Clinical trial NCT01097746
Conditions: Fallopian Tube Carcinoma Fallopian Tube Clear Cell Adenocarcinoma Fallopian Tube Endometrioid Adenocarcinoma Fallopian Tube Mucinous Adenocarcinoma Fallopian Tube Serous Adenocarcinoma Fallopian Tube Transitional Cell Carcinoma Fallopian Tube Undifferentiated Carcinoma FIGO Stage III Ovarian Cancer FIGO Stage IIIA Ovarian Cancer FIGO Stage IIIA1 Ovarian Cancer FIGO Stage IIIA1(i) Ovarian Cancer FIGO Stage IIIA1(ii) Ovarian Cancer FIGO Stage IIIA2 Ovarian Cancer FIGO Stage IIIB Ovarian Cancer FIGO Stage IIIC Ovarian Cancer FIGO Stage IVA Ovarian Cancer FIGO Stage IVB Ovarian Cancer Malignant Ovarian Brenner Tumor Ovarian Clear Cell Adenocarcinoma Ovarian Endometrioid Adenocarcinoma Ovarian Mucinous Adenocarcinoma Ovarian Seromucinous Carcinoma Ovarian Serous Adenocarcinoma Ovarian Transitional Cell Carcinoma Ovarian Undifferentiated Carcinoma Primary Peritoneal Carcinoma Primary Peritoneal Serous Adenocarcinoma
Sponsor: M.D. Anderson Cancer Center
Start date: 2010-04-14; Completion date: 2022-09-13
Enrollment: 33 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well first-line treatment of bevacizumab, carboplatin, and paclitaxel work in treating participants with stage III- IV ovarian, primary peritoneal and fallopian tube cancer. Monoclonal antibodies, such as bevacizumab, may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as carboplatin and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving bevacizumab, carboplatin, and paclitaxel as first-line treatment may work better at treating ovarian, primary peritoneal, and fallopian tube cancer.

Detailed description:
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.

Arms: arm 1: Participants receive paclitaxel 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.
Interventions: intervention 1: Bevacizumab intervention 2: Carboplatin intervention 3: Paclitaxel
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
2009-0186 
Revised April 26, 2016 
Page 1 of 58 
The University of Texas MD Anderson Cancer Center 
 
 
A Phase II Trial of Bevacizumab with Carboplatin and Weekly Paclitaxel as First-Line 
Treatment in Epithelial Ovarian, Primary Peritoneal, and Fallopian Tube Carcinoma 
 
Study Drug 
Bevacizumab (Avastin®) 
Paclitaxel 
Carboplatin 
 
Support Provided By 
Genentech, Inc. 
 
Sponsor Investigator 
Anil K. Sood 
 
Sub-Investigators 
Robert Coleman 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Number: 
 
Protocol 2009-0186 
 
Protocol Version Date: 
Version 1.0, Revised January 14, 2013 


2009-0186 
Revised April 26, 2016 
Page 2 of 58 
TABLE OF CONTENTS 
                                                                                                                                       Page 
1.0 BACKGROUND 
1.1 
Disease Background ............................................................................... 1 
1.2 
New Strategies for Treatment.................................................................. 1 
1.3 
Angiogenesis-Targeted Therapeutics ...................................................... 1 
1.4 
Bevacizumab Clinical Experience ........................................................... 2 
1.5 
Other Study Drug(s) Background ............................................................ 11 
1.6 
Translational Research Related to Anti-VEGF Therapy ........................... 12 
1.7 
Study Rationale ....................................................................................... 13 
2.0 OBJECTIVES 
2.1  
Primary Objective .................................................................................... 15 
2.2  
Secondary Objectives ............................................................................. 16 
2.3 
Translational Research Objectives .......................................................... 16 
3.0 STUDY DESIGN 
3.1 
Description of the Study ............................................................................. 16 
3.2 
Rationale for Study Design......................................................................... 16 
3.3 
Outcome Measures .................................................................................... 17 
3.3.1 
Primary Outcome Measures ........................................................ 17 
3.3.2 
Secondary Outcome Measures ................................................... 17 
4.0 SAFETY PLAN 
4.1 
General Plan to Manage Safety .............................................................. 17 
5.0 STUDY SUBJECTS 
5.1 
Subject Selection ....................................................................................... 18 
5.2 
Inclusion Criteria ........................................................................................ 18 
5.3 
Exclusion Criteria ....................................................................................... 19 
6.0 STUDY DESIGN 
6.1 
Treatment Plan .......................................................................................... 22 
6.2 
Translational Research .............................................................................. 23 
7.0 STUDY MEDICATION 
7.1 
Bevacizumab Dosage and Formulation  ..................................................... 23 
7.1.1 
Bevacizumab Administration ........................................................ 24 
7.1.2 
Bevacizumab Storage .................................................................. 24 


2009-0186 
Revised April 26, 2016 
Page 3 of 58 
 
7.2 
Protocol-Specified Chemotherapy .............................................................. 24 
 
7.2.1 
Paclitaxel 
 
 
7.2.1.1  Paclitaxel Administration ................................................. 24 
 
 
7.2.1.2  Paclitaxel Storage and Stability ....................................... 25 
 
7.2.2 
Carboplatin 
 
 
7.2.2.1  Carboplatin Administration .............................................. 26 
 
 
7.2.2.2  Carboplatin Dosing ......................................................... 26 
 
7.2.2.3  Carboplatin Storage and Stability .................................... 27 
7.3 
Concomitant Medications ........................................................................... 27 
7.4 
Dose Modifications and Toxicity Management ........................................... 27 
7.4.1 
General Modifications 
 
 
7.4.1.1  Management of Hypersensitivity Reactions .................... 27 
 
 
7.4.1.2  General Guidelines for Hematologic Toxicity................... 29 
 
7.4.1.3  Special Modifications ...................................................... 31 
7.4.2 
Bevacizumab Dose Modification and Toxicity Management......... 32 
7.4.3 
Paclitaxel Treatment Modifications and Toxicity Management ..... 36 
7.4.4 
Carboplatin Treatment Modifications and Toxicity Management .. 37 
8.0 STUDY CALENDAR .............................................................................................. 40 
9.0  SUBJECT DISCONTINUATION ............................................................................ 43 
10.0 STUDY DISCONTINUATION ................................................................................ 44 
11.0 STATISTICAL CONSIDERATIONS 
11.1 Determination of Sample Size .................................................................... 45 
11.2 Planned Efficacy Evaluations ..................................................................... 45 
11.2.1 
Efficacy Variables ........................................................................ 45 
11.2.2 
Methods of Analysis..................................................................... 50 
11.3 Genomic Data Analyses ............................................................................. 51 
11.4 Cytokine Evaluation Analyses .................................................................... 51 
12.0 SAFETY REPORTING OF ADVERSE EVENTS 
12.1 Adverse Events Reporting and Definitions ................................................. 52 
12.2 Reporting of Serious Treatment Emergent Adverse Events ....................... 52 
12.3 Safety Reporting Requirements for IND Exempt Studies ............................ 53 
13.0 RETENTION OF RECORDS ................................................................................. 54 
REFERENCES ............................................................................................................... 55 
 


2009-0186 
Revised April 26, 2016 
Page 4 of 58 
 
 
 
 
 
 
SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor reductive surgery 
Paclitaxel 80 mg/m2 IV qwk (Days 1, 8, and 15 of Cycles 1-6) 
Carboplatin AUC 5 IV q21dys (Day 1 of Cycles 1-6) 
Bevacizumab 15 mg/kg IV q21dys (Day 1 of Cycles 2-6) 
Newly diagnosed ovarian, primary peritoneal, or fallopian tube carcinoma 


2009-0186 
Revised April 26, 2016 
Page 5 of 58 
1.0 
BACKGROUND 
1.1 Ovarian Cancer, Primary Peritoneal Carcinoma, and Fallopian Tube 
Carcinoma 
Over 21,000 new cases of ovarian, primary peritoneal, and fallopian tube 
cancers are expected to be diagnosed in 2008 with approximately 15,520 
deaths caused by these diseases.[1]  Due to a paucity of effective screening 
modalities, most patients are diagnosed in the advanced stages of the 
disease.  The current standard of care consists of a total abdominal 
hysterectomy, bilateral oophorectomy, and extensive tumor debulking followed 
by tri-weekly administration of carboplatin and paclitaxel.   With this treatment 
regimen, over 50% of patients achieve a complete initial clinical response, but 
the majority of patients recur within the first 2 years with only 10-30% 
achieving long-term survival.[2]  Additionally, this treatment combination is 
associated with high rates of fatigue, as well as hematologic and neurologic 
toxicity.[3, 4] New first-line treatment regimens are being investigated in order 
to improve the initial response rate and prolong the time to recurrence in these 
patients while improving dose-delaying toxicity profiles. 
1.2 New Strategies for Treatment 
In order to improve cytotoxic activity through increased dose delivery, several 
phase I and II studies have evaluated the feasibility of weekly paclitaxel and 
carboplatin as first-line and salvage chemotherapy in patients with ovarian 
cancer.[5-8]  Recent data demonstrated that patients treated with dose dense 
weekly administration of paclitaxel at 80 mg/m2 given with carboplatin (AU 6) 
every 3 weeks had longer PFS compared to those treated with standard tri-
weekly carboplatin and paclitaxel (27.9 vs. 17.1 months, p=0.0014).[9]  Overall 
survival at 2 years was also longer in the patients receiving dose dense 
treatment (83.6% vs. 77.7%, p=0.05).  Toxicities were similar between both 
groups except grade 3 and 4 anemia was reported more frequently in the dose 
dense group.   As front-line therapy, Sehouli et al. treated patients with FIGO 
stages IIB-IV disease after optimal tumor resection with weekly paclitaxel (100 
mg/m2) followed carboplatin (AUC 2) and found the median progression free 
survival (PFS) and overall survival (OS) to be 21 and 43 months, 
respectively.[6]  Additionally, patients with recurrent disease treated with 
weekly paclitaxel and carboplatin were found to have an overall response rate 
of 80% with 100% response rate in platinum-sensitive patients.[8, 10]  Toxicity 
profile was also found to be improved with weekly chemotherapeutic dosing.[5-
7]  Reduced myelosuppression and fewer side effects allow patients to 
continue their scheduled chemotherapy with fewer dose delays.  Additionally, 
the use of weekly paclitaxel and carboplatin in advanced breast cancer 
demonstrated comparable efficacy to the traditional tri-weekly regimen with 
decreased incidence of grade 3 and 4 toxicities.[11] 
1.3 Angiogenesis-Targeted Therapeutics 
Angiogenesis and neovascularization are required for tumor growth and 
invasion and play a significant role in disease metastasis.[12, 13]  Several 
studies have demonstrated that analysis of angiogenic factors may be 
correlated with ovarian cancer progression and prognosis.[14-16]  Vascular-
endothelial growth factor (VEGF) is an angiogenic promoter and ligand that 
binds to the VEGF receptor 2 and triggers the angiogenic-signaling pathway.  


2009-0186 
Revised April 26, 2016 
Page 6 of 58 
Specific targeting of VEGF with neutralizing anti-VEGF monoclonal antibodies 
has been identified as a potential mechanism through which tumor 
angiogenesis can be disrupted, and various studies have demonstrated 
potential therapeutic activity using these biological agents.[17, 18] 
1.4 Bevacizumab Clinical Experience 
Bevacizumab has been studied in a multitude of Phase I, II, and III clinical 
trials in more than 5000 patients and in multiple tumor types. In addition, data 
are available from 3,863 patients enrolled in two postmarketing studies in 
metastatic colorectal cancer (CRC).  Approximately 130,000 patients have 
been exposed to bevacizumab as a marketed product or in clinical trials.  The 
following discussion summarizes bevacizumab’s safety profile and presents 
some of the efficacy results pertinent to this particular trial. Please refer to the 
bevacizumab Investigator Brochure for descriptions of all completed Phase I, 
II, and III trials reported to date. 
In a large phase III study (AVF2107g) in patients with metastatic colorectal 
cancer, the addition of bevacizumab, a monoclonal antibody directed against 
vascular endothelial growth factor (VEGF), to irinotecan/5-
fluorouracil/leucovorin (IFL) chemotherapy resulted in a clinically and 
statistically significant increase in duration of survival, with a hazard ratio of 
death of 0.67 (median survival 15.6 vs. 20.3 months; p < 0.001).[19]  Similar 
increases were seen in progression-free survival (6.2 vs. 10.6 months; 
p < 0.001), overall response rate (35% vs. 45%; p < 0.01) and duration of 
response (7.1 vs. 10.4 months; p < 0.01) for the combination arm versus the 
chemotherapy only arm (Bevacizumab Investigator Brochure, October 2005). 
Based on the survival advantage demonstrated in Study AVF2107g, 
bevacizumab was designated for priority review and was approved on 26 
February 2004 in the United States for first-line treatment in combination with 
IV 5-FUbased chemotherapy for subjects with metastatic colorectal cancer.  
Additional data from Phase III trials in metastatic colorectal cancer (E3200), 
nonsmall cell lung cancer (NSCLC; E4599), and metastatic breast cancer 
(E2100) have also demonstrated clinical benefit from bevacizumab when 
added to chemotherapy.[20-22]  In Study E3200, the addition of bevacizumab 
to FOLFOX chemotherapy resulted in improved overall survival compared with 
FOLFOX alone (13.0 vs. 10.8 months, respectively, HR  0.75; p  0.01) in a 
population of previously treated CRC patients.[22]   
There was also improved overall survival in first-line NSCLC patients treated 
with carboplatin/paclitaxel  bevacizumab compared with chemotherapy alone 
(12.3 vs. 10.3 months, respectively; HR  0.80; p = 0.003).[20]  The results 
from this trial were the basis for FDA approval of bevacizumab for use in 
combination with carboplatin  paclitaxel as first-line treatment of patients with 
unresectable, locally advanced, recurrent or metastatic, non-squamous 
NSCLC in October 2006.  Finally, patients with untreated metastatic breast 
cancer (E2100) who received bevacizumab in combination with weekly 
paclitaxel had a marked improvement in PFS compared with chemotherapy 
alone (11.8 vs. 5.9 months, respectively; HR  0.60; p  0.001) [21] (see the 
Bevacizumab Investigator Brochure for additional details). 


2009-0186 
Revised April 26, 2016 
Page 7 of 58 
Bevacizumab Safety Profile 
In the initial Phase I and II clinical trials, four potential bevacizumab-
associated safety signals were identified: hypertension, proteinuria, 
thromboembolic events, and hemorrhage.  Additional completed Phase II and 
Phase III studies of bevacizumab as well as spontaneous reports have further 
defined the safety profile of this agent. Bevacizumab-associated adverse 
events identified in phase III trials include congestive heart failure (CHF) 
primarily in metastatic breast cancer, gastrointestinal perforations, wound 
healing complications, and arterial thromboembolic events (ATE). These and 
other safety signals are described in further detail as follows and in the 
Bevacizumab Investigator Brochure. 
Hypertension: An increased incidence of hypertension has been observed in 
patients treated with bevacizumab.  Grade 4 and 5 hypertensive events are 
rare. Clinical sequelae of hypertension are rare but have included 
hypertensive crisis, hypertensive encephalopathy, and reversible posterior 
leukoencephalopathy syndrome (RPLS).[23, 24]  
There is no information on the effect of bevacizumab in patients with 
uncontrolled hypertension at the time of initiating bevacizumab therapy.  
Therefore, caution should be exercised before initiating bevacizumab therapy 
in these patients.  Monitoring of blood pressure is recommended during 
bevacizumab therapy.  Optimal control of blood pressure according to 
standard public health guidelines is recommended for patients on treatment 
with or without bevacizumab.   
Temporary interruption of bevacizumab therapy is recommended in patients 
with hypertension requiring medical therapy until adequate control is achieved.  
If hypertension cannot be controlled with medical therapy, bevacizumab 
therapy should be permanently discontinued.  Bevacizumab should be 
permanently discontinued in patients who develop hypertensive crisis or 
hypertensive encephalopathy. 
Proteinuria:  An increased incidence of proteinuria has been observed in 
patients treated with bevacizumab compared with control arm patients.  In the 
bevacizumab-containing treatment arms of clinical trials (across all 
indications), the incidence of proteinuria (reported as an adverse event) was 
up to 38% (metastatic CRC Study AVF2192g). The severity of proteinuria has 
ranged from asymptomatic and transient events detected on routine dipstick 
urinalysis to nephrotic syndrome; the majority of proteinuria events have been 
grade 1. NCI-CTC Grade 3 proteinuria was reported in up to 3% of 
bevacizumab-treated patients, and Grade 4 in up to 1.4% of 
bevacizumab-treated patients.  The proteinuria seen in bevacizumab clinical 
trials was not associated with renal impairment and rarely required permanent 
discontinuation of bevacizumab therapy.  Bevacizumab should be 
discontinued in patients who develop Grade 4 proteinuria (nephrotic 
syndrome) 
Patients with a history of hypertension may be at increased risk for the 
development of proteinuria when treated with bevacizumab.  There is 
evidence from the dose-finding, Phase II trials (AVF0780g, AVF0809s, and 
AVF0757g) suggesting that Grade 1 proteinuria may be related to 
bevacizumab dose. 


