Neurofibromatosis Type IPhase 1NCT00727233
Sorafenib to Treat Children and Young Adults With Neurofibromatosis Type 1 and Inoperable Plexiform Neurofibromas
A Phase 1 study testing Nexavar (BAY 43-9006) (Sorafenib), Toxicity, Pharmacokinetics and Pharmacodynamics in people with Neurofibromatosis Type I and Plexiform Neurofibroma, run by National Cancer Institute (NCI) at 2 sites in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 3 to 18 years
- Conditions the study is for
- Neurofibromatosis Type I, Plexiform Neurofibroma
- What is being tested?
- Nexavar (BAY 43-9006) (Sorafenib), Toxicity, Pharmacokinetics and Pharmacodynamics
- How many people
- 9 participants
- Where
- 2 sitesUnited States
- Study dates
- 8 Jul 2008to 16 Jun 2011
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 3 to 18 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
None listed.
Who cannot join
- Pregnant or breast-feeding females are excluded due to risks of fetal and teratogenic adverse events as seen animal studies. Pregnancy tests must be obtained prior to enrollment on this study in girls, age 9 or older. Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method. Abstinence is an acceptable method of birth control.
- Sorafenib is predominantly metabolized via CYP3A4, and patients who take cytochrome P450 enzyme-inducing antiepileptic drugs (phenytoin, carbamazepine or Phenobarbital), rifampin, grape fruit, or St. Johns Wort will not be eligible for the trial. Patients must have discontinued these medications at least 7 days prior to enrollment of trial.
- Patients who have had major surgery within the past 3 months are excluded. Patients having minor surgery (i.e., central line placement) within the past 2 weeks are excluded.
- An investigational agent within the past 30 days.
- Ongoing radiation therapy, chemotherapy, hormonal therapy directed at the tumor, immunotherapy, or biologic therapy.
- Clinically significant uncontrolled unrelated systemic illness such as serious infections or significant cardiac, pulmonary, hepatic or other organ dysfunction.
Show all 16Show fewer
- Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study.
- Inability to swallow tablets, since tablets cannot be crushed or broken.
- Inability to undergo MRI and/or contraindication for MRI examinations following the MRI protocol (Appendix III). Prosthesis or orthopedic or dental braces that would interfere with volumetric analysis of target PN on MRI.
- Prior treatment with sorafenib.
- Evidence of an optic glioma, malignant glioma, malignant peripheral nerve sheath tumor, or other cancer requiring treatment with chemotherapy or radiation therapy.
- Patients with a history of arterial or venous thrombosis with in the prior 3 months.
- Patients who experienced significant hemorrhage (hemoptysis, melena, or hematemesis) within the past 2 weeks or with a history of bleeding diathesis.
- Patients with a history of NF1 related cerebral vascular anomaly.
- Patients requiring systemic full dose anticoagulation with systemic thrombolytics, heparin, coumadin, or low molecular weight heparin or other anticoagulants for therapy of active thrombosis within the prior 3 months.
- Patients on anti-hypertensive medications and patients with baseline hypertension (greater than or equal to 95th % for age and gender, see Appendix II) (treated or untreated).
Trial locations and contacts
2 sites in 1 country.
United States2 sites
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
Children's Hospital of Alabama
Birmingham, Alabama, 35233
About this study
Official title: 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
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.
Read more
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.
...
Read the detailed description
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.
- Conditions
- Neurofibromatosis Type I, Plexiform Neurofibroma
- Being tested
- Nexavar (BAY 43-9006) (Sorafenib), Toxicity, Pharmacokinetics, Pharmacodynamics, Radiographic Evaluation, QOL assessment, Neuropsychological
- Keywords
- Neuroblastosis Type I, Plexiform Neurofibromas, Angiogenesis Inhibitor, Kinase Inhibitor, Neurofibromatosis Type 1, NF1, Plexiform Neurofibroma
- Medical subject headings
- Neurofibromatosis 1, Neurofibroma, Plexiform
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Nexavar (BAY 43-9006) (Sorafenib)Drug
Toxicity, PharmacokineticsDrug
PharmacodynamicsDrug
Radiographic EvaluationDrug
QOL assessment, NeuropsychologicalDrug
Bony ToxicityDrug
What is being measured
The primary outcome is the main question the study is designed to answer.
Maximum tolerated dose, chronic toxicity, pharmacokinetics and pharmacodynamics.
Secondary outcomes (1)
3D MRI of plexiform neurofibromas, pharmacodynamics, cognitive function.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 Aug 2008 (estimated)
- Study start8 Jul 2008
- Primary completion16 Jun 2011
- Study completion16 Jun 2011
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Neurofibromatosis Type IStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 9 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Investigators
- Brigitte C Widemann, M.D., Principal investigator, National Cancer Institute (NCI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00727233
- Sponsor's protocol ID
- 080180
- Other IDs
- 08-C-0180
- Status last verified
- 4 May 2012
- First submitted
- 31 Jul 2008
- Last updated
- 12 Dec 2019
- Results posted
- No
Publications
Widemann BC, Salzer WL, Arceci RJ, Blaney SM, Fox E, End D, Gillespie A, Whitcomb P, Palumbo JS, Pitney A, Jayaprakash N, Zannikos P, Balis FM. Phase I trial and pharmacokinetic study of the farnesyltransferase inhibitor tipifarnib in children with refractory solid tumors or neurofibromatosis type I and plexiform neurofibromas. J Clin Oncol. 2006 Jan 20;24(3):507-16. doi: 10.1200/JCO.2005.03.8638.
