Symptoms and General Pathology

All Conditions

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Nervous System Diseases

Diseases and Abnormalities at or Before Birth

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Sclerosis

Tuberous Sclerosis

Neurofibromatoses

Neurofibromatosis 1

Neurofibroma

Nerve Sheath Neoplasms

Neoplasms, Nerve Tissue

Neoplasms by Histologic Type

Syndrome

Neoplastic Syndromes, Hereditary

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Neurodegenerative Diseases

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Hamartoma

Neoplasms, Multiple Primary

Congenital Abnormalities

Malformations of Cortical Development

Nervous System Malformations

Tuberous Sclerosis Complex

Neurofibromatosis

Neurofibromatosis Type 1

Monozygotic twin pairs with genetically confirmed Neurofibromatosis type I

Monozygotic twin pairs with genetically confirmed Tuberous Sclerosis Complex

Ype Elgersma, Prof.

André Rietman, MSc.

Both Neurofibromatosis type 1 (NF1) and Tuberous Sclerosis Complex (TSC) are highly heterogeneous diseases. Cognitive features seem to vary widely even between family members carrying the same mutation. This phenotypic variability is not well understood, but is generally assumed to be caused by modifier genes which regulate the affected pathways. However, recent studies brought forward an alternative explanation for the phenotypic variability. Post-mortem studies showed that second hit mutations causing loss of the second ('healthy') allele are more widespread than previously believed. These loss of heterozygosity (LOH) mutations cause bi-allelic loss of the disease-linked gene and are known to cause the gross of somatic features in both diseases (like neurofibromas and hamartomas). Hence, it could be the stochastic occurrence of second-hit mutations in the brain are the cause of the variable cognitive phenotypes.

To investigate to what extent these LOH mutations in the brain contribute to the phenotype and to what extent this variation is due to genetic modifiers factors is unknown. The investigators therefore propose to elucidate this variability by comparing the correlation of cognitive features of monozygotic twins with NF1 or TSC to healthy twins in the population. If modifier genes are the cause of the variability of cognitive features in NF1 and TSC the investigators expect that the variability in cognitive tests in monozygotic twins is the same as monozygotic twins in the healthy population. However, if the variability is caused by the occurrence of LOH mutations, the investigators expect to have a lower correlation in our monozygotic patients compared to the healthy twins.

The Cognitive Variability in NF1 and TSC Monozygotic Twins

The Cognitive Variability in Neurofibromatosis Type I and Tuberous Sclerosis Complex Monozygotic Twins

Depending on age and cognitive development: Bayley Scales of Infant Development (BSID-III) or Wechsler Scale of Intelligence (Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III) or Wechsler Intelligence Scale for Children (WISC-III) or Wechsler Adult Intelligence Scale (WAIS-III) )

Child Behaviour Checklist or Adult Behaviour Checklist (CBCL/ABCL)

Erasmus Medical Center

Prof. Y. Elgersma

Neurofibroma, Plexiform

Oculocerebral Syndrome With Hypopigmentation

Antineoplastic Agents

All Drugs and Chemicals

Tipifarnib

Patients receive oral R115777 (Tipifarnib) first followed by placebo. 200 mg/m\^2/dose BSA every 12 hours by mouth (po)on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Patients receive oral placebo first followed by R115777 (Tipifarnib). 200 mg/m\^2/dose BSA every 12 hours by mouth (po)every 12 hours on days 1-21. Courses repeat as in arm I.

Given orally, 200 mg/m\^2/dose BSA every 12 hours by mouth (po) daily x 21 days, Course is every 28 days

tipifarnib

Patients receive oral placebo every 12 hours on days 1-21. Courses repeat as in arm I.

placebo

Brigitte Widemann, M.D.

This study will examine whether the experimental drug R115777 (Tipifarnib) can shrink or slow the growth of plexiform neurofibromas in children and young adults with neurofibromatosis type 1 (NF1) and determine what side effects are related to treatment. Plexiform tumors arise from nerves; the only effective treatment is surgical removal. Often, however, not all the tumors can be removed, because of their number or location.

Patients with NF1 have a reduced amount of the protein neurofibromin. Neurofibromin is thought to help control the activity of another protein, called ras, which regulates cell growth. Too little neurofibromin, therefore, may allow for uncontrolled cell growth and tumor formation. R115777 interferes with the function of the ras and other proteins. In test tube and animal studies, R115777 has blocked the growth of cancer cells. This study will examine whether the drug is effective against plexiform tumors.