2009-0186 
Revised April 26, 2016 
Page 8 of 58 
Proteinuria will be monitored by urine protein:creatinine (UPCR) ratio at least 
every 6 weeks.   
Thromboembolic Events: Both venous and arterial thromboembolic (TE) 
events, ranging in severity from catheter-associated phlebitis to fatal, have 
been reported in patients treated with bevacizumab in the colorectal cancer 
trials and, to a lesser extent, in patients treated with bevacizumab in NSCLC 
and breast cancer trials.  
Venous thromboembolism (including deep venous thrombosis, pulmonary 
embolism, and thrombophlebitis:  In the phase III pivotal trial in metastatic 
CRC, there was a slightly higher rate of venous TE events in patients treated 
with bevacizumab plus chemotherapy compared with chemotherapy alone 
(19% vs. 16%).  
In Study AVF2107g, a Phase III, pivotal trial in metastatic CRC, VTE events, 
including deep venous thrombosis, pulmonary embolism, and 
thrombophlebitis, occurred in 15.2% of patients receiving chemotherapy alone 
and 16.6% of patients receiving chemotherapy  bevacizumab.  
The incidence of NCI-CTC Grade  3 venous VTE events in one NSCLC trial 
(E4599) was higher in the bevacizumab-containing arm compared to the 
chemotherapy control arm (5.6% vs. 3.2%).  One event (0.2%) was fatal in the 
bevacizumab-containing arm; not fatal events were reported in the 
carboplatin/paclitaxel arm (see Bevacizumab Investigator Brochure).  
In metastatic CRC clinical trials, the incidence of VTE events was similar in 
patients receiving chemotherapy  bevacizumab and those receiving the 
control chemotherapy alone.  
In clinical trials across all indications the overall incidence of VTE events was 
2.8%17.3% in the bevacizumab-containing arms compared with 3.2%15.6% 
in the chemotherapy control arms.  The use of bevacizumab with 
chemotherapy does not substantially increase the risk of VTE event compared 
with chemotherapy alone.  However, patients with metastatic CRC who 
receive bevacizumab and experienced a VTE event may be at higher risk for 
recurrence of VTE event. 
Arterial Thromboembotic Events:  An increased incidence of ATE events 
was observed in patients treated with bevacizumab compared with those 
receiving control treatments.  ATE events include cerebrovascular accidents, 
myocardial infarction, transient ischemic attacks (TIAs), and other ATE events.  
In a pooled analysis of data from five randomized Phase II and III trials 
(mCRC [AVF2107g, AVF2192g, AVF0780g]; locally advanced or metastatic 
NSCLC [AVF0757g]; metastatic breast cancer [AVF2119g]), the incidence rate 
of ATE events was 3.8% (37 of 963) in patients who received 
chemotherapy  bevacizumab compared with 1.7% (13 of 782) in patients 
treated with chemotherapy alone.  ATE events led to a fatal outcome in 0.8% 
(8 of 963) of patients treated with chemotherapy  bevacizumab and 0.5% (4 
of 782) of patients treated with chemotherapy alone.  Cerebrovascular 
accidents (including TIAs) occurred in 2.3% of patients treated with 
chemotherapy  bevacizumab and 0.5% of patients treated with 
chemotherapy alone.  Myocardial infarction occurred in 1.4% of patients 
treated with chemotherapy  bevacizumab compared with 0.7% of patients 


2009-0186 
Revised April 26, 2016 
Page 9 of 58 
treated with chemotherapy alone (see the Bevacizumab Investigator Brochure 
for additional details). 
Aspirin is a standard therapy for primary and secondary prophylaxis of arterial 
thromboembolic events in patients at high risk of such events, and the use of 
aspirin ≤ 325 mg daily was allowed in the five randomized studies discussed 
above. Use of aspirin was assessed routinely as a baseline or concomitant 
medication in these trials, though safety analyses specifically regarding aspirin 
use were not preplanned. Due to the relatively small numbers of aspirin users 
and arterial thromboembolic events, retrospective analyses of the ability of 
aspirin to affect the risk of such events were inconclusive. However, similarly 
retrospective analyses suggested that the use of up to 325 mg of aspirin daily 
does not increase the risk of grade 1-2 or grade 3-4 bleeding events, and 
similar data with respect to metastatic colorectal cancer patients were 
presented at ASCO 2005.[25]  Further analyses of the effects of concomitant 
use of bevacizumab and aspirin in colorectal and other tumor types are 
ongoing. 
Gastrointestinal perforation: Patients with metastatic carcinoma may be at 
increased risk for the development of gastrointestinal perforation and fistula 
when treated with bevacizumab and chemotherapy. Bevacizumab should be 
permanently discontinued in patients who develop gastrointestinal perforation. 
A causal association of intra-abdominal inflammatory processes and 
gastrointestinal perforation to bevacizumab treatment has not been 
established. Nevertheless, caution should be exercised when treating patients 
with intra-abdominal inflammatory processes with bevacizumab. 
Gastrointestinal perforation has been reported in other trials in non-colorectal 
cancer populations (e.g., ovarian, renal cell, pancreas, breast, and NSCLC) 
and may be higher in incidence in some tumor types. 
Fistula:  Bevacizumab use has been associated with serious cases of fistulae 
including events resulting in death.  Fistulae in the GI tract are common (1%–
10% incidence) in patients with metastatic CRC, but uncommon (0.1%1%) or 
rare (0.01%–0.1%) in other indications.  In addition, fistulae that involve areas 
of the body other than the GI tract (e.g., tracheoesophageal, bronchopleural, 
urogenital, biliary) have been reported uncommonly (0.1%–1%) in patients 
receiving bevacizumab in clinical studies and postmarketing reports.  Events 
were reported at various timepoints during treatment, ranging from 1 week to 
 1 year following initiation of bevacizumab, with most events occurring within 
the first 6 months of therapy. 
Permanently discontinue bevacizumab in patients with tracheoesophageal 
fistulae or any Grade 4 fistula.  Limited information is available on the 
continued use of bevacizumab in patients with other fistulae.  In cases of 
internal fistula not arising in the GI tract, discontinuation of bevacizumab 
should be considered. 
Wound healing complications: Wound healing complications such as wound 
dehiscence have been reported in patients receiving bevacizumab. In an 
analysis of pooled data from two trials in metastatic colorectal cancer, patients 
undergoing surgery 28-60 days before study treatment with 5-FU/LV plus 
bevacizumab did not appear to have an increased risk of wound healing 
complications compared to those treated with chemotherapy alone.[26]  


2009-0186 
Revised April 26, 2016 
Page 10 of 58 
Surgery in patients currently receiving bevacizumab is not recommended. No 
definitive data are available to define a safe interval after bevacizumab 
exposure with respect to wound healing risk in patients receiving elective 
surgery; however, the estimated half life of bevacizumab is 21 days. 
Bevacizumab should be discontinued in patients with severe wound healing 
complications. 
Hemorrhage: Overall, grade 3 and 4 bleeding events were observed in 4.0% 
of 1132 patients treated with bevacizumab in a pooled database from eight 
phase I, II, and III clinical trials in multiple tumor types (Bevacizumab 
Investigator Brochure, October 2005). The hemorrhagic events that have been 
observed in bevacizumab clinical studies were predominantly tumor-
associated hemorrhage (see below) and minor mucocutaneous hemorrhage.  
Tumor-Associated Hemorrhage:  Major or massive pulmonary hemorrhage 
or hemoptysis has been observed primarily in patients with NSCLC.  
Life-threatening and fatal hemoptysis was identified as a bevacizumab-related 
adverse event in NSCLC trials.  These events occurred suddenly and 
presented as major or massive hemoptysis.  Among the possible risk factors 
evaluated (including squamous cell histology, treatment with 
anti-rheumatic/anti-inflammatory drugs, treatment with anticoagulants, prior 
radiotherapy, bevacizumab therapy, previous medical history of 
atherosclerosis, central tumor location, and cavitation of tumors during 
therapy), the only variables that showed statistically significant correlations 
with bleeding were bevacizumab therapy and squamous cell histology. 
GI hemorrhages, including rectal bleeding and melena have been reported in 
patients with CRC, and have been assessed as tumor-associated 
hemorrhages. 
Tumor-associated hemorrhages were also seen rarely in other tumor types 
and locations, including a case of CNS bleeding in a patient with hepatoma 
with occult CNS metastases and a patient who developed continuous oozing 
of blood from a thigh sarcoma with necrosis. 
Mucocutaneous Hemorrhage:  Across all bevacizumab clinical trials, 
mucocutaneous hemorrhage has been seen in 20%-40% of patients treated 
with bevacizumab. These were most commonly NCI-CTC Grade 1 epistaxis 
that lasted less than 5 minutes, resolved without medical intervention and did 
not require any changes in bevacizumab treatment regimen.  
There have also been less common events of minor mucocutaneous 
hemorrhage in other locations, such as gingival bleeding and vaginal bleeding.  
Reversible Posterior Leukoencephalopathy Syndrome:  There have been 
rare reports of bevacizumab-treated patients developing signs and symptoms 
that are consistent with RPLS, a rare neurologic disorder that can present with 
the following signs and symptoms (among others):  seizures, headache, 
altered mental status, visual disturbance, or cortical blindness, with or without 
associated hypertension.  Brain imaging is mandatory to confirm the diagnosis 
of RPLS.  In patients who develop RPLS, treatment of specific symptoms, 
including control of hypertension, is recommended along with discontinuation 
of bevacizumab.  The safety of reinitiating bevacizumab therapy in patients 
previously experiencing RPLS is not known.[23, 24]   


2009-0186 
Revised April 26, 2016 
Page 11 of 58 
Congestive heart failure:  In clinical trials CHF was observed in all cancer 
indications studied to date, but predominantly in patients with metastatic 
breast cancer.  In the Phase III clinical trial of metastatic breast cancer 
(AVF2119g), 7 (3%) bevacizumab-treated patients experienced CHF, 
compared with two (1%) control arm patients.  These events varied in severity 
from asymptomatic declines in left ventricular ejection fraction (LVEF) to 
symptomatic CHF requiring hospitalization and treatment.  All the patients 
treated with bevacizumab were previously treated with anthracyclines 
(doxorubicin cumulative dose of 240360 mg/m2).  Many of these patients also 
had prior radiotherapy to the left chest wall.  Most of these patients showed 
improved symptoms and/or left ventricular function following appropriate 
medical therapy.[27] 
In a randomized, Phase III trial of patients with previously untreated metastatic 
breast cancer (E2100), the incidence of LVEF decrease (defined as NCI-CTC 
Grade 3 or 4) in the paclitaxel  bevacizumab arm was 0.3% versus 0% for 
the paclitaxel alone arm  
No information is available on patients with preexisting CHF of New York 
Heart Association (NYHA) Class IIIV at the time of initiating bevacizumab 
therapy, as these patients were excluded from clinical trials. 
Prior anthracyclines exposure and/or prior radiotherapy to the chest wall may 
be possible risk factors for the development of CHF.  Caution should be 
exercised before initiating bevacizumab therapy in patients with these risk 
factors. 
A Phase II trial in patients with refractory acute myelogenous leukemia 
reported 5 cases of cardiac dysfunction (CHF or LVEF decrease to  40%) 
among 48 patients treated with sequential cytarabine, mitoxantrone, and 
bevacizumab.  All but 1 of these patients had significant prior exposure to 
anthracyclines as well.[28]  
Two additional studies investigated concurrent administration of 
anthracyclines and bevacizumab.  In 21 patients with inflammatory breast 
cancer treated with neoadjuvant docetaxel, doxorubicin, and bevacizumab, no 
patients developed clinically apparent CHF; however, patients had 
asymptomatic decreases in LVEF to  40%.[29]  In a small Phase II study in 
patients with soft tissue sarcoma, 2 of the 17 patients treated with 
bevacizumab and high-dose doxorubicin (75 mg/m2) developed CHF 
(one Grade 3 event after a cumulative doxorubicin dose of 591 mg/m2, one 
Grade 4 event after a cumulative doxorubicin dose of 420 mg/m2); an 
additional 4 patients had asymptomatic decreases in LVEF.[30] 
Other studies in patients with various tumor types and either a history of 
anthracycline exposure or concomitant use with bevacizumab are ongoing.  
Patients receiving concomitant anthracyclines or with prior exposure to 
anthracyclines should have a baseline MUGA scans or echocardiograms 
(ECHOs) with a normal LVEF. 
Neutropenia:  Increased rates of severe neutropenia, febrile neutropenia, or 
infection with severe neutropenia (including some fatalities) have been 
observed in patients treated with some myelotoxic chemotherapy regimens 
plus bevacizumab in comparison to chemotherapy alone.[20] 


2009-0186 
Revised April 26, 2016 
Page 12 of 58 
Additional Adverse Events:  See the Bevacizumab Investigator Brochure for 
additional details regarding the safety experience with bevacizumab. 
1.5 Other Study Drug(s) Background  
1.5.1  Paclitaxel (Taxol®) 
Paclitaxel is a poorly soluble plant product from the western yew, Taxus 
brevifolia. Improved solubility requires a mixed solvent system with 
further dilutions of either 0.9% sodium chloride or 5% dextrose in water. 
It is commercially available from Bristol-Myers Oncology and is supplied 
as a sterile solution concentrate, 6 mg/ml available in 5 ml (30 mg/vial), 
16.7 ml (100 mg/vial) and 50 ml (300 mg/vial) in polyoxyethylated castor 
oil (Cremophor EL) 50% and dehydrated alcohol, USP, 50%. The 
contents of the vial must be diluted just prior to clinical use.  
Paclitaxel Safety Profile 
Hematologic: Myelosuppression 
Gastrointestinal: Nausea and vomiting, diarrhea, stomatitis, mucositis, 
pharyngitis, typhlitis, ischemic colitis, neutropenic enterocolitis 
Heart: Arrhythmia, heart block, ventricular tachycardia, myocardial 
infarction (MI), bradycardia, atrial arrhythmia 
Pulmonary: Pneumonitis 
Blood Pressure: Hypotension, hypertension (possibly related to 
concomitant medication--Dexamethasone) 
Neurologic: Sensory (taste), peripheral neuropathy, seizures, mood 
swings, hepatic encephalopathy, encephalopathy 
Skin: Infiltration: erythema, induration, tenderness, rarely ulceration, 
radiation recall reactions 
Allergy: Anaphylactoid and urticarial reactions (acute), flushing, rash, 
pruritus 
Liver: Increased SGOT, SGPT, bilirubin and alkaline phosphatase, 
hepatic failure, hepatic necrosis 
Vision: Sensation of flashing lights, blurred vision, scintillating 
scotomata 
Other: Alopecia, fatigue, arthralgia, myalgia, light-headedness, 
myopathy 
1.5.2 Carboplatin (Paraplatin®) 
Carboplatin is a DNA alkylating agent which produces predominantly 
cell-cycle nonspecific interstrand DNA cross-links.  It is commercially 
available from Bristol-Myers Squibb and is supplied as a sterile, 
pyrogen-free, 10mg/mL aqueous solution in multi-dose vials containing 
50mg/5mL, 150mg/15mL, 450mg/45mL, or 600g/60mL of carboplatin.   
Carboplatin Safety Profile 
Hematologic: Myelosuppression, bleeding  


2009-0186 
Revised April 26, 2016 
Page 13 of 58 
Gastrointestinal: Nausea and vomiting, diarrhea, constipation, 
stomatitis, mucositis, abdominal pain 
Heart: Heart failure, stroke, thrombosis 
Pulmonary: Bronchospasm 
Blood Pressure: Hypotension, hypertension (possibly related to 
concomitant medication--Dexamethasone) 
Neurologic:  Muscle weakness, peripheral neuropathy, dizziness, 
confusion, visual changes, tinnitus, ototoxicity, sensory changes (taste) 
Skin: Discomfort at injection site, erythema, swelling, pain, necrosis 
associated with extravasation 
Allergy: Anaphylactoid and urticarial reactions (acute), flushing, rash, 
pruritus 
Liver: Increased SGOT, SGPT, bilirubin and alkaline phosphatase, 
hepatic failure, hepatic necrosis 
Renal: Increased BUN and creatinine, renal failure, abnormal blood 
electrolytes (hyponatremia, hypokalemia, hypocalcemia, 
hypomagnesemia) 
Vision: Vision loss 
Other: Alopecia, infection, asthenia 
1.6  TRANSLATIONAL RESEARCH RELATED TO ANTI-VEGF THERAPY 
1.6.1  Genomic Analysis 
The genomic research component of this protocol will focus on the 
discovery and validation of genes who expression may predict 
progression-free survival in patients with advanced stage ovarian 
cancer.  Despite treatment with surgery and chemotherapy at the time 
of initial diagnosis, the disease usually recurs, and most patients die 
within two years of diagnosis.  However, a small subset of patients 
experience a more indolent disease course and may be disease free for 
a substantial period of time.  These patients may survive five years or 
more and should perhaps be monitored and treated differently than 
those with more rapid, progressive disease.   At this time, no tool exists 
to predict the clinical course of disease from the time of initial diagnosis. 
Transcription profiling utilizes large-scale gene-expression analysis 
technology to identify differentially expressed genes and molecular 
signatures.[31, 32]  Data obtained from expression analyses has been 
used to examine tumor biology and to identify potential biomarkers as 
clinical correlates.[32]    We hypothesize that transcription profiling will 
provide differential gene signatures in patients with advanced staged 
ovarian cancer who experience different progression-free survival times 
and may require individualized treatment regimens.  Thus, these 
discoveries will help determine the molecular and biochemical basis of 
disease in patients with advanced staged ovarian, fallopian tube, and 
primary peritoneal carcinoma. 
1.6.2  Cytokine Analysis 


