A PILOT STUDY OF A POLYVALENT VACCINE-KLH CONJUGATE + OPT-821 GIVEN IN COMBINATION WITH BEVACIZUMAB IN PATIENTS WITH RECURRENT EPITHELIAL OVARIAN, FALLOPIAN TUBE, OR PRIMARY PERITONEAL CANCER WHO ARE IN SECOND OR GREATER COMPLETE OR PARTIAL CLINICAL REMISSION
Phase: NA
Conditions: Fallopian Tubes Cancer, Ovarian Cancer, Peritoneal Cancer
Sponsor: Memorial Sloan Kettering Cancer Center

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A PILOT STUDY OF A POLYVALENT VACCINE-KLH CONJUGATE + OPT-821 GIVEN IN 
COM BINATION WITH BEVACIZUM AB IN PATIENTS WITH RECURRENT EPITHELIAL 
OVARIAN, FALLOPIAN TUBE, OR PRIM ARY PERITONEAL CANCER WHO ARE IN 
SECOND OR GREATER COMPLETE OR PARTIAL CLINICAL REMISSION 
PROTOCOL FACE PAGE FOR 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
 
 
Principal Investigator/Department: 
Paul Sabbatini, MD 
Department of Medicine, 
Gynecologic Medical Oncology 
Co-Principal 
Investigator(s)/Department: 
Roisin O’Cearbhaill, MB BCh, BAO 
Gynecologic Medical Oncology 
Investigator(s)/Department: 
David Spriggs, MD 
Carol Aghajanian, MD 
Martee L. Hensley, MD 
William Tew,  MD 
Jason  Konner, MD 
Katherine Bell-McGuinn, MD, PhD 
Vicky Makker, MD 
Rachel N. Grisham, MD 
Alexia Iasonos, PhD 
Svetlana Mironov, MD 
Gynecologic Medical Oncology 
Gynecologic Medical Oncology 
Gynecologic Medical Oncology 
Gynecologic Medical Oncology 
Gynecologic Medical Oncology 
Gynecologic Medical Oncology 
Gynecologic Medical Oncology 
Gynecologic Medical Oncology 
Biostatistics 
Department of Radiology 
Consenting 
Professional(s)/Department: 
Paul Sabbatini, MD 
David Spriggs, MD 
Carol Aghajanian, MD 
Roisin O’Cearbhaill, MB BCh, BAO 
Martee L. Hensley, MD 
William Tew,  MD 
Jason  Konner, MD 
Katherine Bell-McGuinn, MD, PhD 
Vicky Makker, MD 
Rachel N. Grisham, MD 
Gynecologic Medical Oncology 
Gynecologic Medical Oncology 
Gynecologic Medical Oncology 
Gynecologic Medical Oncology 
Gynecologic Medical Oncology 
Gynecologic Medical Oncology 
Gynecologic Medical Oncology 
Gynecologic Medical Oncology 
Gynecologic Medical Oncology 
Gynecologic Medical Oncology 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, NY 10065 

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Table of Contents 
1.0 
PROTOCOL SUMM ARY AND/OR SCHEM A ...................................................................... 5 
2.0 
OBJECTIVES AND SCIENTIFIC AIM S ............................................................................... 6 
3.0 
BACKGROUND AND RATIONALE................................................................................ 7 
3.1 
Disease Background ......................................................................................... 7 
3.2 
Antibody Inducing Vaccines in Ovarian Cancer ................................................... 7 
3.2.1 Background of Antibody Inducing  Vaccines in Ovarian Cancer ............................... 7 
3.2.2 Choice of Antigen and Adjuvant Used  in  Polyvalent Vaccine ..................................... 9 
3.2.3 Safety Profile of  Antibody Inducing Vaccines in Ovarian Cancer .............................. 9 
3.3 
Bevacizumab ................................................................................................... 10 
3.3.1 Clinical Experience  with Bevacizumab in Ovarian Caner ............................................ 10 
3.3.2 Safety Profile of Bevacizumab ......................................................................................... 10 
3.4 
Correlative Studies .......................................................................................... 10 
3.4.1 Angiogenesis Multiplex: ............................................................................................ 10 
3.4.2 Cytokine Multiplex: .................................................................................................... 11 
3.5 
Rationale for the proposed study ......................................................................... 11 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ....................................................11 
4.1 
Design ......................................................................................................... 11 
4.2 
Intervention .................................................................................................. 11 
4.2.1 Polyvalent Vaccine-KLH Conjugate ................................................................................. 11 
4.2.2 Bevacizumab ....................................................................................................................... 12 
4.2.3 Correlative Studies ............................................................................................................. 12 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ........................................................................... 12 
5.1 
Polyvalent Vaccine-KLH Conjugate + OPT-821 ............................................... 12 
5.1.1 Antigens .............................................................................................................................. 12 
5.1.2 Conjugation to KLH ........................................................................................................... 12 
5.1.3 OPT-821 Adjuvant ................................................................................................................... 13 
5.1.4 Animal Studies of Polyvalent Vaccine and OPT-821 ................................................... 13 
5.1.5 Vaccine Administration ................................................................................................ 14 
5.1.6 Vaccine Storage/Supply ............................................................................................... 14 
5.2 
Bevacizumab ................................................................................................... 14 
5.2.1 Bevacizumab Administration ........................................................................................... 14 
5.2.2 Bevacizumab Storage .......................................................................................................... 15 

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5.2.3 Concomitant Medications with Bevacizumab ............................................................... 15 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY .....................................................................15 
6.1 
Subject Inclusion Criteria .............................................................................. 15 
6.2 
Subject Exclusion Criteria .................................................................................... 16 
7.0 
RECRUITM ENT PLAN ......................................................................................................................... 17 
8.0 
PRETREATM ENT EVALUATION ................................................................................................. 18 
9.0 
TREATMENT/INTERVENTION PLAN ................................................................................ 18 
9.1 
Agent Administration ....................................................................................... 18 
9.1.1 Polyvalent-KLH Vaccine + OPT 821 ................................................................................ 18 
9.1.2 Bevacizumab ....................................................................................................................... 19 
9.2 
Duration of Therapy ............................................................................................. 19 
9.3 
Dose Delays/ Dose Modifications .................................................................. 20 
9.3.1 Polyvalent-KLH Vaccine + OPT 821 .......................................................................... 20 
9.3.2 Bevacizumab ...................................................................................................................... 20 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION ............................................ 26 
10.1 Immune Function ............................................................................................. 26 
10.2 Assessment ................................................................................................. 27 
10.2.1 Clinical and Laboratory Assessment ............................................................................ 27 
10.2.2 Extent of disease evaluation ................................................................................... 29 
10.2.3 Radiographic imaging ..................................................................................................... 29 
10.2.4 Length of follow-up .......................................................................................................... 29 
11.0 
TOXICITIES/SIDE EFFECTS ................................................................................. 29 
11.1 Toxicity Evaluation ............................................................................................... 29 
11.2 Vaccination Toxicity ..................................................................................... 29 
11.3 Bevacizumab Toxicity .......................................................................................... 31 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOM E ASSESSM ENT......................... 35 
12.1 Baseline Assessment ...................................................................................... 36 
12.2 Response Criteria .................................................................................................. 37 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ................................................................................ 40 
14.0 
BIOSTATISTICS ......................................................................................................................... 41 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 42 
15.1 Research Participant Registration ............................................................................. 44 

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16.0 
DATA MANAGEM ENT ISSUES .................................................................................. 43 
16.1 Quality Assurance ............................................................................................... 43 
16.2 Data and Safety Monitoring ......................................................................... 43 
17.0 
PROTECTION OF HUM AN SUBJECTS .................................................................... 43 
17.1 Privacy ........................................................................................................ 43 
17.2 Serious Adverse  Event (SAE) Reporting ........................................................... 44 
17.2.1   Genentech Adverse Event Reporting Definitions ...................................................... 46 
18.0 
INFORMED CONSENT PROCEDURES ................................................................................. 45 
19.0 
REFERENCES ......................................................................................................................46 
20.0 
APPENDICES ............................................................................................................................. 48 
APPENDIX  A:  Laboratory Standard Operating Procedures ......................................................... 49 
A.1   Correlative Studies ........................................................................................................... 49 
APPENDIX B: FIGO Stage  Grouping for Primary Carcinoma of the Ovary (1985) ................... 54 
APPENDIX C:  New York Heart Association ................................................................................... 56 
APPENDIX D: Procedure  for  Obtaining  a Urine Protein / Creatinine Ratio ................................ 56 

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1.0 
PROTOCOL SUMM ARY AND/OR SCHEM A 
 
The majority of patients with advanced epithelial ovarian carcinoma will enter 
clinical remission following optimal primary surgical cytoreduction and completion of 
platinum and taxane based chemotherapy. However, almost 70% of these patients will 
relapse.[1] Many patients will have some degree of response to  subsequent 
chemotherapy. Although some patients can obtain a second or third complete remission 
with further chemotherapy, subsequent remissions are of progressively shorter duration 
until chemotherapy resistance uniformly develops.[2]  Effective  consolidation  strategies 
are needed to prevent relapse or prolong remission. 
This is a non-randomized pilot, open label study that will enroll women with 
recurrent epithelial ovarian, primary peritoneal or fallopian tube cancer who are in clinical 
remission or have persistent low volume asymptomatic measurable disease following 
retreatment. We will evaluate the safety and immunogenicity of immunization with a 
polyvalent antigen – KLH vaccine construct + OPT- 821 in  combination  with 
bevacizumab. 
Previous studies have demonstrated that the presence of both antibodies  and 
tumor infiltrating T cells are associated with longer survival in patients with epithelial  
ovarian cancer. We previously completed a phase I safety  and  immunogenicity  pilot 
study of the polyvalent vaccine-KLH conjugate plus QS-21 in patients with epithelial 
ovarian, fallopian tube, or peritoneal cancer in a first, second or greater complete clinical 
remission. The administered vaccine contained GM2, Globo-H, Ley, Tn-MUC1, Tn(c), 
STn(c) and TF(c) individually conjugated to KLH and mixed with adjuvant QS-21. In this 
study, we demonstrated the safe induction of antibody responses against  five  of  the 
seven antigens contained in the vaccine.[3] Based on cumulative safety data from 299 
patients treated at MSK with a variety of similar vaccine constructs (i.e. X antigen-KLH + 
QS-21), we have a pending phase II multivalent  vaccine-KLH + OPT-821  (adjuvant)  trial 
(n = 164 patients) which randomizes  patients in second or  third remission to  the vaccine 
or adjuvant alone (NCT00693342 with BB-IND 14076) to be conducted with the  
Gynecology Oncology Group. 
Simultaneously, the role of anti-angiogenic agents in the treatment of ovarian 
cancer is under investigation. Angiogenesis has been shown to play a pivotal role in 
disease progression. Key ongoing phase III trials (GOG 218, OCEANS) will likely show a 

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benefit for the addition of bevacizumab to standard platinum and  taxane  chemotherapy 
for ovarian cancer. These trials have the potential for changing  the  standard  of care so 
that the majority of patients will begin bevacizumab therapy in first  line  therapy,  or  will 
have it added to second line therapy if not already receiving it. If our phase  II  vaccine  
study also meets its endpoint in the second line setting, illustrating the utility of immune 
based therapy, the obvious question is whether the vaccine can be safely administered  
with bevacizumab (as most ovarian cancer patients will likely be receiving it). 
The safety profiles of both bevacizumab and our vaccine have been individually 
established, however, we do not have safety data for the combination of these two new 
novel approaches. 
 
Table 1 
Study Schema 
(+/- 3 day windows are allowed) 
 
Immunization 
Weekly x3 
4 Week break 
4 Week break 
6 Week break 
Study 
end 
Immunization 
Number 
#1 
#2 
#3 
#4 
#5 
#6 
Bevacizumab 
Once every 2 weeks starting with vaccine #1 on week 1 until week 11 then q3 weeks until 
disease progression/study end 
Bevacizumab 
* 
* 
* 
* 
* 
* 
* 
* 
* 
Research 
Studies 
↑ 
↑ 
↑ 
↑ 
↑ 
Weeks 
1 
2 
3 
4 
5 
6 
7 
8 9 10 
11 
12 13 14 15 16 
17 
20 or 
end of 
study 
 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIM S 
 
Primary Objective: 
1. To establish the safety of immunization with polyvalent antigen – KLH + OPT-821 
vaccine conjugate in combination with bevacizumab in patients with recurrent epithelial 
ovarian, fallopian tube or primary peritoneal cancer 
Secondary Objectives: 
1. To assess the immunogenicity of the vaccine when given in the presence of 
bevacizumab 
2. To explore the relationship between a multiplex biomarker panel of angiogenesis 
markers and progression-free survival 
. 

