Pharmacokinetic-Driven Individualization of Pazopanib Therapy in Patients With Solid Tumors: a Phase I Study

Inclusion Criteria:

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

- Measurable disease

- No known standard therapy for the patient's disease that is potentially curative or
definitely capable of extending life expectancy

- No subjects with known brain metastases

- Hemoglobulin (Hgb) ≥ 8.0 g/dL

- Absolute neutrophil count (ANC) ≥ 1,500/μL

- Platelet (PLT) ≥ 100,000/μL

- Activated partial thromboplastin time(APTT) < 1.5 times upper limit of normal (ULN)

- International normalized ratio(INR) < 1.5 times ULN

- Direct bilirubin ≤ ULN (subjects with Gilbert syndrome and elevations of indirect
bilirubin only are eligible)

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) ≤
ULN

- Creatinine ≤ 1.5 times ULN OR measured creatinine clearance of ≥ 60mL/min

- 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

- No 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

- No QTc > 500 msec and/or receiving any concomitant medications that are associated
with a risk of QTc prolongation and/or Torsades de Pointes; these medications should
be discontinued or replaced with drugs that do not carry these risks

- No 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 6weeks

- Arterial thrombosis

- Symptomatic peripheral vascular disease

- Class III or IV heart failure as defined by the 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

- No blood pressure (BP) > 140 mm Hg (systolic) and > 90 mm Hg (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 mm Hg

- None of the following:

- Pregnant women

- Nursing women

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

- No immunocompromised patients (other than that related to the use of corticosteroids)
including patients known to be HIV positive with CD4count < 200/μL

- No 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

- No 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

- No 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

- None of the following conditions:

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

- 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 (½ teaspoon) within8 weeks prior to
first dose of study drug

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

- HIV-positive patients on combination antiretroviral therapy

- No 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 disease) or other
gastrointestinal conditions which increase the risk of perforation

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

- No failure to fully recover from acute, reversible effects of prior chemotherapy
(other anti-neoplastic therapy) and radiation therapy

- Not 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

- None of the following 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

- No current use of therapeutic warfarin

- Low molecular weight heparin and prophylactic low-dose warfarin (INR < 1.2 times
ULN) are permitted

- Prothrombin time(PT)/partial thromboplastin time(PTT) must meet the
inclusion criteria

- No other concurrent chemotherapy, immunotherapy, radiotherapy, or anyancillary
therapy considered investigational (utilized for a non-Food and Drug Administration
[FDA]-approved indication and in the context of a research investigation)

- Concomitant use of zoledronic acid, pamidronate, or denosumab is allowed (and
can be initiated while patients are on study therapy at investigator discretion)

- Not receiving any other investigational agent

- No prior use of pazopanib (prior use of other kinase inhibitors allowed)

- Not receiving any medications or substances that are strong or moderate inhibitors of
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

- Not receiving any medications or substances that are inducers of CYP3A4 (efavirenz,
nevirapine, carbamazepine, modafinil, phenobarbital, phenytoin, pioglitazone,
rifabutin, rifampin, St. John wort); use of the aforementioned inducers is prohibited
≤ 7 days prior to registration

- Not receiving mitotane within 6 months of enrolling on the study