Sunitinib Malate in Treating Patients With Persistent or Recurrent Clear Cell Ovarian Cancer

PRIMARY OBJECTIVES:

I. To evaluate the anti-tumor activity of SU11248 (sunitinib malate), a highly potent,
selective tyrosine kinases inhibitor, in patients with persistent or recurrent clear cell
ovarian carcinoma.

II. To examine the nature and degree of toxicity in this cohort of patients treated with this
regimen.

SECONDARY OBJECTIVES:

I. To characterize the distribution of progression-free survival and overall survival for
patients treated with SU11248 (sunitinib malate).

TERTIARY OBJECTIVES:

I. To determine the pre-cycle 1, pre-cycle 4 and off-treatment levels of pro-angiogenic
proteins (e.g., angiogenin, soluble vascular cell adhesion molecule [VCAM]-I, basic
fibroblast growth factor [bFGF], platelet-derived growth factor [PDGF], placental growth
factor [PlGF], vascular endothelial growth factor [VEGF], and hypoxia-inducible factor
[HIF]1alpha).

II. To identify changes in serum and plasma angiogenesis markers at baseline (pre-cycle 1),
during treatment (cycle 4), and at progression in association with primary and secondary
clinical endpoints associated with clinical response or progression-free survival.

OUTLINE:

Patients receive sunitinib malate orally (PO) once daily (QD) for 4 weeks. Courses repeat
every 6 weeks in the absence of disease progression or unacceptable toxicity.

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

Inclusion Criteria:

- Patients must have recurrent or persistent clear cell ovarian cancer; primary tumors
must be at least 50% clear cell histomorphology in order to be eligible or have a
histologically documented recurrence with at least 50% clear cell histomorphology; in
addition, the tumors should be negative for expression of Wilms tumor (WT)-1 antigen
and estrogen receptor (ER) antigen by immunohistochemistry; appropriate tissue
sections must be available for histologic evaluation for central pathology review by
Gynecologic Oncology Group (GOG); immunohistochemical stained slides for ER and WT-1
antigen must be available for review by GOG

- If the primary tumor had at least 50% clear cell histomorphology, a biopsy of the
recurrent or persistent tumor is not required; however, immunohistochemical
studies of the primary tumor for ER and WT-1 antigens should be performed and the
slides submitted to the GOG for review; the percentage of clear cell
histomorphology must be documented in the pathology report or in an addendum to
the original report; if slides of the primary tumor are not available for review
due to disposal of slides by the histology laboratory (typically 10 years after
diagnosis), biopsy of recurrent or persistent disease is required

- If the primary tumor had less than 50% clear cell histomorphology (or if slides
of the primary tumor are not available for review), a biopsy of the recurrent or
persistent tumor is required to confirm at least 50% clear cell histomorphology
and lack of immunoreactivity for ER and WT-1 antigens by immunohistochemistry;
the percentage of involvement must be documented in the pathology report or in an
addendum to the original report

- All patients must have measurable disease as defined by Response Evaluation Criteria
In Solid Tumors (RECIST) 1.1; measurable disease is defined as at least one lesion
that can be accurately measured in at least one dimension (longest diameter to be
recorded); each lesion must be >= 10 mm when measured by computed tomography (CT),
magnetic resonance imaging (MRI) or caliper measurement by clinical exam; or >= 20 mm
when measured by chest x-ray; lymph nodes must be >= 15 mm in short axis when measured
by CT or MRI

- Patients must have at least one "target lesion" to be used to assess response on this
protocol as defined by RECIST 1.1; tumors within a previously irradiated field will be
designated as "non-target" lesions unless progression is documented or a biopsy is
obtained to confirm persistence at least 90 days following completion of radiation
therapy; thus, a confirmed biopsy in an irradiated area at a date longer than 90 days
post-completion of radiation can be considered a target lesion to assess progression
and response

- Patients must have had one prior platinum-based chemotherapeutic regimen for
management of primary disease containing carboplatin, cisplatin, or another
organoplatinum compound; this initial treatment may have included intraperitoneal
therapy, consolidation, or extended therapy administered after surgical or
non-surgical assessment

- Patients are allowed to receive, but are not required to receive, one additional
cytotoxic regimen for management of recurrent or persistent disease according to the
following definition:

- Cytotoxic regimens include any agent that targets the genetic and/or mitotic
apparatus of dividing cells, resulting in dose-limiting toxicity to the bone
marrow and/or gastrointestinal mucosa

- Patients who have received only one prior cytotoxic regimen (platinum-based regimen
for management of primary disease) must have a platinum-free interval of less than 12
months, or have progressed during platinum-based therapy, or have persistent disease
after a platinum-based therapy

- Patients may have received prior biologic therapy, but must not have had any prior
therapy with agents which inhibit VEGF, vascular endothelial growth factor receptor
(VEGFR) or PDGF such as, bevacizumab, sorafenib, sunitinib, pazopanib, brivanib,
aflibercept cediranib, BIBF 1120, imatinib, dasatinib

