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

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Brief Title

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

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

Brief Summary


      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.


      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.


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


      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


Detailed Description


        -  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


        -  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

        -  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

        -  To determine the effect of sorafenib on the growth rate of PN, quality of life, and
           cognitive function while on treatment with sorafenib.


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


        -  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 Phase

Phase 1

Study Type


Primary Outcome

Maximum tolerated dose, chronic toxicity, pharmacokinetics and pharmacodynamics.

Secondary Outcome

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


Neurofibromatosis Type I


Nexavar (BAY 43-9006) (Sorafenib)


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

Recruitment Information

Recruitment Status


Estimated Enrollment


Start Date

July 8, 2008

Completion Date

June 16, 2011

Primary Completion Date

June 16, 2011

Eligibility Criteria


          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 2.2.

         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 trial.

          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




3 Years - 18 Years

Accepts Healthy Volunteers



Brigitte C Widemann, M.D., , 

Location Countries

United States

Location Countries

United States

Administrative Informations



Organization ID


Secondary IDs


Study Sponsor

National Cancer Institute (NCI)

Study Sponsor

Brigitte C Widemann, M.D., Principal Investigator, National Cancer Institute (NCI)

Verification Date

May 4, 2012