A Phase II Study of GW 786034 (Pazopanib) in Advanced Thyroid Cancer

Inclusion Criteria:

- Histologically or cytologically confirmed thyroid cancer that is now advanced or
metastatic disease

- One of the following subtypes:

- Differentiated thyroid cancer

- Absence of sensitivity to therapeutic radioiodine

- Medullary thyroid cancer

- Anaplastic thyroid cancer

- Patients with confirmed differentiated thyroid cancer (DTC) must be thyroglobulin
antibody negative to be enrolled in the expanded/additional DTC cohort

- Zero, one or two prior therapeutic regimens (this includes cytotoxic plus
non-cytotoxic therapeutic regimens)

- Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by
conventional techniques OR ≥ 10 mm by spiral computed tomography (CT) scan

- Objective evidence of tumor progression within the past 6 months, as assessed by the
following:

- Unequivocal progression of objectively measured disease on successive
appropriate imaging (e.g., CT scan); in cases of uncertainty of tumor
progression, the Principal Investigator of the study will be available to assist
in decisions

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2 OR Karnofsky PS
60-100%

- Life expectancy > 3 months

- Leukocytes ≥ 3,000/mcL

- Absolute neutrophil count ≥ 1,500/mcL

- Platelets ≥ 100,000/mcL

- Total bilirubin ≤ 1.5 times upper limit of normal (ULN) (direct bilirubin ≤ 1.5 times
ULN if patient has Gilbert syndrome)

- Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 2.5 times ULN

- Creatinine ≤ 1.5 times ULN

- Proteinuria ≤ 1+ on urinalysis

- No proteinuria > 1+ (< 30 mg/dL) on two consecutive dipstick or other urine
assessments taken at least 1 week apart

- International normalized ratio (INR) ≤ 1.2 times ULN

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception prior to and during study therapy

- Systolic blood pressure (BP) < 140 mm Hg and diastolic BP < 90 mm Hg

- Initiation or adjustment of BP medication is permitted prior to registration
provided the average of three BP readings at a visit prior to registration is <
140/90 mm Hg

- No sensitivity to therapeutic radioiodine (differentiated only)

- Able to understand and willing to sign a written informed consent document

- Willing to comply with the requirements of the study

- Willing to donate blood for correlative marker studies (only applicable to sites
within the United States)

- No admission for unstable angina, cardiac angioplasty, or stenting within the past 12
weeks

- At least 4 weeks since prior radiotherapy

- At least 4 weeks since prior major surgery

- No prior surgical procedure affecting absorption

- No requirement for IV alimentation

- No prior radiotherapy to ≥ 25% of bone marrow

- No concurrent octreotide

- Concurrent octreotide allowed provided tumor progression on this drug has been
demonstrated

- No other concurrent investigational agents

- No cytochrome (CYP) interactive medications prior to, during, and for at least 1-2
weeks after discontinuation from the study

- No concurrent antiretroviral therapy for human immunodeficiency virus (HIV)-positive
patients

- No concurrent medications or substances known to affect or with the potential to
affect the activity or pharmacokinetics of pazopanib hydrochloride

- No concurrent investigational or commercial agents or therapies other than those used
for this study with the intent to treat the patient's malignancy

- No concurrent therapeutic warfarin

- Low molecular weigh the paring and prophylactic low-dose warfarin allowed

- No more than 2 total prior cytotoxic or noncytotoxic therapeutic regimens

- Up to two total prior noncytotoxic or cytotoxic therapeutic regimens are allowed
provided therapy ceased > 21 days prior to registration

- No concurrent medications that are associated with a risk of QTc prolongation and/or
Torsades de Pointes

Exclusion Criteria:

- Thyroid lymphomas, sarcomas, or metastatic disease from other sites of origin to
thyroid

- Disease that is measurable by physical examination only

- Known active and/or untreated brain metastases and/or brain metastases requiring
ongoing therapy (e.g., corticosteroids)

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to pazopanib hydrochloride or other agents used in the study

- QTc prolongation (defined as a QTc interval ≥ 4800 msecs) or other significant
electrocardiogram (ECG) abnormalities (e.g., frequent ventricular ectopy or evidence
of ongoing myocardial ischemia); NOTE: the Principal Investigator of the study should
be contacted in the event of uncertainty related patient eligibility based upon ECG
changes

- Any condition that impairs the ability to swallow and retain pazopanib hydrochloride,
including any of the following:

- Gastrointestinal tract disease resulting in an inability to take oral medication

- Active peptic ulcer disease

- Any of the following conditions:

- Serious or nonhealing wound, ulcer, or bone fracture

- History of abdominal fistula

- Gastrointestinal perforation

- Active diverticulitis

- Intra-abdominal abscess or gastrointestinal tract bleeding within the past 28
days prior to registration

- History of cerebrovascular accident (CVA) within the past 6 months

- History of myocardial infarction, cardiac arrhythmia within the past 12 weeks

- History of venous thrombosis within the past 12 weeks

- NYHA class III or IV heart failure

- History of bleeding disorder including hemophilia, disseminated intravascular
coagulation, or any other abnormality of coagulation potentially predisposing
patients to bleeding

- Poorly controlled depression or anxiety disorder, or recent (≤ 6 months)suicidal
ideation

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection or psychiatric illness/social situations that would or might reasonably be
expected to limit compliance with study requirements