Cabozantinib S-Malate in Treating Younger Patients With Recurrent or Refractory Solid Tumors

PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose (MTD) and/or recommended phase 2 dose of XL184
(cabozantinib) (cabozantinib S-malate) administered orally to children with refractory solid
tumors including central nervous system (CNS) tumors.

II. To define and describe the toxicities of XL184 (cabozantinib) administered on this
schedule.

III. To characterize the pharmacokinetics of XL184 (cabozantinib) in children with refractory
solid tumors.

SECONDARY OBJECTIVES:

I. To preliminarily define the antitumor activity of XL184 (cabozantinib) within the confines
of a phase 1 study.

II. To assess the biologic activity of XL184 (cabozantinib). III. To assess the biomarker
response (carcinoembryonic antigen [CEA] and calcitonin) in patients with medullary thyroid
cancer treated with XL184.

IV. To evaluate overall survival from study entry through a five-year follow-up period.

OUTLINE: This is a dose-escalation study. (Complete as of 4/16/2014)

Patients receive cabozantinib S-malate orally (PO) once daily (QD) on days 1-28. Courses
repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, 6 months, and then
annually for up to 60 months.

Inclusion Criteria:

- Patients must have a body surface area >= 0.44 m^2 when enrolling on dose level -1;
patients must have a body surface area >= 0.35 m^2 when enrolling on dose level 1, 2,
or 3

- PART A: Patients with relapsed or refractory solid tumors (excluding medullary thyroid
cancer) including CNS tumors and malignant melanoma are eligible; patients must have
had histologic verification of malignancy at original diagnosis or relapse except in
patients with intrinsic brain stem tumors, optic pathway gliomas, or patients with
pineal tumors and elevations of cerebrospinal fluid (CSF) or serum tumor markers
including alpha-fetoprotein or beta-human chorionic gonadotropin (HCG)

- Part B: Patients with medullary thyroid cancer (MTC), with or without bone marrow
involvement, will be eligible for Part B; these patients will be enrolled at dose
level 2, the recommended phase 2 dose determined in the dose escalation part of the
study

- Patients must have either measurable or evaluable disease

- 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

- Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50 for patients =< 16
years of age

- Note: neurologic deficits in patients with CNS tumors 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 up in a wheelchair, will be considered
ambulatory for the purpose of assessing the performance score

- Patients must have fully recovered from the acute toxic effects of all prior
anti-cancer chemotherapy:

- Myelosuppressive chemotherapy: at least 21 days after the last dose of
myelosuppressive chemotherapy (42 days if prior nitrosourea)

- Hematopoietic growth factors: at least 14 days after the last dose of a
long-acting growth factor (e.g. Neulasta) or 7 days for short-acting growth
factor; for agents that have known adverse events occurring beyond 7 days after
administration, this 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 study chair

- Biologic (anti-neoplastic agent): at least 7 days after the last dose of a
biologic agent; for agents that have known adverse events occurring beyond 7 days
after administration, this 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 study chair

- Immunotherapy: at least 42 days after the completion of any type of
immunotherapy, e.g. tumor vaccines

- Monoclonal antibodies: at least 3 half-lives of the antibody after the last dose
of a monoclonal antibody

- Radiation therapy (XRT): at least 14 days after local palliative XRT (small
port); at least 150 days must have elapsed if prior total-body irradiation (TBI),
craniospinal XRT or if >= 50% radiation of pelvis; at least 42 days must have
elapsed if other substantial bone marrow (BM) radiation

- Stem cell infusion without TBI: no evidence of active graft versus (vs.) host
disease and at least 56 days must have elapsed after transplant or stem cell
infusion

- For patients with solid tumors without known bone marrow involvement:

- Peripheral absolute neutrophil count (ANC) >= 1000/mm^3

- Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving
platelet transfusions for at least 7 days prior to enrollment)

- Patients with known bone marrow metastatic disease will be eligible for study provided
they meet the blood counts (may receive transfusions provided they are not known to be
refractory to red cell or platelet transfusions); these patients will not be evaluable
for hematologic toxicity; at least 5 of every cohort of 6 patients with a solid tumor
must be evaluable for hematologic toxicity in the dose-escalation part of the study;
if dose-limiting hematologic toxicity is observed, all subsequent patients enrolled
must be evaluable for hematologic toxicity

- Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
ml/min/1.73 m^2 or a serum creatinine based on age/gender as follows:

- 2 to < 6 years: 0.8 mg/dL

- 6 to < 10 years: 1 mg/dL

- 10 to < 13 years: 1.2 mg/dL

- 13 to < 16 years: 1.5 mg/dL (male), 1.4 mg/dL (female)

- >= 16 years: 1.7 mg/dL (male), 1.4 mg/dL (female)

- Urine protein: =< 30 mg/dl in urinalysis or =< 1+ on dipstick, unless quantitative
protein is < 1000 mg in a 24 hour (h) urine sample

- Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for
age

- Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 110
U/L; for the purpose of this study, the ULN for SGPT is 45 U/L

- Serum albumin >= 2.8 g/dL

- Prothrombin time (PT) and international normalized ratio (INR) =< 1.5 x ULN

- Serum amylase =< 1.5 x ULN

- Serum lipase =< 1.5 x ULN

- A blood pressure (BP) =< the 95th percentile for age, height, and gender, and not
receiving medication for treatment of hypertension; please note that 3 serial blood
pressures should be obtained and averaged to determine baseline BP

- Central nervous system function defined as: patients with seizure disorder may be
enrolled if receiving non-enzyme inducing anticonvulsants and well controlled

- No history of congenital prolonged corrected QT interval (QTc) syndrome, New York
Heart Association (NYHA) class III or IV congestive heart failure (CHF)

- No clinically significant cardiac arrhythmias, stroke or myocardial infarction within
6 months prior to enrollment

- QTc =< 480 msec; Note: 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)

- 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

- Archival tumor tissue slides from either initial diagnosis or relapse must be sent; if
tumor tissue is unavailable, the study chair must be notified prior to enrollment

Exclusion Criteria:

- Pregnant or breast-feeding women will not be entered on this study; 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 contraceptive method of birth control - during
protocol therapy and for at least 4 months after the last dose of XL184; abstinence is
an acceptable method of birth control

- 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

- Patients who are currently receiving another investigational drug are not eligible

- Patients who are currently receiving other anti-cancer agents are not eligible

- Patients who are receiving cyclosporine, tacrolimus or other agents to prevent
graft-versus-host disease post bone marrow transplant are not eligible for this trial

- Patients must not be receiving any of the following potent cytochrome P450 family 3,
subfamily A, polypeptide 4 cytochrome (CYP3A4) inducers or inhibitors: erythromycin,
clarithromycin, ketoconazole, azithromycin, itraconazole, grapefruit juice or St.
John's wort

- Patients who are receiving systemic treatment anticoagulation are not eligible;
patients receiving prophylactic systemic anticoagulation will be allowed as long as
eligibility PT/INR requirements are met

- Patients must not have received enzyme-inducing anticonvulsants within 14 days prior
to enrollment

- Patients who are receiving drugs that prolong QTc are not eligible

- Patients must be able to swallow intact tablets; patients who cannot swallow intact
tablets are not eligible

- Patients with active bleeding are not eligible; specifically, no clinically
significant gastrointestinal (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

- Patients with evidence of an acute intracranial or intratumoral hemorrhage on computed
tomography (CT) or magnetic resonance imaging (MRI) are not eligible (patients with
evidence of resolving hemorrhage will be eligible)

- Patients who have had or are planning to have the following invasive procedures are
not eligible:

- Major surgical procedure, laparoscopic procedure, open biopsy or significant
traumatic injury within 28 days prior to enrollment

- Central line placement or subcutaneous port placement is not considered major
surgery but must be placed at least 3 days prior to enrollment for external lines
(e.g. Hickman or Broviac) and at least 7 days prior to enrollment for
subcutaneous port

- Core biopsy within 7 days prior to enrollment

- Fine needle aspirate within 7 days prior to enrollment

- Surgical or other wounds must be adequately healed prior to enrollment

- Patients on antihypertensive therapy for control of blood pressure at the time of
enrollment are not eligible

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

- Patients who have an uncontrolled infection are not eligible

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

- 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