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3.0 
BACKGROUND AND RATIONALE 
 
3.1 
Dise ase Background 
Epithelial Ovarian Cancer (EOC) 
 
Epithelial ovarian cancer is one of the most  common  gynecologic malignancies 
and the fifth most frequent cause of cancer death in women in the United States. Over 
21,000 cases are diagnosed annually, and there are an estimated  15,000  deaths  per 
year. [4] The majority of patients have widespread disease at presentation.[2] The 5-year 
survival for advance-stage disease remains less than 30%.[5]  Although  a  complete 
clinical remission following initial chemotherapy can be anticipated for many patients, a 
review of second-look laparotomy indicates that less than 50% of patients  are  actually 
free of disease.[6] Furthermore, nearly half of patients with a negative second look 
procedure are destined to relapse and require additional treatment. [7-8] Many  patients  
will achieve a second complete clinical response with additional chemotherapy.[9]  
However, almost all the patients will relapse after a short remission interval  of  9-11 
months supporting the concept of persistent minimal residual disease. Effective 
strategies to prolong remission or to prevent relapse are required, as subsequent 
remissions are of progressively shorter duration until chemotherapy resistance broadly 
develops. 
Immune directed therapy is theoretically suited for evaluation when disease 
burden is lowest. Antibodies have been shown to curtail early tissue invasion.[10] 
Preclinical models have demonstrated the clearance of circulating tumor cells and the 
elimination of systemic micrometastasis through the use of both passively administered 
and vaccine induced antibodies. An activated immune response has been shown to be 
associated with improved clinical outcome in patients  with  advanced  ovarian  cancer. 
This was demonstrated by Zhang et al, who showed that the  presence  of  tumor 
infiltrating T cells within tumor cell islets was associated with improvement in both 
progression free and overall survival. [11] Conversely, the  infiltration  of  T-regulatory 
cells, associated with immunosuppression, appears to confer a worse prognosis. 
In recent years, ovarian cancer has been targeted by a variety of novel immune 
based approaches. Antibody therapy has included oregovomab, a monoclonal antibody 
therapy targeting the CA125 antigen;[12] abagovomab,[13] an anti-idiotypic antibody 
targeting CA-125; and trastuzumab,[14] a monoclonal humanized anti-HER2 antibody. 
Other strategies have included cytokine therapy such as Interferon-γ[15-16] and IL-2.[17] 
Active immunization with peptides  such  as  Lewisy,[18]  MUC1,[19] the peptide  NY-ESO- 
1, [20] the HLA restricted peptide NY-ESO-1b and the  KH-1-KLH conjugate  [20]  have 
also been evaluated. 
 
3.2 
Antibody Inducing Vaccines in Ovarian Cancer 
3.2.1 Background of Antibody Inducing Vaccines in Ovarian Cancer 
We recently performed a pilot trial of a heptavalent vaccine-KLH conjugate plus 
QS-21 in patients with epithelial ovarian, fallopian tube, or peritoneal cancer in either a  
first (following persistence and additional treatment), second, or third remission.[3] 
Vaccinations were administered at weeks 1, 2, 3, 7, 11 and 15. The vaccine was 
administered in 1 cc total volume using a 25-gauge needle subcutaneously into the 
buttocks, thighs, abdomen or arms. Dose modification or delay was not  permitted. 
Patients were to be removed from study for a dose  limiting  toxicity,  defined  using  the 
NCT toxicity criteria, as 1) >grade 2 allergic reaction, >grade 2 autoimmune reaction, 

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>grade 3 hematologic or non-hematologic toxicity including  fever, or  grade  3 injection  
site reaction. Patients were removed from study for disease progression. Patients had 
repeat complete blood cell counts, comprehensive biochemistry panel, and  serum 
amylase at regular intervals, and at off-study visit. CT imaging was performed every 3 
months while on study, or sooner  to restage  patients if signs or  symptoms,  blood  tests, 
or physical examination suggested disease progression. 
Serum samples for immune testing were obtained at weeks 1, 5, 7, 9, 13, 15, and 
17. ELISA assays were tested against the following target antigens:  Tn-MUC1-32mer, 
GM2, Globo-H ceramide, Ley ceramide, desialated ovine submaxillary mucin (DOSM) 
expressing Tn, OSM expressing STn, and desialated  porcine  submaxillary  mucin 
(DPSM) expressing TF. IgM and IgG antibody titers were measured by ELISA as 
described previously.[21-23] Fluorescent-activated  cell-sorting  (FACS)  was  performed as 
previously described to demonstrate antibody binding  to  the  cell  surface of  the  cell line 
MCF-7. MC-7 was chosen as it is known to express each of the  7 antigens.[21-23] The 
colon cancer cell line, LSC, and the ovarian cancer cell lines  OVCAR3  were  also used as 
targets. Complement-dependent cytotoxicity was assayed on MCF-7 cell lines using a 2-
hour 51-chromium release assay, as previously described and assessed  pre  and at the 
time of peak ELISA reactivity (week 6 or 8).[21-23] 
 
We used the same criteria for immunogenicity as used in the preceding individual 
pilot trials: Patients had to have a peak IgM titer >1:40, or a peak 8-fold increase in 
prevailing antibody titer if present at baseline.  Eleven  patients  were included  in  the 
safety analysis; nine of the 11 patients remained on study for at least two  weeks  past 
fourth vaccination and were included in the immunologic analysis (2 withdrew due to 
disease progression). The vaccine was well tolerated. Self-limited and mild fatigue 
(maximum grade 2 in two patients), fever, myalgia, and localized injection site reactions 
were most frequent. No clinically relevant hematologic abnormalities were noted. No  
clinical or laboratory evidence of autoimmunity was seen. 
Serologic responses by ELISA were largely IgM against each antigen with the 
exception of Tn-MUC 1 where both IgM and IgG responses were induced. Antibody 
responses were generally undetectable prior  to  immunization. After  immunization, 
median IgM titers were as follows: Tn-MUC 1 1:640 (IgG 1:80), Tn 1:160, TF 1:640, Globo-
H 1:40, and STn 1:80. Only one response was seen against Ley and two against GM2. 
Eight of 9 patients developed responses against at least three antigens. Antibody titers 
peaked at weeks 4-8 in all patients. FACS and complement-dependent cytotoxicity analysis 
showed substantially increased reactivity against MCF7 cells in seven of nine patients, with 
some increase seen in all patients.[24] 

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Table 2: Summary of Heptavalent Vaccine Responses in Relation to Prior Monovalent 
Vaccines 
 
 
Antigen 
Median IgM ELISA titers after 
vaccination (based on previous 
studies)* 
Median IgM ELISA titers after 
vaccination* 
Monovalent vaccines 
Heptavalent vaccine 
Pre 
Post 
Ref 
Pre 
Post 
Tn-M UC1 
20 
1280 
[22] 
0 
640 
Tn (DOSM) 0 
640 
[25] 
0 
160 
TF (DPSM) 0 
1280 
[26] 
0 
640 
Globo-H 
20 
80 
[21] 
0 
40 
GM 2 
0 
160 
[27-28] 
0 
0 
Lewis-Y 
0 
0 
[18] 
0 
0 
STn (OSM) 10 
640 
[29] 
0 
80 
 
 
Patients with IgM titer >1:40, or an 8-fold increase in prevailing antibody titer if 
present at baseline are considered “responders”. 
3.2.2 Choice of Antigen and Adjuvant Used in Polyvalent Vaccine 
 
Based on the compilation of prior data, and considering which antigens are best 
suited for GMP manufacturing and further testing, the polyvalent vaccine to be evaluated 
here and as part of the planned GOG-0255 study will include 1) GM2-KLH, 2) Globo-H- 
KLH,   3)   Tn-MUC1-32mer-KLH,   4)   TF-KLH          +   OPT-821.   OPT-821  will   be the 
immunological   adjuvant   used.   It   is   derived   from   the   same   plant   source  Quillaja 
Saponaria Molina as QS-21. (See Section 5.1 for discussion of OPT-821 and its 
relationship with QS-21, as well as detailed description of the polyvalent-KLH vaccine 
construct +OPT-821). 
3.2.3 
Safety Profile of Antibody Inducing Vaccines in Ovarian Cancer 
 
Approximately 90 patients have been enrolled in a series of monovalent vaccine 
trials at MSK in patients with ovarian cancer in order to characterize the  most 
immunogenic antigens for inclusion in a polyvalent construct. To date,  no  systemic 
toxicity related to autoimmunity has been seen. The most common adverse events are 
localized erythema and induration at the injection site which resolves in 5-7 days, mild to 
moderate fever for 24 hours in some patients, and occasionally mild fatigue or myalgia 

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for several days following vaccination. No patients  have  been removed  from  study  for 
any of these side effects. Hypothyroidism has been seen in a small number of patients 
receiving a similar vaccine construct with breast cancer. It is unclear whether this finding 
was related to vaccination, or reflected the demographics of the population in which 
autoimmune hypothyroidism is more common. An assessment of thyroid function  has 
been added to the routine screening tests. Specifically,  no  hypothyroidism  has  been 
seen in patients with ovarian cancer receiving previous vaccines at MSK. Detailed side 
effects are outlined in Section 11.2 
 
3.3 
Bevacizumab 
3.3.1 Clinical Experience with Bevacizumab in Ovarian Caner 
The bevacizumab Investigator Brochure contains descriptions of all completed 
Phase I, II, and III trials reported to date and details the safety profile. 
Angiogenesis is a key process leading to invasion and metastasis of ovarian 
cancer.[30-31] Elevated VEGF expression is correlated with poor prognosis.[31-33] 
Inhibitors of VEGF have been shown to both suppress tumor growth and augment the 
antitumor effects of antineoplastic drugs in both preclinical  and  human  studies.[34-40] 
The anti-VEGF monoclonal antibody, bevacizumab, is an active agent in patients with 
recurrent ovarian cancer. Response rates of 15.9% and 21% have been reported when 
used as single agent, and 24% was seen in conjunction with oral cyclophosphamide.[41- 
43] Bevacizumab has an acceptable toxicity profile in ovarian cancer.[44-46] 
3.3.2 Safety Profile of Bevacizumab 
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. 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 in Section 11 and in the bevacizumab Investigator 
Brochure. 
 
3.4 
Correlative Studies 
We will perform 2 separate multiplex assays evaluating markers of angiogenesis 
and other cytokines. These assays have recently been  validated  at  MSKCC.  These 
novel, automated, immunoassay platforms will simultaneously  evaluate  multiple 
biomarkers in a single reaction vessel. Approximately 400μL of whole blood will be 
collected in an ethylenediaminetetraacetic acid (EDTA) purple top tube. Samples will be 
taken on day 1 of week 1 (baseline), day 1 of week 17 (postvaccination),  end of  study  
visit (post-bevacizumab), or upon progression of disease or significant adverse event. 
Patient serum will be removed and stored  at  -80oC  for the  multiplex analyses.  Please 
see Appendix A for laboratory procedures. 
3.4.1 Angiogenesis Multiplex: 
 
We will perform a 10-plex angiogenesis assay. The angiogenesis panel  will  
include monoclonal antibodies specific for interleukin-8 (Il-8), VEGF, VEGF-R2, 
intracellular adhesion molecule 1 (ICAM-1), tyrosine kinase with immunoglobulin and 

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EGF homology domains-2 (TIE-2), placental growth factor (PLGF), tissue inhibitor of 
metalloproteinase-1 (TIMP-1), hepatocyte growth factor(HGF), fibroblast growth factor- 
basic (FGF-basic) and E-selectin. Values will be  correlated with  PFS, and baseline  will  
be compared with progression. 
3.4.2 Cytokine Multiplex: 
We will perform an 8-plex cytokine assay. The cytokine panel will include tumor 
necrosis factor (TNF) and the following interleukins (IL): IL1-β,  IL -2,  IL-5,  IL-6,  IL-8,  IL- 
10 and IL-12. Cytokines are  a diverse group of soluble proteins and peptides  which  act 
as regulators of normal and  pathological conditions to modulate  the  functional activities 
of individual cells and tissues. These proteins mediate interactions between cells directly 
and regulate processes taking place in the extracellular environment. They function on a 
variety of cell types, having stimulatory or inhibitory effects on proliferation, differentiation 
and maturation. Given this pleotrophic effect, measuring the level of only a  single 
cytokine in a biological system provides only limited information on  the  systemic 
response. The ability to detect and quantitate multiple cytokines simultaneously will 
facilitate better understanding of the immune response to the heptavalent-KLH vaccine 
and adjuvant. Values will be correlated with PFS, and baseline will be compared with 
progression. 
 