2009-0186 
Revised April 26, 2016 
Page 14 of 58 
Cytokine levels have been evaluated as potential diagnostic and 
prognostic markers in ovarian cancer.  They function primarily to 
regulate immunity, hematopoeisis, and inflammation.  Systemic cytokine 
levels differ in cancer patients, possibly due to an interaction between 
the disease and the immune system resulting in cytokine 
production.[33]   Various cytokines, including IL-6, IL-7, and IL-8, have 
been associated with ovarian cancer and identified as potential 
therapeutic and diagnostic tools for the disease.[34-36]  Additionally, 
levels of vascular endothelial growth factor (VEGF) have been found to 
correlate significantly with patient survival and to be an independent 
prognostic indicator in overall survival in patients with ovarian 
cancer.[37]  
Plasma studies are included as an optional procedure to evaluate the 
correlation between cytokine levels with progression-free and overall 
survivals in patients treated with the bevacizumab, carboplatin, and 
weekly paclitaxel.  Previous studies indicate that the pre-treatment 
levels of VEGF in plasma, not serum, are associated with progression-
free and overall survival in patients with persistent or recurrent 
endometrial cancer or uterine leiomyosarcoma.[38, 39]  The exact 
choice of biomarkers to be evaluated and assays to be performed on 
plasma specimens will be reevaluated based on evolving data in the 
field.  At the appropriate time, the current translational research 
objectives will be amended to incorporate a definitive translational 
research objective regarding angiogenic markers and cytokines that can 
be tested and validated utilizing specimens submitted for this protocol.  
A summary of relevant laboratory data will also be provided at that time 
to establish the background and rationale for that amendment. 
1.7  Study Rationale  
The use of bevacizumab in gynecologic oncology has been studied in the 
setting of recurrent epithelial ovarian cancer.  GOG-0170-D utilized single 
agent bevacizumab in persistent or recurrent ovarian or primary peritoneal 
cancer and examined clinical response by NCI/RECIST criteria and proportion 
surviving progression-free for at least 6 months.[40]  Sixty-two patients were 
treated with bevacizumab 15 mg/kg intravenously every 21 days.  Thirteen 
patients had clinical responses with approximately 40% surviving progression 
free for at least six months.  Median PFS and overall survival were 4.7 and 17 
months, respectively.  Additionally, Genentech AVF 2949 found a median PFS 
and overall survival of 4.4 and 10.7 months, respectively when 44 patients with 
platinum-resistant ovarian or primary peritoneal cancers were treated in a 
phase II study with single agent bevacizumab 15 mg/kg every 3 weeks.[41] 
The combination of bevacizumab with other cytotoxic therapies stems from 
preclinical models suggesting possible synergistic interactions.[42]  It is 
hypothesized that increased sensitization to apoptosis or reversal of 
chemotherapeutic drug resistance occurs when the VEGF pathway is 
interrupted.[43]  In a study published by Chura et al., 15 patients were treated 
with biweekly intravenous bevacizumab 10 mg/kg plus oral cyclophosphamide 
50 mg daily.[44]  Two patients (13.3%) had a complete response to treatment 
with 6 patients (40%) experiencing a partial response and 3 with stable 
disease.   Median PFS was 4.4 months for these patients.  Another study 


2009-0186 
Revised April 26, 2016 
Page 15 of 58 
evaluated 10 patients with advanced, recurrent, refractory ovarian cancer who 
were treated with biweekly bevacizumab (10 mg/kg) and weekly paclitaxel.[45]  
During the study, all evaluable patients experienced a decrease in CA125 
within the first treatment cycle, and all experienced improved levels of pain, 
nausea, and ascites.  No grade 3 or 4 toxicities were found.   
Improved PFS or overall survival has been demonstrated in several phase III 
trials in metastatic colorectal, breast, and non-small cell lung cancer.[19-22]  A 
phase III trial randomized 722 breast cancer patients to receive either weekly 
paclitaxel alone or with bevacizumab (10 mg/kg) on days 1 and 15.[21]  
Prolonged PFS (median 11.8 vs. 5.9 months, p<0.001) and objective response 
rate (36.9% vs. 21.2%, p<0.001) was noted in patients receiving the 
combination of paclitaxel and bevacizumab. 
The observed spectrum and degree of toxicity, such as arterial thrombotic and 
renovascular events, is similar in these trials. However, GOG 170-D observed 
no gastrointestinal perforations or fistulae, unlike Genentech AVF 2949.  
During this trial, 5 such events occurred in 44 patients.  This led to early 
termination of AVF 2949 and an IND Action Letter in 2005.  Some of the 
events occurred after discontinuing bevacizumab for disease progression.  
The potential for gastrointestinal perforations or fistulae is unknown at this 
time in patients with advanced recurrent ovarian cancer, and statistical 
variation cannot be excluded without a controlled trial.  Han et al. reviewed 
published data of open-labeled trials using bevacizumab in ovarian cancer and 
revealed an overall 5.2% incidence rate of gastrointestinal perforation. [46]  
The management of the perforations and fistulas has involved either surgery 
or abscess drainage with bowl rest.  Specific risk factors for these events have 
not been identified and are currently under investigation in GOG 0218.  
Limited data exists for the utilization of bevacizumab as first-line therapy in 
newly diagnosed ovarian cancer patients.  Currently GOG 0218 and ICON7 
are in the process of examining the use of bevacizumab in front-line ovarian 
cancer therapy.  GOG 0218 is a three-arm placebo-controlled trial to compare 
the overall survival in patients with stage III or IV disease who receive 
carboplatin/paclitaxel alone, carboplatin/paclitaxel administered concurrently 
with bevacizumab, or carboplatin/paclitaxel administered concurrently with 
bevacizumab for an additional 16 cycles.  ICON7 includes all patients with at 
least high-risk, early-stage disease and evaluates the PFS in a two-arm trial, 
carboplatin/paclitaxel alone compared to carboplatin/paclitaxel given 
concomitantly with bevacizumab for an extended 12 cycles.   
A phase II study evaluated the response rate and toxicity of intravenous 
paclitaxel (175 mg/m2), carboplatin (AUC 5), and bevacizumab (15 mg/kg) 
administered every 21 days as primary induction therapy for patients with 
stage III or IV ovarian, primary peritoneal, or fallopian tube 
`adenocarcinoma.[47]  Eighteen patients were evaluated with a total response 
rate of 80% (6 CR, 10 PR).  A total of 116 cycles were administered with grade 
3 and 4 neutropenia in 23.3% and 25% of cycles and no incidence of grades 3 
or 4 thrombocytopenia or anemia.  No incidence of bowel perforations 
occurred, and 2 patients developed grade 3 hypertension.   
Dose dense administration of paclitaxel with weekly carboplatin prolongs PFS 
and overall survival.[9]  Additionally, bevacizumab appears to be active as a 


2009-0186 
Revised April 26, 2016 
Page 16 of 58 
single agent in patients with recurrent ovarian and primary peritoneal cancer.  
Past studies have demonstrated improved response rate and prolonged PFS 
in breast and ovarian cancer patients when bevacizumab was given in 
combination with paclitaxel.  Overall side effects to the combination of 
bevacizumab with carboplatin and paclitaxel appear to be tolerable.  Based on 
this data, the combination of bevacizumab with carboplatin and weekly 
paclitaxel may be a potential therapeutic treatment option as front-line therapy 
for patients with newly diagnosed ovarian, fallopian tube, and primary 
peritoneal cancer. 
 
2.0 
OBJECTIVES 
2.1 Primary 
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. 
2.2 Secondary 
2.2.1 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. 
 
2.2.2 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. 
2.3 Translational Research Objectives 
2.3.1 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. 
2.3.2 To assess the relationship among cytokines/chemokines, angiogenic 
factors, novel targets of interest, and clinical outcome including tumor 
response and progression-free survival in patients treated with 
bevacizumab, carboplatin, and weekly paclitaxel. 
 
3.0 
STUDY DESIGN  
3.1 Description of the Study 
Patients with newly diagnosed ovarian, primary peritoneal, or fallopian tube 
cancer will receive as induction therapy carboplatin (AUC 5) and paclitaxel (80 
mg/m2) on Day 1 of Cycle 1.  They will also receive paclitaxel (80 mg/m2) on 
Days 8 and 15 of Cycle 1.  On Day 1 of Cycles 2 through 6, patients will 
receive carboplatin (AUC 5), paclitaxel (80 mg/m2) and bevacizumab (15 
mg/kg).  They will continue to receive paclitaxel (80 mg/m2) on Days 8 and 15.  


2009-0186 
Revised April 26, 2016 
Page 17 of 58 
Patients will be treated for a total of 6 cycles.  One cycle of therapy consists of 
21 days.   
3.2 Rationale for Study Design 
A recent study performed by the Japanese Gynecologic Oncology Group 
(JGOG) found the median progression-free survival and overall survival to be 
longer in ovarian cancer patients receiving weekly paclitaxel with carboplatin 
compared to tri-weekly carboplatin and paclitaxel.[9]  Grade 3 and 4 anemia 
occurred more frequently, however, in the group receiving weekly treatment.  
Overall 60% of patients received at least 6 cycles of chemotherapy treatment 
on the study.  A prospective trial utilizing tri-weekly carboplatin (AUC 6), bi-
weekly bevacizumab (10 mg/kg), and weekly paclitaxel (80 mg/m2) in 
melanoma patients found the regimen to be moderately well-tolerated with 
62.2% of patients requiring dose reduction for toxicity.[48]  This study is 
designed to evaluate the tolerability of combination bevacizumab and 
carboplatin with weekly paclitaxel as first-line treatment in patients with 
epithelial ovarian, primary peritoneal, and fallopian tube cancers in a  single-
arm, non-randomized, open label phase II study.  
3.3  Outcome Measures  
3.3.1 Primary Outcome Measures 
The primary study outcome will be treatment success, defined as a 
patient completing at least 4 cycles of combination therapy 
(bevacizumab with carboplatin and weekly paclitaxel) regardless of 
delay or dose modification.  
3.3.2 Secondary Outcome Measures 
3.3.2.1  A secondary endpoint will be the evaluation of progression-free 
survival in patients treated with bevacizumab and carboplatin 
with weekly paclitaxel.  
3.3.2.2  The evaluation of response proportion based on RECIST v1.1 
criteria will be examined in patients treated with bevacizumab 
and carboplatin with weekly paclitaxel. 
 
4.0 
Safety Plan 
See Section 4.1 for complete details of the safety evaluation for this study.  
4.1 General Plan to Manage Safety  
a.  Bevacizumab-Specific 
A number of measures will be taken to ensure the safety of patients 
participating in this trial.  These measures will be addressed through exclusion 
criteria (see Section 5.3) and routine monitoring as follows. 
Patients enrolled in this study will be evaluated clinically and with standard 
laboratory tests before and at regular intervals during their participation in this 
study.  Safety evaluations will consist of medical interviews, recording of 
adverse events, physical examinations, blood pressure, and laboratory 
measurements.   Patients will be evaluated for adverse events (all grades), 
serious adverse events, and adverse events requiring study drug interruption 


2009-0186 
Revised April 26, 2016 
Page 18 of 58 
or discontinuation at each study visit for the duration of their participation in 
the study.  Patients discontinued from the treatment phase of the study for any 
reason will be evaluated ~30 days (28–42 days) after the decision to 
discontinue treatment (see Section 7.4.2) unless patients are discontinued 
from the study due to an ongoing bevacizumab-related Grade 4 or serious 
adverse event. These patients will continue to be followed until resolution of 
the event or until the event is considered irreversible. 
Specific monitoring procedures are as follows: 
 
Hypertension will be monitored through routine evaluation of blood 
pressure prior to each bevacizumab treatment.  Optimal control of blood 
pressure according to standard public health guidelines is recommended 
for patients on treatment with or without bevacizumab. 
 
Proteinuria will be monitored by urine protein-creatinine ratio (UPCR) at 
least every 6 weeks.  
Other Study Drug(s)-Specific 
Please see Section 7.4.2 for detailed instructions for the management of study 
drug–related toxicities. 
 
5.0 
Study Subjects 
5.1 Subject Selection 
5.2 Inclusion Criteria 
5.2.1 Patients with a histologic diagnosis of epithelial ovarian cancer, 
peritoneal primary carcinoma or fallopian tube cancer; 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.”   
5.2.2 The histologic features of the tumor must be compatible with a primary 
Müllerian 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 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. 


2009-0186 
Revised April 26, 2016 
Page 19 of 58 
5.2.3 Patients must be entered no later than 12 weeks after initial surgery 
performed for the combined purpose of diagnosis, staging and 
cytoreduction. 
5.2.4 Patients with measurable and non-measurable disease are eligible. 
Patients may or may not have cancer-related symptoms. 
5.2.5 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. 
5.2.6 Patients with an ECOG Performance Status of 0, 1, or 2 (Appendix D). 
5.2.7 Patients must have normal organ and marrow function as defined 
below: 
- 
leukocytes 
>3,000/mcL 
- 
absolute neutrophil count >1,500/mcL 
- 
platelets 
>100,000/mcL 
- 
total bilirubin 
<1.5 X institutional upper limits of normal 
- 
AST(SGOT)/ALT(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 m2 for patients with  
 
creatinine levels above institutional normal 
5.2.8 Ability to understand and the willingness to sign a written informed 
consent document. 
5.3  Exclusion Criteria 
5.3.1 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. 
5.3.2 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. 
5.3.3 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 


2009-0186 
Revised April 26, 2016 
Page 20 of 58 
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. 
5.3.4 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. 
5.3.5 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. 
5.3.6 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.   
5.3.7 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.   
5.3.8 Patients with acute hepatitis or active infection that requires parenteral 
antibiotics. 
5.3.9 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. 
5.3.10 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.  
5.3.11  History of hemoptysis ( 1/2 teaspoon of bright red blood per episode) 
within 1 month prior to Day 1. 
5.3.12 Patients with history or evidence upon physical examination of 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. 
5.3.13 Patients with clinically significant cardiovascular disease.  This includes: 


2009-0186 
Revised April 26, 2016 
Page 21 of 58 
5.3.13.1 
Uncontrolled hypertension, defined as systolic > 140 mm Hg 
or diastolic > 90 mm Hg. 
5.3.13.2 
Myocardial infarction or unstable angina < 6 months prior to 
registration. 
5.3.13.3 
New York Heart Association (NYHA) Grade II or greater 
congestive heart failure (Appendix E). 
5.3.13.4 
Serious cardiac arrhythmia requiring medication. This does 
not include asymptomatic, atrial fibrillation with controlled 
ventricular rate. 
5.3.13.5 
CTCAE Grade 2 or greater peripheral vascular disease (at 
least brief (<24 hrs) episodes of ischemia managed non-
surgically and without permanent deficit). 
5.3.13.6 
Prior history of hypertensive crisis or hypertensive 
encephalopathy 
5.3.13.7 
Significant  vascular disease (e.g., aortic aneurysm, 
requiring surgical repair or recent peripheral arterial 
thrombosis) within 6 months prior to Day 1  
5.3.14 Patients with known hypersensitivity to Chinese hamster ovary cell 
products or other recombinant human or humanized antibodies 
5.3.15 Patients with known hypersensitivity to any component of bevacizumab  
5.3.16 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.[49, 50]  
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).  
5.3.17 Patients with or with anticipation of invasive procedures as defined 
below: 
5.3.17.1 Major surgical procedure within 28 days from 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.   
5.3.17.2 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 
5.3.18 Patients with ECOG Performance Grade of 3 or 4 (Appendix D). 


