Carboplatin and Paclitaxel With or Without Bevacizumab in Treating Patients With Stage III or Stage IV Ovarian Epithelial, Primary Peritoneal, or Fallopian Tube Cancer

PRIMARY OBJECTIVE:

I. To determine if the addition of 5 concurrent cycles of bevacizumab to 6 cycles of standard
therapy (carboplatin and paclitaxel) (Arm II) increases the duration of progression-free
survival (PFS) when compared to 6 cycles of standard therapy alone (Arm I) in women with
newly diagnosed stage III (with any gross residual disease) and stage IV, epithelial ovarian,
peritoneal primary or fallopian tube cancer.

II. To determine if the addition of 5 concurrent cycles of bevacizumab plus extended
bevacizumab for 16 cycles beyond the 6 cycles of standard therapy (carboplatin and
paclitaxel) (Arm III) increases progression-free survival when compared to 6 cycles of
standard therapy (Arm I) in women with newly diagnosed stage III (with any gross residual
disease) and stage IV, epithelial ovarian, peritoneal primary or fallopian tube cancer.

SECONDARY OBJECTIVES:

I. In the event that both Arm II and Arm III regimens are superior to the Arm I regimen with
respect to progression-free survival, to determine whether the Arm III regimen prolongs
progression-free survival when compared to the Arm II regimen.

II. To determine whether the Arm II or Arm III regimen increases the duration of overall
survival when compared with the Arm I regimen.

III. To compare each of the experimental regimens to the Arm I regimen with respect to the
incidence of severe toxicities or serious adverse events.

IV. To determine the impact on Quality of Life (QOL, as measured by the Functional Assessment
of Cancer Therapy-Ovarian [FACT-O] trial outcome index [TOI]) following treatment with the
above regimens.

TERTIARY OBJECTIVES:

I. To assess the relationship between angiogenic markers and clinical outcome including tumor
response, progression-free survival and overall survival in patients randomized to standard
cytotoxic chemotherapy (paclitaxel and carboplatin) without bevacizumab, with concurrent
bevacizumab or with extended bevacizumab.

II. To assess the predictive value of a set of genes whose expression correlates with
survival of patients with stage III (with any gross residual disease) and stage IV,
epithelial ovarian, peritoneal primary or fallopian tube cancer.

III. To bank whole blood for research. IV. To determine if genetic variations in genes
associated with essential hypertension including WNK lysine deficient protein kinase 1
(WNK1), G protein-coupled receptor kinase 4 (GRK4) and kallikrein B (KLKB1) predict which
patients are likely to develop bevacizumab-induced hypertension.

OUTLINE: Patients are randomized to 1 of 3 treatment arms.

ARM I: Patients receive paclitaxel intravenously (IV) over 3 hours and carboplatin IV over 30
minutes on day 1. Beginning in course 2, patients also receive placebo IV over 30-90 minutes
on day 1. Treatment repeats every 21 days for 6 courses. Beginning in course 7, patients
receive placebo alone IV over 30-90 minutes on day 1. Treatment with placebo repeats every 21
days for up to 22 courses in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive paclitaxel and carboplatin as in arm I. Beginning in course 2,
patients also receive bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21
days for 6 courses. Beginning in course 7, patients receive placebo alone IV over 30-90
minutes on day 1. Treatment with placebo repeats every 21 days for up to 22 courses in the
absence of disease progression or unacceptable toxicity.

ARM III: Patients receive paclitaxel and carboplatin as in arm I. Beginning in course 2,
patients also receive bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21
days for 6 courses. Beginning in course 7, patients receive bevacizumab alone IV over 30-90
minutes on day 1. Treatment with bevacizumab repeats every 21 days for up to 22 courses in
the absence of disease progression or unacceptable toxicity.

