Pilot Study of Cabozantinib for Recurrent or Progressive High-Grade Glioma in Children

Inclusion Criteria

1. Age: Patients must be ≥2 years and ≤21 years of age

2. Diagnosis: Patients with relapsed or refractory high grade glioma (HGG) defined was
histologically confirmed WHO grade III or WHO grade IV glioma (i.e. glioblastoma
multiforme or anaplastic astrocytoma). Patients must have had histologic verification
of malignancy at original diagnosis or relapse. Metastatic disease to the spine is
eligible. Patients may be in first, second, or third relapse. Subjects with intrinsic
brain stem gliomas may be eligible if histologically confirmed. Please contact study
chair prior to enrollment.

3. Disease Status: Patients must have measurable disease. Linear enhancement of
leptomeningeal without measurable mass is excluded.

4. Therapeutic Options: Patient's current disease state must be one for which there is no
known curative therapy or therapy proven to prolong survival with an acceptable
quality of life. For patients in whom surgery is feasible, maximal surgical resection
must have occurred.

5. Performance Level: Karnofsky ≥ 50% for patients > 16 years of age and Lansky ≥ 50 for
patients ≤ 16 years of age (See Appendix 1). Note: Neurologic deficits in patients
must have been relatively stable for at least 7 days prior to study enrollment.
Patients who are unable to walk because of paralysis, but who are in a wheelchair,
will be considered ambulatory for the purpose of assessing the performance score.

6. Subjects must have a reasonable life expectancy of at least 2 months.

7. Prior Therapy

a. Patients must have fully recovered from the acute toxic effects of all prior
anti-cancer chemotherapy i. Cytotoxic chemotherapy (including investigational agents)
or biologic agents (eg. Cytokines or antibodies): At least 3 weeks after the last
dose.

ii. Nitrosoureas/mitomycin C: At least 6 weeks from the last dose. iii. XRT: At least
14 days after local palliative XRT (small port); At least 150 days must have elapsed
if prior TBI, craniospinal XRT or if ≥ 50% radiation of pelvis; At least 42 days must
have elapsed if other substantial BM radiation. e.g. Stem cell Infusion without TBI:
No evidence of active graft vs. host disease and at least 56 days must have elapsed
after transplant or stem cell infusion.

8. Organ Function Requirements:

a. Adequate bone marrow function defined as: absolute neutrophil count (ANC ≥1000/mm3)
i. Platelet count ≥ 100,000/ mm3 (transfusion independent, defined as not receiving
platelet transfusions for at least 7 days prior to enrollment) ii. Patients with bone
marrow metastatic disease will not be eligible. b. Adequate renal function defined as:
i. Creatinine clearance or radioisotope GFR ≥ 70mL/min/1.73 m² or a serum creatinine
based on age/gender as follows:

Age Maximum Serum Creatinine (mg/dL) Male Female 2 to < 6 years 0.8 0.8 6 to < 10
years 1 1 10 to < 13 years 1.2 1.2 13 to < 16 years 1.5 1.4

≥ 16 years 1.7 1.4 The threshold creatinine values in this table 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.

ii. Urine protein: ≤ 30 mg/dL in urinalysis or ≤ 1+ on dipstick, unless quantitative
protein is < 1000 mg in a 24 hour urine sample.

c. Adequate Liver Function Defined as:

i. Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of normal (ULN)
for age ii. SGPT (ALT) ≤ 110 U/L. For the purpose of this study, the ULN for SGPT is
45 U/L.

iii. Serum albumin ≥ 2.8 g/dL. d. Adequate coagulation status defined as:PT and INR

- 1.5x ULN e. Adequate pancreatic function defined as: Serum amylase and lipase

- 1.5 x ULN f. Adequate blood pressure control defined as: A blood pressure (BP) ≤
the 95th percentile for age, height and gender (Appendix II) despite optimal
antihypertensive treatment within 7 days of the first dose of the study
treatment. Please note that 3 serial blood pressures should be obtained and
averaged to determine baseline BP.

g. Central nervous system function defined as:Patients with seizure disorder may
be enrolled if receiving non-enzyme inducing anticonvulsants and well controlled.
See Appendix III for a list of recommended non-enzyme inducing anticonvulsants.

h. Adequate cardiac function defined as: i. No history of congenital QTc
syndrome, NYHA Class III or IV congestive heart failure (CHF) ii. No clinical
significant cardiac arrhythmias, stroke or myocardial infarction within 6 months
prior to enrollment iii. QTc

- 480 msec. Note: Three ECGs must be performed for eligibility determination. If
the average of these three consecutive results for QTcF is ≤ 480 msec, the
subject meets eligibility in this regard.Patients with Grade 1 prolonged QTc
(450-480 msec) at the time of study enrollment should have correctable causes of
prolonged QTc addressed if possible (i.e. electrolytes, medications). See
Appendix IV for a list of drugs that prolong QTc.