2009-0186 
Revised April 26, 2016 
Page 22 of 58 
5.3.19 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. 
5.3.20 Patients under the age of 18. 
5.3.21 Patients who have received prior therapy with any anti-VEGF drug, 
including bevacizumab. 
5.3.22 Patients with clinical symptoms or signs of gastrointestinal obstruction 
and who require parenteral hydration and/or nutrition. 
5.3.23 Patients with medical history or conditions not otherwise previously 
specified which in the opinion of the investigator should exclude 
participation in this study. 
5.3.24 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.  
5.3.25 Known 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. 
5.3.26 Inability to comply with study and/or follow-up procedures 
 
6.0 
STUDY DESIGN 
6.1 Treatment Plan 
6.1.1 This is an outpatient regimen. Patients will receive a total of 6 cycles of 
study medications.  On days 1, 8, and 15, patients will receive 80 
mg/m2 paclitaxel intravenously infused over 3 hours. On day 1 of Cycle 
1, following paclitaxel administration, patients will receive carboplatin 
AUC 5.  For Cycles 2-6, on Day 1, patients will receive carboplatin AUC 
5 and bevacizumab 15 mg/kg infused intravenously following paclitaxel 
80 mg/m2 administration. 


2009-0186 
Revised April 26, 2016 
Page 23 of 58 
6.1.2 Paclitaxel will be infused first followed by carboplatin and bevacizumab. 
Cycles will be repeated every 21 days. 
6.1.3 Maximum body surface area used for dose calculations of paclitaxel will 
be 2.0 m2. There will be no maximum milligram dosage of bevacizumab. 
6.1.4 Patient weight at baseline will be used to determine the bevacizumab 
dose to be used for the duration of the study. 
6.1.5 Doses of paclitaxel, carboplatin and bevacizumab may be rounded to 
the nearest 5 mg.  After initial treatment, doses of paclitaxel and 
bevacizumab should be re-calculated based on any body weight 
change ≥ 10%.   
6.1.6 Protocol therapy can be administered 1 day prior to or up to 1 week 
after scheduled administration date to allow for calendar events in 
patient’s life (e.g. holidays, weddings, vacations, etc.)  Any other 
deviations require Study Chair approval. 
6.1.7 The minimum treatment period will be three cycles of protocol-directed 
therapy or a minimum of two cycles of bevacizumab. 
6.1.8 Changes to chemotherapy regimen in patients found to have persistent 
disease after 6 cycles of protocol-directed therapy will be made at the 
discretion of the patient’s treating physician. 
6.2 Translational Research 
6.2.1 Gene Expression Microarrays 
The tumor repository will supply frozen tissue samples from 10 patients 
with PFS <= 6 mos and 10 patients with PFS >= 21 months. These 
subgroups will be chosen so that effects due to optimal/suboptimal 
debulking are separately estimable – we will avoid complete 
confounding. Once acquired, these samples will be profiled using gene 
expression microarrays (Affymetrix HGU133+v2) run 
contemporaneously as part of one operating batch, or in balanced 
blocks if multiple batches are needed.  Genomic analysis will identify 
distinct molecular signatures and provide a foundation for the discovery 
of tumor response biomarkers in future larger, collaborative studies.  
The exact choice of biomarkers to be evaluated and validated will be 
reevaluated based on evolving data in the field. 
6.2.2 Plasma Specimens 
A pre-treatment plasma specimen collected prior to initiating front-line 
chemotherapy will be an optional procedure for all patients who have 
given informed consent for their blood to be drawn to prepare plasma 
for use in this research study Additional plasma specimens will be 
drawn prior to cycle 3 and after completion of the study.  The exact 
choice of biomarkers to be evaluated and assays to be performed on 
plasma specimens will be reevaluated based on evolving data in the 
field.  We will also examine CD5L/CD5, MSMP/MSMP interacting 
genes, inflammatory cytokines/chemokines and angiogenic factors in 
plasma and exosomes from these patients. 
6.2.3 Immunohistochemistry 


2009-0186 
Revised April 26, 2016 
Page 24 of 58 
Immunohistochemistry will be performed for testing the predictive 
markers and novel genes involved in adaptive resistance to anti-VEGF 
therapy in the paraffin sections from this patients. 
 
7.0 
STUDY MEDICATION  
7.1  Bevacizumab dosage and formulation 
Bevacizumab will be given at 15 mg/kg IV on Day 1 of each 21 day cycle, 
beginning with Cycle 2.  Bevacizumab is a clear to slightly opalescent, 
colorless to pale brown, sterile liquid concentrate for solution for intravenous 
(IV) infusion.  Bevacizumab will be supplied in 20-cc (400-mg) glass vials 
containing 16 mL bevacizumab (25 mg/mL).  Vials contain bevacizumab with 
phosphate, trehalose, polysorbate 20, and Sterile Water for Injection (SWFI), 
USP.  Vials contain no preservative and are suitable for single use only. 
For further details and molecule characterization, see the Bevacizumab 
Investigator Brochure. 
7.1.1 Bevacizumab Administration 
Bevacizumab will be diluted in a total volume of 100mL of 0.9% Sodium 
Chloride Injection, USP.  Administration will be as a continuous IV 
infusion.  Anaphylaxis precautions should be observed during study 
drug administration.  It is not necessary to correct dosing based on ideal 
weight. 
The initial dose will be delivered over 9015 minutes.  If the first infusion 
is tolerated without infusion-associated adverse events (fever and/or 
chills), the second infusion may be delivered over 6010 minutes.  If the 
60-minute infusion is well tolerated, all subsequent infusions may be 
delivered over 3010 minutes.   
If a subject experiences an infusion–associated adverse event, he or 
she may be premedicated for the next study drug infusion; however, the 
infusion time may not be decreased for the subsequent infusion.  If the 
next infusion is well tolerated with premedication, the subsequent 
infusion time may then be decreased by 3010 minutes as long as the 
subject continues to be premedicated.  If a subject experiences an 
infusion-associated adverse event with the 60-minute infusion, all 
subsequent doses should be given over 9015 minutes.  Similarly, if a 
subject experiences an infusion-associated adverse event with the 
30-minute infusion, all subsequent doses should be given over 6010 
minutes. 
7.1.2 Bevacizumab Storage 
Upon receipt of the study drug, vials are to be refrigerated at 2C–8C  
(36F–46F) and should remain refrigerated until just prior to use.  DO 
NOT FREEZE.  DO NOT SHAKE.  Vials should be protected from light. 
Opened vials must be used within 8 hours.  VIALS ARE FOR SINGLE 
USE ONLY.  Vials used for 1 subject may not be used for any other 
subject.  Once study drug has been added to a bag of sterile saline, the 
solution must be administered within 8 hours. 


2009-0186 
Revised April 26, 2016 
Page 25 of 58 
7.2 PROTOCOL SPECIFIED CHEMOTHERAPY 
7.2.1 Paclitaxel 
7.2.1.1  Paclitaxel Administration 
Paclitaxel (Taxol) is a poorly soluble plant product from the 
western yew, Taxus brevifolia. Improved solubility requires a 
mixed solvent system with further dilutions of either 0.9% 
sodium chloride or 5% dextrose in water. Paclitaxel is 
commercially available from Bristol-Myers Oncology. A sterile 
solution concentrate, 6 mg/ml available in 5 ml (30 mg/vial), 
16.7 ml (100 mg/vial) and 50 ml (300 mg/vial) in 
polyoxyethylated castor oil (Cremophor EL) 50% and 
dehydrated alcohol, USP, 50%. The contents of the vial must 
be diluted just prior to clinical use. 
Paclitaxel, at the appropriate dose, will be diluted in 250- 1000 
cc of 0.9% Sodium Chloride injection, USP or 5% Dextrose 
injection, USP [D5W (500 cc's is adequate if paclitaxel is a 
single agent]. Paclitaxel must be prepared in glass or polyolefin 
containers due to leaching of diethylhexlphthalate (DEHP) 
plasticizer from polyvinylchloride (PVC) bags and intravenous 
tubing by the Cremophor vehicle in which paclitaxel is 
solubilized. NOTE: Formation of a small number of fibers in 
solution (within acceptable limits established by the USP 
Particulate matter test for LVP's) has been observed after 
preparation of paclitaxel. Therefore, in-line filtration is 
necessary for administration of paclitaxel solutions. In-line 
filtration should be accomplished by incorporating a hydrophilic, 
microporous filter of pore size not greater than 0.22 microns 
(e.g.: IVEX-II, IVEX-HP, or equivalent) into the IV fluid pathway 
distal to the infusion pump. Although particulate formation does 
not indicate loss of drug potency, solutions exhibiting excessive 
particulate matter formation should not be used. 
Thirty minutes before the paclitaxel infusion is to begin the 
patient is further premedicated with dexamethasone 20 mg IV, 
diphenhydramine 50mg IV, and an H2 receptor antagonist: 
cimetidine 300 mg IV, or ranitidine 50 mg IV, or famotidine 20 
mg IV. 
Paclitaxel, at the appropriate dose and dilution, will be given as 
a continuous IV infusion over 180 minutes + 15 minutes. 
Paclitaxel will be administered via an infusion control device 
(pump) using non-PVC tubing and connectors, such as the IV 
administration sets (polyethylene or polyolefin), which are used 
to infuse parenteral Nitroglycerin. Nothing else other than 0.9% 
sodium chloride is to be infused through the line where 
paclitaxel is being administered. 
7.2.1.2  Paclitaxel Storage and Stability 
The intact vials should be stored under refrigeration (2-8°C). 
Commercially available paclitaxel will be labeled with an 


2009-0186 
Revised April 26, 2016 
Page 26 of 58 
expiration date. All solutions of paclitaxel exhibit a slight 
haziness directly proportional to the concentration of drug and 
the time elapsed after preparation, although when prepared as 
described above, solutions of paclitaxel (0.3 - 1.2 mg/ml) are 
physically and chemically stable for 27 hours. 
7.2.2 Carboplatin  
7.2.2.1  Carboplatin Administration 
Carboplatin is supplied as a sterile, pyrogen-free, 10mg/mL 
aqueous solution in multi-dose vials containing 50mg/5mL, 
150mg/15mL, 450mg/45mL, or 600g/60mL of carboplatin.  
Carboplatin aqueous solution can be further diluted to 
concentrations as low as 0.5mg/mL with 5% Dextrose in Water 
or 0.9% Sodium Chloride for Injection, USP. 
Carboplatin infusion will be administered following paclitaxel, at 
the appropriate dose and dilution and will be given as a 
continuous IV infusion over 30 minutes + 15 minutes. 
Carboplatin will be administered via an infusion control device 
(pump) using non-PVC tubing and connectors. 
7.2.2.2. Carboplatin Dosing 
The Carboplatin dose will be calculated to reach a target area 
under the curve (AUC) according to the Calvert formula using 
an estimated glomerular filtration rate (GFR) from the 
Cockcroft-Gault formula.  
The initial dose of carboplatin will be calculated using GFR. In 
the absence of new renal obstruction or other renal toxicity 
greater than or equal to CTCAE Grade 2 [serum creatinine >1.5 
x ULN] or toxicity requiring dose modification, the dose of 
carboplatin will NOT be recalculated for subsequent cycles, but 
will be subject to dose modification as noted in the protocol. 
Carboplatin doses are based on the patient’s weight at baseline 
and will not be recalculated unless the patient has a weight 
change of greater than or equal to 10% from baseline. 
In patients with abnormally low serum creatinine (less than 0.7 
mg/dl), the creatinine clearance will be estimated using a 
minimum value of 0.7 mg/dl.  
Calvert formula: Carboplatin dose (mg) = target AUC x (GFR + 
25) 
Note: The GFR used in the Calvert formula should not exceed 
125 ml/min.  
The maximum Carboplatin dose (mg) = target AUC (mg/ml x 
min) x 150 ml/min 
The maximum allowed doses of Carboplatin are: 
AUC 5 = 750 mg 
AUC 4 = 600 mg 


2009-0186 
Revised April 26, 2016 
Page 27 of 58 
For the purposes of this protocol, the GFR is considered 
equivalent to the estimated creatinine clearance. The estimated 
creatinine clearance (ml/min) is calculated by the method of 
Cockcroft-Gault using the following formula: 
Creatinine Clearance (mL/min) = [140–age (yrs)] x weight (kg) x 0.85 
 
72 x serum creatinine (mg/dl) 
Actual weight is used for estimation of GFR for patients with a 
BMI of less than 25. Adjusted weight is used for patients with a 
BMI of greater than or equal to 25. 
Dose Modification for toxicity: 
If the creatinine at the time of dose modification is lower than 
the creatinine used to calculate the previous dose, use the 
previous (higher) creatinine; if the creatinine at the time of a 
dose modification is higher than the creatinine used to calculate 
the previous dose, use the current (higher) creatinine. This 
ensures that the patient is actually receiving a dose reduction.  
7.2.2.3  Carboplatin Storage and Stability 
Unopened vials of carboplatin are stable to the date indicated 
on the package when stored at 25°C (77°F).  Excursions from 
15 to 30°C (59 to 86°F) are permitted.  Protect from light.  
Carboplatin multi dose vials maintain microbial, chemical, and 
physical stability for up to 14 days at 25°C following multiple 
needle entries.   When prepared as directed, carboplatin 
aqueous solutions are stable for 8 hours at room temperature 
(25°C / 77°F).  Since no antibacterial preservative is contained 
in the formulation, it is recommended that carboplatin solutions 
be discarded 8 hours after dilution. 
Aluminum reacts with carboplatin causing precipitate formation 
and loss of potency; therefore, needles or intravenous sets 
containing aluminum parts that may come in contact with the 
drug must NOT be used for the preparation or administration of 
carboplatin. 
7.3 CONCOMITANT MEDICATIONS 
Low-dose aspirin (≤ 325 mg/d) may be continued in subjects at higher risk for 
arterial thromboembolic disease. Subjects developing signs of arterial 
ischemia or bleeding on study should be evaluated for possible bevacizumab 
toxicity and dose modification per Section 7.4.2 Table 1, Bevacizumab Dose 
Management Due To Adverse Events. 
 
7.4  DOSE MODIFICATIONS AND TOXICITY MANAGEMENT 
7.4.1  General Modifications 
7.4.1.1  Management of Hypersensitivity Reactions 
In general, the occurrence of a hypersensitivity reaction to 
paclitaxel, carboplatin, or bevacizumab is not considered a 


2009-0186 
Revised April 26, 2016 
Page 28 of 58 
dose-limiting toxicity.  Patients may be retreated at full doses 
after administration of medication to prevent hypersensitivity 
reactions, and adjustments to infusion rates should be made.  
However, if despite these safety measures repeat attempt at 
infusion of the inciting drug results in a recurrent 
hypersensitivity reaction, the inciting drug should be 
discontinued for the remainder of the study.   
7.4.1.1.1 Hypersensitivity to bevacizumab  
Infusion of bevacizumab should be interrupted for 
subjects who develop dyspnea or clinically significant 
hypotension. Subjects who experience a CTCAE 
Grade 3 or 4 allergic reaction / hypersensitivity, adult 
respiratory distress syndrome, or bronchospasm 
(regardless of grade) will be discontinued from 
bevacizumab treatment. 
The infusion should be slowed to 50% or less or 
interrupted for subjects who experience any infusion-
associated symptoms not specified above. When the 
subject’s symptoms have completely resolved, the 
infusion may be continued at no more than 50% of 
the rate prior to the reaction and increased in 50% 
increments every 30 minutes if well tolerated. 
Infusions may be restarted at the full rate during the 
next cycle.  
In the event of a prior bevacizumab hypersensitivity 
reaction, subsequent infusions should be delivered 
over 90 minutes, and the following prophylactic 
regimen is recommended upon re-exposure: 
 H1 blocker (diphenhydramine 25-50 mg IVP or 
orally one hour prior to injection; or an equivalent 
dose of an alternate H1 blocker such as loratadine 
10 mg or fexofenadine 60 mg). 
 H2 blocker (famotidine 20 mg IVP or orally one 
hour prior to injection; or an equivalent dose of an 
alternate H2 blocker).  
 Dexamethasone (10 mg administered PO 12 and 
6 hours prior to bevacizumab injection). 
7.4.1.1.2 Hypersensitivity to paclitaxel 
Hypersensitivity reactions to paclitaxel or its vehicle 
(Cremophor) occur almost universally during the first 
few minutes of infusion. Continued treatment may be 
considered if the reaction was not life-threatening; 
however, patients must be cautioned of potential 
recurrences of the reaction. Should the patient 
decide to continue with treatment it is preferable that 
this be done on the same day of the occurrence.  