3.5 
Rationale for the proposed study 
Key ongoing phase III trials (GOG  218, OCEANS)  will  likely show a  benefit for  
the addition of bevacizumab for patients with ovarian cancer. If these trials are positive 
patients will begin bevacizumab therapy in first line therapy, or will have  it  added  to  
second line therapy if not already receiving it. At any rate, the already demonstrated 
response rate for bevacizumab in ovarian cancer will prompt its use  in  the  recurrent 
setting and many patients will continue it beyond response. If our phase II polyvalent 
vaccine study also meets its endpoint in the second  line  setting,  illustrating  the 
importance of immune based therapy in ovarian cancer, the important questions are 1) 
whether the vaccine can be safely administered with bevacizumab (as most patients will 
likely be receiving it) and 2) whether immunogenicity to the vaccine and adjuvant is 
maintained in the presence of bevacizumab. Our correlative studies are aimed  at 
exploring markers that may predict benefit from anti-angiogenic therapies. 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.1 
Design 
 
This is a single institution, open label, pilot study of bevacizumab and the polyvalent 
vaccine-KLH conjugate + OPT-821 in patients with recurrent epithelial ovarian, fallopian 
tube, or primary peritoneal cancer. Eligible patients will have relapsed and completed 
additional cytotoxic chemotherapy. Patients may be in complete remission or have 
residual asymptomatic measurable disease. 
4.2 
Intervention 
4.2.1 Polyvalent Vaccine-KLH Conjugate 
The intervention includes the subcutaneous injection of polyvalent vaccine-KLH 
conjugate for 6 vaccinations using the dose and schedule described in section 9.1. 

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4.2.2 Bevacizumab 
The intervention includes the intravenous of bevacizumab q 2 weekly initially and 
then q 3 weeks using the dose and schedule described in section 9.1 
4.2.3 Correlative Studies 
Whole blood samples will be collected into EDTA purple top tubes (approximately 
4ml) on day 1 of week 1 (baseline), day 1 of  week 17  (post vaccination), end of study  
visit (post-Bevacizumab), or upon POD or significant adverse event. Please see 
Appendix A for further details on laboratory procedures. 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
5.1 
Polyvalent Vaccine-KLH Conjugate + OPT-821 
The IND application is held by MSKCC. 
5.1.1 Antigens 
This trial will be conducted using the following antigens conjugated to  KLH 
(carrier) with OPT-821 as the adjuvant: 
 
Glycosylated MUC-1 termed Tn-MUC1 (BB-IND  6013)  was  synthesized by 
Pepceuticals LLD (Leicester, England). The 32 amino acid sequence of the MUC-1 
peptide to be used is: CHGVT*S*APDT*RPAPGSTAPPAHGVTSAPDTRPA. 
This 32 amino acid MUC1 sequence contain ~11/2 repeats of the core 20  amino 
acid sequence and is partially glycosylated with  Tn  molecules at the  * indicated  serines  
or threonines above. An additional terminal cysteine is placed to facilitate attachment of 
KLH. The Tn-MUC1 is conjugated to KLH using an MBS linker. The dose of Tn-MUC1 is 
3µg. 
 
Globo H (BB-IND 6861): The globo H hexasaccharide-KLH was synthesized and 
conjugated under GMP by Optimer Pharmaceuticals Inc. (San Diego, CA). The dose of 
Globo H is 30µg. 
 
GM 2 (BB-IND pending): Ganglioside GM2 is extracted from brains obtained from a 
colony of cats with Tay Sachs Disease (an autosomal recessive GM2 gangliosidosis) by 
Matreya Inc. (Philadelphia, PA). It was conjugated to KLH by Althea Technologies (San 
Diego, CA). The dose of GM2 is 30 mcg. 
 
TF (c) (BB IND 7862): TF (c) was  synthesized  by  MSKCC  Carbohydrate  Synthesis Core. 
The TF disaccharide is covalently attached to a single threonine and then using  Fmoc 
technology the 3 threonine-TF constructs are linked together with  a  terminal cysteine for 
attachment to KLH. The dose of TF(c) is 3 mcg. 
5.1.2 Conjugation to KLH 
Covalent attachment of KLH to TF(c) and Tn-MUC1 is achieved with m- 
maleimidobenzoyl-N-hydroxysuccinimide ester (MBS) which  couples the  free  SH group  
of cysteine on the antigen to  the  N terminus and lysine side chains on KLH.  Conjugation 
of KLH to the glycolipid antigens Globo H is by attachment with the MMCCH linker 4-(4- N-
maleimidomethyl) cyclohexane-1-carboxyl hydrazide. Conjugation of GM2 to KLH is 
achieved directly using reductive amination methods. 

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5.1.3 OPT-821 Adjuvant 
OPT-821 is an immunological adjuvant obtained from Optimer Pharmaceuticals  
Inc. (San Diego, CA). It is mixed with the multiple antigen conjugates at  a dose of 100  
mcg at the time of vaccine. OPT-821 was derived from the same plant source Quillaja 
saponaria Molina as QS-21. Optimer started with a commercially obtainable QuilA, a 
partially purified saponin form bark of Quillaja saponaria from Brenntag Biosector, 
Frederikssund, Denmark. The purification consists of a normal phase (silica gel) purification 
followed by two consecutive reverse phase (C5 and  C8)  column purifications as 
described. Solid Quil A was fractionated by silica gel chromatography. Individual fractions 
containing the desired components were analyzed by an analytical  HPLC (Vydac 4 
column) and pooled together. Solvents were removed under reduced pressure and the 
resultant residue was taken up in water before lyophilization. Preparative reverse-phase 
HPLC (C5 column) under cGMP was used for further purification. After a desalting step 
through a C8 column, the fractions were pooled and lyophilized to obtain cGMP OPT-821. 
The product was further analyzed with an analytical  HPLC  using  a Vydac C4 column with 
a very predominant peak at 27.2 min and a very small shoulder  peak at 26.5 min. The 
MALDI-TOF mass analysis of OPT-821 showed a dominant  peak  at 2012 (M + Na). Other 
peaks observed were: 2034 (M + 2Na), 2028 (M + K), 2050 (M 
+ Na + K), and 1990 (M + H). 
OPT-821 was evaluated in murine models with the Globo H-KLH  conjugate 
vaccine with various doses purified adjuvant OPT-821 and with saponin adjuvant. 
Adjuvant activity was measured by production of antibodies by ELISA. Groups of mice 
(C57BL/6J) were immunized three times at one-week interval with 5 µg of Globo H-KLH 
(containing 5 µg of Globo H hexasaccharide) plus different dose of OPT-821 (20, 50 and 
100µg) subcutaneously in the abdomen or groin. Mice were bled  and  sera  were 
collected prior to the initial vaccination and at 7  days after  third  vaccination.  Antibody 
titers were measured by ELISA. Our various preclinical experiments showed that the 
adjuvant OPT-821 is immunologically active (Dr. Ragupathi, personal communication). 
Optimer has purified OPT-821 under cGMP for clinical use. 
5.1.4 Animal Studies of Polyvalent Vaccine and OPT-821 
Repeat dose toxicity studies were performed with OPT-821 with or without the 
antigenic components (GM2-KLH, Globo H-KLH, MUC1-Tn-KLH and Tf(c)-KLH) 
administered once weekly for four weeks. Male  and  female  mice  (C57BL/6J)  were  
dosed subcutaneously with the vehicle (0.9% normal saline), or OPT-821 at 5 
mcg/mouse/dose, or the polyvalent vaccine (GM2-KLH,  Globo  H-KLH,  MUC1-Tn-KLH 
and Tf(c)-KLH with OPT-821) at two different dose levels. The  lower  dose  level 
contained 1.5 mcg/mouse/dose of each of the GM2-KLH and Globo H-KLH, and 0.15 
mcg/mouse/dose of each of MUC1-Tn-KLH and Tf(c)-KLH,  and  5 mcg/mouse/dose  of 
the OPT-821 adjuvant. The doses of each  vaccine  component  including  the  adjuvant 
were 4-fold higher in higher dose-level group. The  no  observable  adverse  effect level 
was 1.5 mcg/mouse/dose for each GM2-KLH and Globo H-KLH conjugates and 
0.15 mcg/mouse/dose   for   each    Tn-MUC1-KLH   and    TF(c)-KLH   conjugates   and 
5 mcg/mouse for OPT-821. No treatment related effects were seen in appearance, 
behavior, body weight or clinical chemistry parameters over the study duration when 
compared to the control group. A mild to moderate increase in the lymphocyte and 
monocyte counts was noted at the higher dosing level. Additional information is found in 
the investigators brochure. 

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5.1.5 Vaccine Administration 
The intervention includes the subcutaneous injection of polyvalent vaccine-KLH 
conjugate for 6 vaccinations using the dose and schedule described in Table 1. The 
preparation will be supplied in approximately 1.2 cc total volume and administered 
subcutaneously in one syringe to a site in the shoulders, buttocks, or thighs. The vaccine 
will be administered prior to bevacizumab treatment. 
5.1.6 Vaccine Storage/Supply 
Vials containing vaccine KLH-OPT-821 have 1.2 ml normal saline as the diluent. 
Vials are to be stored at –30 to –80° Celsius. The antigen doses to be administered are 
GM2 (30 µg), TF(c) (3 µg), Globo-H (30 µg), Tn-MUC1 (3 µg), KLH (  600 µg) with 
adjuvant OPT-821(100µg). Antigen doses were selected based on previous Phase I 
monovalent vaccine trials as follows: Tn-MUC1-32mer, 3µg [22]; Globo-H, 30µg [21, 23]; 
GM2, 30µg [47]; Tn(c), 3µg [25]; TF(c), 3µg [26]. OPT-821 is given at 100µg [23, 47]. 
These conjugates and OPT-821 are vialed together at MSKCC in 1.2 ml  normal saline. 
The vaccines will be distributed by Memorial  Sloan  Kettering  Investigational Pharmacy. 
All drug should be discarded according to institutional Standard Operating Procedures, 
and their disposition should be recorded. 
5.2 
Bevacizumab 
Bevacizumab will be given at 7.5 mg/kg via intravenous infusion over  20-30 
minutes beginning on day 1 of week 1 once every two weeks initially and then q 3 weeks  
as outlined, until progression, unacceptable toxicity, or withdrawal of  consent. 
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, (at 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. It is not 
necessary to correct dosing based on ideal weight. 
For further details and molecule characterization, see the bevacizumab 
Investigator Brochure. 
5.2.1 Bevacizumab Administration 
Bevacizumab will be administered as per Memorial Sloan-Kettering Cancer 
Center ADULT Chemotherapy/Biologic Therapy Guidelines: 
 
o Add the calculated dose of bevacizumab to 100 ml of 0.9% Sodium Chloride Injection. 
o 7.5 mg/kg IV infused over 20 mins once every 14 days until week 11 and then once 
every 3 weeks. Administration will be as a continuous IV infusion. 
o Alternatively at the instruction of the prescriber, it may be infused in as much  as 30  
mins. 
 
o Anaphylaxis precautions should be observed during study drug administration. 
o If an infusion is not tolerated well (ie. fever, chills) then the subsequent  infusion(s) 
should be given over a prolonged infusion time (i.e. 60-90 min). 
o If a subject experiences an infusion associated adverse event with the 60-minute 
infusion, all subsequent doses should be given over 9015 minutes. 

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5.2.2 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. 
5.2.3 Concomitant Medications with Bevacizumab 
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  discontinuation  per 
Table 4, Bevacizumab Dose Management Due To Adverse Events. 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.1 
Subject Inclusion Criteria 
 
Eligible patients are those with the following characteristics: 
 
1. Histologically documented epithelial carcinoma arising in the ovary, fallopian tube or 
peritoneum 
 
2. Patients who have received cytoreductive surgery and chemotherapy with at least one 
platinum 
based 
chemotherapy 
regimen. 
Patients 
who 
received 
neoadjuvant 
chemotherapy are eligible. 
 
