Sequential Angiogenic Blockade for the Treatment of Recurrent Mullerian Malignancies

OBJECTIVES:

Primary

- Assess the efficacy of a sequential antiangiogenic blockade regimen of bevacizumab then
cyclophosphamide with bevacizumab at disease progression in patients with recurrent
ovarian cancer as measured by the proportion of patients who remain on study at three
months (4 cycles)

- Assess the safety profile with respect to gastrointestinal perforations

Secondary

- Assess other toxicity/ safety profile of this metronomic antiangiogenic approach

- Assess preliminary response rate and proportion of patients on study at 6 months

- Assess progression-free survival, time to progression and overall survival

Correlative

- Determine if biological correlates of angiogenesis are altered by the addition of
sequential therapy

- Determine if changes in biological markers are correlated with clinical state of cancer

- Determine whether biomarkers of angiogenesis can predict and measure response

- Determine whether oncogenic mutations predict response

- Determine whether hypertension and urinary biomarkers such as varying levels of
albuminuria predict response to bevacizumab

- Determine patient risk factors for hypertension and proteinuria as toxicities of
bevacizumab

STATISTICAL DESIGN:

This study used a two-stage design to evaluate safety and efficacy of sequential
antiangiogenic blockade with a regimen of bevacizumab then cyclophosphamide added at disease
progression. Safety was measured by the incidence of grade 3-5 gastrointestinal perforation
(GIP) during the first 3 months of therapy and efficacy by completion of at least 3 months of
therapy. The sample size was determined based on efficacy with the null and alternative
therapy completion rate of 50% and 80%, respectively. If 6 or more patients enrolled in the
stage one cohort (n=9 patients) completed at least 3 months of therapy then accrual would
proceed to stage two (n=11 patients) if there were fewer than 2 cases of grade 3-5 GIP. There
was 0.75 probability of stopping the trial at stage one if the true therapy completion rate
was 50%. If 13 or fewer patients remained on therapy for at least 3 months by the end of
stage two, this regimen would be deemed ineffective. The power to reject the null hypothesis
with a one-sided binomial test was 87% assuming 5% significance.

Inclusion Criteria:

- Histologically confirmed diagnosis of epithelial ovarian cancer, primary peritoneal
cancer, or fallopian tube cancer.

- Recurrent cancer and have received and failed a previous platinum-based chemotherapy
regimen.

- Up to 2 prior lines of chemotherapy in the recurrent setting (either platinum-based or
non-platinum regimens). Biologic therapies count as a prior line but hormonal
therapies do not count.

- Platinum-resistant or platinum-sensitive recurrence.

- Must be able to take oral medications and have no evidence of bowel obstruction or
partial bowel obstruction

- Measurable disease by either RECIST or Rustin criteria

- No chemotherapy, radiation therapy, nor biologic therapy within the last three weeks
prior to initiating therapy

- ECOG score of 0 or 1

- Life expectancy of 12 weeks or greater

- 18 years of age or older

- Laboratory values as outlined in the protocol

- Patients with treated limited stage basal cell or squamous cell carcinoma of the skin
or carcinoma in situ of the breast or cervix are eligible. Subjects with stage I or II
cancer treated with curative intent and no evidence of recurrent disease are also
eligible.

- No evidence of preexisting hypertension. If patient has hypertension, it must be
controlled medically (less than 150/90) prior to starting bevacizumab

- Normal blood coagulation parameters

- No prior treatment with any other antiangiogenic agents or cyclophosphamide

- For patients who have received prior doxorubicin or pegylated doxorubicin, LVEF must
be 50% or greater.

Exclusion Criteria:

- Current, recent (within 4 weeks of the first study infusion), 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

- Uncontrolled diarrhea

- Prior history of hypertensive crisis or hypertensive encephalopathy

- 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 CNS 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 within 6 months prior to day 1

- History of hemoptysis 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 of 1.0 or greater at screening

- 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