2009-0186 
Revised April 26, 2016 
Page 29 of 58 
A suggested procedure would be to repeat the 
patient’s premedication with dexamethasone 20mg 
IV, cimetidine 300mg (or ranitidine 50mg) IV, and 
diphenhydramine 50mg IV 30 minutes before the 
paclitaxel reinfusion is to begin. Slowly infuse the 
paclitaxel by administering the drug first with 1 ml of 
the original IV solution diluted in 100 ml over one 
hour, then 5 ml in 100 ml over one hour, then 10 ml 
in 100 ml over one hour, and finally the original 
solution at the original infusion rate. No additional 
dose adjustments should be made for other 
hypersensitivity reactions.  
7.4.1.2  General Guidelines for Hematologic Toxicity 
7.4.1.2.1  Initial treatment modifications will consist of cycle 
delay and/or dose reduction as indicated below. The 
use of hematopoietic cytokines and protective 
reagents are restricted as noted: 
7.4.1.2.2  Treatment decisions will be based on the absolute 
neutrophil count (ANC) rather than the total white cell 
count (WBC). 
7.4.1.2.3  Lower Limits for ANC and Platelet Count 
Subsequent treatment with bevacizumab, 
carboplatin, and paclitaxel on Day 1 of each cycle will 
not be given until the ANC is ≥ 1500 cells/mm3 
(CTCAE Grade 1) and the platelet count is ≥ 
100,000/ul. Therapy will be delayed for a maximum 
of three weeks until these values are achieved. 
Patients who fail to recover adequate counts within a 
three-week delay will be removed from study. 
Treatment with weekly paclitaxel on Days 7 and 14 of 
each cycle will not be given unless ANC is ≥ 1000 
cells/mm3 and the platelet count is ≥ 75,000/ul.  
Paclitaxel therapy will be delayed for a maximum of 
three weeks until these values are achieved. Patients 
who fail to recover adequate counts within a three-
week delay will be removed from study.  If day 7 
dosing criteria are not met, hold the paclitaxel dose 
and treat on day 14 as planned if toxicity has 
resolved.  If day 14 dosing criteria are not met, hold 
the paclitaxel dose.  Start the next full cycle (ie. Day 
1 treatment) one week later if toxicity has resolved.   
Exceptions: 
 Patients who received G-CSF prior to the current 
cycle may begin with ANC ≥ 1000 cells/mm3, if 
clinically appropriate, to allow for transient 
reductions in ANC after discontinuation of G-CSF. 


2009-0186 
Revised April 26, 2016 
Page 30 of 58 
 Patients who are delayed more than 7 days may 
begin with ANC ≥ 1000 cells/mm3, if clinically 
appropriate, as they will receive G-CSF with 
subsequent therapy. 
7.4.1.2.4  Use of Hematopoeitic Cytokines and Protective Agents 
 
Patients will NOT receive prophylactic growth 
factors [filgrastim (GCSF), sargramostim (GM-
CSF)] unless they experience recurrent 
neutropenic complications after treatment 
modifications specified below (Section 7.4.4).  In 
particular, hematopoietic growth factors should 
not be used to avoid initial chemotherapy dose 
modifications as stipulated in the protocol.  
However, patients may also receive growth 
factors for management of neutropenic 
complications in accordance with clinical 
treatment guidelines.  If required, it is 
recommended that growth factors be initiated the 
day after the last dose of chemotherapy and 
typically continuing until the ANC is sustained 
above > 1000/ mm3.  Growth factors should be 
discontinued if the ANC exceeds 10,000/mm3 and 
should not be used within 72 hours of a 
subsequent dose of chemotherapy.   
 
Patients will not be eligible to receive PEG-
filgrastim (Neulasta) on study due to the weekly 
dose schedule of paclitaxel. 
 
Patients will NOT receive prophylactic 
thrombopoietic agents unless they experience 
recurrent grade 4 thrombocytopenia after 
treatment modifications as specified below 
(Section 7.4.4). 
 
Patients may receive erythropoietin (EPO), iron 
supplements, and/or transfusions as clinically 
indicated for management of anemia.  Treating 
physicians should be aware of the recent 
changes in prescribing information for the 
erythropoiesis stimulating agents (including 
Aranesp, Epogen, and Procrit) which note that 
there is a potential risk of shortening the time to 
tumor progression or disease-free survival and 
that these agents are administered only to avoid 
red blood cell transfusions.  They do not alleviate 
fatigue or increase energy.  They should not be 
used in patients with uncontrolled hypertension.  
They can cause an increased incidence of 
thrombotic events in cancer patients on 
chemotherapy.  The updated package inserts 


2009-0186 
Revised April 26, 2016 
Page 31 of 58 
should be consulted.  
http://www.fda.gov/Medwatch/safety/2007/safety0
7.htm 
 
Patients may NOT receive amifostine or other 
protective agents. 
 
For first occurrence of febrile neutropenia, and/or 
documented grade 4 neutropenia persisting ≥ 7 
days, add growth factors. In this circumstance, it 
is recommended that growth factors (G-CSF) at a 
dose of 5 μg/kg/day (or equivalent dose of 
sargramostim) will be administered 
subcutaneously starting the day after the last 
dose of chemotherapy and continuing through 
hematopoietic recovery. Growth factors should 
not be used within 72 hours of a subsequent dose 
of chemotherapy. 
7.4.1.2.5  Dose modifications for the management of 
hematologic toxicity (Section 7.4.4) are applicable to 
carboplatin unless specifically indicated. 
7.4.1.3  Special Modifications 
7.4.1.3.1  For any CTCAE Grade 3 non-hematologic adverse 
event (except controllable nausea/emesis) 
considered to be at least possibly related to study 
treatment, protocol directed treatment should be held 
until symptoms resolve to <= CTCAE Grade 1. If a 
CTCAE Grade 3 adverse event persists for > three 
weeks or recurs after resumption of therapy, the 
patient may be taken off protocol directed treatment 
after consulting with the Study Chair. 
7.4.1.3.2   For any CTCAE Grade 4 non-hematologic adverse 
event (except controllable nausea/emesis), the 
patient may be taken off protocol directed treatment 
therapy after consulting with the Study Chair. 
7.4.1.3.3  Unanticipated Major Surgical Procedures – For any 
unanticipated (emergent/urgent or elective) major 
surgical procedure performed, patients will be 
removed from study.  Treatment delay nor study 
removal is not required for minor procedures 
including a) cystoscopy, b) the removal or insertion of 
a central venous catheter, nephrostomy tube, or 
ureteral stent or c) thoracentesis or paracentesis for 
symptom relief in the absence of disease progression 
according to section 11.2.   
7.4.1.3.4  Dose re-escalation will not be permitted if dose 
reduction is required for toxicity management. 


2009-0186 
Revised April 26, 2016 
Page 32 of 58 
7.4.1.3.5  It is recommended that routine medical measures be 
employed to manage nausea, emesis, constipation, 
and diarrhea. 
7.4.2 Bevacizumab Dose Modification and Toxicity Management 
There are no reductions in the bevacizumab dose. If adverse events 
occur that require holding bevacizumab, the dose will remain the same 
once treatment resumes. 
Any toxicities associated or possibly associated with bevacizumab 
treatment should be managed according to standard medical practice. 
Discontinuation of bevacizumab will have no immediate therapeutic 
effect. Bevacizumab has a terminal half-life of 21 days; therefore, its 
discontinuation results in slow elimination over several months. There is 
no available antidote for bevacizumab.  
Subjects should be assessed clinically for toxicity prior to, during, and 
after each infusion. If unmanageable toxicity occurs because of 
bevacizumab at any time during the study, treatment with bevacizumab 
should be discontinued.  
Adverse events requiring delays or permanent discontinuation of 
bevacizumab are listed in Table 1.  
Patients requiring permanent discontinuation of bevacizumab due to 
bevacizumab toxicities will continue on study with protocol-directed 
carboplatin and paclitaxel alone (unless otherwise indicated in Table 1), 
so long as a patient has not developed progressive cancer as per 
section 11.2 and has not yet received 6 cycles of carboplatin/paclitaxel 
therapy. 


2009-0186 
Revised April 26, 2016 
Page 33 of 58 
Table1:  
Bevacizumab Dose Management Due to Adverse Events 
Event 
Action to be Taken 
Hemorrhage 
Grade 1 or 2 
Non-pulmonary and non-
CNS events 
No dose modification. 
Grade 3 
Non-pulmonary and non-
CNS hemorrhage 
Subjects experience CTCAE Grade 3 hemorrhage and who are also 
receiving full-dose anticoagulation will be discontinued from receiving 
bevacizumab for the remainder of the study.   
All other subjects will have bevacizumab held until all of the following criteria  
are met: 
 
The bleeding has resolved and hemoglobin is stable. 
 
There is no bleeding diathesis that would increase the risk of 
therapy. 
 
There is no anatomic or pathologic condition that significantly 
increases the risk of hemorrhage recurrence. 
If the above criteria are not met by 3 weeks after holding treatment with 
bevacizumab, treatment with bevacizumab should be discontinued for the 
remainder of the study.   
Subjects who experience a repeat Grade 3 hemorrhagic event will be 
discontinued from receiving bevacizumab for the remainder of the study. 
Grade 4 
non-pulmonary or non-
CNS hemorrhage 
Discontinue bevacizumab for the remainder of the study. 
Grade 1 pulmonary or CNS 
hemorrhage 
Subjects who are also receiving full-dose anticoagulation will be 
discontinued from receiving bevacizumab.   
All other subjects will have bevacizumab held until all of the following criteria  
are met: 
 
The bleeding has resolved and hemoglobin is stable. 
 
There is no bleeding diathesis that would increase the risk of 
therapy. 
 
There is no anatomic or pathologic condition that significantly 
increases the risk of hemorrhage recurrence. 
If the above criteria are not met by 3 weeks after holding treatment with 
bevacizumab, treatment with bevacizumab should be discontinued for the 
remainder of the study.   
Grade 2, 3, or 4 pulmonary 
or CNS hemorrhage 
Discontinue bevacizumab for the remainder of the study 
 


2009-0186 
Revised April 26, 2016 
Page 34 of 58 
Venous Thrombosis 
Grade 1 or 2 
No dose modification. 
Grade 3 or 4 
Hold bevacizumab.  If the planned duration of full-dose anticoagulation is ≤2 
weeks, bevacizumab should be held until the full-dose anticoagulation 
period is over.  If the planned duration of full-dose anticoagulation is >2 
weeks, bevacizumab may be resumed during the period of full-dose 
anticoagulation if all of the following criteria  are met: 
 
The subject must have an in-range INR (usually between 2 and 
3) if on warfarin; LMWH, warfarin, or other anticoagulant dosing 
must be stable prior to restarting evacizumab treatment. 
 
The subject must not have had a Grade 3 or 4 hemorrhagic 
event while on anticoagulation. 
 
The subject must not have pathological conditions that carry 
high risk of bleeding (ie. tumor involving major vessels). 
For patients with PT/INR > therapeutic range while on therapeutic warfarin, 
treatment with bevacizumab will be held until PT/INR is within the 
therapeutic range.   
Patients experiencing treatment delay > 3 weeks because of failure to meet 
the above criteria will be taken off bevacizumab for the remainder of the 
study. 
Arterial Thromboembolic event 
(New onset, worsening, or unstable angina, myocardial infarction, transient ischemic attack, 
cerebrovascular accident, and any other arterial thromboembolic event) 
 Any grade 
Discontinue bevacizumab for the remainder of the study. 
Congestive Heart Failure (Left ventricular systolic dysfunction) 
Grade 1 or 2 
No dose modification. 
Grade 3 
Hold bevacizumab until resolution to Grade ≤ 1. 
Patients experiencing treatment delay > 3 weeks because of failure to meet 
the above criteria will be taken off bevacizumab for the remainder of the study. 
Grade 4 
Discontinue bevacizumab for the remainder of the study. 
Proteinuria 
Grade 1 or 2 
(UPCR <3.5) 
No dose modification. 
Grade 3 
(UPCR ≥ 3.5)   
Hold bevacizumab treatment until UPCR ratio recovers to <3.5.  If therapy is 
held for > 2 months due to proteinuria, discontinue evacizumab. 
Grade 4 (nephritic 
syndrome) 
Discontinue bevacizumab for the remainder of the study. 


2009-0186 
Revised April 26, 2016 
Page 35 of 58 
 
GI Perforation 
Discontinue bevacizumab for the remainder of the study.. 
Fistula  
 
Any grade (TE fistula) 
Discontinue bevacizumab for the remainder of the study.. 
Grade 4 fistula 
Discontinue bevacizumab for the remainder of the study.. 
Bowel Obstruction* 
 
Grade 1 
Continue patient on study for partial obstruction NOT requiring medical 
intervention. 
Grade 2 
Hold bevacizumab for partial obstruction requiring medical intervention.  
Patient may restart upon complete resolution. 
Grade 3 
Hold bevacizumab for complete obstruction.  If surgery is necessary, patient 
will be removed from study. 
Grade 4 
Discontinue bevacizumab for the remainder of the study. 
Wound dehiscence  
 
Prior to initiation of 
bevacizumab 
In the event of superficial wound separation healing by secondary intention 
with no evidence of fascial dehiscence or infection, therapy with bevacizumab 
may be initiated with weekly wound examinations until closure. 
After initiation of 
bevacizumab, any grade 
Discontinue bevacizumab for the remainder of the study. 
Reversible Posterior Leukoencephalopathy   
Any grade 
(confirmed by MRI) 
Discontinue bevacizumab for the remainder of the study. 
Other Unspecified Bevacizumab-Related Adverse Events 
Grade 3 
Grade 4 
Hold bevacizumab until recovery to ≤ Grade 1 
Discontinue bevacizumab for the remainder of the study. 
* Since the development of intestinal obstruction could be a result of cancer progression, 
the investigator should take steps to evaluate such patients for the possibility of disease 
progression according to Section 11.2, using clinical, laboratory, and radiographic 
information as clinically indicated.  In the event of disease progression as per Section 
11.2, all protocol-directed therapy would be discontinued. 


2009-0186 
Revised April 26, 2016 
Page 36 of 58 
Hypertension 
Patients should be monitored prior to each bevacizumab dose with measurement 
of blood pressure. Medication classes used for management of patients with 
Grade 3 hypertension receiving bevacizumab include angiotensin-converting 
enzyme inhibitors, beta blockers, diuretics, and calcium channel blockers. The goal 
for blood pressure control should be consistent with general medical practice 
guidelines (i.e. <140/90 mmHg). The use of anxiolytics in conjunction with specific 
anti-hypertensive agents is not prohibited.  
 
For controlled hypertension, defined as systolic <140 mm Hg and diastolic <90 
mm Hg, continue therapy. 
 
For uncontrolled hypertension (systolic >140 mm Hg or diastolic >90) or 
symptomatic hypertension less than CTCAE Grade 4, hold bevacizumab and 
initiate or modify anti-hypertensive therapy as needed. 
 If hypertension is controlled and symptomatic hypertension has resolved by one 
week after holding all therapy, continue all therapy. 
 If hypertension remains uncontrolled or symptomatic hypertension less than 
CTCAE Grade 4 persists one week after holding treatment, the next treatment 
cycle should contain paclitaxel and carboplatin only with bevacizumab omitted.  
Patient may receive bevacizumab therapy if hypertension is controlled for 
subsequent treatment cycles. 
 If uncontrolled or symptomatic hypertension has not resolved by 3 weeks after 
holding treatment with bevacizumab, treatment with bevacizumab should be 
discontinued for the remainder of the study. 
 For any CTCAE Grade 4 hypertension (including hypertensive 
encephalopathy), discontinue bevacizumab for the remainder of the study. 
7.4.3  Paclitaxel Treatment Modifications and Toxicity Management 
Table A.  Dose levels for paclitaxel 
 
-2 
-1 
0 
Paclitaxel 
60 mg/m2 
70 mg/m2 
80 mg/m2 
7.4.3.1  Non-hematologic toxicity 
7.4.3.1.1  Grade 2 (or greater) peripheral neuropathy requires 
reduction of one dose level and delay in all 
subsequent protocol-directed therapy course for a 
maximum of 3 weeks until recovered to grade 1.  If 
peripheral neuropathy fails to recover to Grade 1 by a 
maximum delay of 3 weeks from time therapy is due, 
then patient will be removed from study.   
7.4.3.1.2  Grade 3 (or greater) elevations in SGOT (AST), 
SGPT (ALT), alkaline phosphatase or bilirubin 
requires reduction of one dose level and delay in 
subsequent therapy course for a maximum of 3 