3. Patients with relapsed ovarian, fallopian tube or primary peritoneal cancer who have now 
completed chemotherapy and/or surgery for recurrent disease.  Eligible  patients  are 
those who would be appropriate to enter a period  of  observation if  standard 
management were considered 
 
4. Patients who have asymptomatic residual measurable disease on CT scan or who are in 
complete clinical remission. Patients may have an elevated CA-125. (Complete clinical 
remission is defined as serum CA-125 ≤ 35 IU/ml, negative physical examination and 
without objective evidence of disease by computed tomography  (CT)  of the  abdomen  
and pelvis.) 
 
5. Adequate hematologic, coagulation, renal and hepatic function. 
a. ANC > 1,000 cells/mm3; platelets > 100,000 cells/mm3 
b. PT such that international normalized ratio (INR) is < 1.5 (or an in-range INR, usually 
between 2 and 3, if a patient is on a stable dose of therapeutic warfarin) Serum 
creatinine < 1.5 mg/dl 
c. Bilirubin, SGOT, Alk Phos < 2.5x upper limit of normal 
 
6. Urine protein: creatinine (UPC) ratio must be < 1. If UPC ratio > 1, collection of 24-hour 
urine measurement of urine protein is recommended as part of the patient’s medical 
management off-study. See Appendix D for further details. 
 
7. Karnofsky performance status > 70% 

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8. Expected survival of at least 4 months 
 
9. Age ≥ 18 years. This protocol does not include children because the number of children 
with cancer is limited, and because a nationwide pediatric cancer  research  network 
already accesses the majority. Furthermore, the incidence of ovarian, fallopian tube, or 
peritoneal cancer in children is extremely infrequent. 
 
10. Patients who are > 4 weeks from completion of prior cytotoxic chemotherapy. Prior 
bevacizumab and/or immunotherapy treatment are permitted 
 
6.2 
Subject Exclusion Criteria 
Patients are excluded from study with the following characteristics: 
1. Inability to comply with study and/or follow-up procedures 
 
2. Current or recent (within 4 weeks of the first infusion of this study) participation in 
another experimental drug study. 
3. Active malignancy, other than superficial basal cell and superficial squamous (skin) 
cell, or carcinoma in situ of the cervix within last five years 
4. Patients must have undergone standard cytoreductive surgery as part of primary 
treatment to be eligible for this study and therefore are not of childbearing potential. 
Nursing mothers are excluded. 
5. Inadequately controlled hypertension (defined as systolic blood pressure 150 
mmHg and/or diastolic blood pressure > 90 mmHg) 
6. Prior history of hypertensive crisis or hypertensive encephalopathy 
7. New York Heart Association (NYHA) Grade II or greater congestive heart failure (see 
Appendix C) 
8. History of myocardial infarction or unstable angina within 6 months prior to Day 1 
9. History of stroke or transient ischemic attack within 6 months prior to Day 1 
10. Known CNS disease, except for treated brain metastasis 
11. Treated brain metastases are defined as having no evidence of progression or 
hemorrhage after treatment and no ongoing requirement for dexamethasone, as 
ascertained by clinical examination and brain imaging (MRI or CT) during the 
screening period. Anticonvulsants (stable dose) are allowed. Treatment for brain 
metastases may include whole brain radiotherapy (WBRT), radiosurgery (RS; 
Gamma Knife, LINAC, or equivalent) or a combination as deemed appropriate by the 
treating physician. Patients with CNS  metastases  treated  by neurosurgical resection 
or brain biopsy performed within 3 months prior to Day 1 will be excluded 
12. Significant 
vascular disease (e.g., aortic aneurysm, requiring surgical repair or 
recent peripheral arterial thrombosis) within 6 months prior to Day 1 
13. History  of  hemoptysis  ( 1/2  teaspoon   of   bright  red  blood  per  episode)   within 
1 month prior to Day 1 

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14. Evidence of bleeding diathesis or significant coagulopathy (in the absence of 
therapeutic anticoagulation) or tumor involving major vessels. 
15. Major surgical procedure such as laparotomy, open biopsy, or significant traumatic 
injury within 28 days prior to Day 1 or anticipation of  need  for  major  surgical 
procedure during the course of the study 
16. Core biopsy or other minor surgical procedure, excluding placement of a vascular 
access device, within 7 days prior to Day 1 
17. History of abdominal fistula or gastrointestinal perforation within 6 months prior to 
Day 
18. Patients with clinical symptoms or signs of GI obstruction who require parenteral 
hydration, parenteral nutrition, or tube feeding 
19. Patients with evidence of abdominal free air not explained by paracentesis or recent 
surgical procedure 
20. Serious, non-healing wound, active ulcer, or untreated bone fracture 
21. Known hypersensitivity to any component of bevacizumab 
22. Allergy to seafood 
 
23. Active autoimmune disease (i.e. rheumatoid arthritis, ulcerative colitis  etc);  or  
immune deficiency (HIV, hypogammaglobulinemia); or known active infections with 
Hepatitis B or Hepatitis C; or those receiving immunosuppressive drugs (such as 
chronic systemic corticosteroids or cyclosporin, etc); or those receiving chronic anti- 
inflammatory drugs (intermittent use of anti-inflammatory drugs is permitted). 
 
7.0 
RECRUITM ENT PLAN 
Potential research subjects will be identified by a member of the  patient’s  
treatment team, the protocol investigator, or research team at Memorial Sloan-Kettering 
Cancer Center (MSKCC). If the investigator is a member of the treatment team, s/he will 
screen their patient’s medical records for suitable research study participants and 
discuss the study and their potential for enrolling in the research  study. Potential  
subjects contacted by their treating physician will be referred to  the  investigator/  research 
staff of the study. 
The principal investigator may also screen the medical records of patients with 
whom they do not have a treatment relationship for the limited purpose of identifying 
patients who would be eligible to enroll in the study and to record appropriate contact 
information in order to approach these  patients regarding  the  possibility of enrolling in 
the study. 
During the initial conversation between the investigator/research staff and the 
patient, the patient may be asked to provide  certain  health  information  that  is necessary 
to the recruitment and enrollment process. The investigator/research  staff  may  also 
review portions of their medical records at MSKCC in order to further assess eligibility. 
They will use the information provided by the  patient  and/or  medical record to  confirm 
that the patient is eligible and to contact the patient regarding study enrollment.  If  the 
patient turns out to be ineligible for the research study, the research staff will destroy all 
information collected on the patient during the initial conversation and medical records 
review, except for any information that must be maintained for screening log purposes. 

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8.0 
PRETREATM ENT EVALUATION 
 
Clinical: (within 2 weeks before first study treatment) 
o 
History (demographics, recording of pertinent concurrent medications, adverse 
event evaluation) and physical examination including vital signs: temperature, 
heart rate, respiratory rate, and blood pressure assessment. 
o 
Karnofsky performance status 
 
Laboratory: (within 2 weeks before first study treatment) 
o Complete blood cell count with differential 
o Comprehensive serum chemistry profile (includes Albumin, alkaline 
phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, 
glucose, potassium, total protein, SGOT [AST], SGPT [ALT], sodium.) 
o Serum magnesium 
o Serum CA-125 
o Serum TSH 
o PT/INR 
o Urine protein: creatinine ratio or urine dipstick (and 24 hour collection if indicated) 
o Amylase 
 
Imaging and other diagnostic studies: (within 4 weeks before first study treatment) 
o Computed tomography (CT) of abdomen and pelvis. 
o Chest radiograph (or CT chest) 
o Electrocardiogram 
 
9.0 
TREATMENT/INTERVENTION PLAN 
 
9.1 
Agent Administration 
9.1.1 Polyvalent-KLH Vaccine + OPT 821 
The administered polyvalent vaccine will contain GM2 (30 µg), Globo-H (30 µg), 
Tn-MUC1 (3 µg) and TF(c) (3 µg), individually conjugated to KLH ( 600  µg) and mixed 
with adjuvant OPT-821 (100 µg). Total vial volume is 1.2 ml. 21 patients  will  be 
vaccinated. 
The vaccine will be administered subcutaneously at  weekly  intervals  for  three  doses. 
This will be followed by a four week break, then a fourth vaccination, another four week 
break, then a fifth vaccination and finally a further six week break and a  sixth  vaccination. 

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Table 3: Immunization and Bevacizumab Schedule (+/- 3 day windows are allowed) 
 
Immunization 
Weekly x3 
4 Week 
break 
4 Week 
break 
6 Week break 
Study 
end 
Immunization 
Number 
#1 #2 #3 
#4 
#5 
#6 
Bevacizumab 
Starting with vaccine #1 on week 1 once every 2 weeks until week 11 and then q3 weeks 
until disease progression/study end 
Bevacizumab 
* 
* 
* 
* 
* 
* 
* 
* 
* 
Correlative 
Studies 
↑ 
↑ 
↑ 
Immune 
Studies 
↑ 
↑ 
↑ 
Weeks 
1 
2 
3 
4 5 
6 7 
8 9 10 11 12 
13 
14 
15 
16 
17 
20 or 
end of 
study 
9.1.2 Bevacizumab 
Bevacizumab will be given via intravenous infusion at 7.5 mg/kg over 20-30 
minutes, beginning on day 1 of week 1, once every two  weeks  initially and  then q 3  
weeks as outlined. 
9.2 
Duration of Therapy 
A maximum of 6 doses of the polyvalent-KLH vaccine and OPT-821  will  be  administered  to 
each patient as per the schedule outlined in Table 3. Bevacizumab will  be administered  once 
every two weeks until week 11 and then once every three weeks according to the schedule 
outlined in Table 3. When the 6 vaccinations of the polyvalent-KLH vaccine +OPT821 are 
completed, patients may still continue to receive bevacizumab on the once every three week 
schedule. 
 
The protocol treatment will be discontinued for: 
 
• disease progression (as defined by RECIST) 
 
• unacceptable toxicity associated with the polyvalent-KLH vaccine or bevacizumab (outlined in 
Section 9.3) 
 
• withdrawal of consent 

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9.3 
Dose Delays/ Dose Modifications 
 
9.3.1 Polyvalent-KLH Vaccine + OPT 821 
Dose reduction or delay of vaccine are  not  permitted.  Patients are  removed 
from study for a vaccine-related Dose Limiting Toxicity (DLT) DLT is defined by: 
 
≥ Grade 2 allergic reaction. (Grade 2 is defined as asymptomatic bronchospasm,  
or urticaria; Grade 3 is defined as symptomatic bronchospasm, requiring 
parenteral medications, with or without urticaria, allergy related edema or 
angioedema; Grade 4 is defined as anaphylaxis.) 
 
 
≥ Grade 2 autoimmune reaction (Grade 2 is defined as evidence of autoimmune 
reaction involving a non-essential organ or function (e.g. hypothyroidism)  
requiring treatment other than immunosuppressive drugs.) 
 
 
≥ Grade 3 hematologic or non-hematologic toxicity  including  fever.  (Grade  3 
fever is > 40° C for ≤ 24 hours). 
 
≥ Grade 3 injection site reaction. (Grade 3 is defined as ulceration, or necrosis  
that is severe or prolonged, or requiring surgery). 
Any patient with Grade 2 or greater toxicity is followed with  appropriate  studies 
until results return to baseline. 
9.3.2 Bevacizumab 
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. 
Missed doses of bevacizumab will not be made up. Regardless of the reason for holding 
the bevacizumab, the maximum allowable length  of  treatment  interruption  is 2  months. 
No dose escalation is planned for this study. 
 
Permanent discontinuation of bevacizumab for related adverse events or other criteria: 
 
Any adverse event,  laboratory abnormality or intercurrent illness which, in the  judgment   
of the Investigator, presents a substantial clinical risk to the  patient  with  continued 
dosing. If bevacizumab is permanently discontinued, the patient may complete the 
schedule of vaccinations with the polyvalent-KLH vaccine and OPT-821 as per the 
schedule outlined above in Table 3. 

