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
1. 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.
2. 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
3. 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.
4. 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.
- Patients who received prior medical therapy for their PN must have recovered
from the toxic effects of all prior therapy before entering this study.
5. Performance status: Patients greater than 10 years of age must have a Karnofsky
performance level of greater than or equal to 50%, and children less than or equal to
10 years old must have a Lansky performance of greater than or equal to 50% (Appendix
6. Hematologic Function: Patients must have an absolute neutrophil count greater than or
equal to 1500/microl, hemoglobin greater than or equal to 9g/dl, and platelet greater
than or equal to 100,000/microl.
7. Coagulation: Patients must have adequate hemostatic function defined as PT and PTT
less than or equal to 1.5 times ULN. Patients receiving prophylactic anticoagulation
for thrombosis are eligible if they meet criteria for adequate hemostatic function
(PT and PTT less than or equal to 1.5 times ULN) and thrombotic episode occurred 3
months prior to enrollment. Use of anticoagulants or thrombolytics for care and
maintenance of central venous catheters is acceptable.
8. Hepatic Function: Patients must have bilirubin within the upper limit of normal for
age, and ALT within the upper limit of normal for age.
9. Serum lipase and amylase within upper limits of normal.
10. Renal Function: Patients must have a creatinine clearance or radioisotope GFR greater
than or equal to 60ml/min/1.73 m(2) or a normal serum creatinine based on age
described in the table below.
Age (years) less than or equal to 5 Maximum Serum Creatinine (mg/dL) 0.8
Age (years) 5 less than or equal to 10 Maximum Serum Creatinine (mg/dL) 1.0
Age (years) 10 less than or equal to 15 Maximum Serum Creatinine (mg/dL) 1.2
Age (years) greater than 15 Maximum Serum Creatinine (mg/dL) 1.5
11. Blood pressure: Patients must have a systolic and diastolic blood pressure less than
95th percentile for age and gender (Appendix II) measured as described in section
12. Informed Consent: Diagnostic or laboratory studies performed exclusively to determine
eligibility for this trial must only be done after obtaining written informed consent
from all patients or their legal guardians (if the patient is less than 18 years
old). When appropriate, pediatric patients will be included in all discussions. This
can be accomplished through one of the following mechanisms: a) the NCI, POB
screening protocol, b) an IRB-approved institutional screening protocol or c) the
study-specific protocol. Documentation of the informed consent for screening will be
maintained in the patient's research chart. Studies or procedures that were performed
for clinical indications (not exclusively to determine eligibility) may be used for
baseline values even if the studies were done before informed consent was obtained.
13. Durable Power of Attorney (DPA): All patients greater than 18 years of age will be
offered the opportunity to assign DPA so that another person can make decisions about
their medical care if they become incapacitated or cognitively impaired.
1. 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.
2. 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
3. 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
4. An investigational agent within the past 30 days.
5. Ongoing radiation therapy, chemotherapy, hormonal therapy directed at the tumor,
immunotherapy, or biologic therapy.
6. Clinically significant uncontrolled unrelated systemic illness such as serious
infections or significant cardiac, pulmonary, hepatic or other organ dysfunction.
7. Patients who in the opinion of the investigator may not be able to comply with the
safety monitoring requirements of the study.
8. Inability to swallow tablets, since tablets cannot be crushed or broken.
9. 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.
10. Prior treatment with sorafenib.
11. Evidence of an optic glioma, malignant glioma, malignant peripheral nerve sheath
tumor, or other cancer requiring treatment with chemotherapy or radiation therapy.
12. Patients with a history of arterial or venous thrombosis with in the prior 3 months.
13. Patients who experienced significant hemorrhage (hemoptysis, melena, or hematemesis)
within the past 2 weeks or with a history of bleeding diathesis.
14. Patients with a history of NF1 related cerebral vascular anomaly.
15. 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.
16. 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