Pazopanib Hydrochloride in Treating Patients With Advanced or Refractory Solid Tumors

PRIMARY OBJECTIVES:

I. To assess the feasibility and safety of individualizing pazopanib (pazopanib
hydrochloride) monotherapy based upon attained pazopanib plasma concentrations so as to
achieve desired target pazopanib plasma concentration in the highest possible fraction of
treated patients.

SECONDARY OBJECTIVES:

I. To assess whether patient cytochrome P450 (CYP) or other polymorphisms may correlate with
attained pazopanib levels in response to standard pazopanib dosing.

II. To assess whether patient trough pazopanib levels attained 24 hours after initiation of
800 mg daily fasting may predict steady state trough pazopanib levels after 14 days of
pazopanib administration.

III. To assess whether patient trough pazopanib levels may correlate with observed pazopanib
toxicities.

OUTLINE: This is a dose-escalation study.

Patients receive pazopanib hydrochloride orally (PO) once daily (QD) on days 1-28. Courses
repeat every 28 days in the absence of disease progression or unacceptable toxicity. Course
length can be extended to 56 days at the discretion of the treating physician after 12
courses (1 year) of treatment on study.

After completion of study treatment, patients are followed up for 3 months.

Inclusion Criteria:

- Histologic proof of cancer which is now not amenable to alternative curative or
clearly superior standard treatment options

- Measurable disease

- Hemoglobin (Hgb) >= 8.0 g/dL

- Absolute neutrophil count (ANC) >= 1,500/uL

- Platelet (PLT) = 100,000/uL

- Activated partial thromboplastin time (APTT) < 1.2 times upper limit of normal (ULN);
(Note: use of warfarin is prohibited; low molecular weight heparin is allowed, so long
as these criteria are met)

- International normalized ratio (INR) < 1.2 times ULN; (Note: use of warfarin is
prohibited; low molecular weight heparin is allowed, so long as these criteria are
met)

- Direct bilirubin =< 1.5 X upper limit of normal (ULN) (subjects with Gilbert's
syndrome and elevations of indirect bilirubin only are eligible)

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =<
2.5 X ULN

- Creatinine =< 1.5 times ULN OR measured creatinine clearance of >= 60 mL/min 1.73 m^2

- Urine protein/creatinine ratio < 1 or 24-hour urine < 1 gram

- < Grade 2 hypo/hyperkalemia

- < Grade 3 hypo/hypercalcemia

- < Grade 3 hypo/hyperphosphatemia

- < Grade 3 hypo/hypermagnesemia

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1

- Ability to provide informed consent

- Willing to return to Mayo Clinic for follow up

- Life expectancy >= 84 days (3 months)

- Willingness to provide mandatory blood samples for pazopanib drug level assessments
required for dosage adjustments, as well as for required pharmacogenomic studies

- Women of childbearing potential only: negative serum pregnancy test done =< 14 days
prior to registration

Exclusion Criteria:

- Known standard therapy for the patient's disease that is potentially curative or
definitely capable of extending life expectancy

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Corrected QT interval (QTc) >= 480 msec and/or 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

- Subjects 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; a subject who has a history of class II heart
failure and is asymptomatic on treatment may be considered eligible

- Active cardiac arrhythmia (except sinus arrhythmia, atrial fibrillation,
asymptomatic premature ventricular contractions [PVCs])

- Ejection fraction < institutional lower limit of normal (LLN) and/or history of
cardiomyopathy

- Receiving a medication with known risk of torsades de pointes; the following
medications are specifically prohibited: amiodarone, arsenic trioxide, bepridil,
chloroquine, chlorpromazine, cisapride, clarithromycin, disopyramide, dofetilide,
dolasetron, droperidol, erythromycin, halofantrine, haloperidol, ibutilide
levomethadyl, mesoridazine, methadone, pentamidine, pimozide, procainamide, quinidine,
sotalol, sparfloxacin, and thioridazine; patients should be watched carefully for
indications of torsades de pointes, such as syncope; performing additional
electrocardiograms (EKGs) on subjects who must take one or more of these medications
is not required; however, additional investigations, including EKGs, may be performed
as per the treating physician's judgment

- 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

- Any of the following prior therapies:

- Chemotherapy =< 28 days prior to registration

- Mitomycin C/nitrosoureas =< 42 days prior to registration

- Immunotherapy =< 28 days prior to registration

- Biologic therapy =< 28 days prior to registration

- Radiation therapy =< 28 days prior to registration

- Radiation to > 25% of bone marrow

- Failure to fully recover from acute, reversible effects of prior chemotherapy (other
anti-neoplastic therapy) and radiation therapy

- Subjects with known brain metastases

- Any of the following:

- Pregnant women

- Nursing women

- Men or women of childbearing potential who are unwilling to employ adequate
contraception

- Other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy
considered investigational (utilized for a non-Food and Drug Administration
[FDA]-approved indication and in the context of a research investigation); Note:
concomitant use of zoledronic acid, pamidronate or denosumab is allowed (and can be
initiated while patients are on study therapy at investigator discretion)

- Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment
of the investigator, would make the patient inappropriate for entry into this study or
interfere significantly with the proper assessment of safety and toxicity of the
prescribed regimens

- Immunocompromised patients (other than that related to the use of corticosteroids)
including patients known to be human immunodeficiency virus (HIV) positive with
cluster of differentiation (CD)4 counts < 200

- Receiving any other investigational agent

- Other active malignancy =< 3 years prior to registration; EXCEPTIONS: non-melanotic
skin cancer or carcinoma-in-situ of the cervix; NOTE: if there is a history or prior
malignancy, they must not be receiving other specific treatment (e.g. hormonal or
chemotherapy) for their cancer

- Prior use of pazopanib (prior use of other kinase inhibitors allowed)

- Receiving any medications or substances that are strong or moderate inhibitors of
cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) (indinavir, nelfinavir,
atazanavir, ritonavir, clarithromycin, itraconazole, voriconazole, ketoconazole,
nefazodone, saquinavir, telithromycin, aprepitant, erythromycin, fluconazole,
grapefruit juice, verapamil, diltiazem); use of the aforementioned strong or moderate
inhibitors is prohibited < 7 days prior to registration

- Receiving any medications or substances that are inducers of CYP3A4 (efavirenz,
nevirapine, carbamazepine, modafinil, phenobarbital, phenytoin, pioglitazone,
rifabutin, rifampin, St. John's wort); use of the aforementioned inducers is
prohibited =< 7 days prior to registration

- Receiving mitotane within 6 months of enrolling on the study

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

- Any lesion, whether induced by tumor, radiation or other conditions, which makes
it difficult to swallow capsules or pills

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

- Active peptic ulcer disease

- Malabsorption syndrome

- Any of the following conditions:

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

- Current use of therapeutic warfarin; Note: low molecular weight heparin is
allowed; prothrombin time (PT)/partial thromboplastin time (PTT) must meet the
inclusion criteria

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

- History of hemoptysis in excess of 2.5 mL (1/2 teaspoon ) within 8 weeks prior to
first dose of study drug

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

- HIV-positive patients on combination antiretroviral therapy; appropriate studies
will be undertaken in patients receiving combination antiretroviral therapy when
indicated

- Subjects 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