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Table 4: 
Summary of Bevacizumab Dose Management Due to Adverse Events 
 
 
Event 
Action to be Taken 
Hypertension 
No dose modifications for grade 1 events 
Grade 2 or 3 
If not controlled to 150/90 mmHg with optimal medical management refer to 
section 9.3.2.1 below 
Grade 4 (includi ng 
hypertensive 
encephalopathy) 
Discontinue bevacizumab. 
Hemorrhage 
No dose modifications for grade 1 or 2 non-pulmonary or non-CNS hemorrhage 
Grade 3 
non-pulmonary or non- 
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. 
Subjects who experience a repeat grade 3 hemorrhagic event or who 
experience a delay in resolution according to the above criteria for >3 weeks, 
will be discontinued from receiving bevacizumab. 
Grade 4 
non-pulmonary or 
non-CNS hemorrhage 
Discontinue bevacizumab. 
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. 
Grade 2, 3, or 4 pulmonary 
or CNS hemorrhage 
Discontinue bevacizumab 

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Venous Thrombosis 
No dose modifications for grade 1 or 2 events 
Grade 3 or 4 
Hold bevacizumab treatment. 
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 
 
LMW H, warfarin, or other anticoagulant dosing must be stable 
prior to restarting bevacizumab 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 (e.g. tumor involving major vessels). 
Patients with recurrent/worsening venous thromboembolic events after 
resumption of bevacizumab treatment will be taken off bevacizumab. 
Arterial Thromboembolic Event 
 
New onset or worsening of any arterial thromboembolic event since starting bevacizumab including 
unstable angina, myocardial infarction, transient ischemic attack, cerebrovascular accident, peripheral 
arterial ischemia or visceral arterial ischemia or any other arterial thromboembolic event 
≥ Grade 1 
Discontinue bevacizumab. 
Coagulopathy 
 
No dose modifications for grade 1 or 2 events 
Grade 3 or 4 
Hold bevacizumab, until PT/PTT resolve to grade 1 
For patients on therapeutic warfarin with PT/INR higher than the intended 
therapeutic range, 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 therapy. 
Congestive Heart Failure (Left ventricular systolic dysfunction) 
No dose modifications for grade 1 or 2 events 
Grade 3 
Hold bevacizumab until resolution to Grade ≤ 1. 
Grade 4 
Discontinue bevacizumab. 

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Proteinuria 
No dose modifications for grade 1 or 2 events 
Grade 3 
(UPC> 3.5, urine collection 
> 3.5 g/24 hr) 
Hold bevacizumab treatment until  Grade 2, as determined by either UPC 
ratio ≤ 3.5 or 24 hr collection ≤ 3.5 g. Refer to section 9.3.2.2 below. 
Grade 4 (nephrotic 
syndrome) 
Discontinue bevacizumab 
GI Perforation 
Unexplainable grade 1 
(excluding evidence of 
abdominal free air 
attributable to other causes 
such as paracentesis or 
recent surgical procedure) 
or ≥ Grade 2 (including 
intra-abdominal abscess or 
GI fistul a) 
Discontinue bevacizumab. 
Fistula 
≥ 1 Grade 
tracheoesophageal 
fistula 
Discontinue bevacizumab. 
≥ 2 Grade other fistula 
Discontinue bevacizumab. 
Bowel Obstruction 
Refer to section 9.3.2.3 
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 or 4 
Hold bevacizumab for complete obstruction. If surgery is necessary, patient 
may restart bevacizumab after full recovery from surgery, and at 
investigator’s discretion. 
Wound dehiscence 
Any grade (requiri ng 
medical or surgical 
therapy) 
Discontinue bevacizumab. Refer to section 9.3.2.4 
Reversible Posterior Leukoencephalopathy 
Any grade 
(confirmed by MRI) 
Discontinue bevacizumab. Refer to section 9.3.2.5 
Hypersensitivity Reactions 
Refer to section 9.3.2.6 

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Other Unspecified Bevacizumab-Related Adverse Events 
Refer to section 9.3.2.7 
Grade 3 
Hold bevacizumab until recovery to ≤ Grade 1. 
Grade 4 
Discontinue bevacizumab. 
 
9.3.2.1 Hypertension: 
Hypertension is a known and potentially serious adverse event associated with 
bevacizumab treatment. Patients receiving bevacizumab should be monitored prior  to 
each dose with measurement of blood pressure. If the patient’s blood  pressure  is  
elevated (>150/90) at any time, even at outside clinic visits, they should contact their 
treating physician. 
 
Medications used 
Medication classes used for management of patients with grade 2 or 3 hypertension 
receiving bevacizumab include angiotensin-converting enzyme inhibitors, beta blockers, 
diuretics, and calcium channel blockers. The use of anxiolytics in conjunction  with 
specific anti-hypertensive agents is not prohibited. The goal for blood pressure control 
should be consistent with general medical practice guidelines (i.e. < 140/90 mmHg in 
general and < 130/80 mmHg for patients with diabetes). 
Grade 2 and 3 hypertension (CTCAE v4) 
Grade 2 hypertension includes systolic BP 140 - 159 mm Hg or  diastolic  BP  90-99 
mmHg) that is recurrent or persistent (>24 hours) where medical intervention with anti- 
hypertensives is indicated. Grade 2 hypertension also  includes a symptomatic increase  
by >20 mm Hg (diastolic) or to >140/90 mm Hg if previously within normal limits where is 
monotherapy indicated. 
Grade 3 hypertension includes systolic BP ≥160 mmHg or diastolic  BP  ≥100  mmHg 
where medical intervention is indicated and more than one drug or more  intensive  
therapy than previously used is indicated. 
Dose Delays 
 
For controlled hypertension, defined as systolic ≤ 150 mm Hg and diastolic ≤ 90 
mm Hg, continue bevacizumab therapy. 
 
For grade 2 or 3 hypertension that is not controlled with optimal medical 
management or for symptomatic hypertension < grade 4, hold bevacizumab 
treatment for up to 2 weeks. In the interim, antihypertensive therapy should be 
initiated or continued. 
 
 
If hypertension is controlled (systolic ≤ 150  mm Hg  and diastolic ≤ 90  mm Hg)  
and symptomatic hypertension has resolved by two weeks  after  holding  
treatment, continue bevacizumab therapy. 
 
If hypertension remains uncontrolled or symptomatic hypertension <grade 4 
persists two weeks after holding treatment, continue to hold bevacizumab. If 
symptomatic hypertension has not resolved by 6 weeks after holding treatment 

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with bevacizumab, treatment with bevacizumab should be discontinued for the 
remainder of the study. 
 
Bevacizumab should be discontinued for the remainder of the  study  in  any 
patient developing grade 4 hypertension. 
9.3.2.2 Proteinuria: 
Patients receiving bevacizumab should be monitored by urine analysis for urine protein: 
creatinine (UPC) ratio prior to every other dose of bevacizumab: 
 
UPC ratio < 3.5  Continue bevacizumab. 
 
UPC ratio ≥ 3.5 and/ or urine  collection  >3.5g/24hr  Hold  bevacizumab until 
UPC ratio recovers to < 3.5 or urine collection <3.5g/24 hr. 
 
If therapy is held for > 6 weeks due to proteinuria, discontinue bevacizumab. 
 
If patient develops grade 4 proteinuria or nephrotic syndrome, discontinue 
bevacizumab. 
9.3.2.3 Intestinal obstruction: 
Bevacizumab  will  be  held  for  occurrence  of CTCAE Grade 3  toxicity, until resolution to 
≤CTCAE Grade  1 and  will  be permanently discontinued  for occurrence of CTCAE Grade 
4 toxicity. 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, using clinical, laboratory and radiographic 
information as clinically indicated; in the event of disease progression, all  protocol- 
directed therapy would be discontinued. 
9.3.2.4 Wound Disruption/Bowel Perforation, Fistula, or GI Leak: 
Treatment with bevacizumab will be discontinued in the event of wound disruption 
requiring medical or surgical intervention, bowel perforation or fistula (including tracheo- 
esophageal fistula). 
 
Prior to Initiation of bevacizumab – In the event of  superficial wound  separations healing 
by secondary intention with no evidence of fascial dehiscence or infection, therapy with 
bevacizumab may be initiated with weekly wound examinations until complete closure. 
After initiation of bevacizumab – bevacizumab will be discontinued for any new event, 
regardless of grade. 
 
 
9.3.2.5 Reversible Posterior Leukoencephalopathy Syndrome (RPLS): 
Bevacizumab should be held in patients with symptoms/signs suggestive of  RPLS, 
pending work-up and management, including control of blood pressure. Bevacizumab 
should be discontinued upon diagnosis of RPLS. 
Note: Resumption of bevacizumab may be considered in patients who have documented 
benefit from the agent, provided that RPLS was mild and has completely  resolved 
clinically and radiographically within 2 to 4 weeks; decision to resume bevacizumab in 
these patients must be discussed with the study chair and approved by the sponsor. 

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9.3.2.6 Hypersensitivity Reaction: 
In general, the occurrence of a hypersensitivity reaction to bevacizumab  is  not 
considered a dose-limiting toxicity. Patients may be retreated at full doses after 
administration of medication to prevent hypersensitivity reactions, and adjustments in 
infusion rates should be made (see guidelines for re-treatment with bevacizumab  in 
section 5.2.1). However, if despite these safety measures repeat attempt at  infusion  of 
the inciting drug results in a recurrent hypersensitivity reaction, the drug should be 
discontinued for the remainder of the study. In the event of any grade 3 or 4 allergic or 
infusion reaction to bevacizumab it will be permanently discontinued. 
 
9.3.2.7 Other: 
There will be no dose modifications for alopecia, nausea, constipation, or diarrhea. It is 
recommended that routine medical measures be employed to manage nausea, 
constipation, and diarrhea. 
Unanticipated Major Surgical Procedures: For any unanticipated (emergent/urgent) 
major surgical procedure such as laparotomy performed for reasons other than disease 
progression or CTCAE at least possibly related to bevacizumab treatment  should  be 
held > 28 days post-operatively prior to resumption. Treatment delay 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. 
Special Modifications Study Treatment: Potential modifications for other non- 
hematologic toxicities with an impact on organ function of grade 2 (or greater) require 
discussion with one of the study co-chairs except where noted immediately below: 
 
For any CTCAE Grade 3 non-hematologic adverse events (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. 
 
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. 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION 
10.1 
Immune Function 
Peripheral blood (10-20ml) will be drawn according to the schedule in Table 5 
(Section 10.2). 
Antibodies against appropriate antigens will be studies by ELISA and  FACS 
where appropriate. One plain red top tube will be collected at weeks 1 and 7. 
Collect 10 ml (cc) of whole blood in a plain red top tube. Allow the blood to clot 
upright at 4ºC at room temperature for a minimum of 30 min but for no longer than 3 hrs. 
The faster the blood can be processed after the 30 min clotting  step  the  better.  The 
blood must be centrifuged to separate the serum (pale  straw-colored  liquid)  from  the 
blood cells. When the appropriate equipment is available, please centrifuge the blood at 

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~3,500 x g at 4oC for 10 min.  The minimum centrifugation requirements will be  ~1000  x  
g at room temperature for 15 min. The longer centrifugation time  will  help compensate  
for the slower speed. Avoid centrifugations without refrigeration longer than 15 min as 
excess heat may build up in the unit and damage the serum. 
Immediately freeze serum upright if possible using an appropriate type of 
freezing/storage space. Ultra-cold conditions such as an ultra cold freezer (  -70oC) or 
liquid nitrogen are ideal. Freezing by direct exposure with dry ice is also acceptable. 
Serum frozen under ultra-cold conditions represents the highest quality  specimen  
suitable for all types of laboratory testing including proteomic analysis. 
Ideally, serum processing time (from the time the blood is drawn to freezing the 
specimen) should be ≤2 hours and must occur within  4 hours. The  faster  the specimen 
can be processed from blood draw to freezing  the  better.  Serum  processed  within  1-2 
hrs is the highest quality. Serum processed within 2-4 hrs is a lower quality. Serum 
processed more than 4 hrs after drawing the blood is the poorest quality for testing. 
Tracking the processing time is critical in assessing specimen quality and suitability for 
testing. 
 
On week 14, 100ml of heparinized blood will be drawn to evaluate the B-cell 
response at the clonal level by production of monoclonal antibodies against the 
immunizing antigens. This will be performed in collaboration with MabVax Therapeutics 
(San Diego, CA). It will make possible more detailed analysis of the most immunogenic 
epitopes on these antigens, and more detailed comparison  of the  avidity of the  induced 
IgG and IgM antibodies than is possible with sera. If the patient  goes off study prior to  
week 14, an additional sample (10-20ml) will be obtain to assess  immune  status at  the  
off study visit. 
 
