Cabozantinib for Plexiform Neurofibromas (PN) in Subjects With NF1 in Children and Adults

Inclusion Criteria:

1. Clinical or molecular diagnosis of Neurofibromatosis Type 1
2. Plexiform neurofibroma that is progressive OR causing significant morbidity.
3. Measurable disease amenable to volumetric MRI imaging defined as lesion seen on at least 3 consecutive MRI slices and at least 3 mL in volume. Select tumors \<3 cm may be eligible on review.
4. Central review or MRI required prior to enrollment.
5. Age ≥ 3 years of age at the time of study entry. Subjects ≥ 16 years will be enrolled in Cohort A. Subjects 3 - 15 years will be enrolled in Cohort B.
6. Performance Level Karnofsky ≥ 50%. Subjects unable to walk because of paralysis, but up in a wheel chair will be considered ambulatory for purpose of assessing performance score.
7. Complete resection of plexiform neurofibroma is not feasible or if subject refuses surgery.
8. Fully recovered from acute toxic effects of all prior chemotherapy or radiotherapy.
9. No myelosuppressive chemotherapy within 4 weeks of study entry.
10. At least 7 days since completion of hematopoietic growth factors.
11. At least 14 days since completion of biologic agent.
12. At least 4 weeks since receiving any investigational drug.
13. Physiologic or stress doses of steroids allowed in patients with endocrine deficiencies.
14. At least 6 months from radiation therapy to index tumor and at least 6 weeks from radiation to areas outside of index plexiform neurofibroma.
15. At least 3 months from major surgery or at least 1 month from minor surgery. No major surgery anticipated within 3 months of enrollment.
16. Adequate bone marrow function.
17. Adequate renal function.
18. Adequate liver function.
19. Blood pressure within upper limit of normal.

Exclusion Criteria:

1. Active optic glioma or other low-grade glioma requiring treatment with chemotherapy or radiation therapy.
2. Malignant glioma, malignant peripheral nerve sheath tumor, or other malignancy requiring treatment in the last 12 months.
3. Dental braces or prosthesis that interferes with volumetric analysis of the neurofibroma(s).
4. Unable to swallow tablets.
5. Women who are pregnant or breast-feeding.
6. Subjects of reproductive potential who have not agreed to use effective contraception.
7. Subject has not recovered to baseline or CTCAE ≤ Grade 1 from toxicity due to all prior therapies except alopecia and other non-clinically significant adverse events (AEs).
8. Subject requires anticoagulants. Low dose aspirin, low-dose warfarin, and prophylactic low molecular weight heparin are permitted.
9. Concomitant treatment of strong CYP3A4 inducers or inhibitors.
10. History of noncompliance to medical regimens
11. A known history of HIV seropositivity or known immunodeficiency. HIV testing will not be required as part of this trial, unless HIV is clinically suspected.
12. Impairment of gastrointestinal function or gastrointestinal disease that may affect the absorption of cabozantinib. (e.g. ulcerative disease, malabsorption syndrome, or small bowel resection). Nasogastric tube (NG) tube is allowed.

    * Any of the following within 28 days before the first dose of study treatment:

      1. intra-abdominal tumor/metastases invading GI mucosa
      2. active peptic ulcer disease
      3. inflammatory bowel disease (including ulcerative colitis and Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis
      4. malabsorption syndrome
    * Any of the following within 6 months before the first dose of study treatment:

      1. abdominal fistula
      2. gastrointestinal perforation
      3. bowel obstruction or gastric outlet obstruction
      4. intra-abdominal abscess. Complete resolution of an intra-abdominal abscess must be confirmed prior to initiating study treatment even if abscess occurred more than 6 months before the first dose of study treatment.
    * Other disorders associated with a high risk of fistula formation including percutaneous endoscopic gastrostomy (PEG) tube placement within 3 months before the first dose of study therapy
13. Patients who have an uncontrolled infection.
14. Clinically-significant gastrointestinal bleeding within 6 months before the first dose of study treatment
15. Hemoptysis of ≥0.5 teaspoon (2.5 mL) of red blood within 3 months before the first dose of study treatment
16. Any other signs indicative of pulmonary hemorrhage within 3 months before the first dose of study treatment
17. Radiographic evidence of cavitating pulmonary lesion(s).
18. Concurrent severe and/or uncontrolled medical disease which could compromise participation in the study (e.g. uncontrolled diabetes, uncontrolled hypertension, severe infection, severe malnutrition, chronic liver or renal disease, active upper GI tract ulceration)
19. Cardiovascular disorders including:

    * Congestive heart failure (CHF): New York Heart Association (NYHA) Class III (moderate) or Class IV (severe) at the time of screening
    * Concurrent uncontrolled hypertension defined as sustained BP \> 140 mm Hg systolic, or \> 90 mm Hg diastolic despite optimal antihypertensive treatment within 7 days before the first dose of study treatment
    * Any history of congenital long QT syndrome
    * Baseline heart-rate corrected QT (QTc) interval \>470 msec in women and \>450 msec in men
    * Concomitant treatment with medications that prolong the QT interval and have a known risk of Torsades de Pointes is not contraindicated, but should be avoided if possible and will require more frequent EKG monitoring.
    * Any of the following within 6 months before the first dose of study treatment:

      1. unstable angina pectoris
      2. clinically-significant cardiac arrhythmias
      3. stroke (including transient ischemic attack (TIA), or other ischemic event)
      4. myocardial infarction
      5. thromboembolic event requiring therapeutic anticoagulation (Note: subjects with a venous filter (e.g. vena cava filter) are not eligible for this study)
20. Other clinically significant disorders such as:

    * Active infection requiring systematic treatment within 28 days before the first dose of study treatment
    * Serious non-healing wound/ulcer/bone fracture within 28 days before the first dose of study treatment
    * History of organ transplant
    * Concurrent uncompensated hypothyroidism or thyroid dysfunction within 7 days before the first dose of study treatment
21. Complete wound healing from prior surgery must be confirmed at least 28 days before the first dose of study treatment irrespective of time from surgery.