Pazopanib Hydrochloride in Treating Patients With Advanced Thyroid Cancer
Pazopanib Hydrochloride in Treating Patients With Advanced Thyroid Cancer
This phase II trial studies the side effects and how well pazopanib hydrochloride works in
 treating patients with advanced thyroid cancer. Pazopanib hydrochloride may stop the growth
 of tumor cells by blocking some of the enzymes needed for cell growth and by stopping blood
 flow to the tumor.
PRIMARY OBJECTIVE:

 I. To establish the safety and efficacy of GW786034 (pazopanib hydrochloride) as a
 therapeutic in patients afflicted with differentiated, medullary and anaplastic thyroid
 cancers.

 CORRELATIVE OBJECTIVES:

 I. Assessment of the impact of therapy with GW786034 on serum/plasma vascular endothelial
 growth factor (VEGF) levels.

 II. To explore the potential relationship between changes in thyroglobulin levels and tumor
 response in patients with advanced differentiated thyroid cancer known to be thyroglobulin
 antibody negative.

 OUTLINE:

 Patients receive pazopanib hydrochloride orally (PO) once daily (QD) on days 1-28. Cycles
 repeat every 28 days in the absence of disease progression or unacceptable toxicity.

 After completion of study treatment, patients are followed up every 6 months for up to 3
 years after registration.
Inclusion Criteria:

 -  Histologically or cytologically confirmed differentiated, medullary or anaplastic
 thyroid cancer that is now advanced or metastatic; NOTE: patients with thyroid
 lymphomas or sarcomas are specifically excluded, as are patients with metastatic
 disease from other sites of origin to thyroid

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

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

 -  Absence of sensitivity to therapeutic radioiodine (differentiated only)

 -  Measurable disease, defined as at least one lesion that can be accurately measured in
 at least one dimension (longest diameter to be recorded) as > 20 mm with conventional
 techniques or as > 10 mm with spiral computed tomography (CT) scan; NOTE: disease that
 is measurable by physical examination only is not eligible

 -  Life expectancy > 3 months

 -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2
 (Karnofsky >= 60%)

 -  Leukocytes > 3,000/mcL obtained =< 7 days prior to registration

 -  Absolute neutrophil count > 1,500/mcL obtained =< 7 days prior to registration

 -  Platelets > 100,000/mcL obtained =< 7 days prior to registration

 -  Total bilirubin =< 1.5 X institutional upper limit of normal (ULN) obtained =< 7 days
 prior to registration (if there is reason to believe that the patient has Gilbert's
 syndrome, the bilirubin can be fractionated; if the fractionated bilirubin is
 consistent with Gilbert's syndrome and there is no other possible explanation for the
 elevated indirect bilirubin, the patient may be eligible for the study if and only if
 the direct bilirubin is =< 1.5 X institutional ULN)

 -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) <
 2.5 X institutional ULN obtained =< 7 days prior to registration

 -  Creatinine =< 1.5 X ULN obtained =< 7 days prior to registration

 -  Proteinuria =< + on urinalysis (may re-check) obtained =< 7 days prior to registration

 -  International normalized ratio (INR) =< 1.2 X the ULN obtained =< 7 days prior to
 registration

 -  Blood pressure (BP) < 140 mmHg (systolic) and < 90 mmHg (diastolic); initiation or
 adjustment of BP medication is permitted prior to registration provided that the
 average of three BP readings at a visit prior to registration is < 140/90 mmHg

 -  Objective evidence of tumor progression in the 6 month period prior to GW786034
 initiation as assessed by:

 -  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

 -  Women of child-bearing potential must have a negative serum pregnancy test =< 7 days
 prior to registration; NOTE: women of child-bearing potential and men must agree to
 use adequate contraception (hormonal or barrier method of birth control; abstinence)
 prior to study entry and for the duration of study participation; should a woman
 become pregnant or suspect she is pregnant while participating in this study, she
 should inform her treating physician immediately; effective contraception is required
 for all fertile participants in the trial

 -  Ability to understand and the willingness to sign a written informed consent document

 -  Willingness to comply with the requirement of the study

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

 Exclusion Criteria:

 -  Anaplastic, differentiated, medullary: a total of > 2 prior therapeutic regimens (this
 total includes cytotoxic plus non-cytotoxic regimens); Note: enrollment of anaplastic,
 differentiated, and medullary patients who have had zero, one or two prior therapeutic
 regimens (cytotoxic plus non-cytotoxic regimens) is allowed - provided therapy ceased
 > 21 days prior to registration;

