Natural History and Biology of Skin Neurofibromas in Neurofibromatosis Type 1

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Brief Title

Natural History and Biology of Skin Neurofibromas in Neurofibromatosis Type 1

Official Title

Natural History and Biology of Dermal Neurofibromas in Neurofibromatosis Type 1

Brief Summary

      This study will explore the growth of dermal neurofibromas (skin tumors) in patients with
      neurofibromatosis type 1 (NF1). Investigators will try to learn: 1) how fast (or slow) these
      benign tumors grow in NF1, 2) how often new tumors appear and 3) what genes are involved in
      the growth of the tumors.

      Men and women between 20 and 50 years of age diagnosed with NF1 and their biological parents
      are eligible for this study.

      Patients with NF1 are evaluated at the NIH Clinical Center with the following tests and
      procedures:

        -  Medical examination and drawing of family tree.

        -  Photos of the back, abdomen and thigh in order to count the number of skin tumors.

        -  Photos of the skin taken with a special camera (Primos camera) that takes very detailed
           pictures of a small area of skin.

        -  Photos of the skin taken with a dermatoscope, which takes very detailed pictures of a
           small area of skin under high magnification.

        -  Biopsy of at least one skin tumor and biopsy of a small piece of normal skin.

        -  Blood sample collection for genetic testing of the gene NF1 and to establish a cell
           line.

        -  Other medical tests (e.g., x-rays or MRI) if needed.

      Patients and their families will also have a genetic counseling session and an opportunity to
      ask questions about neurofibromatosis type 1.

      Patients return to the NIH after 3, 6, 12, 18 and 24 months for follow-up photographs and
      possibly blood samples.

      Biological parents of patients provide a blood sample for genetic testing.

      ...
    

Detailed Description

      This protocol results from a funded 2005 Bench-to-Bedside Award and explores the genetic
      basis of disease severity in neurofibromatosis type 1 (NF1) and the evaluation of three
      methods to measure disease progression of dermal neurofibromas. NF1 is a common multisystem
      genetic disorder associated with the development of benign and malignant tumors, primarily of
      the nervous system. NF1 is 100% penetrant and features variable expressivity and limited
      phenotype/genotype correlation. No standard treatment other than surgery exists for most
      NF1-associated tumors. Many aspects of the natural history of NF1-associated tumors are not
      fully characterized and require investigation to assess the effects of potential new
      treatments, in future clinical trials. The development of medical treatments for
      NF1-associated tumors is an important goal given their morbidity and the lack of non-surgical
      treatment options. The ability to predict the ultimate severity of disease would have a
      significant impact on the management and treatment of individuals with NF1.

      Sorafenib (BAY 43-9006) is a novel, orally bioavailable agent that targets downstream
      effectors in the Ras signaling pathway (a key dysregulated pathway in NF1). It has thus a
      strong scientific rationale for evaluation in NF1 related tumors. Dermal neurofibromas occur
      in nearly every individual with NF1, and are a significant cosmetic problem and a major cause
      of morbidity. This protocol will 1) quantify the growth of dermal neurofibromas in NF1 with 3
      different imaging modalities 2) use an innovative gene expression method to identify genetic
      modifiers of dermal neurofibroma burden, and 3) evaluate dermal neurofibromas and normal skin
      for the presence of targets of sorafenib. Successful validation of reliable quantitative
      imaging methods of dermal neurofibroma growth is a logical prerequisite to subsequent
      clinical trials with medical treatments, which will evaluate the effect of new agents on the
      growth rate of dermal neurofibromas. Identification of genetic modifiers may permit
      prediction of ultimate tumor burden. Evaluation of targets of new agents in dermal
      neurofibromas will allow for more rationale drug development for NF1. Given the paucity of
      protocols for adults with NF1 and dermal neurofibromas, this study will likely generate great
      interest among affected individuals and have rapid accrual.
    


Study Type

Observational


Primary Outcome

Quantify the growth of dermal neurofibromas in NF1 with 3 different imaging modalities.