Samples should be delivered to Dr Philip Livingston’s laboratory (Laboratory of 
Tumor Vaccinology), MSKCC. The immunology tests will be  performed  under  the 
direction of the Ludwig Center (as will the immunology tests from the larger randomized 
GOG trial). 
10.2 
Assessment 
10.2.1 Clinical and Laboratory Assessment 
The clinical and laboratory assessment schedule is outlined below and includes 
parameters to assess the safety of the vaccine, as well as evaluate for signs of disease 
recurrence and progression. Abnormal findings will be evaluated per standard medical 
practice, and the abnormality will be classified as related to treatment, disease 
progression, or neither. 

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Table 5: Schedule of Asse ssment (+/- 3 days windows allowed) 
 
 
Week # 
0 1 
2 
3 
5 
7 
9 
11 
14 
17 
20 and q3 wks 
till end of study 
Vaccine# 
1 
2 
3 
4 
5 
6 
Bevacizumab 
* 
* * * * 
* 
* 
* 
* 
Office visit 
(toxicity assessment) 
* * 
* 
* * * * 
* 
* 
* 
* 
Hx and PE 
(including BP) 
* * 
* * * * 
* 
* 
* 
* 
Ca- 125 
* 
* 
* 
* 
* 
* 
* (alt visits and 
study end) 
CBC, differential 
* 
* * * * 
* 
* 
* 
* 
Comprehensive 
Metabolic Panel 
* 
* 
* 
* 
* 
* 
* (alt visits and 
study end) 
Amylase 
* 
Urine protein: 
creatinine ratio 
* 
* 
* 
* 
* 
* (alt visits and 
study end) 
PT 
* 
* 
TSH 
* 
* 
EKG 
* 
Radiographic 
Imaging 
* 
* 
* and every 
three months 
while on 
study 
Correlative Studies 
* 
* 
* 
Immune studies 
* 
* 
* 

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10.2.2 Extent of disease evaluation 
Extent of disease evaluation: Patients in clinical remission  are  by definition 
without clinical or radiographic evidence of disease at protocol entry. Patients with 
asymptomatic residual disease may have an elevated  CA-125 at protocol  entry. Criteria 
for therapeutic response/outcome assessment are determined using RECIST criteria 
v1.1.[48] 
10.2.3 Radiographic imaging 
Radiographic imaging (CT abdomen and pelvis) will be  obtained  q  3  months  
while on study, or if any clinical symptoms/examination findings warrant  further 
evaluation, or at any time at the discretion of the investigator. 
In addition, patients with a normal serum CA-125 level at protocol entry will have 
radiographic imaging performed if serum CA-125 rises to > 70 (per time  to  treatment 
failure criteria), confirmed by repeat value. 
10.2.4 Length of follow-up 
The primary endpoint of the study in this pilot trial is safety. Patients will  be 
followed for the duration of the study. In  previous  trials,  antibodies  were  generally 
present by the seventh week. We will proceed with the proposal for additional studies to 
evaluate efficacy if no systemic toxicity is seen in any patient at the ninth week 
assessment. Patients will be followed until time to treatment failure. 
11.0 
TOXICITIES/SIDE EFFECTS 
11.1 
Toxicity Evaluation 
Toxicity will be evaluated according to  the  National  Cancer  Institute  CTCAE 
Scale (Version 4.0, published May 28, 2009).[49] 
11.2 
Vaccination Toxicity 
The expected safety of the proposed vaccine is based on accumulating clinical 
experience with these vaccines in patients with a variety of  malignancies  including 
ovarian cancer. Vaccination with the individual components has been well tolerated as 
previously described.[18, 21, 25-27] In addition, no symptomatic autoimmunity  was 
detected in the pilot heptavalent vaccine trial, with self limited fever,  myalgia  and 
injection site reactions as the most common toxicities (all < grade 2). No grade 3 or 4 
toxicity was seen.[3] The lack  of  symptomatic autoimmunity  has  been  hypothesized  to 
be related to the preponderance of antigen expression on the secretory borders of cells 
where they are relatively sequestered from the immune system. 
Finally, composite safety data for serious adverse events on single  antigen 
vaccine studies at MSKCC are as follows: 

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Table 6: Serious Adverse Events in Monovalent Vaccine Trials\ 
 
 
Antigen 
Total # pts 
# SAE’s 
Protocols 
SAE Type 
GM2 
71 
0 
94-041 
None 
GLOBO-H 
74 
1 
96-055,97-086 
G2 Angioedema 
LEWIS Y 
18 
1 
00-075,02-103 
Dermatomyositis 
MUC-1 
90 
4 
94-130,99-023 
Thyroid (3) 
Erythema nodosum 
(1) 
TN 
25 
0 
98-002 
None 
TF 
21 
0 
98-048 
None 
 
In the total 299 patients above, 6/299 (2%) of patients  had  events  meeting 
criteria for SAE and were reported as such. Three of these  cases  were hypothyroidism. 
An extensive evaluation of these three patients with hypothyroidism, yielded no evidence 
for vaccine-induced dysfunction, and hypothyroidism is seen de novo in this patient 
demographic. These patients received thyroid hormone  supplementation  without 
sequelae. However, thyroid studies are now included as part of vaccine safety 
monitoring. The patient with dermatomyositis carried this diagnosis equivocally prior to 
enrollment. It is unclear if the erythema nodosum as described  was  related  to 
vaccination and it has not been seen in other patients. Finally, grade 2 angioedema was 
seen in 1/299 patients (0.3%) and has not been reported in others. Patients are routinely 
observed for 30 minutes following vaccination. In reviewing all trials taken together, the 
most common adverse events are grade 1 or 2 local erythema and induration at the 
injection site, which resolves in one to three days. Approximately, 25% of patients have 
mild flu-like symptoms for six to 24 hours after one or more vaccinations. 
 
Side Effects from Vaccine for Patients on Study: 
Likely: 
1.  Mild tiredness 
2.   Redness and tenderness at vaccination site which resolves in 2-3 days without 
treatment. The site may become inflamed with significant erythema, and this has been 
managed conservatively with cool  soaks,  analgesics  for  discomfort,  acetaminophen 
most commonly) and it resolves with time. If it occurs, it generally  may  increase  in 
intensity with the first several vaccinations, and then tends to lessen with subsequent 
vaccinations. 
 
3.   Low grade fever for 24 – 48 hours after vaccination. This may be managed with 
observation or an anti-pyretic if desired (acetaminophen most commonly used). 

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Less Likely: 
1. Abnormal blood counts 
2. High fever 
3.  Mild elevation in liver function tests (transaminases) 
4.   Hypothyroidism (This was seen in 3/299 patients previously treated with similar 
vaccines. While there was no serologic evidence it was related, the protocol requires 
assessment of thyroid function.) 
5.  Vasovagal syncope after receiving SC injection (unrelated to vaccine) 
6. Nausea 
Rare but Serious: 
1.  Angioedema after vaccination. Grade 2 angioedema was seen in 1/299 previously 
vaccinated patients (0.3%). Severe allergic reactions have not been reported to date with 
similar vaccines. 
2.  Symptoms related to autoimmunity (mastitis, pancreatitis, hepatitis, etc). This entity has 
not been previously reported with similar vaccines but is theoretically possible. 
(See Section 9.1.1 for detailed description of potential side-effects and their management) 
11.3 
Bevacizumab Toxicity 
The most recent safety update is detailed in the current Avastin® Prescribing 
Information. 
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. Any patient  whose  treatment 
is delayed must be evaluated on a weekly basis until adequate hematologic and non- 
hematologic parameters have been met. Missed doses of bevacizumab will not be made 
up. Regardless of the reason for holding the bevacizumab,  the  maximum  allowable  
length of treatment interruption is 2 months. No dose escalation is planned for this study. 
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  
6.2) 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 or discontinuation at each study visit for the duration of 

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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. 
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. 
More likely toxicities are: 
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).(Ozcan et al., 2006; Glusker et al., 2006). 
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. 
Less likely toxicities are: 
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 

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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 Thromboembolic Events: An increased incidence of ATE events was 
observed in patients treated with bevacizumab compared with those receiving control 
treatment. 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 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 (Hambleton et al., 2005). Further analyses of the effects of 
concomitant use of bevacizumab and aspirin in colorectal and other tumor types are 
ongoing. 

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Rare but serious toxicities are: 
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 time-points during 
treatment, ranging from 1 week to  1 year following initiation of bevacizumab, with most 
events occurring within the first 6 months of therapy. 
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 (Scappaticci et al., 2005). 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. 

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Additional Reported Adverse Events and Potential Risks with Bevacizumab 
(Avastin®) are: 
Infusional reaction: fever, chills, rigor, rash, urticaria, dyspnea 
Cardiovascular: hypertension (including hypertensive crisis), hypotension, pericardial 
effusion*, decrease in cardiac function*, cardiac troponin I elevation, arrhythmias 
Hematologic: arterial and venous thrombosis/embolism (including pulmonary embolism, 
mesenteric vein thrombosis, ischemic bowel, cerebral vascular accident); hemorrhage 
(including epistaxis, CNS bleeding, GI bleeding, hemoptysis, pulmonary hemorrhage), 
neutropenia. 
Constitutional: headache, infection without neutropenia, asthenia 
Skin: rash, urticaria, delay in wound healing or dehiscence of healed wound, 
pruritus/itching 
Gastrointestinal: nausea, vomiting, colitis, stomatitis/pharyngitis, intestinal obstruction, 
bowel perforation, bowel anastomotic dehiscence, anorexia. 
Hepatic: LFT abnormalities 
Pulmonary: pulmonary infiltration*, dyspnea 
Renal/Genitourinary: proteinuria, nephrotic syndrome 
Musculoskeletal: arthralgia, chest pain 
Neurologic: dizziness; leukoencephalopathy syndrome, including reversible posterior 
leukoencephalopathy syndrome (RPLS). 
Other: allergic rhinitis 
* indicates reported events with relationship to bevacizumab unclear 
(See Section 9.3.2 for detailed description of the management) 
 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOM E ASSESSM ENT 
 
Eligible patients may have asymptomatic residual measurable disease  on  
physical examination and/or CT scan, and/or may have an elevated CA-125; or 
may be in complete clinical remission. 
 
Complete clinical remission is defined as a serum CA-125 < 35 IU/ml, CT scan 
without objective evidence of disease, and normal physical examination. RECIST 
criteria 1.1 will be used to determine disease response in those patients with 
measurable disease.[48] 
 
 
CA-125 measurements will be followed but will not be used to determine 
progression free survival. A rising CA-125 may, at the discretion  of  the 
investigator, prompt an earlier CT scan. 

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12.1 
Base line Assessment 
 
Measurable disease (“Target”) is defined as at least one lesion that can be accurately 
measured in at least one dimension (longest  diameter  to  be  recorded).  Each  lesion 
must be  10 mm when measured by CT (CT scan slice  thickness  no greater  than  5 
mm*); > 10 mm caliper measurement by clinical exam (lesions which cannot be 
accurately measured with calipers should be recorded  as non-measurable);  and  > 20  
mm by chest x-ray. 
*If CT scan with slice thickness > 5 mm is used, the minimum lesion size must have a 
longest dimension twice the actual slice thickness. 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a 
lymph node must be > 15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm). At baseline  and in follow-up, only 
the short axis will be measured and followed. 
Clinical lesions will only be considered measureable when they are superficial and > 10 
mm diameter as assessed using calipers (e.g. skin nodules). When lesions can be 
evaluated by both clinical exam and imaging, imaging evaluation should be undertaken 
since it is more objective and my also be reviewed at the end of the study. 
CT is the  best currently available and reproducible method to  measure lesions selected   
for response assessment. MRI may be substituted for contrast enhanced CT for some 
sites (e.g. for abdomen and/or pelvis), but NOT lung. The minimum  size  for 
measurability is the same as for CT (10 mm) as long as the scans are  performed  with  
slice thickness of 5 mm and no gap. In the event the  MRI is performed  with  thicker  
slices, the size of a measurable lesion at baseline should be two times  the  slice 
thickness. 
Tumors within a previously irradiated field will be designated as  “non-target”  lesions  
unless progression is documented or a biopsy is obtained to confirm persistence at least 
90 days following completion of radiation therapy. 
Bone lesions: Bone scan, PET scan or plain films are NOT  considered  adequate  
imaging techniques to measure bone lesions. Lytic bone lesions or mixed lytic-blastic 
lesions, with identifiable soft tissue components, that can  be  evaluated  by  cross 
sectional imaging techniques such as CT or MRI can be considered as measurable if the 
soft tissue component meets the definition of measurability  described  above.  Blastic 
bone lesions are non-measurable. 
Cystic lesions: Lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions  (neither  measurable  nor non- 
measurable). Cystic lesions thought to represent cystic metastases can be considered 
measurable lesions, if they meet the definition of measurability  described  above. 
However, if non-cystic lesions are present in the same patient, these are preferred for 
selection as target lesions. 
Non-measurable disease (“Non-Target”) is defined as  all other  lesions, including 
small lesions (<10 mm or pathological lymph nodes with > 10 to < 15 mm short axis) as 
well as truly non-measurable lesions. 

