1 patients develop pNFs and
the lifetime risk of developing MPNST is 8-13%. The only possible cure for MPNST is complete
resection with wide negative margins. This is only feasible if the lesion can be clearly
defined and removed without life-threatening morbidity. A major challenge to clearly
differentiating between MPNSTs and pNFs is that the vast majority of MPNSTs arise within
pNFs. This intimate association makes it hard to distinguish MPNST clinically,
radiologically, and pathologically from surrounding benign tissue, thus leading to delayed
diagnosis until after symptoms (such as severe pain and loss of neurologic function) have
emerged and the chance for cure is greatly diminished or lost. A great deal of time, resource
and worry from patients, the patients loved ones and medical providers is dedicated to
detecting MPNSTs early at great expense and unclear benefit.
Existing clinical factors and imaging markers of MPNST do not accurately identify patients at
risk of developing either MPNST or the patients precursor tumors. Retrospective studies from
various centers have suggested several clinical factors associated with the development of
MPNST including: number and volume of internal PNSTs, presence of subcutaneous neurofibromas,
younger age, presence of pain, microdeletion of the NF1 gene, family and personal history of
MPNST, and presence of atypical neurofibromas (aNF)/ANNUBPs. None of the imaging diagnostic
tools studied in NF1 patients have been prospectively assessed to identify aNF/ANNUBP.
Natural history studies and clinical trials using MRI have identified nodular target lesions
within pre-existing pNFs on standard anatomic MRI as potential precursor lesions to MPNST
that may represent aNF/ANNUBP. These lesions have been coined "distinct nodular lesions"
(DNLs) and described as greater than 3 cm in largest diameter, well demarcated, distinct from
the patients underlying tissue (i.e. the surrounding pNF), and lacking the target sign
typical of benign pNFs (defined as a central hypointense region on T2-weighted images). In a
recent retrospective review of 76 histologically confirmed aNFs, all aNFs fulfilled the
criteria for DNLs on MRI and 50 of 56 aNFs with available 18F-2-fluoro-2-deoxy-D-glucose
fluorodeoxyglucose positron emission testing computed tomography (18F-FDG PET/CT)
demonstrated elevated maximum standardized uptake value (SUVmax) (>3.5), supporting the
hypothesis that DNLs may be the imaging correlate of pre-malignant tumors.
The investigators hypothesize that NF1 patients with aNF/ANNUBP represent a subset of
individuals who have not developed cancer yet but who are at high risk of developing a
malignancy, possibly in the short term. the investigators further hypothesize that a subset
of DNLs are imaging correlates of aNF/ANNUBP that can be characterized with advanced imaging
techniques such as Diffusion weighted imaging (DWI) and 18F-FDG PET/CT. Imaging
identification of ANNUBPs and characterization of DNLs will enable early diagnosis and
management of lesions destined to become malignant, thereby potentially dramatically
improving outcomes for People with NF1 at highest risk for development of MPNST.
Defining the prevalence of DNL in a population clinically to be at high-risk for future
development of malignancy, the behavior of DNLs over time and the multi-parametric imaging
features of DNLs will allow the generation of imaging markers to: (1) identify the specific
lesions at highest risk for malignancy in a sea of lesions, (2) understand the biologic
significance of these lesions and, (3) create the data about the optimal imaging marker for
these lesions to inform evidence based guidelines for imaging in people with NF1.
2. Objectives (include all primary and secondary objectives):
- To evaluate the prevalence, multi-parametric imaging features of distinct nodular
lesions "DNLs" and natural history in people with NF1 with clinical and genetic features
deemed "high-risk" for malignancy.
- To assess the relationship between individual clinical, genetic and imaging factors that
have been suggested to be risk factors for MPNST and the confirmation of aNF/ANNUBP or
MPNST on pathology.
