Intensity-Modulated Radiation Therapy and Paclitaxel With or Without Pazopanib Hydrochloride in Treating Patients With Anaplastic Thyroid Cancer

PRIMARY OBJECTIVES:

I. To evaluate the safety of IMRT, paclitaxel, and pazopanib (pazopanib hydrochloride)
suspension. (Run-in component) II. To evaluate and compare overall survival at 1 year from
study registration. (Phase II component)

SECONDARY OBJECTIVES:

I. To evaluate local-regional control at 6 and 12 months. (Phase II component) II. To
evaluate the rate of grade 4 (Common Terminology Criteria for Adverse Events version 4.0
[CTCAE, v. 4.0]) hemorrhage, grade 4 febrile neutropenia, or any grade 5 adverse event
assessed to be definitely, probably, or possibly related to the induction or concurrent
treatment components of the protocol regimen. (Phase II component) III. To evaluate the rates
of other adverse events (CTCAE, v. 4.0) assessed to be definitely, probably, or possibly
related to the induction or concurrent treatment components of the protocol regimen. (Phase
II component) IV. To evaluate the rate of treatment discontinuation due to toxicity during
the induction or concurrent treatment components of the protocol regimen. (Phase II
component) V. To evaluate response (as per Response Evaluation Criteria in Solid Tumors
[RECIST]) of the primary site following the treatment component in subjects with measurable
disease prior to chemoradiation. (Phase II component)

OUTLINE:

RUN-IN COMPONENT: Patients receive paclitaxel intravenously (IV) over 1 hour once weekly and
pazopanib hydrochloride orally (PO) once daily (QD) for 2-3 weeks. Patients then receive
concurrent paclitaxel IV over 1 hour once weekly and pazopanib hydrochloride PO QD for 6-7
weeks (or until radiation treatment is completed) and intensity-modulated radiotherapy (IMRT)
5 days per week for 6.5 weeks (total of 66 Gy in 33 fractions). Beginning 25-31 days after
the completion of IMRT, patients receive paclitaxel IV over 1 hour once weekly and pazopanib
hydrochloride PO QD. Treatment repeats every 3 weeks for 4 courses (for patients with no
measurable disease) or continues in the absence of disease progression or unacceptable
toxicity (for patients with measurable disease).

RANDOMIZED PHASE II COMPONENT: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive paclitaxel IV over 1 hour once weekly and pazopanib hydrochloride PO
QD for 2-3 weeks. Patients then receive concurrent paclitaxel IV over 1 hour once weekly and
pazopanib hydrochloride PO QD for 6-7 weeks (or until radiation treatment is completed) and
IMRT 5 days per week for 6.5 weeks (total of 66 Gy in 33 fractions). Beginning 25-31 days
after the completion of IMRT, patients receive paclitaxel IV over 1 hour once weekly and
pazopanib hydrochloride PO QD. Treatment repeats every 3 weeks for 4 courses (for patients
with no measurable disease) or continues in the absence of disease progression or
unacceptable toxicity (for patients with measurable disease).

ARM II: Patients receive paclitaxel IV over 1 hour once weekly and placebo PO QD for 2-3
weeks. Patients then receive concurrent paclitaxel IV over 1 hour once weekly and placebo PO
QD for 6-7 weeks (or until radiation treatment is completed) and IMRT 5 days per week for 6.5
weeks (total of 66 Gy in 33 fractions). Beginning 25-31 days after the completion of IMRT,
patients receive paclitaxel IV over 1 hour once weekly and placebo PO QD. Treatment repeats
every 3 weeks for 4 courses (for patients with no measurable disease) or continues in the
absence of disease progression or unacceptable toxicity (for patients with measurable
disease).

After completion of study treatment, patients are followed up every 3 months for 2 years,
every 6 months for 1 year, and then annually thereafter.