2009-0186 
Revised April 26, 2016 
Page 37 of 58 
weeks until recovered to grade 1 or patient will be 
removed from study. 
7.4.3.1.3  There will be no dose modifications for alopecia or 
fatigue. 
7.4.3.1.4  It is expected that patients with nausea, emesis, 
diarrhea, or constipation will receive appropriate 
medical management without dose modification. 
However, patients with persistent (greater than 24 
hours) grade 3 (or greater) toxicity in spite of optimal 
medical management require reduction of one dose 
level and delay in subsequent therapy for a maximum 
of 3 weeks until recovered to grade 1 or patient will 
be removed from study. 
7.4.3.1.5  Other non-hematologic toxicities with an impact on 
organ function of Grade 2 (or greater) require 
reduction of one dose level and delay in subsequent 
therapy for a maximum of 3 weeks until recovered to 
grade 1, or pre-therapy baseline or patient will be 
removed from study.  If recovery is not reached as 
specified after a 3-week delay, the patient is taken off 
the study. 
7.4.3.1.6  If a treatment had to be omitted during the preceding 
cycle due to toxicities mentioned in Section 7.4.3.1, 
the subsequent cycle will be given with a paclitaxel 
level 1 dose reduction. 
7.4.3.1.7  If after a level 1 dose reduction again treatment had 
to be omitted due to toxicities mentioned in Section 
7.4.3.1, the next cycle will be given with a paclitaxel 
level 2 dose reduction. 
7.4.3.1.8  Patients requiring substitution of docetaxel instead of 
paclitaxel or greater than level 2 dose reduction will 
be removed from study. 
7.4.4  Carboplatin Treatment Modifications and Toxicity Management 
Table B. Dose levels for carboplatin  
 
-2 
-1 
0 
Carboplatin 
Off Study 
AUC 4 
AUC 5 
7.4.4.1 Hematologic toxicity 
Treatment modifications for the management of hematologic 
toxicity are applicable to carboplatin unless specifically 
indicated. 
7.4.4.1.1  Dose-Limiting Neutropenia (DLT-ANC) is defined by 
the occurrence of febrile neutropenia or prolonged 
Grade 4 neutropenia persisting ≥ 7 days.  There will 


2009-0186 
Revised April 26, 2016 
Page 38 of 58 
be no modifications for uncomplicated Grade 4 
neutropenia lasting less than 7 days.  Febrile 
neutropenia is defined within the CTCAE as fever with 
or without clinically or microbiologically documented 
infection with ANC less than 1,000/mm3 and fever ≥ 
38.50C. 
7.4.4.1.2  Dose limiting thrombocytopenia (DLT-PLT) is defined 
by any occurrence of Grade 4 thrombocytopenia 
(<25,000/mm3) or bleeding associated with Grade 3 
thrombocytopenia (25,000 to <50,000mm3).  There will 
be no modifications for uncomplicated Grade 3 
thrombocytopenia. 
7.4.4.1.3  Initial occurrence of dose-limiting neutropenia or dose-
limiting thrombocytopenia as defined in Sections 
7.4.4.1.1 and 7.4.4.1.2 will be handled according to 
Table C using regimen modifications in Table B. 
7.4.4.1.4  For recurrent febrile neutropenia, and/or recurrent 
documented grade 4 neutropenia persisting ≥ 7 days 
(after initial dose reduction), continue growth factors 
and reduce carboplatin by one dose level on 
subsequent cycles.  
7.4.4.1.5  There will be no dose modifications on the basis of 
uncomplicated granulocyte nadirs ≤ Grade 3 lasting 
less than 7 days. 
Table C.  Modification Instructions for Dose-Limiting Hematologic 
Toxicities 
DLT 
ANC 
DLT 
PLT 
First Occurrence 
Second 
Occurrence 
Third Occurrence 
Yes  
No  
Reduce carboplatin 
one dose level 
Add G-GSF and 
maintain all current 
drug doses 
Discontinue All 
Protocol-Directed 
Cytotoxic Therapy 
Yes  
Yes  
Reduce carboplatin 
one dose level 
Add G-GSF and 
decrease 
carboplatin one 
dose level 
Discontinue All 
Protocol-Directed 
Cytotoxic Therapy 
No  
Yes  
Reduce carboplatin 
one dose level 
Decrease 
carboplatin one 
dose level 
Discontinue All 
Protocol-Directed 
Cytotoxic Therapy 
7.4.4.1.6  Carboplatin delay on the basis of neutropenia (Delay-
ANC) is defined if the ANC is less than 1,500 
cells/mm3 (CTCAE Grade 2 or worse) within 24 hours 
prior to scheduled therapy, or less than 1,000 cells/ 


2009-0186 
Revised April 26, 2016 
Page 39 of 58 
mm3, if the patient received G-CSF during the 
previous cycle. 
7.4.4.1.7  Carboplatin delay on the basis of thrombocytopenia 
(Delay-PLT) is defined if the platelet count is less than 
100,000/ mm3 within 24 hours prior to scheduled 
therapy. 
7.4.4.1.8  Modifications noted below are only required for 
management of delays in the absence of dose 
reductions stipulated by nadir DLT-ANC and/or DLT-
PLT (as noted Table C). In other words, if the patient 
experiences DLT-ANC and Delay- ANC, make the 
modifications as indicated for the nadir counts without 
additional modifications based on delayed recovery. 
Table D. Modifications for Delayed Hematologic Recovery 
Category 
Delay (days) 
Modification 
Delay-ANC 
1-7 
No change 
8-21 
Add G-CSF to next cycle 
>21 
Discontinue protocol-directed cytotoxic 
chemotherapy 
Delay-PLT 
1-7 
No change 
8-21 
Add G-CSF to next cycle 
>21 
Discontinue protocol-directed cytotoxic 
chemotherapy 
7.4.4.2  Non-hematologic toxicity 
Renal toxicity (associated with reduction in GFR) is not expected 
as a direct complication of chemotherapy in this untreated patient 
population using the prescribed dose and schedule of each 
regimen. As such, there are no specific dose modifications for 
renal toxicity. However, the target AUC dose of carboplatin must 
be recalculated each cycle in any patient who develops renal 
insufficiency defined by non-IDMS serum creatinine greater than 
1.5 x institutional upper limit normal (ULN), CTCAE Grade ≥ 2. 


2009-0186 
Revised April 26, 2016 
Page 40 of 58 
8.0 
Study Calendar 
 
Pre-Study 
During Chemotherapy Treatment 
Off Study 
 
Observations & Tests 
 
Prior to Initial 
Study 
Treatment 
 
Each Cycle 
 
Day 8 
 
Day 15 
(within 4 weeks 
of last 
protocol-
directed 
therapy) 
 
Every 3 months 
Paclitaxel 
 
X 
X 
X 
 
 
Carboplatin 
 
X 
 
 
 
 
Bevacizumab 
 
22 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
History & Physical Exam 
(including weight) 
1 
14 
 
 
X 
X 
Pelvic exam 
1 
15 
 
 
16 
16 
Vital signs 
1 
14 
X 
X 
X 
X 
Toxicity Assessment 
2 
X 
 
 
X 
21 
Performance status 
1 
 
 
 
X 
X 
CBC w/diff, plts 
2 
3 
X 
X 
4 
4 
Serum chemistry (BUN/Cr, 
Magnesium, Calcium, SGOT, 
SGPT, Alkaline phosphatase, 
Total bilirubin, electrolytes) 
2 
3 
 
 
5 
5 
PT/PTT/INR 
1, 6 
6 
 
 
5, 6 
5, 6 
CA-125 
1, 11 
12 
 
 
X 
X 
Radiographic Disease 
Assessment 
18 
9 
 
 
9 
5,9 
EKG 
1 
 
 
 
5 
5 
CXR 
1, 10 
 
 
 
5 
5 
UPCR for proteinuria 
2, 17 
18 
 
 
19 
19 
Serum Pregnancy Test (if 
childbearing potential exists) 
2 
 
 
 
 
 
Incision check 
2 
13 
 
 
 
 
Blood draw for cytokine analysis 
2 
Pre cycle 3 
 
 
20 
 
Biomarker evaluation of tumor 
tissue 
23 
 
 
 
 
24 
a 
Patients who are considered inevaluable or patients who have disease progression or 
are non-responders as per Section 11.2 at time of off-study evaluation are not required 
to adhere to follow-up protocol. 
1. 
Must be obtained within 28 days prior to initiating protocol therapy. 


2009-0186 
Revised April 26, 2016 
Page 41 of 58 
2. 
Must be obtained within 14 days prior to initiating protocol therapy. 
3. 
Must be obtained within 4 days of re-treatment with protocol therapy. 
4. 
Weekly until counts recover from nadir. 
5. 
When clinically indicated. 
6. 
For patients on prophylactic or therapeutic anticoagulation with warfarin, PT/INR 
should be monitored before each treatment.  Treatment should be held for PT/INR of > 
1.5 on prophylactic warfarin of > therapeutic range if on full-dose warfarin. 
7. 
For patients with a history of hearing loss; repeat as clinically indicated. 
8. 
An initial CT scan or MRI of at least the abdomen and pelvis is required to 
establish post-surgical baseline for the extent of residual disease within 4 weeks of 
registration and beginning of treatment.   
9. 
Follow-up Radiographic Assessment of Disease.  In the absence of disease 
progression by criteria in Section 11.2, imaging using the same modality and 
encompassing the same field as in the initial pre-treatment evaluation should be 
repeated with the following schedule, regardless of whether or not the patient had 
measurable disease on initial CT or MRI:  
a)  Patients considered suboptimal will receive radiographic disease assessment after 
completion of 3 cycles of study therapy and within 4 weeks after completion of 
protocol directed chemotherapy. 
b)  Patients considered optimal will receive radiographic disease assessment after 
completion of protocol directed chemotherapy. 
c)  All patients, during or after completion of all protocol therapy, may receive 
radiographic disease assessment as clinically indicated at any time for clinical 
suspicion of progressive disease. 
If based on any of these evaluations a response (CR or PR) is documented, a same 
modality imaging study should be performed after no less than 4 weeks in order to 
confirm persistence of response by RECIST criteria.[51]  Imaging assessments as part 
of this protocol should be discontinued if disease progression is confirmed according to 
guidelines in Section 11.2, regardless of means of confirmation, except that when 
disease progression is defined by CA-125 criteria alone, imaging using the same 
modality and encompassing the same field as in the initial pre-treatment evaluation 
should be obtained within two weeks that such progression is documented.  
10. Not required if CT or MRI of chest already performed at pre-treatment baseline. 
11. Baseline pre-chemotherapy value is required.  When available, also include pre-
surgical value. 
12. Progression can be based upon serum CA-125, only during the period following 
completion of cytotoxic chemotherapy, if one of the three conditions is met: 1. Patients 
with elevated CA-125 pretreatment and normalization of CA-125 must show evidence 
of CA-125 greater than or equal to two times the upper normal limit on two occasions 
at least one week apart or 2. Patients with elevated CA-125 pretreatment, which never 
normalizes must show evidence of CA-125 greater than or equal to two times the nadir 
value on two occasions at least one week apart or 3. Patients with CA-125 in the 
normal range pretreatment must show evidence of CA-125 greater than or equal to 
two times the upper normal limit on two occasions at least one week apart. When 


2009-0186 
Revised April 26, 2016 
Page 42 of 58 
disease progression is defined by CA-125 criteria alone, imaging using the same 
modality and encompassing the same field as in the initial pre-treatment evaluation 
should be obtained within 2 weeks that such progression is documented (see Section 
8.4).If the patient does not meet criteria for disease progression on the basis of CA-
125 elevations, then CA-125 monitoring should be continued according to schedule.  
13. Patients with granulating incisions healing by secondary intention with no evidence of 
fascial dehiscence or infection are eligible but require weekly would examinations until 
complete closure.  Any occurrence of fascial dehiscence or deterioration related to the 
incision should be addressed according to guidelines for treatment modification 
(Section 7.4.2) and Adverse Events reporting (Section 12.0). 
14. Within one week before and as close to the beginning of the next applicable course as 
possible. 
15. Pelvic examination is required only if this method is used to evaluate measurable 
disease or for clinical suspicion of disease progression or recurrence. 
16. Pelvic examination is required during follow-up to evaluate for disease progression or 
recurrence. 
17. Urine protein should be screened by UPCR (see Section 5.3.16 for details). Patients 
must have a UPCR < 1.0 to allow participation in the study. 
18. Patients receiving bevacizumab should be monitored by urine analysis for urine 
protein: creatinine (UPCR) ratio prior to every other dose of bevacizumab: 
UPCR ratio < 3.5 
Continue bevacizumab. 
UPCR ratio ≥ 3.5 
Hold bevacizumab until UPCR ratio recovers to < 
3.5.  If therapy is held for > 2 months due to 
proteinuria, discontinue bevacizumab 
Grade 4 or nephrotic syndrome 
Discontinue bevacizumab. 
19. Check UPCR at first post-treatment visit.  Check the UPCR at subsequent post-
treatment follow-up intervals only if the value is > 1.0. 
20. Performed only at the first follow-up evaluation in patients who have received at 
minimum two cycles of bevacizumab. 
21. Patients discontinued from the treatment phase of the study for any reason will be 
evaluated ~30 days (28–42 days) after the decision to discontinue treatment (see 
Section 7.4.2) unless patients are discontinued from the study due to an ongoing 
bevacizumab-related Grade 4 or serious adverse event. These patients will continue to 
be followed until resolution of the event or until the event is considered irreversible. 
22. Bevacizumab dosing will start on Day 1 of Cycle 2. 
23. Tissue from the tumor bank repository will be stored at the time of initial cytoreductive 
surgery if the patient consented to tumor bank storage prior to surgery. 
24. Genetic analyses of tumor tissue samples will be conducted after disease progression 
has been determined or after 24 months of follow-up, whichever comes first. 


2009-0186 
Revised April 26, 2016 
Page 43 of 58 
9.0 
SUBJECT DISCONTINUATION 
Subjects who meet the following criteria should be discontinued from study 
treatment:  
1. Completed protocol-directed treatment 
2. Inability to tolerate the lowest doses because of toxicity. 
3. The patient may withdraw from the study at any time for any reason. 
4. Patients with deterioration of performance status may be removed from study 
at the investigator's discretion 
5. Non-compliance  
6. Subjects who experience a CTCAE Grade 3 or 4 allergic reaction / 
hypersensitivity, adult respiratory distress syndrome, or bronchospasm 
(regardless of grade)  
7. Radiographic evidence of disease progression (see section 11.2.1) 
8. Grade 4 hypertension or Grade 3 hypertension not controlled with medication 
9. Reversible posterior leukoencephalopathy syndrome (RPLS) 
10. Nephrotic syndrome 
11. Grade ≥ 2 pulmonary or CNS hemorrhage; any Grade 4 hemorrhage 
12. Symptomatic Grade 4 venous thromboembolic event (for lung protocols: any 
venous thromboembolic event requiring full dose warfarin or equivalent (i.e., 
unfractionated or low molecular weight heparin)  
13. Any grade arterial thromboembolic event 
14. Grade 4 congestive heart failure 
15. Gastrointestinal perforation  
16. Tracheoesophageal fistula (any grade) or Grade 4 fistula 
17. Grade ≥ 2 bowel obstruction that has not fully recovered despite medical or 
surgical intervention 
18. Wound dehiscence requiring medical or surgical intervention 
19. Unwillingness or inability of subject to comply with study requirements 
20. Determination by the investigator that it is no longer safe for the subject to 
continue therapy 
21. All Grade 4 events thought to be related to bevacizumab by the investigator 
22. Patients requiring surgery for any reason while receiving protocol-related 
therapy 
Patients who have an ongoing bevacizumab-related Grade 4 or serious 
adverse event at the time of discontinuation from study treatment will continue 
to be followed until resolution of the event or until the event is considered 
irreversible. 


2009-0186 
Revised April 26, 2016 
Page 44 of 58 
10.0 
STUDY DISCONTINUATION 
Patients will receive treatment until disease progression, the development of 
adverse events requiring discontinuation of protocol treatment, or completion of 6 
cycles of protocol-directed treatment, whichever comes first.  No form of therapy 
targeted against a patient’s cancer other than that specified in this protocol will be 
administered while on study. 