Patients with NF1 and progressive plexiform neurofibromas between 3 and 25 years of age may be eligible for this study. Patients whose tumors can be successfully removed surgically may not participate in this study. Candidates are screened with a medical history and physical and eye examinations, blood and urine tests, and magnetic resonance imaging (MRI). Photographs are taken of tumors visible on the body surface.

Study participants are randomly assigned to receive either R115777 or placebo (an inactive substance). They take R115777 or placebo tablets every 12 hours for 21 days, followed by a 7-day rest period. This constitutes one 28-day treatment cycle. Treatment continues for as long as the tumors remain stable or shrink and side effects are tolerable. The treatment is switched (for example, from placebo to R115777) or stopped if the tumors grow or if side effects become unacceptable. Patients (or their parents) keep a record of side effects.

For the first 3 treatment cycles, patients have a physical examination and blood tests every other week. Blood tests are also done before starting treatment, and at one time point after at least 14 days of treatment to measure the effect of R115777 on proteins in blood cells. A blood sample is obtained before starting treatment and before cycles 4, 7 and 10 and then after every 6 cycles to measure the level of a substance called nerve growth factor. The analysis of nerve growth factor is used to determine if it can predict which patients might be at risk of developing side effects from R115777.

R115777 (Tipifarnib) is a farnesyltransferase inhibitor that blocks the post-translational isoprenylation of ras and other farnesylated proteins. The ras proteins are integral in cell signaling pathways, and farnesylation is essential for the function of both mutant and non-mutant ras proteins. Patients with neurofibromatosis type 1 (NF1) have an increased risk of developing tumors of the central and peripheral nervous system, and there are no standard treatment options, other than surgery, available for these tumors. Neurofibromin, which is the product of the NF1 gene, contains a domain with significant homology to ras GTPase-activating proteins (GAP). Although NF1 patients lack germline ras mutations, the decreased levels of neurofibromin have been shown to be associated with a constitutively activated ras-GTP status. Thus, upstream inhibition of ras farnesylation may inhibit growth of tumors in NF1 patients. A randomized, cross-over, double-blinded, placebo-controlled pediatric phase II trial of oral R115777 will be performed in children and young adults with NF1, who have progressive, plexiform neurofibroma(s) to determine the effect of this novel anticancer drug on the rate of growth of neurofibromas. The endpoint of the trial is time to progression. R115777 will be administered orally at a dose of 200 mg/m(2) twice daily for cycles of 21 days followed by a 7 day rest period based on the results of our prior pediatric phase I trial.

R115777 to Treat Children With Neurofibromatosis Type 1 and Progressive Plexiform Neurofibromas

A Phase II Randomized, Cross-Over, Double-Blinded, Placebo-Controlled Trial of the Farnesyltransferase Inhibitor R115777 in Pediatric Patients With Neurofibromatosis Type I and Progressive Plexiform Neurofibromas

Median time to progression is defined as ≥20% increase in diameter based on volumetric analysis using the 1-dimensional RECIST method. Start of phase A or phase B to time of progression.

Median time to progression is defined as ≥25% increase in area based on volumetric analysis using the 2-dimensional WHO solid tumor method.

Median time to progression is defined as a greater than or equal to 20% increase increase in the sum of the volume of all index lesions based on volumetric analysis utilizing magnetic resonance imaging (MRI).Start of phase A or phase B to time of progression.

Here are the number of participants with adverse events. For the detailed list of adverse events see the adverse event module.

Parents of participants aged 6-18 years completed the Impact of Pediatric Illness (IPI) Scale about their child prior to the start of cycles 1, 4, 7, and 10 and then after every 6 cycles. The IPI Scale assesses QOL in 4 domains: adaptive behavior, emotional functioning, medical/physical status, and cognitive functioning. Responses to the 43 items are made on a 5-point Likert scale (1-5) ranging from "not al all" to "a lot". Higher mean scores indicate better QOL. Parent total scores for participants on placebo were compared with scores from participants receiving tipifarnib on phase A.

National Cancer Institute (NCI)

Principal Investigator

Adverse event data is in compliance with DSMB(Data Safety Monitoring Board).