 -  NOTE: the principal investigator of the study should be contacted in the event of
 uncertainty related patient eligibility based upon prior therapies

 -  Disease that is measurable by physical examination only

 -  Any of the following:

 -  Radiotherapy =< 4 weeks prior to registration

 -  Major surgery =< 4 weeks prior to registration

 -  Radiotherapy to >= 25% of bone marrow

 -  Concurrent therapy with octreotide unless tumor progression on this therapy has
 been demonstrated

 -  Any other ongoing investigational agents

 -  History of allergic reactions attributed to compounds of similar chemical or biologic
 composition to GW786034 (pazopanib) or other agents used in the study

 -  > +1 proteinuria (< 30 mg/dL) on two consecutive dipstick or other urine assessments
 taken at least 1 week apart; NOTE: (in cases where questions arise related to
 disparate proteinuria measurements, the study principal investigator [PI] should be
 consulted for assistance in determining patient study eligibility)

 -  Corrected QT interval (QTc) prolongation (defined as a QTc interval >= 480 msecs) or
 other significant electrocardiogram (ECG) abnormalities (e.g. frequent ventricular
 ectopy, 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

 -  Receiving cytochrome P450 (CYP) interactive concomitant medications; certain
 medications that act through the CYP450 system are specifically prohibited in patients
 receiving GW786034 (pazopanib) because in vitro data indicate that the agent has the
 potential to interact with the cytochrome P450 isoenzymes cytochrome P450, family 2,
 subfamily C, polypeptide 9 (CYP2C9) and cytochrome P450, family 3, subfamily A,
 polypeptide 4 (CYP3A4); certain other agents should be used with caution

 -  Any condition (e.g., gastrointestinal tract disease resulting in an inability to take
 oral medication or a requirement for IV alimentation, prior surgical procedures
 affecting absorption, or active peptic ulcer disease) that impairs their ability to
 swallow and retain GSK786034 (pazopanib)

 -  Any of the following conditions:

 -  Serious or non-healing wound, ulcer, or bone fracture

 -  History of abdominal fistula, gastrointestinal perforation, active
 diverticulitis, intra-abdominal abscess or gastrointestinal tract bleeding =< 28
 days of registration

 -  Any history of cerebrovascular accident (CVA) =< 6 months

 -  Current use of therapeutic warfarin; Note: low molecular weight heparin and
 prophylactic low-dose warfarin (INR < 1.2 X ULN) are permitted; prothrombin time
 (PT)/partial thromboplastin time (PTT) must meet the inclusion criteria

 -  History of myocardial infarction, cardiac arrhythmia, admission for unstable
 angina, cardiac angioplasty or stenting within the last 12 weeks

 -  History of venous thrombosis in last 12 weeks

 -  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 II
 heart failure and is asymptomatic on treatment may be considered eligible

 -  History of bleeding disorder, including patients afflicted with 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

 -  Known active and/or untreated brain metastases and/or brain metastases requiring
 ongoing therapy (e.g. corticosteroids); NOTE: (because of the poor prognosis often
 associated with brain metastases and because of the potential risk of bleeding in
 active brain metastases associated with multi-targeted tyrosine kinase inhibitor
 therapy, patients with active and/or untreated brain metastases and/or those with
 brain metastases requiring ongoing therapy - e.g. corticosteroids - are excluded from
 trial enrollment; enrollment will, however, be permitted in cases of patients with
 longstanding treated and inactive brain metastases not requiring ongoing therapy,
 providing that stability of brain metastases has been demonstrated for a period of 3
 months or greater as assessed by intracranial imaging - and providing that there is no
 indication of increased vascularity of the treated metastases by magnetic resonance
 imaging (MRI) imaging conducted =< 14 days prior to registration; when questions arise
 related to these criteria, the PI of the trial, Dr. Keith Bible, should be contacted
 for assistance on eligibility)

 -  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

 -  Pregnant women; NOTE: (breastfeeding should be discontinued if the mother is treated
 with GW786034/pazopanib)

 -  Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
 therapy; NOTE: (appropriate studies will be undertaken in patients receiving
 combination antiretroviral therapy when indicated)

 -  Receiving any medications or substances known to affect or with the potential to
 affect the activity or pharmacokinetics of GW786034 (pazopanib); NOTE: the eligibility
 of patients will be determined following review of their case by the principal
 investigator; efforts should be made to switch patients who are taking enzyme-inducing
 anticonvulsant agents to other medications

 -  Receiving any concomitant medications that are associated with a risk of QTc
 prolongation and/or Torsades de Pointes; NOTE: these medications should be
 discontinued or replaced with drugs that do not carry these risks, if possible