Condition

Neurofibromatosis Type 1


Study Arms / Comparison Groups

 1
Description:  Men and women between 20 and 50 years of age diagnosed with NF1 and their biological parents are eligible for this study.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information



Estimated Enrollment

17

Start Date

June 8, 2006



Eligibility Criteria

        -INCLUSION CRITERIA - GROUP A INDIVIDUALS:

          1. Clinical diagnosis of NF1. In order to meet the diagnosis of NF1 individuals must have
             2 of the diagnostic criteria listed below:

               -  Six or more cafe-au-lait macules (greater than or equal to 0.5 cm in prepubertal
                  subjects or greater than or equal to 1.5 cm in postpubertal subjects)

               -  Freckling in the axilla or groin

               -  A tumor of the optic pathway

               -  Two or more Lisch nodules

               -  A distinctive bony lesion (dysplasia of the sphenoid bone or dysplasia or
                  thinning of long bone cortex)

               -  A plexiform neurofibroma or two or more neurofibromas

               -  A first-degree relative with NF1 by the above criteria

             We may request the medical records of potential enrollees for our review. Ideally,
             individuals will have been evaluated by a geneticist and a definitive diagnosis made.
             However given the unique, familial (and often unmistakable features) of NF1 it is
             likely the diagnosis can be reliably made by a non-geneticist.

          2. Age at study entry: 20- 50 years (inclusive)

          3. Identification of a physician who will be responsible for follow-up care, if needed

          4. Ability and willingness to travel to the NIH Clinical Center or University of Alabama
             at Birmingham Alabama for multiple evaluations

          5. Ability and willingness of both biologic parents to provide a blood (or saliva) sample

          6. Must have at least one dermal neurofibroma amenable to excisional biopsy. Preferably
             the neurofibroma will be on the thorax or abdomen and be at least the size of a pencil
             eraser.

        INCLUSION CRITERIA - GROUP B INDIVIDUALS:

          1. Biological parents (either affected or unaffected) of Group A individuals

          2. Willingness to donate a blood or saliva sample for genotyping

          3. Willing to undergo a brief skin and eye exam at the NIH CC (to rule out NF1) or
             University of Alabama, if accompanying adult children

        EXCLUSION CRITERIA - GROUP A INDIVIDUALS

        MEDICAL INCLUSIONS:

          1. Any history of administration (or current use) of radiation therapy, chemotherapeutic
             agents or biologic agents (experimental or not) that resulted in a documented
             significant change in dermal neurofibroma tumor burden or growth.

          2. Patients with probable segmental or mosaic NF1 will be excluded from study
             participation and medical records may be reviewed prior to enrollment for this
             determination.

          3. A history of administration of medications within 6 months of study entry that might
             reasonably be expected to alter the natural history of tumor growth (examples include
             pirfenidone, interferon, farnesyl transferase inhibitor (FTI), MTX/VBL, thalidomide,
             growth hormone) or cause significant changes in gene expression profile.

          4. Known or suspected untreated bleeding diathesis or platelet disorder that would
             preclude safe and successful dermal neurofibroma and skin biopsy. Patients prescribed
             aspirin or other known/suspected agent that interferes with platelet function may also
             be excluded if they cannot safely discontinue its use a week ahead of the biopsy.

          5. Clinically significant unrelated systemic illness, such as serious infection, hepatic,
             renal or other organ dysfunction, which in the judgment of the principal investigator
             or associate investigator would compromise the patient's ability to participate in the
             study procedures.

          6. Inability or unwillingness to tolerate the dermal neurofibroma excision and skin
             biopsy or blood draw.

        VULNERABLE POPULATIONS EXCLUSIONS

        1) Cognitive delay to the extent that conscious sedation is required to obtain the dermal
        neurofibroma excision and skin biopsy.

        OTHER EXCLUSIONS

          1. Biologic parents unable or unwilling to provide a blood (or saliva) sample.

          2. Inability to travel to the NIH or to The University of Alabama at Birmingham, AL

          3. Individuals refusing an excisional tumor or skin biopsy.
      

Gender

All

Ages

20 Years - 99 Years

Accepts Healthy Volunteers

No

Contacts

Douglas R Stewart, M.D., , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT00314119

Organization ID

060134

Secondary IDs

06-C-0134

Responsible Party

Sponsor

Study Sponsor

National Cancer Institute (NCI)


Study Sponsor

Douglas R Stewart, M.D., Principal Investigator, National Cancer Institute (NCI)


Verification Date

October 4, 2021