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Lesions considered truly non-measurable include: 
 
Leptomeningeal disease 
 
Ascites 
 
Pleural or pericardial effusion 
 
Inflammatory breast disease 
 
Lymphangitic involvement of skin or lung 
 
Abdominal masses/abdominal organomegaly indentified by 
physical exam that is not measureable by reproducible imaging 
techniques 
Baseline documentation of “Target” and “Non-Target” lesions 
All measurable lesions up to a maximum of 5 lesions total (and a maximum of two 
lesions per organ) representative of all involved organs should be identified as target 
lesions and recorded and measured at baseline. Target  lesions should be selected  on  
the basis of their size (lesions with the longest diameter),  be representative  of  all 
involved organs, but in addition should be those that lend themselves to reproducible 
repeated measurements. A sum of the diameters  (longest for  non-nodal lesions, short 
axis for nodal lesions) for all target lesions will be calculated and reported  as  the  
baseline sum diameters. The baseline sum diameters 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) 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 the treatment. 
The same method of assessment and the same technique should  be  used  to 
characterize each identified and reported lesion at baseline and during  follow-up. 
Imaging based evaluation should ALWAYS be done rather than clinical examination 
unless the lesion(s) being followed cannot be imaged but are  assessable  by  clinical 
exam. 
12.2 Response Criteria 
Complete Response (CR): Disappearance of all target and non-target lesions. Any 
pathological lymph nodes (whether target or non-target)  must  have  reduction  in  short 
axis to <10 mm. Normalization of CA125, if elevated at baseline, is required for 
ovarian/primary peritoneal/fallopian tube cancer studies. 
Partial Response (PR): At least a 30% decrease in the sum of diameters of target 
lesions, taking into reference the baseline sum diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study). In addition to the relative increase  of 20%,  the  sum 
must also demonstrate an absolute increase of at least 5  mm.  (Note:  the 
appearance of one or more NEW lesions is also considered progression.) Unequivocal 
progression of existing non-target lesions is also considered progression (a detailed 
description and examples of unequivocal progression of existing non-target lesions is 
provided in the above cited reference). 

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For equivocal findings of progression (e.g. very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment. If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected. 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
Not evaluable (NE) is when no imaging/measurement is done at all at a particular time 
point. The patient is not evaluable (NE) at that time point. 
 
Early death is defined as having NO repeat tumor assessments following initiation of 
study therapy resulting from the death of the patient due to disease or treatment. 
Patients with global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time will be recorded as 
‘symptomatic  deterioration’. 
Every effort should be made to document objective 
progression even after discontinuation of treatment. 
Confirmation of response (for both CR and PR): Complete or  partial response  may 
only be claimed if the criteria for each are met at a subsequent time  point (> 4  weeks  
later) in studies with a primary endpoint  that  includes response  rate.  When  response 
rate is a secondary endpoint (e.g. randomized phase II  or  III  studies  with  progression- 
free survival or overall survival as primary endpoint) confirmation is NOT required. 
Special note on lymph nodes: Lymph nodes identified as target lesions should always 
have the actual short axis measurement recorded (measured in the same anatomical 
plane as the baseline examination), even if the nodes regress to below 10 mm on study. 
This means that when lymph nodes are included as target lesions, the ‘sum’ of lesions  
may not be zero even if complete response  criteria  are  met,  since a normal lymph  node  
is defined as having a short axis of < 10 mm. For PR, SD and PD, the actual short axis 
measurement of the nodes is to be included in the sum of target lesions. 
Special note on target lesions that become ‘too  small to measure’:  While on study, 
all lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very small (e.g. 2 
mm). However, sometimes lesions or lymph nodes which are recorded as target lesions  at 
baseline become so faint on CT scan that the radiologist may not feel comfortable assigning 
an exact measure and may report them as being  ‘too  small  to  measure’.  When this 
occurs it is important that a value be recorded on the D2M form. If it is the opinion of the 
radiologist that the lesion has likely disappeared, the measurement should  be recorded as 
0 mm. If the lesion is believed to be  present and  is faintly seen but too  small to measure, a 
default value of 5 mm should be assigned (Note:  It  is less likely  that this rule will be 
used for lymph nodes since they usually have a definable size when normal and are 
frequently surrounded by fat  such as in  the retroperitoneum;  however,  if  a lymph node is 
believed to be present and is faintly seen but too small to measure, a default value of 5 
mm should be assigned in this circumstance as well). 

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Evaluation of best overall response is according to Tables 6-7: 
Table 6 is used for patients with measurable disease at baseline. 
Target lesions 
Non-target lesions 
New lesions Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
Table 7 is used for patients with non-measurable disease. 
 
Non-target lesions New lesions Overall response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 

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Duration of response is defined as the time measurement criteria are first met for CR/PR 
until the first date that recurrent or progressive disease is objectively documented  (taking 
as reference for progressive disease the smallest measurement recorded on study). 
Duration of stable disease is measured from the start of the treatment (in randomized 
trials, from the date of randomization) until the criteria for progression are met, taking as 
reference the smallest sum on study (if the baseline sum is the smallest, this is the 
reference for calculation of PD). 
Progression-Free Survival is the period from study entry until recurrent or progressive 
disease is objectively documented (taking as reference for progressive disease the 
smallest measurement recorded on study), death or date of last contact. 
Survival is the observed length of life from entry into the study to death or the date of last 
contact. 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
 
If at any time the patient develops progressive disease she  will  be taken  off  study 
and referred for alternative therapy. 
 
If at anytime the patient develops unacceptable toxicity she will be  removed  from 
study. Patients will be  removed  from study for  any  life-threatening  grade 4 toxicity  or 
a vaccine-related Dose Limiting Toxicity (DLT); defined by: ≥ grade 2  allergic 
reaction, ≥ grade 2 autoimmune reaction, ≥grade 3 hematologic or non-hematologic 
toxicity including fever, ≥ grade 3 injection site reaction. 
 
If at anytime the patient is found to be ineligible for the protocol as designated in the 
section on Criteria for Patient/Subject Eligibility (i.e. a change  in  diagnosis),  the  
patient will be removed from the study. 
 
Subjects who meet the following criteria should be discontinued from the study: 
➢ Grade 4 hypertension or grade 3 hypertension not controlled with medication 
➢ Grade 4 congestive heart failure 
➢ Symptomatic grade 4 venous thromboembolic event 
➢ Nephrotic syndrome. 
➢ Bowel Obstruction that has not fully recovered despite medical or surgical 
intervention 
➢ Grade 4 hemorrhage or repeat grade 3 hemorrhage (≥ grade 2 pulmonary 
hemorrhage or CNS hemorrhage) 
➢ Any grade arterial thromboembolic event 
➢ Treatment delay in cycles bevacizumab >8 weeks 
➢ Gastrointestinal perforation 
➢ Tracheoesophageal fistula (any grade) or grade 4 fistula 
➢ Wound dehiscence requiring medical or surgical intervention 
➢ Determination by the investigator that it is no longer safe for the subject  to 
continue therapy 
➢ Inability to tolerate treatment because of toxicity 
➢ Inability or unwillingness of subject to comply with study requirements 
➢ All grade 4 events thought to be related to bevacizumab by the investigator 

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Any patient with ≥grade 2 vaccine-related DLT will be followed with appropriate 
studies until results return to baseline. Patients who have an ongoing vaccine-related or 
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. (See Section 5.2.3). 
 
In the absence of a vaccine-related DLT, no further bevacizumab will be given  if  
the patient develops any grade of the following toxicities: wound dehiscence 
requiring medical or surgical intervention, arterial thromboembolic event, GI 
perforation,  or  bowel  obstruction  or ≥ grade 2 pulmonary hemorrhage  or ≥ grade 
3 of the following: hypertension, congestive heart failure, venous thrombosis or non-
pulmonary hemorrhage. The patient may continue to receive the vaccine as 
indicated. Any patient with ≥ grade 2 vaccine-related DLT or other ≥  grade  3 
toxicity will be followed with appropriate studies until results return to baseline 
14.0 
BIOSTATISTICS 
The endpoints of this pilot trial are safety and confirmation of immunogenicity  in  
the multivalent setting in combination with bevacizumab. Twenty-one evaluable patients  
will be accrued, with approximately two patients being accrued each month. No systemic 
toxicity has occurred with the administration of prior vaccines at  the  center. Toxicity  is  
not expected with this preparation relative  to  vaccination.  However  toxicities  related  to 
the combination regimen or to bevacizumab alone can be observed since this is  the  first 
trial that evaluates safety of the combination regimen.  All patients who  receive  at  least 
one vaccination and one treatment with bevacizumab will be considered evaluable with 
respect to the safety analysis The trial will be stopped for safety in the event of the 
following toxicities during the treatment phase of the study (i.e. until week 20 week) (see 
Table 8 below) . 
Bevacizumab-related Toxicities: 
1) Gastrointestinal perforation/ Gastrointestinal Leak: Unexplainable grade 1 GI 
perforation (excluding evidence of abdominal free air attributable to other causes such 
as paracentesis or recent surgical procedure) or ≥ Grade 2 (including intra-abdominal 
abscess or GI fistula) 
2) GI fistula: ≥ Grade 1 tracheoesophageal fistula or ≥ Grade 2 other fistula 
 
Vaccine-related Toxicities: 
1) ≥ Grade 2 autoimmune reaction 
2) > Grade 2 allergic reaction 
A repeated significance test that differentiates between acceptable toxicity 
probabilities of 0.01 and 0.1 will be used to monitor this study. The boundary produced 
below  is  based  on  Type  I  error   of   0.1   and   Type   II   error   equal   to   0.24.   
Stop the study if the number of toxicities observed are greater or equal to among the 
following accrued patients. 

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Table 8 Stopping rules for toxicities observed 
 
Stop the study if the number of toxicities 
observed are greater or equal to 
Among the following accrued patients 
1 
10 
2 
21 
 
The same criteria for immunogenicity will be used as that of the individual pilot  
trials: patients must have IgM titer > 1:40, or an eightfold increase in prevailing antibody 
titer if present at baseline. If ≥ 8 of 21 patients  should  meet these  criteria  for  three or 
more antigens based on the immune response criteria, the study will be  considered 
positive. This calculation assumes that the probability of immune response under the null 
hypothesis (i.e. no activity) is 0.2 versus the alternative hypothesis (i.e. target response 
probability) is 0.5 using a single stage binomial proportion test. Type I error is 4.3% and 
Type II error is 0.1. In prior trials, antibodies are generally present by completion of the 
fourth vaccination (week 7) thus immune response will be evaluated by week 7. 
The secondary endpoints of this pilot trial are to characterize the nature and 
duration of the immune response. Antibodies against the individual antigens  will  be 
studied by ELISA, and against the appropriate human tumor antigen FACS using human 
tumor cell lines expressing the respective antigen where appropriate, and  2)  a 
correlation of multiplex biomarker results with PFS, and a  comparison  of  baseline  to 
value at progression will be assessed graphically. The baseline value will  be correlated 
with PFS. 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
15.1 
Research Participant Registration 
 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
 
Obtain informed consent, by following procedures defined in section entitled Informed 
Consent Procedures. 
During the registration process registering individuals will be required to complete a 
protocol specific Eligibility Checklist. 
All participants must be registered through the Protocol Participant Registration (PPR) 
Office at Memorial Sloan-Kettering Cancer Center. PPR is available Monday through 
Friday from 8:30am – 5:30pm at 646-735-8000. The PPR fax numbers are (646) 735- 
0008 and (646) 735-0003. Registrations can be phoned in or faxed. The completed 
signature page of the written consent/verbal script and a completed Eligibility Checklist 
must be faxed to PPR. 