- Any other prior therapy directed at the malignant tumor, including immunologic agents
(e.g. tamoxifen) must be discontinued at least three weeks prior to registration

- Patients must not be eligible for a higher priority (e.g.; Phase III), GOG protocol
for the same population if one exists

- Patients must be recovered from effects of recent surgery (28 days must elapse between
surgery and the start of treatment with sunitinib malate)

- Patents must have >= 4 weeks since prior chemotherapy or radiation (>= 6 weeks for
nitrosoureas or mitomycin C)

- Sunitinib metabolizes via liver enzyme, specifically the cytochrome P450 family 3,
subfamily A, polypeptide 4 (CYP3A4) enzyme; therefore, potential drug interaction with
the CYP3A4 enzyme can occur; eligible patients who are on the CYP3A4 inducer or
inhibitor enzyme should stop 2 weeks prior to study entry if all other eligibility has
been confirmed; the principal investigator will review the case and make all effort to
switch such agent to other medication

- Patients should be free of active infection (with the exception of uncomplicated
urinary tract infections [UTI]) requiring antibiotics

- Patients who have received one prior regimen must have a GOG performance status of 0,
1 or 2; patients who have received two prior regimens must have GOG performance status
of 0 or 1

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

- Platelets greater than or equal 100,000/mcl

- Creatinine less than or equal to 1.5 times the upper limit of normal (ULN)

- Bilirubin less than or equal to 1.5 ULN

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal
to 2.5 times the ULN, unless subjects have liver metastasis, in which case both AST
and ALT must be less than or equal to 5 times the ULN

- Patients who have met the pre-entry requirements

- Patients must have signed an approved informed consent and authorization permitting
release of personal health information

Exclusion Criteria:

- Primary peritoneal or fallopian tube primaries are not eligible

- Patients with serious non-healing wound, ulcer, or bone fracture

- Patients with active bleeding or pathologic conditions that carry high risk of
bleeding, such as known bleeding disorder, coagulopathy, or tumor involving major
vessels

- Patients with history or evidence upon physical examination of central nervous system
(CNS) disease, including primary brain tumor, seizures not controlled with standard
medical therapy, any brain metastases, or history of cerebrovascular accident (CVA,
stroke), transient ischemic attack (TIA) or subarachnoid hemorrhage within 6months of
the first date of treatment on this study

- Patients with clinically significant cardiovascular disease; this includes:

- Poorly controlled hypertension (systolic blood pressure of >= 140 mm Hg or
diastolic blood pressure of >= 90 mm Hg) are ineligible

- Myocardial infarction or unstable angina within 6 months prior to registration

- New York Heart Association (NYHA) grade II or greater congestive heart failure

- Cardiac arrhythmia requiring medication

- Grade II or greater peripheral vascular disease based on National Cancer
Institute Common Terminology Criteria (NCI CTC); e.g. ischemic rest pain, minor
tissue loss, and ulceration or gangrene

- Patients with QTc prolongation (> 500 msec) are excluded

- Patients who require use of therapeutic doses of Coumadin-derivative anticoagulants
such as warfarin are ineligible, although doses of up to 2 mg daily are permitted for
prophylaxis of thrombosis; low molecular weight heparin is permitted provided
patient's prothrombin time (PT) international normalized ratio (INR) is =< 1.5

- Patients with clinically significant peripheral artery disease, e.g., those with
claudication, within 6 months

- Patients with a pre-existing thyroid abnormality who are unable to maintain thyroid
function in the normal range with medication are ineligible; patients with a history
of hypothyroidism are eligible provided they are currently euthyroid

- Patients whose circumstances do not permit completion of the study or the required
follow-up

- Patients who are pregnant or nursing; to date, no fetal studies in animals or humans
have been performed; the possibility of harm to a fetus is likely; this drug
specifically inhibits VEGF, which is responsible for formation of new blood vessels
during development, and antibodies can cross the placenta; therefore, it should not be
administered to pregnant women; subjects will be apprised of the large potential risk
to a developing fetus; it is not known whether the drug is excreted in human milk;
because many drugs are excreted in human milk, this drug should not be administered to
nursing women; women of childbearing potential must agree to use contraceptive
measures during study therapy and for at least 3 months after completion of therapy; a
negative serum pregnancy test within 72 hours of starting drug is required

- Patients who have a major surgical procedure, or significant traumatic injury within
28 days prior to the first date of treatment on this study, or anticipation of need
for major surgical procedure during the course of the study; patients with placement
of vascular access device or core biopsy within 7 days prior to the first date of
treatment on this study

- Patients with other invasive malignancies, with the exception of non-melanoma skin
cancer, who had (or have) any evidence of other cancer present within the last 5 years
or whose previous cancer treatment contraindicates this protocol therapy

- Patients who have received prior therapy with this drug