First-Line Treatment of Bevacizumab, Carboplatin, and Paclitaxel in Treating Participants With Stage III-IV Ovarian, Primary Peritoneal, and Fallopian Tube Cancer

PRIMARY OBJECTIVES:

I. To determine whether patients with newly diagnosed ovarian, primary peritoneal, and
fallopian tube cancers when treated with bevacizumab, carboplatin, and weekly paclitaxel can
tolerate at least 4 cycles of therapy regardless of delay or dose modification.

SECONDARY OBJECTIVES:

I. To estimate the efficacy of bevacizumab combined with carboplatin and weekly paclitaxel in
patients with newly diagnosed ovarian, primary peritoneal, and fallopian tube cancers, as
measured by progression-free survival.

II. To evaluate the response rate in patients with newly diagnosed ovarian, primary
peritoneal, and fallopian tube cancers when treated with bevacizumab, carboplatin, and weekly
paclitaxel.

TRANSLATIONAL RESEARCH OBJECTIVES:

I. To assess the predictive value of a set of angiogenic genes whose expression correlates
with progression-free survival of patients with epithelial ovarian, peritoneal primary or
fallopian tube cancer treated with bevacizumab, carboplatin, and weekly paclitaxel.

II. To assess the relationship among cytokines/chemokines, angiogenesis factors, novel
targets of interest and clinical outcome including tumor response and progression-free
survival in patients treated with bevacizumab, carboplatin, and weekly paclitaxel.

OUTLINE:

Participants receive paclitaxel intravenously (IV) over 3 hours on days 1, 8 and 15 and
carboplatin IV over 1 hour on day 1. Beginning course 2, participants also receive
bevacizumab IV over 1.5 hours on day 1. Treatment repeats every 21 days for up to 6 courses
in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed up every 3 months for 2 years.

Inclusion Criteria:

- Patients with a histologic diagnosis of epithelial ovarian cancer, peritoneal primary
carcinoma or fallopian tube cancer; Federation of Gynecology and Obstetrics (FIGO)
stage III and IV defined surgically at the completion of initial abdominal surgery and
with appropriate tissue available for histologic evaluation. The minimum surgery
required is an abdominal surgery providing tissue for histologic evaluation and
establishing and documenting the primary site and stage, as well as a maximal effort
at tumor debulking. Those patients with stage III cancer in which the largest maximal
diameter of any residual tumor implant at the completion of this initial surgery is no
greater than 1 cm will be defined as optimal; all others will be defined as
suboptimal.

- The histologic features of the tumor must be compatible with a primary mullerian
epithelial adenocarcinoma. Patients with the following histologic epithelial cell
types are eligible: Serous adenocarcinoma, endometrioid adenocarcinoma, mucinous
adenocarcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, mixed
epithelial carcinoma, transitional cell, malignant Brenner's tumor, adenocarcinoma not
otherwise specified (N.O.S). Patients may have co-existing fallopian tube carcinoma
in-situ so long as the primary origin of invasive tumor is ovarian, peritoneal or
fallopian tube.

- Patients must be entered no later than 12 weeks after initial surgery performed for
the combined purpose of diagnosis, staging and cytoreduction.

- Patients with measurable and non-measurable disease are eligible. Patients may or may
not have cancer-related symptoms.

- Patients in this trial may receive ovarian estrogen +/- progestin replacement therapy
as indicated at the lowest effective dose(s) for control of menopausal symptoms at any
time, but not progestins for management of anorexia while on protocol directed
therapy.

- Patients with an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1,
or 2.

- Leukocytes > 3,000/mcL.

- Absolute neutrophil count > 1,500/mcL.

- Platelets > 100,000/mcL.

- Total bilirubin < 1.5 X institutional upper limits of normal.

- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
< 2.5 X institutional upper limit of normal.

- Alkaline phosphatase (AP) < 2.5 X institutional upper limit of normal.

- Creatinine < 1.5X institutional upper limit of normal OR creatinine clearance > 50
mL/min/1.73 m^2 for patients with creatinine levels above institutional normal.

- Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

- Patients with borderline epithelial ovarian tumor (formerly "tumors of low malignant
potential") or recurrent invasive epithelial ovarian, primary peritoneal or fallopian
tube cancer treated with surgery only are not eligible. Patients with a prior
diagnosis of a borderline tumor that was surgically resected and who subsequently
develop an unrelated, new invasive epithelial ovarian, peritoneal primary or fallopian
tube cancer are eligible, provided that they have not received prior chemotherapy for
any ovarian tumor.

- Patients who have received prior radiotherapy to any portion of the abdominal cavity
or pelvis are excluded. Prior radiation for localized cancer of the breast, head and
neck, or skin is permitted, provided that it was completed more than three years prior
to registration, and the patient remains free of recurrent or metastatic disease.

- Patients who have received prior chemotherapy for any abdominal or pelvic tumor
including neo-adjuvant chemotherapy for their ovarian, primary peritoneal or fallopian
tube cancer are excluded. Patients may have received prior adjuvant chemotherapy for
localized breast cancer, provided that it was completed more than three years prior to
registration, and that the patient remains free of recurrent or metastatic disease.