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

Inclusion Criteria:

- Patients with a histologic diagnosis of epithelial ovarian cancer, peritoneal primary
carcinoma or fallopian tube cancer; International Federation of Gynecology and
Obstetrics (FIGO) stage III with any gross (macroscopic or palpable) residual disease
or FIGO stage IV, defined surgically at the completion of initial abdominal surgery
and with appropriate tissue available for histologic evaluation; the minimum surgery
required was 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; if additional surgery was performed, it should have been in
accordance with appropriate surgery for ovarian or peritoneal carcinoma described in
the Gynecologic Oncology Group (GOG) Surgical Procedures Manual; however, the surgeon
is not required to have performed all of the items contained in this section of the
GOG Surgical Procedures Manual; 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;" measurable disease on post-operative imaging studies is
not required for eligibility

- 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
carcinoma, malignant Brenner's Tumor, or adenocarcinoma not otherwise specified
(N.O.S.); however, the histologic features of the tumor must be compatible with a
primary Müllerian epithelial adenocarcinoma; if doubt exists, it is recommended that
the investigator should have the slides reviewed by an independent pathologist or, if
necessary, the Pathology Co-Chair, prior to entry; 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

- Absolute neutrophil count (ANC) greater than or equal to 1,500/µl equivalent to Common
Toxicity Criteria for Adverse Events version (v)3.0 (CTCAE) grade 1; this ANC cannot
have been induced or supported by granulocyte colony stimulating factors

- Platelets greater than or equal to 100,000/µl; (CTCAE grade 0-1)

- Creatinine =< 1.5 x institutional upper limit normal (ULN), CTCAE grade 1

- Bilirubin less than or equal to 1.5 x ULN (CTCAE grade 1)

- Serum glutamic oxaloacetic transaminase (SGOT) and alkaline phosphatase less than or
equal to 2.5 x ULN (CTCAE grade 1)

- Neuropathy (sensory and motor) less than or equal to CTCAE grade 1

- Prothrombin time (PT) such that international normalized ratio (INR) is =< 1.5 (or an
in-range INR, usually between 2 and 3, if a patient is on a stable dose of therapeutic
warfarin for management of venous thrombosis including pulmonary thrombo-embolus) and
a partial thromboplastin time (PTT) < 1.2 times the upper limit of normal

- Patients with a GOG Performance Status of 0, 1, or 2

- Patients must be entered between 1 and 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 who have met the pre-entry requirements

- An approved informed consent and authorization permitting release of personal health
information must be signed by the patient or guardian

- 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
or prior to disease progression

Exclusion Criteria:

- Patients with a current diagnosis of 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 (such as patients with
stage Ia or Ib low grade epithelial ovarian or fallopian tube cancers) 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 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 I-B; 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 non-melanoma skin cancer 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 bone fracture; this includes
history of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess
within 28 days; patients with granulating incisions healing by secondary intention
with no evidence of fascial dehiscence or infection are eligible but require weekly
wound examinations

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

- Patients with clinically significant cardiovascular disease; this includes:

- Uncontrolled hypertension, defined as systolic > 150 mm Hg or diastolic > 90 mm Hg

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

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

- Serious cardiac arrhythmia requiring medication; this does not include asymptomatic,
atrial fibrillation with controlled ventricular rate

- CTCAE grade 2 or greater peripheral vascular disease (at least brief (< 24 hrs)
episodes of ischemia managed non-surgically and without permanent deficit)

- History of CVA within six months

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

- Patients with clinically significant proteinuria; urine protein should be screened by
urine protein-creatinine ratio (UPCR); 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 must have a UPCR < 1.0 to allow
participation in the study

- Patients with or with anticipation of invasive procedures as defined below:

- Major surgical procedure, open biopsy or significant traumatic injury within 28 days
prior to the first date of bevacizumab/placebo therapy (cycle 2)

- Major surgical procedure 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; please consult with the study chair
prior to patient entry for any questions related to the classification of surgical
procedures

- Core biopsy, within 7 days prior to the first date of bevacizumab/placebo therapy
(cycle 2)

- Patients with GOG Performance Grade of 3 or 4

- Patients who are pregnant or nursing; 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-vascular endothelial growth
factor (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; the
investigator should feel free to consult the study chair or study co-chairs for
uncertainty in this regard