Patients receive oral tipifarnib every 12 hours on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Patients receive oral placebo every 12 hours on days 1-21. Courses repeat as in arm I.

Tipifarnib & Placebo

Patients receive oral tipifarnib every 12 hours on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. These are the patients that started on tipifarnib only. This number does not reflect the total amount of patients that crossed over to placebo.

Phase A-Tipifarnib

Patients receive oral placebo every 12 hours on days 1-21. Courses repeat as in arm I. These are the patients that started on placebo only. This number does not reflect the total amount of patients that crossed over to tipifarnib. Two of the 31 patients were deemed ineligible, thus 29 started placebo.

Phase B - Placebo

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

American Indian or Alaska Native

Asian

Native Hawaiian or Other Pacific Islander

Black or African American

White

More than one race

Unknown or Not Reported

Hispanic

Race/Ethnicity, Customized

United States

Region of Enrollment

Placebo

Phase A - Tipifarnib

phase A - 62 started and 2 were ineligible = 60 phase B - 43 started

Median Time to Progression

Adverse event data is in compliance with DSMB (Data Safety Monitoring Board).

Number of Participants With Adverse Events

Baseline

Pre cycle 4

Patients receive oral tipifarnib every 12 hours on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Participants analyzed includes only those whose parents completed the IPI Scale at baseline and pre cycle 4 on phase A.

Quality of Life (QOL)

Phase B - Placebo group is not shown because this outcome measure only applies to the Phase A - Tipifarnib group.

Median Time to Progression Using the Conventional 1-Dimensional Response Evaluation Criteria in Solid Tumors (RECIST) Method

Phase B- Placebo group is not shown because this outcome measure only applies to the Phase A - Tipifarnib group.

Median Time to Progression Using the 2-Dimensional World Health Organization (WHO) Solid Tumor Method

Patients receive oral tipifarnib every 12 hours on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.Patients receive tipifarnib ONLY in the first treatment until they progress to the second treatment/crossover to receive placebo.

Phase A -Tipifarnib

Patients receive oral placebo every 12 hours on days 1-21. Courses repeat as in arm I.Patients receive placebo ONLY in the first treatment until they progress to the second treatment/crossover to receive tipifarnib.

Period 1-First Treatment

Period 2-crossover

Amino Acids

Angiogenesis Inhibitors

Tyrosine Kinase Inhibitors

Sorafenib

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

Nexavar (BAY 43-9006) (Sorafenib)

Toxicity, Pharmacokinetics

Pharmacodynamics

Radiographic Evaluation

QOL assessment, Neuropsychological

Bony Toxicity

Brigitte C Widemann, M.D.

Background:

Patients with neurofibromatosis type 1 are at increased risk of developing tumors called plexiform neurofibromas (PN) that arise from nerves. These tumors are usually non-cancerous, but they can cause serious medical problems.

Sorafenib was recently approved to treat patients with kidney cancer and is now being tested in children with cancer. It affects several pathways thought to be important for the development and growth of PN and may therefore shrink these tumors or slow their growth.

Objectives:

To determine the highest dose of sorafenib that can safely be given to children and young adults with PN.

To identify the side effects of sorafenib in these patients.

To study how the body handles sorafenib by measuring the amount of drug in the bloodstream over time

To determine how the drug affects blood flow and blood cells and proteins.

To determine if sorafenib can shrink or slow the growth of PN.

To determine the effects of sorafenib on learning, attention, memory, and quality of life.

Eligibility:

Patients between 3 and 18 years of age with NF1 who have inoperable PN that can cause significant disability.

Design:

Patients take sorafenib tablets twice a day in 28-day treatment cycles. They may continue treatment until their tumor grows or they develop unacceptable drug side effects. In this dose escalation study, the dosage is increased with every 3 to 6 children who are enrolled until the highest safe dose is determined. In any case, the dose will not exceed that used in children with cancer.

Patients are monitored regularly with physical examinations, blood and urine tests, MRI scans and quality-of-life questionnaires.

Patients whose bones are still growing have periodic x-rays of the hips and lower legs to monitor for possible changes in the structure of growing bones.

Patients have periodic tests of learning and memory before starting treatment and before cycles 4, 12, 18 and 24.