2009-0186 
Revised April 26, 2016 
Page 45 of 58 
11.0 
STATISTICAL CONSIDERATIONS 
11.1 Determination of Sample Size 
We will enroll and evaluate a minimum of 15 patients with a target completed 
sample size of 30 patients.  Patients will be enrolled at a rate of 1-2 patients per 
month.  Our primary outcome is treatment success, defined as a patient completing 
at least 4 cycles of combination therapy (Bevacizumab with Carboplatin and 
weekly Paclitaxel) regardless of delay or dose modification.  Our target treatment 
success rate is 60%. 
We will employ a Bayesian monitoring rule following the example of Thall and 
Simon.[52] We will stop the trial early if Pr(treatment success rate  60% | data 
from the trial) < 0.05.  That is, given the outcomes from the patients who have 
already been evaluated, if we determine that there is less than a 5% chance that 
the treatment success rate is 60% or more we will stop the trial.  This decision rule 
gives the following stopping rule.  We assume a uniform prior distribution for the 
treatment success rate.  Stop the trial if 
 [ # of pts with treatment success / # of pts evaluated ] 
≤ 5/15, 6/16, 7/18, 8/20, 9/22, 10/24, 11/26, 12/27, 13/29 
The operating characteristics of this study design are shown in Table 1. 
Table 1.  Operating Characteristics of Feasibility Monitoring Rule 
 
 
Sample Size 
Success Rate 
Probability of 
Stopping Early 
P25 
P50 
P75 
 
 
 
 
 
0.35 
0.929 
15 
15 
18 
0.40 
0.819 
15 
16 
27 
0.45 
0.649 
15 
22 
30 
0.50 
0.446 
18 
30 
30 
0.55 
0.249 
30 
30 
30 
0.60 
0.125 
30 
30 
30 
0.65 
0.046 
30 
30 
30 
0.70 
0.014 
30 
30 
30 
Once we have completed the study we will estimate the treatment success rate with 
90% credible interval.  If we find 23 of the 30 patients with treatment success, then 
our 90% credible interval for the treatment success rate will be 61.7% to 86.5%.  We 
will also report the posterior probability that the treatment success rate is 60% or 


2009-0186 
Revised April 26, 2016 
Page 46 of 58 
more. For example, if we complete the trial with 21 of 30 patients with treatment 
success, the posterior probability that the treatment success rate is at least 60% will 
be 0.857. 
11.2  Planned Efficacy Evaluations 
 11.2.1  Efficacy Variables 
11.2.1.1 
Parameters of Response – RECIST Criteria Version 1.1  
Measurable disease is defined as at least one lesion that 
can be accurately measured in at least one dimension 
(longest dimension to be recorded). Each lesion must be ≥10 
mm when measured by conventional techniques, including 
caliper measurements on clinical exam, CT, and MRI, or ≥20 
mm by chest x-ray.[51]  PET scanning information will not be 
evidence of disease progression or measurable disease.  
PET CT Fusion studies may not meet technical 
requirements. 
To be considered pathologically enlarged and measurable, a 
lymph node should be ≥15mm by short axis on CT scan. 
11.2.1.2 Baseline Documentation of “Target” and “Non-Target” 
Lesions 
 All measurable lesions up to a maximum of 2 lesions per 
organ and 5 lesions in total representative of all involved 
organs should be identified as target lesions and will be 
recorded and measured at baseline. Target lesions 
should be selected on the basis of their size (lesions with 
the longest dimension) and their suitability for accurate 
repetitive measurements by one consistent method of 
assessment (either by imaging techniques or clinically).  A 
sum of diameters for all target lesions will be calculated 
and reported as the baseline sum.  Only the short axis of 
lymph nodes classified as measurable will contribute to 
the baseline sum. The baseline sum will be used as 
reference to further characterize the objective tumor 
response of the measurable dimension of the disease.  
 All other lesions (or sites of disease), including 
pathological lymph nodes ≥ 10 to <15 mm short axis, 
should be identified as non-target lesions and should also 
be recorded at baseline. Measurements are not required 
and these lesions should be followed as “present” or 
“absent”.  
 All baseline evaluations of disease status should be 
performed as close as possible to the start of treatment 
and never more than 4 weeks before the beginning of 
treatment. 
 Tumor lesions that are situated in previously irradiated 
area might or might not be considered measurable. 


2009-0186 
Revised April 26, 2016 
Page 47 of 58 
11.2.1.3 
Best Response 
Measurement of the longest dimension of each lesion size is 
required for follow-up. Change in the sum of these 
dimensions affords some estimate of change in tumor size 
and hence therapeutic efficacy. All disease must be 
assessed using the same technique as baseline. Reporting 
of these changes in an individual case should be in terms of 
the best response achieved by that case since entering the 
study. 
 Complete Response (CR) is disappearance of all target and 
non-target lesions and no evidence of new lesions 
documented by two disease assessment.  Any pathological 
lymph node (whether target or non-target) must have 
reduction in short axis to <10mm.   
 Partial Response (PR) is at least a 30% decrease in the sum 
of diameters of all target measurable lesions taking as 
reference the baseline sum of diameters.  There can be no 
unequivocal progression of nontarget lesions and no new 
lesions. Documentation by two disease assessments at least 
4 weeks apart is required. In the case where the ONLY 
target lesion is a solitary pelvic mass measured by physical 
exam, which is not radiographically measurable, a 50% 
decrease in the LD is required. 
 Increasing Disease is at least a 20% increase in the sum of 
diameters of target lesions taking as references the smallest 
sum on study.  In addition to the 20% relative increase, the 
sum must also have an absolute increase of at least 5 mm.  
The appearance of one or more new lesions is also 
considered progressive disease.  Unequivocal progression 
of existing non-target lesions, other than pleural effusions 
without cytological proof of neoplastic origin, in the opinion of 
the treating physician within 8 weeks of study entry is also 
considered increasing disease (in this circumstance an 
explanation must be provided). In the case where the ONLY 
target lesion is a solitary pelvic mass measured by physical 
exam, which is not radiographically measurable, a 50% 
increase in the LD is required. 
 Symptomatic deterioration is defined as a global 
deterioration in health status attributable to the disease 
requiring a change in therapy without objective evidence of 
progression. 
 Stable Disease is any condition not meeting the above 
criteria. 
 Inevaluable for response is defined as having no repeat 
tumor assessments following initiation of study therapy for 
reasons unrelated to symptoms or signs of disease. 


2009-0186 
Revised April 26, 2016 
Page 48 of 58 
 The cytological confirmation of the neoplastic origin of any 
effusion that appears or worsens during treatment when the 
measurable tumor has met criteria for response or stable 
disease is mandatory to differentiate between response or 
stable disease (an effusion may be a side effect of the 
treatment) and progressive disease. 
 Progression Based on Serum CA-125:    
Progression can be based upon serum CA-125, only during 
the period following completion of cytotoxic chemotherapy, if 
one of the three conditions is met: 
1. Patients with elevated CA-125 pretreatment and 
normalization of CA-125 must show evidence of CA-125 
greater than or equal to two times the upper normal limit on 
two occasions at least one week apart 
2. 
Patients with elevated CA-125 pretreatment, which 
never normalizes must show evidence of CA-125 greater 
than or equal to two times the nadir value on two occasions 
at least one week apart 
3. 
Patients with CA-125 in the normal range 
pretreatment must show evidence of CA-125 greater than or 
equal to two times the upper normal limit on two occasions 
at least one week apart 
When disease progression is defined by CA-125 criteria 
alone, imaging using the same modality and encompassing 
the same field as in the initial pre-treatment evaluation 
should be obtained within 2 weeks that such progression is 
documented. 
 Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of 
disease progression at that time should be reported as 
“symptomatic deterioration”.  Every effort should be made to 
document the objective progression even after 
discontinuation of treatment.  
 In some circumstances, it may be difficult to distinguish 
residual disease from normal tissue.  When the evaluation of 
complete response depends on this determination, it is 
recommended that the residual lesion be investigated (ie. 
fine needle aspiration/biopsy) before confirming the 
complete response status. 
 In some cases a discrepancy may exist between trends in 
CA-125 levels and data from either imaging or physical 
examination.  In such cases, disease status by CT or MRI 
(and physical examination) should take precedence over 
CA-125.  For example, if there is evidence of disease on CT, 
MRI, or physical examination, and none of these areas 


2009-0186 
Revised April 26, 2016 
Page 49 of 58 
demonstrate any progression then rising CA-125 levels 
would be insufficient to determine disease progression. 
 Patients who are not evaluated for response will be 
classified as either: having no target lesions at the time of 
enrollment onto the study, not reassessed due to early 
death, or unknown (not assessable, or insufficient data).  
11.2.1.4 
Confirmatory Measurement/Duration of 
Response 
Confirmation:  In order for a patient to be assigned a status 
of PR or CR, changes in tumor measurements must be 
confirmed by repeat assessments that should be performed 
no less than 4 weeks after the criteria for response are first 
met. 
Duration of overall response:  The duration of overall 
response is measured from the time measurement criteria 
are met for CR or PR (whichever is first recorded) until the 
first date that recurrent or progressive disease is objectively 
documented (taking as reference for progressive disease the 
smallest measurements recorded since the treatment 
started). 
The duration of overall CR is measured from the time 
measurement criteria are first met for CR until the first date 
that recurrent disease is objectively documented. 
 
Duration of stable disease:  Stable disease is measured from 
the start of the treatment until the criteria for progression are 
met, taking as reference the smallest measurements 
recorded since the treatment started.  
11.2.1.5    Progression-Free Survival 
Progression-Free Survival is the period from study entry until 
disease progression, death or date of last contact. 
The defined date of disease progression will depend on the 
method of determination as follows:  
11.2.1.5.1  For disease progression defined by imaging or 
palpation of at least a 20% increase in the sum of 
the LD of target lesions, the appearance of one or 
more new lesions, or unequivocal progression of 
existing nontarget lesions, the date of progression 
will be defined as the date such lesions were first 
found to be progressed by imaging or palpation.  
11.2.1.5.2  For disease progression defined by development 
or worsening of ascites or pleural effusions, the 
date of progression will be defined as the date of 
cytologic verification.  
11.2.1.5.3 For disease progression defined by CA125 
criteria alone, the date of progression will be 


2009-0186 
Revised April 26, 2016 
Page 50 of 58 
defined as the first date of the initial CA125 of 
greater than or equal to two times the nadir value 
or upper limit of normal, whichever of these is 
applicable.  Given that imaging using the same 
modality and encompassing the same field as in 
the initial pretreatment evaluation is required 
within 2 weeks of the confirmatory (second) 
CA125 value, if imaging criteria are met for 
progression, then the date of progression would 
be defined as the date of the imaging study.  
11.2.1.5.4 In the case where the ONLY target lesion is a 
solitary pelvic mass measured by physical exam 
which is not radiographically measurable, a 50% 
increase in the LD is required taking as reference 
the smallest LD recorded since study entry. 
11.2.1.5.5  Death due to disease without prior objective 
documentation of progression. 
11.2.1.5.6 Global deterioration in health status attributable to 
the disease requiring a change in therapy without 
objective evidence of progression. 
11.2.1.6 
Overall Survival 
Overall Survival is the observed length of life from entry into 
the study to death, regardless of cause or the date of last 
contact. 
11.2.1.7 
Subjective Parameters  
Subjective Parameters including performance status, 
specific symptoms, and side effects are graded according to 
the CTCAE v3.0.  
11.2.2 
Methods of Analysis 
 
This is a traditional phase II study and, hence, no 
randomization or comparison group is involved. 
 
The principal parameters employed to evaluate the efficacy of 
each agent are: 
11.2.2.1 Progression-free survival (PFS) 
We will estimate the PFS with the Kaplan-Meier 
product-limit estimator stratified by debulking status 
(optimal, sub-optimal).[53]  We will use the Cox 
proportional hazards regression model [54] to assess 
the association of gene expression and cytokines with 
PFS as described below. 
11.2.2.2 The frequency and duration of objective response. 
We will estimate the frequency of objective response 
with a 95% confidence interval separately for optimally 
debulked patients and sub-optimally debulked patients. 


2009-0186 
Revised April 26, 2016 
Page 51 of 58 
For those patients who achieve an objective response 
we will estimate the duration of objective response with 
a 95% confidence interval separately for optimally 
debulked patients and sub-optimally debulked patients. 
We will use logistic regression methods to assess the 
association between cytokines and objective response. 
The frequency and severity of observed adverse effects. 
We will tabulate the frequency and severity of observed 
adverse events separately for optimally debulked 
patients and sub-optimally debulked patients, as well as 
for all patients together. 
11.3 Genomic Data Analyses 
Expression arrays will be quantified using Robust Multichip Analysis.[55]  
After quantification, we will fit Cox proportional hazards models on a gene by 
gene basis, with gene expression levels and debulking status as covariates; 
we seek cases where the gene expression coefficients are significant.  We 
will adjust for multiple comparisons using beta-uniform mixture (BUM) models 
[56],  and seek genes that remain significant at a false discovery rate (FDR) 
of 0.2. Given the mechanism of action for bevacizumab, this analysis will be 
repeated with attention restricted to the subset of genes associated with 
angiogenesis according to Gene Ontology.   
11.4 Cytokine Evaluation Analyses 
We anticipate profiling the paired pre and post-treatment plasma samples for 
the expression levels of a small number of cytokines (on the order of 20 to 
50). We are primarily interested in relating two quantities with PFS: (1) 
baseline cytokine levels at time of initial measurement, and (2) post-pre 
differences in cytokine levels. In both cases, we will assess significance by 
fitting Cox proportional hazards models with debulking status as an additional 
covariate, and looking at the significance of the cytokine coefficient term. We 
will correct for multiple testing using a conservative Bonferroni adjustment, 
dividing the target p-value for significance by the total number of tests 
performed.  


2009-0186 
Revised April 26, 2016 
Page 52 of 58 
 
12.0 
SAFETY REPORTING OF ADVERSE EVENTS 
12.1 
ADVERSE EVENT REPORTING AND DEFINITIONS 
In the event of an adverse event the first concern will be for the safety of the 
subject.   
Investigators are required to report to Genentech Drug Safety ANY serious 
treatment emergent adverse event (STEAE) as soon as possible.   
A STEAE is any sign, symptom or medical condition that emerges during 
Bevacizumab treatment or during a post-treatment follow-up period that (1) 
was not present at the start of Bevacizumab treatment and it is not a chronic 
condition that is part of the patient’s medical history, OR (2) was present at the 
start of Bevacizumab treatment or as part of the patient’s medical history but 
worsened in severity and/or frequency during therapy, AND that meets any of 
the following regulatory serious criteria: 
 Results in death  
 Is life-threatening  
 Requires or prolongs inpatient hospitalization  
 Is disabling  
 Is a congenital anomaly/birth defect  
 Is medically significant or requires medical or surgical intervention to 
prevent one of the outcomes listed above. 
12.2 
REPORTING OF SERIOUS TREATMENT EMERGENT ADVERSE 
EVENTS  
All STEAEs should be recorded on a MedWatch 3500a Form and faxed to: 
1)  Genentech Drug Safety  Fax: 
(650) 225-4682 or (650) 225-5288 
AND 
2)  Judith Wolf, Principal Investigator  Phone: (713)792-7310   Fax: 
(713)745-8276  
AND 
3) MDACC IRB Contact: Mary Fields or Barbara Groves   Fax: (713) 794-
4589 
Please use safety reporting fax cover sheet in Appendix G for your fax 
transmission. 
MedWatch 3500a Reporting Guidelines: 
In addition to completing appropriate patient demographic and suspect 
medication information, the report should include the following information 
within the Event Description (section 5) of the MedWatch 3500a form: 
 Treatment regimen (dosing frequency, combination therapy) 
 Protocol description (and number, if assigned) 


2009-0186 
Revised April 26, 2016 
Page 53 of 58 
 Description of event, severity, treatment, and outcome, if known 
 Supportive laboratory results and diagnostics 
 Investigator’s assessment of the relationship of the adverse event to each 
investigational product and suspect medication 
Follow-up information: 
Additional information may be added to a previously submitted report by any 
of the following methods: 
 
Adding to the original MedWatch 3500a report and submitting it as 
follow-up 
 
Adding supplemental summary information and submitting it as follow-
up with the original MedWatch 3500a form  
 
Summarizing new information and faxing it with a cover letter including 
subject identifiers (i.e. D.O.B. initial, subject number), protocol 
description and number, if assigned, suspect drug, brief adverse event 
description, and notation that additional or follow-up information is being 
submitted  (The subject identifiers are important so that the new 
information is added to the correct initial report) 
Occasionally Genentech may contact the reporter for additional information, 
clarification, or current status of the subject for whom and adverse event was 
reported.  
Assessing Causality: 
Investigators are required to assess whether there is a reasonable possibility 
that bevacizumab caused or contributed to an adverse event.  The following 
general guidance may be used. 
Yes: if the temporal relationship of the clinical event to bevacizumab 
administration makes a causal relationship possible, and other drugs, 
therapeutic interventions or underlying conditions do not provide a 
sufficient explanation for the observed event. 
No: if the temporal relationship of the clinical event to bevacizumab 
administration makes a causal relationship unlikely, or other drugs, 
therapeutic interventions or underlying conditions provide a sufficient 
explanation for the observed event. 
12.3 
Safety Reporting Requirements for IND Exempt Studies 
For Investigator Sponsored IND Exempt Studies, there are some reporting 
requirements for the FDA in accordance with the guidance set forth in 21 CFR 
314.80. 
Postmarketing 15-Day “Alert Report”: 
The Sponsor-Investigator is required to notify the FDA of any fatal or life-
threatening adverse event that is unexpected and assessed by the 
investigator to be possibly related to the use of Bevacizumab. An 
unexpected adverse event is one that is not already described in the 
Investigator Brochure. Such reports are to be submitted to the FDA (2 copies) 


2009-0186 
Revised April 26, 2016 
Page 54 of 58 
at the following address: Central Document Room, 12229 Wilkins Avenue, 
Rockville, MD 20852. 
All Postmarketing 15-Day “Alert Reports” submitted to the FDA by the 
Sponsor-Investigator must also be faxed to: Genentech Drug Safety  
Fax: 
(650) 225-4682 or (650) 225-5288 (Please use the safety reporting 
fax cover sheet attached to this document for your fax transmission) 
For questions related to safety reporting, contact: 
Genentech Drug Safety 
Tel: 
1-888-835-2555 
         or 
Fax: 
(650) 225-4682 or (650) 225-5288 
(Please use the safety reporting fax cover sheet attached to this document for 
your fax transmission) 
 
13.0 
RETENTION OF RECORDS 
We will retain all documentation of adverse events, records of study drug receipt 
and dispensation, and all IRB correspondence for at least 2 years after the 
investigation is completed. 


