Vandetanib to Treat Children and Adolescents With Medullary Thyroid Cancer

BACKGROUND:

Hereditary medullary thyroid carcinoma (MTC), which is a rare calcitonin-producing tumor
arising from the parafollicular C cells of the thyroid, is often a manifestation of multiple
endocrine neoplasia (MEN) types 2A and 2B and can be detected in children as young as five
years in MEN 2A and one year in those with MEN 2B

MEN results from an activating mutation in the RET proto-oncogene resulting in a
constitutively activated receptor tyrosine kinase (RTK)

Vandetanib is an orally bioavailable multi-RTK inhibitor that blocks the mutant RET gene
product and has anti-tumor activity in adults with hereditary MTC

OBJECTIVES:

To assess the activity of vandetanib in children and adolescents with hereditary MTC using
RECIST (primary endpoint), tumor biomarkers and tumor-related diarrhea

To assess the safety and tolerance of navdetanib in children and adolescents at a dose
equivalent to the recommended dose in adults

To assess the pharmacokinetics of vandetanib at steady state in children and adolescents

Secondary objectives include monitoring progression-free and overall survival, assessing RET,
EGFR, VEGFR andsomatostatin receptor expression in archival tumor tissue, assessing changes
in DNA mutations in RET in tumor tissue vs germ line in PBMC and after treatment; assessing
gene expression and gains/lossess of DNA in tumor tissue at baseline, during treatment and at
the time of progression; establishment of pediatric MTC cell lines sensitive and resistant
cells lines in vitro

ELIGIBILITY:

Children and adolescents 5 to 18 years of age (inclusive) with unresectable, recurrent or
metastatic hereditary medullary thyroid carcinoma

Measurable disease by RECIST (Response Evaluation Criteria in Solid Tumors)

DESIGN:

Vandetanib will be administered as a once daily dose, continuously (1 cycle equals 28 days)
at a dose of 150 mg,m(2), per day

To ensure the safety of the adult dose in children and adolescents, a limited intra-patient
dose escalation will be performed in the initial cohort of patients, with older patients (13
to18yrs) being studied before younger patients (5 to12 yrs)

Patients wil be enrolled at a dose of 100mg, m(2), per day (180 mg per day in adults) for two
28 day cycles and escalated to 150 mg, m(2), per day (270 mg, per day in adults) on cycle 3,
if dose limiting toxicity was not observed at the lower dose. If the 150mg, m(2), per day
dose level is tolerable on cycles 3 and 4, all subsequent patients will be enrolled at this
dose level

Pharmacokinetics of vandetanib will be studied at steady state at the end of cycle 2 and
trough levels will be obtained prior to the second dose on cycle 1, and on day 1 of cycles
2-5.

Responsible of measurable tumors will be assessed by RECIST. Biomarker and clinical response
will also be monitored. Twenty one patients will be studied to determine if the response rate
in children and adolescents with hereditary MTC is consistent with the 28 percent objective
response rate in adults

- INCLUSION CRITERIA:

Age: Participants must be 5 to 18 years of age, inclusive. The first cohort of 3 to 6
participants enrolled on the trial will be at least 13 years of age.

Diagnosis: Hereditary (MEN 2A or MEN 2B) medullary thyroid carcinoma (histologically
confirmed) that is unresectable, recurrent or metastatic. Participants must have previously
had a characteristic germline mutation in the RET proto-oncogene documented. Results of the
germline mutation testing will be obtained from the referring institution.

Participants must have measurable disease as defined in RECIST as the presence of at least
one lesion that can be accurately measured in at least one dimension with longest diameter
of at least 20 mm using conventional techniques or at least 10 mm with spiral CT scan.
Superficial (easily palpable) lymph nodes will be considered measurable.

Participants must be able to take one of theoral formulations of vandetanib.

Prior therapy: There are no standard chemotherapy regimens known to be effective for MTC.
Therefore, previously untreated partipants are eligible if their tumor(s) are not
surgically resectable.

Participants must be at least 4 weeks from prior surgical procedures and surgical incisions
must be healed.

Participants must have had their last fraction of external beam radiation therapy at least
4 weeks prior to enrollment.

