Study of Sutent®/Sunitinib (SU11248) in Subjects With NF-1 Plexiform Neurofibromas
Condition: Neurofibromatosis; NF1; Plexiform Neurofibromas
MeSH terms: Neurofibromatoses; Neurofibromatosis 1; Neurofibroma; Neurofibroma, Plexiform
Intervention: Sutent®/Sunitinib
Intervention description: Upon enrollment, subjects will receive Sutent® orally. Adults (Age >18) will receive 25mg. Children will receive 10mg/m2/day. All subjects will take the daily dose for 28 days followed by a 14 day rest period. If subjects tolerate the initial dose, adults will be increased to 37.5mg and children will be increased to 15mg/m2/day. Again, subjects will take that dose for 28 days followed by a rest period of 14 days. Adults who tolerate the increase will go up to the maximum dose of 50mg. The maximum dose for children is 15mg/m2/day.
Intervention MeSH terms: Sunitinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 19.0
Sex: All
Minimum age: 3 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: NF1; plexiform neurofibromas; Sunitinib; Sutent®

Summary:

      This is a pilot study to determine if adults and children with neurofibromatosis type 1 who
      have plexiform tumors given Sutent® respond to this drug therapy.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Age: patients must be ≥3 years of age and ≤65 years of age at the time of study entry

          2. Diagnosis: Patients must meet clinical diagnostic criteria of neurofibromatosis type 1
             (NF1). Patients must have clinically significant plexiform neurofibromas (biopsy
             proven if possible with tissue blocks available). Clinically significant tumors are
             those which are potentially life threatening or are impinging on vital structures or
             significantly impair the quality of life from pain or other symptoms.

          3. Disease status: Patients must have measurable disease.

          4. Performance Level: Karnofsky ≥50 for patients >10 years of age and Lansky ≥50 for
             patients ≤10 years of age. Patients who are unable to walk because of paralysis, but
             who are up in a wheelchair, will be considered ambulatory for the purpose of assessing
             the performance score.

          5. Prior therapy: Patients must have fully recovered from the acute toxic effects of all
             prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.

               1. Myelosuppressive chemotherapy: Must not have received within 3 weeks of entry
                  onto this study.

               2. Hematopoietic growth factors: At least 14 days since completion of therapy with a
                  growth factor.

               3. Biologic (anti-neoplastic agent): At least 7 days since the completion of therapy
                  with a biologic agent. For agents that have known adverse events occurring beyond
                  7 days after administration, the period must be extended beyond the time during
                  which adverse events are known to occur. The duration of this interval must be
                  discussed with the principal investigator.

               4. XRT: ≥2 weeks for local palliative XRT (small port); ≥6 months must have elapsed
                  if ≥50% radiation of pelvis; ≥6 weeks must have elapsed if other substantial BM
                  radiation.

          6. Organ function requirements

             a. Adequate bone marrow function defined as i. Peripheral absolute neutrophil count
             (ANC) ≥1000/µL ii. Platelet count ≥100,000/ µL(transfusion independent, iii.
             Hemoglobin ≥8.0 gm/dL(may receive RBC transfusions) b. Adequate renal function defined
             as i. Creatinine clearance or radioisotope GFR ≥70 mL/min/1.73 m2 or ii. A serum
             creatinine based on age/gender as follows (Maximum Serum Creatinine (mg/dL)): Males: 6
             to <10 years:1; 10 to <13 years: 1.2; 13 to <16 years: 1.5; >16 years 1.7. Females: 6
             to <10 years:1; 10 to <13 years 1.2; 13 to <16 years: 1.4; >16 years: 1.4.

             The threshold creatinine values above were derived from the Schwartz formula for
             estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing child length and
             stature data published by the CDC.

             c. Adequate Liver Function Defined As: i. Total bilirubin (sum of
             conjugated+unconjugated)≤1.5 times upper limit of normal (ULN) for age, and ii.
             SGPT(ALT)<2.5 upper limit of normal ULN). For the purpose of this study, the ULN for
             SGPT is 45 U/L iii. Serum albumin ≥2 g/dL d. Adequate cardiac function defined as: i.
             Shortening fraction or ejection fraction greater than the LLN (institutional norm),
             and ii. Corrected QT interval ≤450 msec e. Normal Pancreatic function defined as: i.
             Serum amylase ≤1.5xULN and ii. Serum lipase ≤1.5xULN. f. Blood pressure within the
             upper limit of normal defined as: i. A blood pressure (BP) ≤ 95th percentile for age,
             height, and gender and not receiving medication for treatment of hypertension.