2009-0186 
Revised April 26, 2016 
Page 55 of 58 
REFERENCES 
 
[1] 
Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ. Cancer statistics, 2008. CA 
Cancer J Clin 2008;58:71-96. 
[2] 
Cannistra SA. Cancer of the ovary. N Engl J Med 2004;351:2519-29. 
[3] 
Ozols RF, Bundy BN, Greer BE, Fowler JM, Clarke-Pearson D, Burger RA, Mannel RS, 
DeGeest K, Hartenbach EM, Baergen R. Phase III trial of carboplatin and paclitaxel 
compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian 
cancer: a Gynecologic Oncology Group study. J Clin Oncol 2003;21:3194-200. 
[4] 
Neijt JP, Engelholm SA, Tuxen MK, Sorensen PG, Hansen M, Sessa C, de Swart CA, 
Hirsch FR, Lund B, van Houwelingen HC. Exploratory phase III study of paclitaxel and 
cisplatin versus paclitaxel and carboplatin in advanced ovarian cancer. J Clin Oncol 
2000;18:3084-92. 
[5] 
Wu CH, Yang CH, Lee JN, Hsu SC, Tsai EM. Weekly and monthly regimens of paclitaxel 
and carboplatin in the management of advanced ovarian cancer. A preliminary report on 
side effects. Int J Gynecol Cancer 2001;11:295-9. 
[6] 
Sehouli J, Stengel D, Mustea A, Camara O, Keil E, Elling D, Ledwon P, Christiansen B, 
Klare P, Gebauer G, Schwarz M, Lichtenegger W. Weekly paclitaxel and carboplatin (PC-
W) for patients with primary advanced ovarian cancer: results of a multicenter phase-II 
study of the NOGGO. Cancer Chemother Pharmacol 2008;61:243-50. 
[7] 
Pignata S, Breda E, Scambia G, Pisano C, Zagonel V, Lorusso D, Greggi S, De Vivo R, 
Ferrandina G, Gallo C, Perrone F. A phase II study of weekly carboplatin and paclitaxel as 
first-line treatment of elderly patients with advanced ovarian cancer. A Multicentre Italian 
Trial in Ovarian cancer (MITO-5) study. Crit Rev Oncol Hematol 2008;66:229-36. 
[8] 
Havrilesky LJ, Alvarez AA, Sayer RA, Lancaster JM, Soper JT, Berchuck A, Clarke-
Pearson DL, Rodriguez GC, Carney ME. Weekly low-dose carboplatin and paclitaxel in the 
treatment of recurrent ovarian and peritoneal cancer. Gynecol Oncol 2003;88:51-7. 
[9] 
Isonishi S, Yasuda M, Takahashi F, Katsumata N, Kimura E, Aoki D, Jobo T, Terauchi F, 
Tsuda H, Sugiyama T. Randomized phase III trial of conventional paclitaxel and carboplatin 
(c-TC) versus dose dense weekly paclitaxel and carboplatin (dd-TC) in women with 
advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer: Japanese 
Gynecologic Oncology. J Clin Oncol 2008 (abstr 5506);26. 
[10] 
Kikuchi A, Sakamoto H, Yamamoto T. Weekly carboplatin and paclitaxel is safe, active, and 
well tolerated in recurrent ovarian cancer cases of Japanese women previously treated with 
cisplatin-containing multidrug chemotherapy. Int J Gynecol Cancer 2005;15:45-9. 
[11] 
Loesch D, Robert N, Asmar L, Gregurich MA, O'Rourke M, Dakhil S, Cox E. Phase II 
multicenter trial of a weekly paclitaxel and carboplatin regimen in patients with advanced 
breast cancer. J Clin Oncol 2002;20:3857-64. 
[12] 
Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 
1995;1:27-31. 
[13] 
Fidler IJ, Ellis LM. The implications of angiogenesis for the biology and therapy of cancer 
metastasis. Cell 1994;79:185-8. 
[14] 
Yoneda J, Kuniyasu H, Crispens MA, Price JE, Bucana CD, Fidler IJ. Expression of 
angiogenesis-related genes and progression of human ovarian carcinomas in nude mice. J 
Natl Cancer Inst 1998;90:447-54. 
[15] 
Hollingsworth HC, Kohn EC, Steinberg SM, Rothenberg ML, Merino MJ. Tumor 
angiogenesis in advanced stage ovarian carcinoma. Am J Pathol 1995;147:33-41. 
[16] 
Gasparini G, Bonoldi E, Viale G, Verderio P, Boracchi P, Panizzoni GA, Radaelli U, Di 
Bacco A, Guglielmi RB, Bevilacqua P. Prognostic and predictive value of tumour 
angiogenesis in ovarian carcinomas. Int J Cancer 1996;69:205-11. 
[17] 
Kim KJ, Li B, Winer J, Armanini M, Gillett N, Phillips HS, Ferrara N. Inhibition of vascular 
endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 
1993;362:841-4. 


2009-0186 
Revised April 26, 2016 
Page 56 of 58 
[18] 
Luo JC, Toyoda M, Shibuya M. Differential inhibition of fluid accumulation and tumor growth 
in two mouse ascites tumors by an antivascular endothelial growth factor/permeability 
factor neutralizing antibody. Cancer Res 1998;58:2594-600. 
[19] 
Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, 
Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F. 
Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. 
N Engl J Med 2004;350:2335-42. 
[20] 
Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson 
DH. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N 
Engl J Med 2006;355:2542-50. 
[21] 
Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, Shenkier T, Cella D, 
Davidson NE. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast 
cancer. N Engl J Med 2007;357:2666-76. 
[22] 
Giantonio BJ, Catalano PJ, Meropol NJ, O'Dwyer PJ, Mitchell EP, Alberts SR, Schwartz 
MA, Benson AB, 3rd. Bevacizumab in combination with oxaliplatin, fluorouracil, and 
leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the 
Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 2007;25:1539-44. 
[23] 
Ozcan C, Wong SJ, Hari P. Reversible posterior leukoencephalopathy syndrome and 
bevacizumab. N Engl J Med 2006;354:980-2; discussion 980-2. 
[24] 
Glusker P, Recht L, Lane B. Reversible posterior leukoencephalopathy syndrome and 
bevacizumab. N Engl J Med 2006;354:980-2; discussion 980-2. 
[25] 
Hambleton J, Skillings J, Kabbinavar F, Bergsland E, Holmgren E, Holden SN, Hurwitz H, 
Scappaticci F. Safety of low-dose aspirin (ASA) in a pooled analysis of 3 randomized, 
controlled trials (RCTs) of bevacizumab (BV) with chemotherapy (CT) in patients (pts) with 
metastatic colorectal cancer (mCRC). J Clin Oncol (Meeting Abstracts) 2005;23:3554. 
[26] 
Scappaticci FA, Fehrenbacher L, Cartwright T, Hainsworth JD, Heim W, Berlin J, 
Kabbinavar F, Novotny W, Sarkar S, Hurwitz H. Surgical wound healing complications in 
metastatic colorectal cancer patients treated with bevacizumab. J Surg Oncol 2005;91:173-
80. 
[27] 
Miller KD, Chap LI, Holmes FA, Cobleigh MA, Marcom PK, Fehrenbacher L, Dickler M, 
Overmoyer BA, Reimann JD, Sing AP, Langmuir V, Rugo HS. Randomized phase III trial of 
capecitabine compared with bevacizumab plus capecitabine in patients with previously 
treated metastatic breast cancer. J Clin Oncol 2005;23:792-9. 
[28] 
Karp JE, Gojo I, Pili R, Gocke CD, Greer J, Guo C, Qian D, Morris L, Tidwell M, Chen H, 
Zwiebel J. Targeting vascular endothelial growth factor for relapsed and refractory adult 
acute myelogenous leukemias: therapy with sequential 1-beta-d-arabinofuranosylcytosine, 
mitoxantrone, and bevacizumab. Clin Cancer Res 2004;10:3577-85. 
[29] 
Wedam SB, Low JA, Yang SX, Chow CK, Choyke P, Danforth D, Hewitt SM, Berman A, 
Steinberg SM, Liewehr DJ, Plehn J, Doshi A, Thomasson D, McCarthy N, Koeppen H, 
Sherman M, Zujewski J, Camphausen K, Chen H, Swain SM. Antiangiogenic and antitumor 
effects of bevacizumab in patients with inflammatory and locally advanced breast cancer. J 
Clin Oncol 2006;24:769-77. 
[30] 
D'Adamo DR, Anderson SE, Albritton K, Yamada J, Riedel E, Scheu K, Schwartz GK, Chen 
H, Maki RG. Phase II study of doxorubicin and bevacizumab for patients with metastatic 
soft-tissue sarcomas. J Clin Oncol 2005;23:7135-42. 
[31] 
Golub TR, Slonim DK, Tamayo P, Huard C, Gaasenbeek M, Mesirov JP, Coller H, Loh ML, 
Downing JR, Caligiuri MA, Bloomfield CD, Lander ES. Molecular classification of cancer: 
class discovery and class prediction by gene expression monitoring. Science 
1999;286:531-7. 
[32] 
Bonome T, Lee JY, Park DC, Radonovich M, Pise-Masison C, Brady J, Gardner GJ, Hao K, 
Wong WH, Barrett JC, Lu KH, Sood AK, Gershenson DM, Mok SC, Birrer MJ. Expression 
profiling of serous low malignant potential, low-grade, and high-grade tumors of the ovary. 
Cancer Res 2005;65:10602-12. 
[33] 
Tsai JP, Chen HW, Cheng ML, Liu HK, Lee YP, Hsieh CL, Luh KT, Wu CW, Hsu LH, Chao 
TY, Wang WH, Chang CM, Ting CC. Analysis of host versus tumor interaction in cancer 


2009-0186 
Revised April 26, 2016 
Page 57 of 58 
patients: opposing role of transforming growth factor-beta1 and interleukin-6 in the 
development of in situ tumor immunity. Immunobiology 2005;210:661-71. 
[34] 
Lambeck AJ, Crijns AP, Leffers N, Sluiter WJ, ten Hoor KA, Braid M, van der Zee AG, 
Daemen T, Nijman HW, Kast WM. Serum cytokine profiling as a diagnostic and prognostic 
tool in ovarian cancer: a potential role for interleukin 7. Clin Cancer Res 2007;13:2385-91. 
[35] 
Nilsson MB, Langley RR, Fidler IJ. Interleukin-6, secreted by human ovarian carcinoma 
cells, is a potent proangiogenic cytokine. Cancer Res 2005;65:10794-800. 
[36] 
Merritt WM, Lin YG, Spannuth WA, Fletcher MS, Kamat AA, Han LY, Landen CN, Jennings 
N, De Geest K, Langley RR, Villares G, Sanguino A, Lutgendorf SK, Lopez-Berestein G, 
Bar-Eli MM, Sood AK. Effect of interleukin-8 gene silencing with liposome-encapsulated 
small interfering RNA on ovarian cancer cell growth. J Natl Cancer Inst 2008;100:359-72. 
[37] 
Shen GH, Ghazizadeh M, Kawanami O, Shimizu H, Jin E, Araki T, Sugisaki Y. Prognostic 
significance of vascular endothelial growth factor expression in human ovarian carcinoma. 
Br J Cancer 2000;83:196-203. 
[38] 
McMeekin DS, Sill MW, Benbrook D, Darcy KM, Stearns-Kurosawa DJ, Eaton L, Yamada 
SD. A phase II trial of thalidomide in patients with refractory endometrial cancer and 
correlation with angiogenesis biomarkers: a Gynecologic Oncology Group study. Gynecol 
Oncol 2007;105:508-16. 
[39] 
McMeekin DS, Sill MW, Darcy KM, Stearns-Kurosawa DJ, Webster K, Waggoner S, 
Benbrook D. A phase II trial of thalidomide in patients with refractory leiomyosarcoma of the 
uterus and correlation with biomarkers of angiogenesis: a gynecologic oncology group 
study. Gynecol Oncol 2007;106:596-603. 
[40] 
Burger RA, Sill MW, Monk BJ, Greer BE, Sorosky JI. Phase II trial of bevacizumab in 
persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: a Gynecologic 
Oncology Group Study. J Clin Oncol 2007;25:5165-71. 
[41] 
Cannistra SA, Matulonis UA, Penson RT, Hambleton J, Dupont J, Mackey H, Douglas J, 
Burger RA, Armstrong D, Wenham R, McGuire W. Phase II study of bevacizumab in 
patients with platinum-resistant ovarian cancer or peritoneal serous cancer. J Clin Oncol 
2007;25:5180-6. 
[42] 
Sweeney CJ, Miller KD, Sissons SE, Nozaki S, Heilman DK, Shen J, Sledge GW, Jr. The 
antiangiogenic property of docetaxel is synergistic with a recombinant humanized 
monoclonal antibody against vascular endothelial growth factor or 2-methoxyestradiol but 
antagonized by endothelial growth factors. Cancer Res 2001;61:3369-72. 
[43] 
Wildiers H, Guetens G, De Boeck G, Verbeken E, Landuyt B, Landuyt W, de Bruijn EA, van 
Oosterom AT. Effect of antivascular endothelial growth factor treatment on the intratumoral 
uptake of CPT-11. Br J Cancer 2003;88:1979-86. 
[44] 
Chura JC, Van Iseghem K, Downs LS, Jr., Carson LF, Judson PL. Bevacizumab plus 
cyclophosphamide in heavily pretreated patients with recurrent ovarian cancer. Gynecol 
Oncol 2007;107:326-30. 
[45] 
Cohn DE, Valmadre S, Resnick KE, Eaton LA, Copeland LJ, Fowler JM. Bevacizumab and 
weekly taxane chemotherapy demonstrates activity in refractory ovarian cancer. Gynecol 
Oncol 2006;102:134-9. 
[46] 
Han ES, Monk BJ. What is the risk of bowel perforation associated with bevacizumab 
therapy in ovarian cancer? Gynecol Oncol 2007;105:3-6. 
[47] 
Micha JP, Goldstein BH, Rettenmaier MA, Genesen M, Graham C, Bader K, Lopez KL, 
Nickle M, Brown JV, 3rd. A phase II study of outpatient first-line paclitaxel, carboplatin, and 
bevacizumab for advanced-stage epithelial ovarian, peritoneal, and fallopian tube cancer. 
Int J Gynecol Cancer 2007;17:771-6. 
[48] 
Perez DG, Suman VJ, Fitch TR, Amatruda T, 3rd, Morton RF, Jilani SZ, Constantinou CL, 
Egner JR, Kottschade LA, Markovic SN. Phase 2 trial of carboplatin, weekly paclitaxel, and 
biweekly bevacizumab in patients with unresectable stage IV melanoma: a North Central 
Cancer Treatment Group study, N047A. Cancer 2009;115:119-27. 
[49] 
Ginsberg JM, Chang BS, Matarese RA, Garella S. Use of single voided urine samples to 
estimate quantitative proteinuria. N Engl J Med 1983;309:1543-6. 
[50] 
Schwab SJ, Christensen RL, Dougherty K, Klahr S. Quantitation of proteinuria by the use of 
protein-to-creatinine ratios in single urine samples. Arch Intern Med 1987;147:943-4. 


2009-0186 
Revised April 26, 2016 
Page 58 of 58 
[51] 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, 
Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, 
Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline 
(version 1.1). Eur J Cancer 2009;45:228-47. 
[52] 
Thall PF, Simon R. Practical Bayesian guidelines for phase IIB clinical trials. Biometrics 
1994;50:337-49. 
[53] 
Kaplan E, Meier P. Nonparametric estimation from incomplete observations. Journal of the 
American Statistical Association 1958;53:457-481. 
[54] 
Cox DR. Regression models and life tables (with discussion). Journal of the Royal 
Statistical Society 1972;34:187-220. 
[55] 
Irizarry RA, Hobbs B, Collin F, Beazer-Barclay YD, Antonellis KJ, Scherf U, Speed TP. 
Exploration, normalization, and summaries of high density oligonucleotide array probe level 
data. Biostatistics 2003;4:249-64. 
[56] 
Pounds S, Morris SW. Estimating the occurrence of false positives and false negatives in 
microarray studies by approximating and partitioning the empirical distribution of p-values. 
Bioinformatics 2003;19:1236-42. 
[57] 
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. 
Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 
1982;5:649-55.