9. Informed consent: All patients and/or their parents or legally authorized
representatives must sign a written informed consent. Assent, when appropriate will be
obtained according to institutional guidelines.

10. Archival tumor tissue slides must be sent or available.

Exclusion Criteria

1. Pregnancy or Breast-Feeding: Pregnant or breast-feeding women will not be entered on
this study due to risks of fetal and teratogentic adverse events as seen in
animal/human studies. Pregnancy tests must be obtained in girls who are
post-menarchal. Males or females of reproductive potential may not participate unless
they have agreed to use two methods of birth control- a medically accepted barrier
method of contraceptive method (e.g., male or female condom) and a second effective
method of birth control- during protocol therapy and for at least 4 months after the
last dose of cabozantinib. Abstinence is an acceptable method of birth control.

2. Concomitant Medications:

1. Corticosteroids: Patients receiving corticosteroids who have not been on a stable
or decreasing dose of corticosteroid for at least 7 days prior to enrollment are
not eligible.

2. Investigational drugs: Patients who are currently receiving another
investigational drug are not eligible.

3. Anti-cancer agents: patients who are currently receiving other anti-cancer agents
are not eligible.

4. CYP3A4 active agents: Patients must not be receiving any of the following potent
CYP3A4 inducers or inhibitors: erythromycin, clarithromycin, ketoconazole,
azithromycin, itraconazole, grapefruit juice or St. John's wort. A list of other
known CYP3A4 inducers and inhibitors that should be discontinued prior to
initiation of protocol therapy and should be avoided during study therapy if
reasonable alternatives exist is included in Appendix V.

5. Patients who are receiving systemic therapeutic treatment anticoagulation are not
eligible. Patients receiving prophylactic systemic anticoagulation will be
allowed with heparin or LMWH as long as eligibility PT/INR requirements are met.
Concomitant anticoagulation with oral anticoagulations (e.g. warfarin, direct
thrombin and Factor Xa inhibitors) or platelet inhibitors (eg. Clopidogrel) are
not allowed.

6. Enzyme-inducing anticonvulsants: Patients must not have received enzyme-inducing
anticonvulsants within 14 days prior to enrollment (See Appendix III for a list
of unacceptable enzyme inducing anticonvulsants).

7. QTc Agents: Patients who are receiving drugs that prolong QTc are not eligible
(See Appendix IV for a list of agents).

3. Patients must be able to swallow intact tablets. Patients who cannot swallow intact
tablets are not eligible.

4. Patients with active bleeding are not eligible. Specifically, no clinically
significant GI bleeding, GI perforation, intra-abdominal abscess or fistula for 6
months prior to enrollment, no hemoptysis or other signs of pulmonary hemorrhage for 3
months prior to enrollment.

5. Patients with evidence of an acute intracranial or intratumoral hemorrhage on CT or
MRI are not eligible (patients with evidence of resolving hemorrhage will be
eligible).

6. Major surgery within 12 weeks before the first dose of study treatment. Complete wound
healing from major surgery must have occurred 1 month before the first dose of study
treatment. Minor surgery (including uncomplicated tooth extractions) within 28 days
before the first dose of study treatment with complete wound healing at least 10 days
before the first dose of study treatment. Subjects with clinically relevant ongoing
complications from prior surgery are not eligible;

7. Concurrent uncontrolled hypertension defined as sustained blood pressure>95% (systolic
or diastolic) despite optimal antihypertensive treatment within 7 days of the first
dose of study treatment.

8. Patients with any medical or surgical conditions that would interfere with
gastrointestinal absorption of this oral agent are not eligible.

9. Infection: Patients who have an uncontrolled infection are not eligible.

10. Patients who have received a prior solid organ transplantation are not eligible.

11. Patients who in the opinion of the investigator may not be able to comply with the
safety monitoring requirements of the study are not eligible.

12. Subjects who have received cabozantinib or have an allergy to cabozantinib are
excluded. Subjects who have previously received tyrosine kinase inhibitors are
allowed.

13. Subjects who have not received radiation therapy as part of their prior treatment are
excluded.