Phase I/II Trial of Vandetanib (ZD6474, ZACTIMA) in Children and Adolescents With Hereditary Medullary Thyroid Carcinoma

Inclusion Criteria

- 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.