Irinotecan and Bevacizumab for Recurrent Ovarian Cancer

Accumulating data suggests that angiogenesis plays a critical role in the formation and
development of a number of solid tumors including ovarian cancer. For women with ovarian
cancer, a direct relationship between vascular endothelial growth factor (VEGF) expression
and tumor vascularity has been documented. In vivo and in vitro data has demonstrated that
increased angiogenesis and microvessel density are negative prognostic factors for women
with ovarian cancer. These observations have fueled interest in incorporating
anti-angiogenic agents into ovarian cancer treatment regimens.

Several phase II trials of irinotecan in patients with epithelial ovarian cancer showed that
the drug had efficacy in both chemotherapy-naïve patients and in those who had been
previously treated with standard therapies, including platinum-based compounds, radiation,
or both. Combination of bevacizumab, an antibody against VEGF, and irinotecan was studied in
colorectal cancer and malignant brain neoplasms. In these trials, the combination was shown
to be safe and effective.

The purpose of this study is to evaluate the efficacy and toxicity of irinotecan in the
treatment of women with recurrent epithelial ovarian cancer or primary peritoneal cancer
when combined with bevacizumab. In this phase II open-label study patients will be treated
with bevacizumab 15 mg/kg and irinotecan 175mg/m^2 every 3 weeks. Patients will undergo
pre-treatment evaluation within 4 weeks of enrolling into the study. Clinical and laboratory
evaluation will be performed every 3 weeks. Imaging studies and CA-125 measurements will be
used to assess response to treatment.

Inclusion Criteria:

- Women with recurrent epithelial ovarian cancer, fallopian tube cancer, or primary
peritoneal carcinoma

- Patient should have measurable or evaluable disease as defined by the following.

- Measurable disease: At least one lesion that can be accurately measured in at least
one dimension (longest dimension to be recorded). Each lesion must be ≥ 20 mm when
measured by conventional techniques, including palpation, plain x-ray, CT and MRI, or
≥ 10 mm when measured by spiral CT.

- Evaluable (nonmeasurable) disease: Patients who do not meet measurable criteria will
be eligible having known disease with CA125 levels >50 U/mL on two occasions at least
one week apart. They will be considered for CA125 response criteria.

- Any number of prior chemotherapy regimens

- Any number of prior bevacizumab-containing regimens

- No chemotherapy within the last 2 weeks prior to initiating this study.

- Karnofsky Performance status score ≥ 60%.

- Patients must have a life expectancy ≥ 12 weeks.

- Patients must be at least 18 years of age.

- Patients must understand and willingly sign an approved informed consent.

Exclusion Criteria:

- Inability to comply with study and/or follow-up procedures

- Life expectancy of less than 12 weeks

- Current, recent (within 4 weeks of the first infusion of this study), or planned
participation in an experimental drug study other than a Genentech-sponsored
bevacizumab cancer study

- Active malignancy, other than superficial basal cell and superficial squamous (skin)
cell, or carcinoma in situ of the cervix within last five years

Bevacizumab-Specific Exclusions

- Inadequately controlled hypertension (defined as systolic blood pressure > 150 mmHg
and/or diastolic blood pressure > 100 mmHg)

- Prior history of hypertensive crisis or hypertensive encephalopathy

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

- History of myocardial infarction or unstable angina within 6 months prior to Day 1

- History of stroke or transient ischemic attack within 6 months prior to Day 1 Known
central nervous system disease, except for treated brain metastasis

- Treated brain metastases are defined as having no evidence of progression or
hemorrhage after treatment and no ongoing requirement for dexamethasone, as
ascertained by clinical examination and brain imaging (MRI or CT) during the
screening period. Anticonvulsants (stable dose) are allowed. Treatment for brain
metastases may include whole brain radiotherapy (WBRT), radiosurgery (RS; Gamma
Knife, LINAC, or equivalent) or a combination as deemed appropriate by the treating
physician. Patients with CNS metastases treated by neurosurgical resection or brain
biopsy performed within 3 months prior to Day 1 will be excluded

- Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or
recent peripheral arterial thrombosis) within 6 months prior to Day 1

- History of hemoptysis (>= 1/2 teaspoon of bright red blood per episode) within 1
month prior to Day 1

- Evidence of bleeding diathesis or significant coagulopathy (in the absence of
therapeutic anticoagulation)

- Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
prior to Day 1 or anticipation of need for major surgical procedure during the course
of the study

- Core biopsy or other minor surgical procedure, excluding placement of a vascular
access device, within 7 days prior to Day 1

- History of abdominal fistula or gastrointestinal perforation within 6 months prior to
Day 1

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

- Proteinuria as demonstrated by a UPC ratio >= 1.0

- Known hypersensitivity to any component of bevacizumab

- Pregnancy (positive pregnancy test) or lactation. Use of effective means of
contraception (men and women) in subjects of child-bearing potential

- History of abdominal fistula or intra-abdominal abscess within 6 months prior to
start.

- Any history of prior gastrointestinal perforation

- Patients believed to possibly be at higher than average risk of perforation,
including symptoms or findings of partial or complete bowel obstruction, history of
fistula, patients requiring parenteral nutrition and hydration, and those with
history of prior perforation due to tumor or perforation within last 6 months from
other causes will be excluded from study

- Patients with evidence of abdominal free air not explained by paracentesis