          7. Informed Consent: All patients and/or their parents or legal guardians must sign a
             written informed consent. Assent, when appropriate, will be obtained according to
             institutional guidelines.

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        Exclusion Criteria:

          1. Prior anthracycline treatment. Patients previously treated with anthracyclines (any
             dose) are not eligible.

          2. Prior Cardiac Radiation Patients previously treated with a radiation field that
             included the heart are not eligible.

          3. Pregnancy or Breast-Feeding Animal studies indicate an increased risk of death of
             pregnant female rats and rabbits exposed to Sutent®. Cleft lip and palate were
             observed in some fetuses exposed in utero to sunitinib. There is yet no available
             information regarding human fetal or teratogenic toxicities. Pregnancy tests must be
             obtained in girls who are poet-menarchal. Males or females of reproductive potential
             may not participate unless they have agreed to use an effective contraceptive method.

          4. Concomitant Medications

               1. Growth factors(s): Growth factors that support platelet or white cell number or
                  function must not have been administered within the past 14 days

               2. Investigational Drugs: Patients who are currently receiving another
                  investigational drug.

               3. Anti-cancer agents: Patients who are currently receiving other anti-cancer
                  agents.

               4. The following CYP3A4 inducers are prohibited 12 days before the start of Sutent®
                  and during the study with Sutent®: rifampin, rifabutin, carbamazepine,
                  Phenobarbital, phenytoin, St. John's wort, efavirenz, and tipranavir.

               5. Anti-thrombotic and anti-platelet agents: warfarin (Coumadin), heparin, low
                  molecular weight heparin, aspirin, and/or ibuprofen, or other NSAIDs.

               6. The following CYP3A4 inhibitors are prohibited 7 days before the start of
                  sunitinib and during the study with sunitinib: azole antifungals (itraconazole,
                  ketoconazole); clarithromycin, erythromycin, diltiazem, verapamil, HIV protease
                  inhibitors (indinavir, saquinavir, ritonavir, atazanavir, nelfinavir);
                  delavirdine.

          5. Infection: Patients who have an uncontrolled infection.

          6. Pleural-based tumors: Pediatric patients treated on a phase II trial with imatinib had
             a higher than expected rate of hemorrhagic pleural effusions. Sutent® inhibits two of
             the same receptor tyrosine kinases as imatinib, PDGFR and c-KIT. Patients with tumors
             involving or abutting the pleural surface will be excluded from study. Patients with
             pulmonary lesions should be monitored closely for the development of hemorrhagic
             pleural effusions.

          7. Patient size: Due to dosing limitations, patients with body surface area <0.5 m2 will
             be excluded from study.

          8. Patients with a pre-existing thyroid abnormality (hyper-or hypothyroidism) with
             unstable thyroid function will be excluded from study. For the purposes of this study,
             unstable thyroid function will be defined as thyroid function abnormalities requiring
             more than on e change in thyroid medication in the 6 months prior to study entry.

          9. Patients with history of allergic reaction attributed to Sutent® or component of
             Sutent® capsules.

         10. Prior use of Sutent®: Patients who have previously received sunitinib are not eligible
             for study.

         11. Patients who in the opinion of the investigator may not be able to comply with the
             safety monitoring requirements of the study.

         12. Patient is < 5 years free of another primary malignancy except if the other primary
             malignancy is not currently clinically significant nor requiring active intervention,
             or if other primary malignancy is a basal cell skin cancer or a cervical carcinoma in
             situ. Existence of any other malignant disease is not allowed.

         13. Patient with Grade III/IV cardiac problems as defined by the New York Heart
             Association Criteria. (i.e., congestive heart failure, myocardial infarction within 6
             months of study)

         14. Patient has a severe and/or uncontrolled medical disease (i.e., uncontrolled diabetes,
             chronic renal disease, or active uncontrolled infection).

         15. Patient has a known brain metastasis. Non-specific CNS changes on MRI/CT
             characteristic of NF1 are allowed, but not known CNS malignancies.

         16. Patient has known chronic liver disease (i.e., chronic active hepatitis, and
             cirrhosis).

         17. Patient has a known diagnosis of human immunodeficiency virus (HIV) infection.

         18. Patient had a major surgery within 2 weeks prior to study entry.

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