Participants must have had their last dose of cytotoxic chemotherapy at least 28 days prior
to enrollment, their last dose of biological therapy, such as biological response modifiers
(e.g., cytokines), immunomodulatory agents, vaccines, differentiating agents, used to treat
their cancer at least 7 days prior to enrollment, their last dose of a monoclonal antibody
at least 30 days prior to enrollment, and their last dose of any investigational agent at
least 30 days prior to enrollment.

Participants must have received their last dose of short acting colony stimulating factor,
such as filgrastim or sargramostim at least 72 hours prior to enrollment and their last
dose of long-acting colony stimulating factors, such as PEG-filgrastim at least 7 days
prior to enrollment.

Participants must have recovered from the acute toxic effects of prior therapy to a grade 1
(CTCAE v.3.0) level prior to enrollment.

Performance Status: Lansky (for participants 10 years of age or younger) or Karnofsky (for
participants older than 10 years) performance score greater than 50

Concomitant Medications:

Participants who have previously had a thyroidectomy should be on thyroid hormone
replacement therapy.

Hematological Function: The peripheral absolute neutrophil count must be at least 1,500
micro liters and the platelet count must be at least 100,000 micro liters within 72 hours
prior to enrollment.

Coagulation: PT and PTT must not be more than 1.5 x ULN within 72 hours prior to
enrollment. PT and PTT should drawn by venipuncture, rather than from a central venous
catheter when feasible.

Hepatic Function:

Bilirubin must not be more than 1.5 x ULN and the AST and ALT must not be more than 2.5 x
ULN within 72 hours prior to enrollment. AST and ALT may be up to 5 x ULN within 72 hours
prior to enrollment in participants with hepatic metastases.

Renal Function: Participants must have an age-adjusted normal serum creatinine or a
creatinine clearance of at least 60 ml/min/1.73 m2.

Birth Control: Participants of child-bearing or child-fathering potential must be willing
to use a medically effective form of birth control, which includes abstinence, while taking
vandetanib and for 2 months after the last dose.

Negative pregnancy test for women of childbearing potential.

Informed Consent: Participants who are 18 years of age or legal guardians of participants
who are younger than 18 years must sign an informed consent for the POB Screening Protocol
prior to participating in studies required to determine eligibility for this trial. After
confirmation of eligibility, participants or legal guardians of minor participants must
sign an informed consent document for this trial, indicating that they are aware of the
investigational nature of the proposed treatment, the risks and benefits of participating
and the alternatives to participating.

EXCLUSION CRITERIA:

Pregnant or breast feeding females because the anti-angiogenic properties of vandetanib may
be harmful to the developing fetus or nursing infant.

Participants with pheochromocytoma as evidenced by elevated plasma free metanephrines.

Electrolytes: Participants with a serum potassium less than 3.5 mmol/L or a serum calcium
or magnesium below the lower limits of normal. Correction of these electrolyte
abnormalities with supplements is allowed.

Cardiac:

Participants with a history of arrhythmia (multifocal premature ventricular contractions,
bigeminy, trigeminy, ventricular tachycardia, uncontrolled atrial fibrillation, left bundle
branch block) that is symptomatic or requires treatment (except for controlled atrial
fibrillation)

Participants with a history of congenitally prolonged QTc, a first degree relative with
unexplained sudden death under 40 years of age, or a measured QTc (Bazett s correction)
longer than 480 msec on ECG. ECGs should be performed after correction of electrolyte
abnormalities. Participants with a prolonged QTc should have a repeat ECG at least 24 hour
after the first, and the mean of the 2 QTcs should not exceed 480 msec.

Participants who experienced QTc prolongation with other medications requiring
discontinuation of that medication.

Participants receiving a medication that has a known risk of QTc prolongation within 14
days (28 days for levomethadyl) of enrollment.

Hypertension: Diastolic blood pressure above the 95% for age on at least 2 of 3
measurements with an appropriate-size cuff or patients who are currently taking
anti-hypertensive therapy.

Other clinically severe or uncontrolled systemic illness that could compromise the
participants ability to tolerate vandetanib or could compromise study procedures or
endpoints.