Inclusion Criteria:

- Pathologically (histologically or cytologically) proven diagnosis of anaplastic
thyroid cancer (a diagnosis that is noted to be "consistent with anaplastic thyroid
cancer" with the presence of a thyroid mass is acceptable)

- Note: tissue collection for central review is mandatory, but central review is
not required for eligibility; treatment will be started prior to central review

- If there was a total or partial thyroidectomy completed within 3 months of enrollment,
the surgical specimen must show the area of anaplastic thyroid cancer to be at least 1
cm in greatest dimension

- The following minimum diagnostic workup is required:

- History/physical examination within 2 weeks prior to registration

- Imaging of neck and brain (computed tomography [CT] scan or magnetic resonance
imaging [MRI]) and chest/abdominal imaging (chest x-ray or chest CT scan, or full
body positron emission tomography [PET]/CT are acceptable) within 4 weeks prior
to registration

- Note: the CT scan of the neck must be done with contrast or if an MRI is done,
with gadolinium; therefore, the CT portion of a full body PET/CT has to be a high
resolution CT to be acceptable for eligibility

- Abdominal imaging must cover the liver and adrenal glands; therefore, separate
imaging is not required if these areas are covered by a chest CT scan

- Electrocardiogram within 10 days prior to registration

- Zubrod performance status 0-2

- Absolute neutrophil count (ANC) >= 1,500 cells/mm^3

- Platelets >= 100,000 cells/mm^3

- Hemoglobin (Hgb) >= 9.0 g/dL (Note: the use of transfusion or other intervention to
achieve Hgb >= 9.0 g/dL is acceptable)

- Total bilirubin < 1.5 x institutional upper limit of normal (ULN) (except for patients
with Gilbert's syndrome and elevations of indirect bilirubin)

- Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 2.5 x
institutional ULN; note: patients who have both bilirubin > ULN and AST/ALT > ULN are
not eligible (unless they have Gilbert's syndrome and elevations of indirect
bilirubin)

- Spot urine protein to creatinine ratio (UPCR) < 1 or a 24-hour urine protein
collection < 1 gm within 10 days prior to registration

- Creatinine < 1.5 mg/dL or within normal institutional limits within 10 days prior to
registration; Note: if neither criteria is met, the creatinine clearance must be > 50
mL/min/1.73 m^2 per either the Cockcroft-Gault equation, Jeliffe method, or 12- or
24-hour urine collection

- Serum electrolytes including sodium, potassium, blood urea nitrogen (BUN), creatinine,
glucose, magnesium, phosphate, and calcium within 10 days prior to registration

- Documentation of the patient's history of corrected QT interval (QTc) prolongation,
family history of prolonged QTc, and relevant cardiac disease within 10 days prior to
registration

- Evaluation of the patient's medications within 10 days prior to registration with
attempt to change any medication that affects cytochrome P450, family 3, subfamily A,
polypeptide 4 (CYP3A4)

- Blood pressure =< 140/90 within 10 days of registration (must be taken and recorded by
a health care professional); Note: if the systolic blood pressure is > 140 and/or
diastolic blood pressure is > 90 at the time of registration, the patient's blood
pressure must be controlled; systolic blood pressure must be < 140 and diastolic blood
pressure must be < 90 on at least 2 separate measurements prior to the start of
treatment, and the treating physician must believe that this is feasible in order to
enroll the patient

- Prothrombin time (PT)/international normalized ratio (INR)/partial thromboplastin time
(PTT) within 1.2 x the upper limit of normal within 10 days prior to registration
unless the patient is receiving coumadin and has a stable INR that is in range for the
desired level of anticoagulation

- Negative pregnancy test (serum or urine) within 10 days of registration in women of
child-bearing potential

- Women of childbearing potential and male participants who are sexually active must
agree to practice adequate contraception during treatment and for 6 months
post-treatment

- The patient must provide study specific informed consent prior to study entry

Exclusion Criteria:

- Known active invasive malignancy (except for non-melanomatous skin cancer or
anaplastic thyroid cancer; the presence of prostate cancer confined to the prostate
with a prostate-specific antigen [PSA] =< 1 ng/mL for more than 6 months also is
allowed)

- Prior systemic chemotherapy for anaplastic thyroid cancer

- Patients who have had chemotherapy or radiotherapy within 4 weeks of registration
(6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those
who have not recovered from adverse events due to agents administered > 4 weeks
previously

- Patients receiving other investigational agents

- Prior radiotherapy to the region of the study cancer that would result in overlap of
radiation therapy fields

- Patients with any of the following cardiovascular conditions within the past 6 months:

- Cerebrovascular accident (CVA) or transient ischemic attack (TIA)

- Admission for unstable angina

- Myocardial Infarction

- Cardiac angioplasty or stenting

- Coronary artery bypass graft surgery

- Pulmonary embolism, untreated deep venous thrombosis (DVT), or DVT which has been
treated with therapeutic anticoagulation for less than 6 weeks

- Arterial thrombosis

- Symptomatic peripheral vascular disease

- Class III or IV heart failure as defined by the New York Heart Association (NYHA)
functional classification system; Note: a patient who has a history of class III
heart failure and is asymptomatic on treatment may be considered eligible for the
study

- Certain medications that are associated with a risk for QTc prolongation and/or
torsades de pointes, although not prohibited, should be avoided or replaced with
medications that do not carry these risks, if possible

- Patients who require heparin (other than low-molecular weight heparin)

- Patients with any condition that may impair the ability to absorb oral
medications/investigational product including:

- Prior surgical procedures affecting absorption including, but not limited to,
major resection of stomach or small bowel

- Active peptic ulcer disease

- Malabsorption syndrome

- Patients with any condition that may increase the risk of gastrointestinal bleeding or
gastrointestinal perforation, including:

- Active peptic ulcer disease

- Known intraluminal metastatic lesions

- Inflammatory bowel disease (e.g., ulcerative colitis, Crohn's disease) or other
gastrointestinal conditions which increase the risk of perforation

- History of abdominal fistula, gastrointestinal perforation, or intra-abdominal
abscess within 28 days prior to beginning study treatment

- History of hemoptysis within 30 days of registration; Note: patients who have minimal
bleeding from the mouth, which is clearly not related to a source in the lungs, i.e.,
surgery such as a non-lung biopsy, are eligible only after good hemostasis has been
documented

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

- Pregnancy or women of childbearing potential and men who are sexually active and not
willing/able to use medically acceptable forms of contraception

- Prior allergic reaction to the study drug(s) involved in this protocol

- QTc prolongation defined as a QTc interval >= 480 msecs or other significant
electrocardiogram (EKG) abnormalities are ineligible; Note: if unsure about EKG
abnormality, the treating physician should discuss this with Drs. Sherman or Bible

- Known brain metastasis

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy

- Certain medications that act through the cytochrome P450 (CYP450) system are
specifically prohibited in patients receiving pazopanib and others should be avoided
or administered with extreme caution

- Strong inhibitors of CYP3A4 such as ketoconazole, itraconazole, clarithromycin,
atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir,
telithromycin, voriconazole may increase pazopanib concentrations and are
prohibited; although, in exceptional circumstances, they may be administered in
conjunction with lowering the dose of pazopanib by 50% of what would otherwise be
administered; grapefruit juice is also an inhibitor of CYP450 and should not be
taken with pazopanib

- Strong inducers of CYP3A4, such as rifampin, may decrease pazopanib
concentrations, are strictly prohibited

- Medications that have narrow therapeutic windows and are substrates of CYP3A4,
cytochrome P450, family 2, subfamily D, polypeptide 6 (CYP2D6), or cytochrome
P450, family 2, subfamily C, polypeptide 8 (CYP2C8) should be avoided and, if
necessary, administered with caution