Patients have pharmacokinetic studies to examine how the body handles sorafenib. blood samples are drawn before the first dose of sorafenib and then at 30 minutes, 1 hour, 2 hours, 3 hours, 5 hours, 8 hours, 10 to 12 hours, 24 hours and 30 to 36 hours following the first dose.

...

Background:

* Patients with Neurofibromatosis 1 (NF1) have an increased risk of developing tumors of the central and peripheral nervous system, including plexiform neurofibromas (PN), which are benign nerve sheath tumors that are among the most debilitating complications of NF1. Plexiform neurofibromas may be congenital and appear to have the fastest growth rate in young children. There are no standard treatment options for PN other than surgery, which is often difficult due to the extensive growth and invasion of surrounding tissues.
* Plexiform neurofibromas are composed of neoplastic Schwann cells that lack NF1 gene expression resulting in upregulation of Ras, which initiates several signaling cascades regulating cell proliferation. In addition, PN over express epidermal and platelet derived growth factor receptor and vascular endothelial growth factors, which may promote angiogenesis.
* Sorafenib, a novel orally bioavailable, bi-aryl urea, is a potent inhibitor of raf kinase and a number of receptor tyrosine kinases, which is currently undergoing evaluation in adult cancers, and may mediate anti-tumor effects in PN by several mechanisms.

Objectives:

* To determine the maximum tolerated dose (MTD) of oral sorafenib administered daily to pediatric patients with NF1 and inoperable PN.
* To define the acute and chronic toxicities, pharmacokinetics, and pharmacodynamics of sorafenib.
* To evaluate for potential bone toxicities of sorafenib such as growth plate expansion and growth retardation using automated volumetric MRI analysis of growth plates, multiple measures for height and growth, dual-energy x-ray absorptiometry to evaluate bone mineral density, and laboratory measurements for evaluation of bone turnover and metabolism.
* To determine the effect of sorafenib on the growth rate of PN, quality of life, and cognitive function while on treatment with sorafenib.

Eligibility:

- Pediatric Patients (3-18 years) with NF1 and inoperable measurable PN that have the potential to cause significant morbidity.

Design:

* Sorafenib will be administered orally BID on a continuous dosing schedule (28 days = 1 treatment cycle). Limited dose escalations will be performed to define the MTD based on tolerability of sorafenib during the first three treatment cycles.
* Disease status will be evaluated using volumetric MRI analysis at regular intervals.
* The plasma pharmacokinetics and pharmacodynamics of sorafenib will be evaluated.
* Cognitive function and quality of life outcomes will also be assessed in a pilot fashion to define measures to be used in subsequent phase II trials.

Sorafenib to Treat Children and Young Adults With Neurofibromatosis Type 1 and Inoperable Plexiform Neurofibromas

Phase I Trial of the Raf Kinase and Receptor Tyrosine Kinase Inhibitor Sorafenib (BAY 43-9006, Nexavar) in Children and Young Adults With Neurofibromatosis Type 1 and Inoperable Plexiform Neurofibromas

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
The Cognitive Variability in NF1 and TSC Monozygotic Twins	NCT02436746	Neurofibromatos... Tuberous Sclero...		-	Erasmus Medical Center
R115777 to Treat Children With Neurofibromatosis Type 1 and Progressive Plexiform Neurofibromas	NCT00021541	Neurofibroma, P... Neurofibromatos...	tipifarnib placebo	3 Years - 25 Years	National Institutes of Health Clinical Center (CC)
Sorafenib to Treat Children and Young Adults With Neurofibromatosis Type 1 and Inoperable Plexiform Neurofibromas	NCT00727233	Neurofibromatos... Plexiform Neuro...	Nexavar (BAY 43... Toxicity, Pharm... Pharmacodynamic... Radiographic Ev... QOL assessment,... Bony Toxicity	3 Years - 18 Years	National Institutes of Health Clinical Center (CC)
Sorafenib to Treat Children and Young Adults With Neurofibromatosis Type 1 and Inoperable Plexiform Neurofibromas	NCT00727233	Neurofibromatos... Plexiform Neuro...	Nexavar (BAY 43... Toxicity, Pharm... Pharmacodynamic... Radiographic Ev... QOL assessment,... Bony Toxicity	3 Years - 18 Years	National Institutes of Health Clinical Center (CC)

Spots Global Cancer Trial Database for neurofibromatosis type i