Pazopanib Hydrochloride in Treating Patients With Metastatic Kidney Cancer

PRIMARY OBJECTIVES:

I. To determine the efficacy of pazopanib hydrochloride (pazopanib) in non clear cell
metastatic renal cell cancer patients as assessed by the overall survival rate at 12 months.

SECONDARY OBJECTIVES:

I. To determine the rates of best tumor response at the end of the first two treatment cycles
of pazopanib in non clear cell metastatic renal cell cancer patients.

II. To determine the benefit of pazopanib in increasing progression free survival time.

III. To describe toxicity profile of pazopanib in non clear cell metastatic renal cell cancer
patients.

OUTLINE:

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.

After completion of study treatment, patients are followed up for 2 years.

Inclusion Criteria:

- Histological confirmation of non-clear cell renal cancer (including chromophilic
[papillary], chromophobic, oncocytic, sarcomatoid, collecting duct [Bellini's duct]),
translocation-type carcinoma or medullary renal cell carcinoma

- Up to one prior treatment for metastatic non clear cell carcinoma is allowed prior to
registration as long as the agent used to treat was not pazopanib

- Measurable or non-measurable metastatic disease

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2

- Absolute neutrophil count (ANC) >= 1500

- Platelets (PLT) >= 100,000

- Hemoglobin (HgB) > 9.0 g/dL; NOTE: subjects may not have had a transfusion within 7
days of registration

- Total bilirubin < 1.5 x upper limit of normal (ULN); NOTE: concomitant elevations in
bilirubin above 1.0 x ULN is not permitted

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN;
NOTE: concomitant elevations in ALT/AST above 1.0 x ULN is not permitted

- Urine protein to creatinine ratio (UPC) < 1; NOTE: if UPC >= 1, then a 24-hour urine
protein must be assessed; subjects must have a 24-hour urine protein value < 1 g to be
eligible

- Prothrombin time (PT) or international normalized ratio (INR) =< 1.2 x ULN; NOTE:
subjects receiving anticoagulant therapy are eligible if their INR is stable and
within the recommended range for the desired level of anticoagulation

- A female is eligible to enter and participate in this study if she is of:

- Non-childbearing potential (i.e., physiologically incapable of becoming
pregnant), including any female who has had:

- A hysterectomy

- A bilateral oophorectomy (ovariectomy)

- A bilateral tubal ligation

- Is post-menopausal

- Subjects not using hormone replacement therapy (HRT) must have experienced
total cessation of menses for >= 1 year and be greater than 45 years in age,
OR, in questionable cases, have a follicle stimulating hormone (FSH) value >
40 mIU/mL and an estradiol value < 40 pg/mL (< 140 pmol/L)

- Subjects using HRT must have experienced total cessation of menses for >= 1
year and be greater than 45 years of age OR have had documented evidence of
menopause based on FSH and estradiol concentrations prior to initiation of
HRT

- Childbearing potential, including any female who has had a negative serum
pregnancy test, =< 7 days prior to registration

- Agrees to use adequate contraception; acceptable contraceptive methods, when used
consistently and in accordance with both the product label and the instructions
of the physician, are as follows:

- Complete abstinence from sexual intercourse for 14 days before exposure to
investigational product, through the dosing period, and for at least 21 days
after the last dose of investigational product

- Oral contraceptive, either combined or progesterone alone

- Intrauterine device (IUD) or intrauterine system (IUS) with a documented
failure rate of less than 1% per year

- Male partner sterilization (vasectomy with documentation of azoospermia)
prior to the female subject's entry into the study, and this male is the
sole partner for that subject

- Double barrier method: condom and an occlusive cap (diaphragm or
cervical/vault caps) with a vaginal spermicidal agent
(foam/gel/film/cream/suppository)

- Subjects must provide written informed consent prior to performance of study-specific
procedures or assessments, and must be willing to comply with treatment and follow-up;
procedures conducted as part of the subject's routine clinical management (e.g., blood
count, imaging study) and obtained prior to signing of informed consent may be
utilized for screening or baseline purposes provided these procedures are conducted as
specified in the protocol

- Willing to return to Mayo Clinic enrolling institution for follow-up

Exclusion Criteria:

- Any of the following:

- Nursing women

- Pregnant women

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

- 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

- Prior history of receiving pazopanib treatments

- Uncontrolled intercurrent illness including, but not limited to:

- Ongoing or active infection

- Symptomatic anemia, uncontrolled hypertension (defined as systolic blood pressure
[SBP] of >= 140 mmHg or diastolic blood pressure [DBP] of >= 90mmHg)

- Symptomatic congestive heart failure as defined by the New York Heart Association
(NYHA); does not exclude class III congestive heart failure (CHF)

- Previously treated with therapies that are known to negatively impact cardiac
function (e.g. prior treatment with anthracyclines)

- Unstable angina pectoris

- Cardiac arrhythmia

- Evidence of active bleeding or bleeding diathesis

- Psychiatric illness/social situations that would limit compliance with study
requirements

- Or any other serious uncontrolled medical disorders in the opinion of the
investigator

- History of cerebrovascular accident including transient ischemic attack (TIA),
myocardial infarction, pulmonary embolism or untreated deep venous thrombosis (DVT),
coronary artery bypass graft surgery within 6 months prior to registration; Note:
subjects with recent DVT who have been treated with therapeutic anti-coagulating
agents for at least 6 weeks are eligible

- Receiving any other investigational agent which would be considered as a treatment for
the primary neoplasm

- Other active malignancy =< 5 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 for their cancer

- History or clinical evidence of central nervous system (CNS) metastases or
leptomeningeal carcinomatosis, except for individuals who have previously-treated CNS
metastases, are asymptomatic, and have had no requirement for steroids or anti-seizure
medication for 6 months prior to first dose of study drug; screening with CNS imaging
studies (computed tomography [CT] or magnetic resonance imaging [MRI]) is required
only if clinically indicated or if the subject has a history of CNS metastases

- Clinically significant gastrointestinal abnormalities that may increase the risk for
gastrointestinal bleeding including, but not limited to:

- Active peptic ulcer disease

- Known intraluminal metastatic lesion/s with risk of bleeding

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

- History of abdominal fistula, gastrointestinal perforation, or intra-abdominal
abscess =< 28 days prior to registration

- Clinically significant gastrointestinal abnormalities that may affect absorption
of investigational product including, but not limited to:

- Malabsorption syndrome

- Major resection of the stomach or small bowel

- Corrected QT interval (QTc) > 480 msecs using Bazett's formula

- Receiving any medications or substances with risk of torsades de pointes; Note:
medications or substances on the list "Drugs with Risk of Torsades de Pointes" are
prohibited; medications or substances on the list "Drugs with Possible or Conditional
Risk of Torsades de Pointes" may be used while on study with extreme caution and
careful monitoring

- Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels and/or
hemoptysis in excess of 2.5 mL (or one half teaspoon) =< 8 weeks of registration

- Treatment with any of the following anti-cancer therapies: radiation therapy, surgery
or tumor embolization, chemotherapy, immunotherapy, biologic therapy, investigational
therapy or hormonal therapy =< 14 days prior to registration

- Prior autologous or allogeneic organ or tissue transplantation

- Elective or planned major surgery to be performed during the course of the trial

- Receiving any medications or substances that are strong or moderate inhibitors of
cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4); use of the strong or
moderate inhibitors are prohibited =< 7 days prior to registration

- Receiving any medications or substances that are inducers of CYP3A4; use of inducers
are prohibited =< 7 days prior to registration