- Patients who have received any targeted therapy (including but not limited to
vaccines, antibodies, tyrosine kinase inhibitors) or hormonal therapy for management
of their epithelial ovarian or peritoneal primary cancer.

- Patients who are currently participating or planning to participate in an experimental
drug study other than a Genentech-sponsored bevacizumab cancer study or who are
receiving other investigational agents.

- Patients with synchronous primary endometrial cancer, or a past history of primary
endometrial cancer, are excluded, unless all of the following conditions are met:
Stage not greater than IB; no more than superficial myometrial invasion, without
vascular or lymphatic invasion; no poorly differentiated subtypes, including papillary
serous, clear cell or other FIGO Grade 3 lesions.

- With the exception of superficial basal cell and superficial squamous (skin) cell,
carcinoma in situ of the cervix and other specific malignancies as noted above,
patients with other invasive malignancies who had (or have) any evidence of the other
cancer present within the last five years or whose previous cancer treatment
contraindicates this protocol therapy are excluded.

- Patients with acute hepatitis or active infection that requires parenteral
antibiotics.

- Patients with serious non-healing wound, ulcer, or untreated bone fracture. This
includes a history of abdominal fistula or gastrointestinal perforation within 6
months prior to day 1. Patients with granulating incisions healing by secondary
intention with no evidence of fascial dehiscence or infection are eligible but require
weekly wound examinations until closure.

- Patients with active bleeding or pathologic conditions that carry high risk of
bleeding, such as known bleeding disorder, coagulopathy (in the absence of therapeutic
anticoagulation), or tumor involving major vessels.

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

- 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 six months
of the first date of treatment on this study.

- Patients with clinically significant cardiovascular disease. This includes: 1)
Uncontrolled hypertension, defined as systolic > 140 mm Hg or diastolic > 90 mm Hg; 2)
Myocardial infarction or unstable angina < 6 months prior to registration; 3) New York
Heart Association (NYHA) grade II or greater congestive heart failure; 4) Serious
cardiac arrhythmia requiring medication. This does not include asymptomatic, atrial
fibrillation with controlled ventricular rate Common Terminology Criteria for Adverse
Events (CTCAE) grade 2 or greater peripheral vascular disease (at least brief (< 24
hours [hrs]) episodes of ischemia managed non-surgically and without permanent
deficit); Prior history of hypertensive crisis or hypertensive encephalopathy;
Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or
recent peripheral arterial thrombosis) within 6 months prior to day 1.

- Patients with known hypersensitivity to Chinese hamster ovary cell products or other
recombinant human or humanized antibodies.

- Patients with known hypersensitivity to any component of bevacizumab.

- Patients with clinically significant proteinuria at screening as demonstrated by urine
protein:creatinine (UPCR) ratio >= 1.0 at screening. The UPCR has been found to
correlate directly with the amount of protein excreted in a 24 hour urine collection.
Specifically, a UPCR of 1.0 is equivalent to 1.0 gram of protein in a 24 hour urine
collection. Obtain at least 4 ml of a random urine sample in a sterile container (does
not have to be a 24 hour urine). Send sample to lab with request for urine protein and
creatinine levels (separate requests). The lab will measure protein concentration
(mg/dL) and creatinine concentration (mg/dL). The UPCR is derived as follows: protein
concentration (mg/dL)/creatinine (mg/dL).

- Patients with or with anticipation of invasive procedures as defined below: Major
surgical procedure within 28 days of initiating bevacizumab or major procedures
anticipated during the course of the study. This includes, but is not limited to
abdominal surgery (laparotomy or laparoscopy) prior to disease progression, such as
colostomy or enterostomy reversal, interval or secondary cytoreductive surgery, or
second look surgery. Core biopsy or other minor surgical procedure, excluding
placement of a vascular access device, within 7 days prior to the first date of
bevacizumab therapy.

- Patients with ECOG performance grade of 3 or 4.

- Patients who are pregnant (positive pregnancy test) or nursing. Use of effective means
of contraception (men and women) in subjects of child-bearing potential. To date, no
fetal studies in animals or humans have been performed. The possibility of harm to a
fetus is likely. Bevacizumab specifically inhibits VEGF, which is responsible for
formation of new blood vessels during development, and antibodies can cross the
placenta. Therefore, bevacizumab 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 bevacizumab is excreted in human milk. Because many drugs are excreted
in human milk, bevacizumab should not be administered to nursing women. Patients of
childbearing potential must agree to use contraceptive measures during study therapy
and for at least six months after completion of bevacizumab therapy.

- Patients who have received prior therapy with any anti-VEGF drug, including
bevacizumab.

- Patients with clinical symptoms or signs of gastrointestinal obstruction and who
require parenteral hydration and/or nutrition.

- Patients with medical history or conditions not otherwise previously specified which
in the opinion of the investigator should exclude participation in this study.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.

- Known human immunodeficiency virus (HIV)-positive patients on combination
antiretroviral therapy are ineligible because of the potential for pharmacokinetic
interactions with bevacizumab. In addition, these patients are at increased risk of
lethal infections when treated with marrow-suppressive therapy. Appropriate studies
will be undertaken in patients receiving combination antiretroviral therapy when
indicated.

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