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

There are two cohorts: Cohort A is for patients ≥ 16 years of age and Cohort B is for
patients 3 - 15 years of age. Cohort A is closed to enrollment but this study will open to
Cohort B patients. This phase II open label study will evaluate adults and children with
NF1and plexiform neurofibromas treated with cabozantinib (XL184). This study will enroll
subjects who either meet clinical diagnostic criteria or have an identified pathogenetic NF1
mutation. Subjects on study must have clinically significant plexiform neurofibroma defined
as potentially life-threatening, impinging on vital structures or significantly impairing the
quality of life from pain or other symptoms. Patients must not have lesions suspicious for
malignant tumors such as MPNSTs (malignant peripheral nerve sheath tumors) and suspicious
tumors must be proven negative by histopathology prior to enrollment on study. Since Cohort A
is closed to accrual, this study will be open to Cohort B, patients 3 - 15 years of age that
meet eligibility criteria.

For Cohort A, the study will be a Simon two-stage study design. It will be a single-arm
open-label study of cabozantinib and the primary endpoint is the ORR to cabozantinib at 1
year. In the first stage, 9 evaluable subjects will be accrued. If there is at least 1
response, accrual will continue to the second stage and an additional 8 evaluable subjects
will be enrolled. To allow for 25% unevaluable subjects, a maximum of 24 subjects will be
enrolled. Radiographic response will be evaluated as the primary endpoint with 20% volumetric
MRI response of the target lesion being the threshold criteria for tumor response. A target
lesion will be selected at time of enrollment and tumor evaluations will occur serially while
on study.

For Cohort B, a minimum of 17 evaluable subjects will be enrolled. To allow for up to 25%
unevaluable subjects, a minimum of 24 subjects will be enrolled. Based on preliminary
response data and minimal toxicity in Cohort A, a 2-stage design is not felt to be necessary
for Cohort B.

In Cohort A, all subjects will start cabozantinib at 40 mg. The published MTD for
Cabozantinib is 140 mg and the current recommended dose in Phase 3 clinical trials for
subjects with medullary thyroid cancer is 100 mg. Doses of 40 mg and 60 mg continue to show
efficacy in on-going phase 2 and phase 3 trials with reduced toxicity. Subjects who tolerate
40 mg for 2 cycles will escalate to 60 mg. The rationale for this is that the majority of
subjects who develop toxicity do so after >2 weeks on drug as cabozantinib has a long
half-life. Subjects who experience dose-limiting toxicity at 40 mg will dose reduce to 20 mg
when their toxicities resolve. Subjects without toxicity at 40mg will increase to 60mg.
Subjects who experience toxicity at 60 mg will dose reduce to 40 mg. This dosing schema is
designed to maximize safety and tolerability in this new population of patients.

In Cohort B, subjects will start at 30 mg/m2/day dosing. Dose will be escalated at cycle 3 if
tolerated to 40 mg/m2. Subjects who experience DLT at 40 mg/m2/day will dose reduce to 30
mg/m2/day. Subjects who experience DLT at 30 mg/m2/day will dose reduce to 23 mg/m2day.
Actual dosing will be based on the dosing nomogram.

Dosing will be continuous, with 28 days defined as a cycle and each cycle reporting period is
day 1 to day 28. In the absence of progressive disease or dose limiting toxicity (DLT),
subjects may continue on therapy for a total of 12 total cycles. Subjects who have a
radiographic response (20% or greater reduction in tumor volume) on therapy at the end of 12
cycles can continue on therapy for up to an additional year. The maximum duration for
treatment under this study design is 24 cycles. However, subjects who do not achieve at least
15% reduction in index tumor volume after 8 cycles (~8 months) will be considered treatment
failures and taken off study. Subjects entered on the trial will be carefully monitored for
the development of cabozantinib associated toxicities, and target modifications and
interruptions will be performed.

