Trial Information

Phase 2 Study of Bevacizumab in Combination With Carboplatin and Paclitaxel in Patients With Ovarian, Fallopian Tube or Primary Peritoneal Carcinoma

The aim of this study is to determine if the addition of bevacizumab to a regimen of
carboplatin/paclitaxel increases the time to disease recurrence (longer remission for
patients) in women that have Stage III suboptimally reduced or Stage IV ovarian cancer.

The hypothesis is that the addition of bevacizumab to a carboplatin/paclitaxel regimen will
increase progression free survival in subjects that have Stage III suboptimal cytoreduced or
Stage IV ovarian cancer.

Scientific Background and Significance: Vascular endothelial growth factor (VEGF) is
found in most tissues, and is known to regulate angiogenesis in both normal (e.g. ovulation)
and abnormal (e.g. malignant tumors) conditions. VEGF has been found to be overexpressed in
several tumor types, including breast, bladder, uterine, cervical, and relevant to this
application, primary and metastatic tumors of patients with advanced ovarian cancer. It is
widely believed that the overexpression of this factor contributes to tumorigenesis by
supplying a conduit through which oxygen and nutrients can reach and feed the growing
malignancy.

Treatment with an anti-VEGF antibody may help to exert a direct anti-angiogenic effect by
binding to and clearing VEGF from the tumor microenvironment, thus preventing the formation
of new blood vessels. Bevacizumab is a recombinant humanized anti-VEGF monoclonal antibody
that inhibits the growth of a number of human cancers, including ovarian cancer. Additional
antitumor activity may be obtained through the effects of bevacizumab on tumor vasculature,
interstitial pressure, and blood vessel permeability, all of which could allow for enhanced
delivery of concurrently administered chemotherapeutic agents to tumor cells.

Based on preliminary data (Proc Am Soc Clin Oncol 2005; 23:A5000 and A 5009), there is
biologic rationale to use bevacizumab in the treatment of advanced ovarian cancer. These 2
preliminary studies reported an improved progression-free survival in patients with
recurrent ovarian cancer with the use of bevacizumab in combination with chemotherapy. Based
on this activity in the recurrent setting, the activity of bevacizumab needs to be evaluated
in chemotherapy-naïve patients with advanced ovarian cancer. The purpose of this clinical
trial is to determine whether the addition of bevacizumab to a regimen of carboplatin and
paclitaxel significantly improves Progression Free Survival (PFS) in patients with Stage III
suboptimally cytoreduced or Stage IV ovarian, primary peritoneal or fallopian tube
carcinomas.

It is apparent that newer innovative therapies are needed in the front line setting to
decrease recurrences and improve survival. The addition of bevacizumab, the anti-vascular
endothelial growth factor antibody, to the standard carboplatin/taxol treatment paradigm
might help to increase the long-term survival rates in patients newly diagnosed with
advanced suboptimal ovarian cancer. The proposed study addresses this issue. The
investigational plan that will be utilized to test the hypothesis that the addition of
bevacizumab extends the survival time of the affected patients is outlined below.

Women with Stage III or IV ovarian cancer/primary peritoneal cancer/fallopian tube cancer
that have undergone surgery with residual suboptimally cytoreduced disease (suboptimal
defined as >1cm disease) will be eligible for treatment with one 21-day cycle of carboplatin
and paclitaxel and five 21-day cycles of bevacizumab, carboplatin and paclitaxel for a total
of six treatment cycles; bevacizumab treatment is delayed by one cycle to ensure adequate
post-surgical healing. Subjects will be evaluated by CT scans to determine response to
therapy; individuals that progress will be withdrawn from the study. The CT scan conducted
after the completion of therapy will dictate the next course of action. Patients
demonstrating a complete response will be maintained on bevacizumab as consolidation
therapy; subjects demonstrating a partial response will continue to receive bevacizumab,
carboplatin and paclitaxel. The total treatment time for patients with a clinical response
following the initial 6 cycles of therapy will be 12 months. Prior to starting
consolidation therapy, all patients with a complete clinical response or in those for whom
surgery may result in a complete secondary cytoreduction, will be given the option of
undergoing a second look surgery. The findings at surgery in combination with the CT scan
will determine the response to initial therapy. The decision not to participate in the
second look surgery will not affect the follow-up treatment that the patient will receive.