Cabozantinib in Combination With 13-cis-Retinoic Acid in Children With Relapsed or Refractory Solid Tumors

Participants will be treated in an open-label, non-randomized phase I trial to determine the
safety, dose-limiting toxicities, tolerability, and maximum tolerated dose of cabozantinib
combined with 13-cis-retinoic acid in children with relapsed or refractory solid tumors.

Eligible Participants must have a histologically confirmed solid tumor at time of initial
diagnosis, and have either progressive, recurrent, or refractory disease. Cabozantinib will
be given orally once every day with cycles repeated every 4 weeks (28 days, +/- 3 days), with
no rest periods between cycles, combined with 13-cis-retinoic acid at 80mg/m2/dose twice
daily for two consecutive weeks (14 days) out of every four weeks (28 days, +/- 3 days).
Participants with disease response or stable disease at the end of each cycle will be allowed
to continue treatment, and patients may continue to receive therapy until there is evidence
of clinical or radiographic disease progression.

The investigator will perform a phase I trial to define the maximum tolerated dose (MTD) of
cabozantinib in combination with 13-cis-retinoic acid using the standard 3+3 study design.
Cohorts of patients will be enrolled at doses determined as detailed below. The first cycle
will be used to determine the dose-limiting toxicities. Toxicity will be summarized by dose
levels. Response rates will be estimated. Kaplan-Meier curves will be plotted to graphically
present time to progression (PFS) and other time-to-event endpoints. Median PFS and the
corresponding 95% confidence intervals will be reported.

Cabozantinib dosing will be started and modified, if necessary, during the course of the
trial as detailed below. The tablet formulation of the drug will be used with doses in 20mg
increments.

Baseline evaluation to determine eligibility will include medical history (including a review
of current medications), physical examination, blood count with differential, chemistry panel
blood or urine pregnancy test for women of child-bearing potential (not post-menopausal for
at least 12 months and not surgically sterile), echocardiogram, electrocardiogram, and
disease evaluation (appropriate for disease). Samples for correlative studies will be
collected accordingly.

Participants will be evaluated weekly (+/- three days) during the first cycle. The interim
evaluations will consist of interval history (with a review of current medications), physical
examination, blood count with differential, and chemistry panel. Pregnancy tests will be
performed prior to each cycle in women of childbearing potential. After the first cycle,
patients will be evaluated monthly (+/- seven days).

Participants who have had therapy discontinued will undergo end-of-therapy evaluations and
will continue to be monitored with interval histories, physical examinations, and laboratory
evaluations every three months (+/- seven days), with disease evaluations every three months
(+/- 28 days) until they fulfill criteria for removal from study or the study is completed

Inclusion Criteria:

1. Patients must have had histologic verification of a solid tumor, including tumors of
the CNS, at the time of initial diagnosis or relapse, with disease that has progressed
on standard therapy, relapsed after standard therapy, or for which no standard
curative therapy is known

2. Patients must have documentation of either measurable or evaluable disease within 4
weeks of onset of study therapy

3. Performance Status - Lansky play or Karnofsky score of ≥40

4. Prior Therapy: Patients must have fully recovered from the acute toxic effects of all
prior chemotherapy, immunotherapy, or radiotherapy prior to study enrolment with the
exception of hematologic parameters (absolute neutrophil count, hemoglobin, platelet
count), which need to have recovered to meet eligibility criteria

5 Steroids are permitted for control of emesis and for symptom management in patients with
intracranial metastases. However, patients with known CNS disease or CNS metastases who
require increasing doses of steroids are not allowed in the study. Patients MUST be on a
stable or decreasing steroid dose for greater than or equal to 1 week prior to start of
study therapy.

6. Female subjects of childbearing potential must agree to use an adequate method of
contraception for the course of the study. Male subjects must agree to use an adequate
method of contraception for the course of the study

Exclusion Criteria:

1. Evidence of severe or uncontrolled systemic disease

2. Cardiac Disease

3. Blood pressure >95th percentile for age (either systolic or diastolic) or >140/90 for
patients >18 years of age and uncontrolled by oral medication at onset of study
therapy

4. Women who are currently pregnant or breastfeeding.

5. Prior therapy with cabozantinib at any time.

6. Major surgery within 8 weeks before starting study therapy.

7. Prior treatment with allogeneic stem cell transplantation or total body irradiation
(TBI)

8. Therapeutic anticoagulation with heparin, LMWH , or any other agents are not allowed
in subjects with intracranial tumors/metastatses.

9. Concomitant anticoagulation at therapeutic doses with oral anticoagulants (eg,
warfarin, direct thrombin and Factor Xa inhibitors) or platelet inhibitors (eg,
clopidogrel) in patients without primary or metastatic CNS tumors

10. The subject has experienced any of the following:

1. clinically-significant GI bleeding within 6 months before the first dose of study
treatment;

2. any other signs indicative of pulmonary hemorrhage within 3 months before the
first dose of study treatment.

11. The subject has radiographic evidence of cavitating pulmonary lesion(s) and/or the
subject has tumor invading any major blood vessels;

12. The subject has evidence of tumor invading the GI tract (esophagus, stomach, small or
large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor
within 28 days before the first dose of cabozantinib

13. thromboembolic event requiring therapeutic anticoagulation within 6 months of onset of
study treatment

14. GI disorders particularly those associated with a high risk of perforation or fistula
formation

15. Inability to swallow intact tablets