The investigational nature and objectives of this trial, the procedures and treatment
involved, the risks, discomforts, and benefits, and potential alternatives therapies will be
carefully explained to the subject and/or subject's parent(s) or guardian, if subject is a
child,by the site Principal Investigator or designated associate investigator. When
appropriate, pediatric patients will be included in all discussions. A signed informed
consent document will be obtained prior to determining eligibility and entry criteria to this
trial. Subjects entered on this trial will be treated with therapeutic intent and response to
therapy will be closely monitored. This protocol involves greater than minimal risk but
presents the potential for direct benefit to individual subjects

Schedule of study evaluations are summarized below:

Pre-Study:

- Medical history, physical exam with vital signs, blood pressure, and pulse oximetry

- Performance status to assess your ability to perform everyday tasks

- Laboratory tests including blood and urine tests for routine safety tests

- Urine pregnancy test for females of childbearing age

- Electrocardiogram (EKG) to monitor the electrical activity of the heart

- MRI of neurofibromas

- Completion of health-related questionnaires on quality of life, pain assessment, and PN
symptom checklist (upon study entry)

- Research blood draws ( 2 tablespoons) to evaluate the tumor's response to treatment and
the action of cabozantinib in the body over a period of time (Upon study entry on Cycle
1 Day 1, predose and 4-hours post dose)

During Study Treatment:

End of Cycles 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 22, 24 or Early
Termination (additional visit that is not within the specified times mentioned.)

- Medical History

- Physical exam with vital signs, blood pressure and pulse oximetry

- Performance Status

- Review of Subject Diary

- Urine pregnancy test for females of childbearing age at end of cycles 2, 4, 6, 8, 10,
12, 14, 16, 18, 20, 22, 24

- Electrocardiogram (EKG) to monitor the electrical activity of the heart at end of cycles
1, 2, 4, 6, 9, 12, 16, 20, 24

End of Cycles 1 - 24, or Early Termination

- Laboratory tests including blood and urine tests for routine safety tests

End of Cycles 4, 8, 12, 18, 24, or Early Termination

- MRI of neurofibromas

- Completion of health-related questionnaires on quality of life, pain assessment, and PN
symptom checklist

Cycles 1, 2, 3, 4

- Research blood draws ( 2 tablespoons) to evaluate the tumor's response to treatment and
the action of cabozantinib in the body over a period of time

Phone Calls will be made at the end of cycles 13, 15, 17, 19, 21, and 23 to assess drug
compliance and toxicity

The protocol PI and clinical coordinator will review the subject eligibility, study progress,
safety issues, protocol deviations and adverse events. A Data Safety Monitoring Board (DSMB)
and a medical monitor has been established for the purpose of ensuring data compliance and
regular monitoring of this trial. The medical monitor is a qualified physician and is not
associated with this particular protocol. The medical monitor is specifically required to
review all unanticipated problems involving risk to subjects or others, serious adverse
events and deaths associated with the protocol and provide an unbiased written report of the
event.

An early stopping rule will be invoked for both cohorts to potentially prevent accrual of
subjects onto the study in the event that Cabozantinib is associated with a higher than
acceptable rate of dose-limiting toxicity (DLT) requiring removal from study (set at 10% or
higher) during the first 2 cycles. Toxicity will be continuously monitored. If at any time >2
of the first 10 subjects or 4 or more of the first 15 total subjects are removed for DLT,
then accrual will be stopped until the DSMB reviews safety and efficacy data for the study
and recommends termination or despite the DLT (because of the benefit:risk assessment or
other reasoning) recommends reopening recruitment. Boundaries for DSMB for consideration of
terminating each cohort (both cohort A and B) would be the same.

The sample size for this trial is based on the safety and feasibility factors. The data
needed is based on risk versus benefit. For feasibility, we expect at least efficacy of a 25%
response rate. For safety reasons, subjects who do not achieve at least a 15% reduction in
tumor volume will not be continued beyond 8 courses, as the likelihood of achieving a
response (20% reduction in tumor volume) by 12 months is minimal. These subjects will be
discontinued from the trial and counted in an "Intent to Treat" analysis as evaluable and as
failures.

All analyses for outcome results will be based on evaluable subjects. Definitions of
evaluable include: 1.) Evaluation for toxicity (subject who received at least one dose of
study drug and removed from treatment for toxicity are evaluable. Any subject who completed
one full cycle of therapy is evaluable for toxicity); 2.)Evaluation for response (subjects
who have completed at least two cycles of therapy and have had their first follow-up MRI
evaluation. Subjects who did not respond and are later found to have a target tumor other
than a plexiform neurofibroma (e.g. malignant peripheral nerve sheath tumor) are not
evaluable for response).

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 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). 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 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 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 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.