PubMed 16421428Korf BR. Plexiform neurofibromas. Am J Med Genet. 1999 Mar 26;89(1):31-7. doi: 10.1002/(sici)1096-8628(19990326)89:13.0.co;2-w.
PubMed 10469434Friedman JM. Neurofibromatosis 1: clinical manifestations and diagnostic criteria. J Child Neurol. 2002 Aug;17(8):548-54; discussion 571-2, 646-51. doi: 10.1177/088307380201700802.
PubMed 12403552
Study at a glance
From the registry record, last updated by the sponsor on 12 Dec 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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
- ClinicalTrials.gov ID
- NCT00727233
- Acronym / sponsor ID
- 080180
- Conditions
- Neurofibromatosis Type I, Plexiform Neurofibroma
- Keywords
- Neuroblastosis Type I, Plexiform Neurofibromas, Angiogenesis Inhibitor, Kinase Inhibitor, Neurofibromatosis Type 1, NF1, Plexiform Neurofibroma
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 9 participants (actual)
- Lead sponsor
- National Cancer Institute (NCI)US National Institutes of Health
- Study start
- 8 Jul 2008
- Primary completion
- 16 Jun 2011 (actual)
- Study completion
- 16 Jun 2011 (actual)
- First posted
- 1 Aug 2008 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
...
Detailed description
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
Who may qualify
- Ages
- 3 to 18 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (0 listed)
Key exclusion criteria (16 listed)
- Pregnant or breast-feeding females are excluded due to risks of fetal and teratogenic adverse events as seen animal studies. Pregnancy tests must be obtained prior to enrollment on this study in girls, age 9 or older. Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method. Abstinence is an acceptable method of birth control.
- Sorafenib is predominantly metabolized via CYP3A4, and patients who take cytochrome P450 enzyme-inducing antiepileptic drugs (phenytoin, carbamazepine or Phenobarbital), rifampin, grape fruit, or St. Johns Wort will not be eligible for the trial. Patients must have discontinued these medications at least 7 days prior to enrollment of trial.
- Patients who have had major surgery within the past 3 months are excluded. Patients having minor surgery (i.e., central line placement) within the past 2 weeks are excluded.
- An investigational agent within the past 30 days.
- Ongoing radiation therapy, chemotherapy, hormonal therapy directed at the tumor, immunotherapy, or biologic therapy.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Nexavar (BAY 43-9006) (Sorafenib) | Drug | – |
| Toxicity, Pharmacokinetics | Drug | – |
| Pharmacodynamics | Drug | – |
| Radiographic Evaluation | Drug | – |
| QOL assessment, Neuropsychological | Drug | – |
| Bony Toxicity | Drug | – |
Primary outcome
Maximum tolerated dose, chronic toxicity, pharmacokinetics and pharmacodynamics.
1 secondary outcome
3D MRI of plexiform neurofibromas, pharmacodynamics, cognitive function.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 12 Dec 2019.
- Background: PubMed 16421428Widemann BC, Salzer WL, Arceci RJ, Blaney SM, Fox E, End D, Gillespie A, Whitcomb P, Palumbo JS, Pitney A, Jayaprakash N, Zannikos P, Balis FM. Phase I trial and pharmacokinetic study of the farnesyltransferase inhibitor tipifarnib in children with refractory solid tumors or neurofibromatosis type I and plexiform neurofibromas. J Clin Oncol. 2006 Jan 20;24(3):507-16. doi: 10.1200/JCO.2005.03.8638.
- Background: PubMed 10469434Korf BR. Plexiform neurofibromas. Am J Med Genet. 1999 Mar 26;89(1):31-7. doi: 10.1002/(sici)1096-8628(19990326)89:13.0.co;2-w.
- Background: PubMed 12403552Friedman JM. Neurofibromatosis 1: clinical manifestations and diagnostic criteria. J Child Neurol. 2002 Aug;17(8):548-54; discussion 571-2, 646-51. doi: 10.1177/088307380201700802.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Brigitte C Widemann, M.D. principal investigator
National Cancer Institute (NCI)
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Nexavar (BAY 43-9006) (Sorafenib), Toxicity, Pharmacokinetics and Pharmacodynamics in people with Neurofibromatosis Type I and Plexiform Neurofibroma, run by National Cancer Institute (NCI) at 2 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 0 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 12 Dec 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Maximum tolerated dose, chronic toxicity, pharmacokinetics and pharmacodynamics.. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00727233, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Dec 2019.