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

NCT00727233 | Completed Phase 1

• 2 other identifiers: 08018008-C-0180
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 2

Brief 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. 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. ...

Conditions

Neurofibromatosis Type I; Plexiform Neurofibroma

Keywords

Neuroblastosis Type I; Plexiform Neurofibromas; Angiogenesis Inhibitor; Kinase Inhibitor; Neurofibromatosis Type 1; NF1; Plexiform Neurofibroma

Outcome Measures

Primary Outcomes (1)

• Maximum tolerated dose, chronic toxicity, pharmacokinetics and pharmacodynamics.

Secondary Outcomes (1)

• 3D MRI of plexiform neurofibromas, pharmacodynamics, cognitive function.

Interventions

Nexavar (BAY 43-9006) (Sorafenib) DRUG

Toxicity, Pharmacokinetics DRUG

Pharmacodynamics DRUG

Radiographic Evaluation DRUG

QOL assessment, Neuropsychological DRUG

Bony Toxicity DRUG

Eligibility Criteria

• Age: 3 Years - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Age: greater than or equal to 3 years and less than or equal to 18 years of age at the time of study enrollment. The upper age limit is in place because early childhood and puberty are considered to be the greatest risk for disease progression, and where sorafenib may have the most benefit. In addition, an important objective of this study is to characterize the pharmacokinetics of sorafenib in the pediatric population since it has been well studied in adults.
• Diagnosis: Patients with NF1 and inoperable PNs that have the potential to cause significant morbidity, such as (but not limited to) head and neck lesions that could compromise the airway or great vessels, brachial or lumbar plexus lesions that could cause nerve compression and loss of function, lesions that could result in major deformity (e.g., orbital lesions) or significant cosmetic problems, lesions of the extremity that cause limb hypertrophy or loss of function, and painful lesions. Histologic confirmation of tumor is not necessary in the presence of consistent clinical and radiographic findings, but should be considered if malignant degeneration of a PN is clinically suspected.
• A PN is defined as a neurofibroma that has grown along the length of a nerve and may involve multiple fascicles and branches. A spinal PN involves two or more levels with connection between the levels or extending laterally along the nerve. In addition to PN, all study subjects must have either positive genetic testing for NF1 or have at least one other diagnostic criterion for NF1 listed below (NIH Consensus conference:
• Six or more cafe-au-lait spots (greater than or equal to 0.5cm in prepubertal subjects or greater than or equal to 1.5 cm in post pubertal subjects)
• Freckling in axilla or groin
• Optic glioma
• Two or more Lisch nodules
• A distinctive bony lesion (dysplasia of the sphenoid bone or dysplasia or thinning of long bone cortex)
• A first-degree relative with NF1
• Measurable disease: Patients must have at least one measurable PN, defined as a lesion of at least 3 cm measured in one dimension. Patients who underwent surgery for resection of a PN are eligible provided the PN was incompletely resected and is measurable as per criteria above.
• Prior Therapy: Patients with NF1 will only be eligible if complete tumor resection is not feasible, or if a patient with a surgical option refuses surgery.
• Since there is no standard effective chemotherapy for patients with NF1 and PN, patients may be treated on this trial without having received prior medical therapy directed at their PN.
• May have received less than or equal to 1 myelosuppressive regimen for PN or other tumor manifestations associated with NF1 such as optic glioma.
• Patients who have received previous investigational agents or biologic therapy, such as tipifarnib, pirfenidone, Peg-Intron, or other VEGFR inhibitors are eligible for enrollment.
• Growth factors that support platelet or white cell number or function must not have been administered within the past 7 days.

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (2)

Children's Hospital of Alabama

Birmingham, Alabama, 35233, United States

Location

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• 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.

  PMID: 16421428 BACKGROUND

• Korf 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.

  PMID: 10469434 BACKGROUND

• Friedman 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.

  PMID: 12403552 BACKGROUND

MeSH Terms

Conditions

Neurofibromatosis 1; Neurofibroma, Plexiform

Interventions

Sorafenib; Pharmacokinetics

Condition Hierarchy (Ancestors)

Neurofibromatoses; Neurofibroma; Nerve Sheath Neoplasms; Neoplasms, Nerve Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplastic Syndromes, Hereditary; Neurocutaneous Syndromes; Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Peripheral Nervous System Diseases; Neuromuscular Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Peripheral Nervous System Neoplasms; Nervous System Neoplasms

Intervention Hierarchy (Ancestors)

Phenylurea Compounds; Urea; Amides; Organic Chemicals; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Niacinamide; Nicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring; Metabolism; Pharmacological and Toxicological Phenomena; Physiological Phenomena

Study Officials

• Brigitte C Widemann, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH

Study Record Dates

• First Submitted: July 31, 2008
• First Posted: August 1, 2008
• Study Start: July 8, 2008
• Primary Completion: June 16, 2011
• Study Completion: June 16, 2011
• Last Updated: December 12, 2019

Record last verified: 2012-05-04

Locations

US (2)