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16.0 DATA MANAGEM ENT ISSUES 
 
A Research Study Assistant (RSA) will be assigned to the study. The 
responsibilities of the RSA include project compliance, data collection, abstraction and 
entry, data reporting, regulatory monitoring, problem resolution and prioritization, and 
coordinate the activities of the protocol study team.  The data  collected  for  this study will  
be entered into a secure database. Source documentation  will  be  available  to  support 
the computerized patient record. 
16.1 
Quality Assurance 
Weekly registration reports will be generated to monitor patient accruals and 
completeness of registration data. Routine data quality reports will be generated  to 
assess missing data and inconsistencies. Accrual rates and extent and accuracy of 
evaluations and follow-up will be monitored periodically throughout the study period and 
potential problems will be brought to the attention of the study team for discussion and 
action. 
Random-sample data quality and protocol compliance audits will be conducted by the 
study team, at a minimum of two times per year, more frequently if indicated 
16.2 
Data and Safety Monitoring 
The Data and Safety Monitoring (DSM) Plans at Memorial  Sloan-Kettering  Cancer 
Center were approved by the National Cancer Institute in September 2001. The plans 
address the new policies set forth by the NCI in the document entitled “Policy of the 
National Cancer Institute for Data and Safety Monitoring of Clinical Trials” which can be 
found at: http://cancertrials.nci.nih.gov/researchers/dsm/index.html. The DSM Plans at 
MSKCC were established and are monitored by the Office of Clinical Research. The 
MSKCC Data and Safety Monitoring Plans can be found on the MSKCC Intranet at: 
http://mskweb2.mskcc.org/irb/index.htm 
There are several different mechanisms by which clinical trials are monitored for data, 
safety and quality. There are institutional processes in place for quality assurance (e.g., 
protocol monitoring, compliance and data verification audits, therapeutic response, and  
staff education on clinical research QA) and departmental procedures for quality control, 
plus there are two institutional committees that are responsible for  monitoring  the 
activities of our clinical trials programs. The committees: Data and Safety Monitoring 
Committee (DSMC) for Phase I and II clinical trials, and the Data and Safety Monitoring 
Board (DSMB) for Phase III clinical trials, report to the Center’s Research Council and 
Institutional Review Board. 
During the protocol development and review process, each protocol will be 
assessed for its level of risk and degree of monitoring required. Every type of protocol 
(e.g., NIH sponsored, in-house sponsored, industrial sponsored, NCI cooperative group, 
etc.) Will be addressed and the monitoring procedures will be established at the time of 
protocol activation. 
17.0 PROTECTION OF HUM AN SUBJECTS 
17.1 
Privacy 
MSKCC’s Privacy Office may allow the use and disclosure of protected  health 
information pursuant to a completed and signed Research Authorization form. The use 
and disclosure of protected health information  will  be  limited to the individuals  described 
in the Research Authorization  form.  A Research Authorization  form must  be completed  
by the Principal Investigator and approved by the IRB and Privacy Board (IRB/PB). 

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17.2 
Serious Adverse Event (SAE) Reporting 
Any SAE must be reported to the IRB/PB as soon as possible but no later than 5 
calendar days. The IRB/PB requires a Clinical Research Database (CRDB) SAE report 
be submitted electronically to the SAE Office at sae@mskcc.org. The report should 
contain the following information: 
Fields populated from CRDB: 
 
 
Subject’s name (generate the report with only initials if it will be sent outside of 
MSKCC) 
 
Medical record number 
 
Disease/histology (if applicable) 
 
Protocol number and title 
Data needing to be entered: 
 
The date the adverse event occurred 
 
The adverse event 
 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
 
If the AE was expected 
 
The severity of the AE 
 
The intervention 
 
Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject’s condition 
o Indication if the subject remains on the study 
o If an amendment will need to be made to the protocol and/or consent 
form. 
 
The PI’s signature and the date it was signed are required on the completed report. 
For IND/IDE protocols: 
The CRDB AE report should be completed as above and the FDA assigned 
IND/IDE number written at the top of the report. The report will be forwarded to the 
FDA by the Institutional SAE Manager through the IND Office. 
All  SAE reports must also  be forwarded  as  soon as possible to: 
➢ Genentech Drug Safety 
Fax: 
(650) 225-4682 or (650) 225-5288 
For questions related to safety reporting, contact: 
Genentech Drug Safety Tel: 1-888-835-2555 
Genentech may contact the reporter for additional information, clarification, or 
current status of the subject for whom and adverse event was reported. 

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17.2.1 Genentech Adverse Event Reporting Definitions 
 
A serious treatment emergent adverse event (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. 
 
Assessing Causality: 
 
The event should be assessed to decide 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. 
18.0 
INFORMED CONSENT PROCEDURES 
Before protocol-specified procedures are carried out, consenting professionals will explain full 
details of the protocol and study procedures as well as the risks involved to participants prior to 
their inclusion in the study. Participants will also be informed that they are free to withdraw from 
the study at any time. All participants must sign an IRB/PB-approved consent form indicating 
their consent to participate. This consent form meets the requirements of the Code of Federal 
Regulations and the Institutional Review Board/Privacy Board of this Center. The consent form 
will include the following: 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of 
supportive care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions 
and to withdraw from participation at any time. 

MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 10-099 A(3) 
Amended: 6/12/12 
Page 46 of 56 
 
 
Before any protocol-specific procedures can be carried out, the consenting professional will fully 
explain the aspects of patient privacy concerning research specific information. In addition to 
signing the IRB Informed Consent, all patients must agree to the Research Authorization 
component of the informed consent form. 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form.” 
 
19.0 
REFERENCES 
 
1. 
Armstrong, D.K., et al., Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl 
J Med, 2006. 354(1): p. 34-43. 
2. 
Markman, M., et al., Duration of Response to Second-Line, Platinum-Based 
Chemotherapy for Ovarian Cancer: Implications for Patient Management and Clinical 
Trial Design. J Clin Oncol, 2004. 22(15): p. 3120-3125. 
3. 
Sabbatini, P.J., et al., Pilot study of a heptavalent vaccine-keyhole limpet hemocyanin 
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4. 
Jemal, A., et al., Cancer statistics, 2008. CA Cancer J Clin, 2008. 58(2): p. 71-96. 
5. 
Hoskins, W.J., C.A. Perez, and R.C. Young, Principles and practice of gynecologic 
oncology. 3rd ed. 2000, Philadelphia: Lippincott Williams & Wilkins. xxi, 1268 p. 
6. 
Barnhill, D.R., et al., The second-look surgical reassessment for epithelial ovarian 
carcinoma. Gynecol Oncol, 1984. 19(2): p. 148-54. 
7. 
Rubin, S.C., et al., Recurrence after negative second-look laparotomy for ovarian 
cancer: analysis of risk factors. Am J Obstet Gynecol, 1988. 159(5): p. 1094-8. 
8. 
Cain, J.M., et al., A review of second-look laparotomy for ovarian cancer. Gynecol 
Oncol, 1986. 23(1): p. 14-25. 
9. 
Markman, M., et al., Second-line platinum therapy in patients with ovarian cancer 
previously treated with cisplatin. J Clin Oncol, 1991. 9(3): p. 389-93. 
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Zhang, H., et al., Antibodies can eradicate cancer micrometastasis. Cancer Research, 
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11. 
Zhang, L., et al., Intratumoral T cells, recurrence, and survival in epithelial ovarian 
cancer. N Engl J Med, 2003. 348(3): p. 203-13. 
12. 
Berek, J.S., et al., Randomized, placebo-controlled study of oregovomab for 
consolidation of clinical remission in patients with advanced ovarian cancer. J Clin 
Oncol, 2004. 22(17): p. 3507-16. 
13. 
Reinartz, S., et al., Vaccination of patients with advanced ovarian carcinoma with the 
anti-idiotype ACA125: immunological response and survival (phase Ib/II). Clin Cancer 
Res, 2004. 10(5): p. 1580-7. 
14. 
Bookman, M.A., et al., Evaluation of monoclonal humanized anti-HER2 antibody, 
trastuzumab, in patients with recurrent or refractory ovarian or primary peritoneal 
carcinoma with overexpression of HER2: a phase II trial of the Gynecologic Oncology 
Group. J Clin Oncol, 2003. 21(2): p. 283-90. 
15. 
Allavena, P., et al., Intraperitoneal recombinant gamma-interferon in patients with  
recurrent ascitic ovarian carcinoma: modulation of cytotoxicity and cytokine production in 
tumor-associated effectors and of major histocompatibility antigen expression on tumor 
cells. Cancer Res, 1990. 50(22): p. 7318-23. 
16. 
Pujade-Lauraine, E., et al., Intraperitoneal recombinant interferon gamma in ovarian 
cancer patients with residual disease at second-look laparotomy. J Clin Oncol, 1996. 
14(2): p. 343-50. 

MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 10-099 A(3) 
Amended: 6/12/12 
Page 47 of 56 
 
 
17. 
Recchia, F., et al., Interleukin-2 and 13-cis retinoic acid as maintenance therapy in 
advanced ovarian cancer. Int J Oncol, 2005. 27(4): p. 1039-46. 
18. 
Sabbatini, P.J., et al., Immunization of ovarian cancer patients with a synthetic Lewis(y)- 
protein conjugate vaccine: a phase 1 trial. Int J Cancer, 2000. 87(1): p. 79-85. 
19. 
Nicholson, S., et al., A phase I trial of idiotypic vaccination with HMFG1 in ovarian 
cancer. Cancer Immunol Immunother, 2004. 53(9): p. 809-16. 
20. 
Magid Diefenbach, C., et al. Phase I safety and immunogenicity study of NY-ESO-1b 
peptide and Montanide ISA-51 vaccination of patients with ovarian cancer (OC) in high 
risk first remission. in Proceedings of the American Society of Clinical Oncology. 2006. 
21. 
Gilewski, T., et al., Immunization of metastatic breast cancer patients with a fully 
synthetic globo H conjugate: a phase I trial. Proc Natl Acad Sci U S A, 2001. 98(6): p. 
3270-5. 
22. 
Gilewski, T., et al., Vaccination of high-risk breast cancer patients with mucin-1 (MUC1) 
keyhole limpet hemocyanin conjugate plus QS-21. Clin Cancer Res, 2000. 6(5): p. 1693- 
701. 
23. 
Slovin, S.F., et al., Immunogenicity of a fully synthetic globo-H hexasaccharide 
conjugate in man. Proc Natl Acad Sci USA, 1999. 96: p. 5710-5715. 
24. 
Sabbatini, P., et al., Pilot study of a heptavalent vaccine-KLH conjugate plus QS-21 in 
patients with epithelial ovarain, fallopian tube, or peritoneal cancer. Clin Cancer Res, 
2007. In Press. 
25. 
Slovin, S.F., et al., Fully synthetic carbohydrate-based vaccines in biochemically 
relapsed prostate cancer: clinical trial results with alpha-N-acetylgalactosamine-O- 
serine/threonine conjugate vaccine. J Clin Oncol, 2003. 21(23): p. 4292-8. 
26. 
Slovin, S.F., et al., Thomsen-Friedenreich (TF) antigen as a target for prostate cancer 
vaccine: clinical trial results with TF cluster (c)-KLH plus QS21 conjugate vaccine in 
patients with biochemically relapsed prostate cancer. Cancer Immunol Immunother, 
2005. 54(7): p. 694-702. 
27. 
Helling, F., et al., GM2-KLH conjugate vaccine: increased immunogenicity in melanoma 
patients after administration with immunological adjuvant QS-21. Cancer Res, 1995. 
55(13): p. 2783-8. 
28. 
Chapman, P.B., et al., Induction of antibodies against GM2 ganglioside by immunizing 
melanoma patients using GM2-keyhole limpet hemocyanin + QS21 vaccine: a dose- 
response study. Clin Cancer Res, 2000. 6(3): p. 874-9. 
29. 
Adluri, S., et al., Immunogenicity of synthetic TF-KLH (keyhole limpet hemocyanin) and 
sTn-KLH conjugates in colorectal carcinoma patients. Cancer Immunology, 
Immunotherapy, 1995. 41(3): p. 185-192. 
30. 
Hollingsworth, H.C., et al., Tumor angiogenesis in advanced stage ovarian carcinoma. 
Am J Pathol, 1995. 147(1): p. 33-41. 
31. 
Alvarez, A.A., et al., The prognostic significance of angiogenesis in epithelial ovarian 
carcinoma. Clin Cancer Res, 1999. 5(3): p. 587-91. 
32. 
Gasparini, G., et al., Prognostic and predictive value of tumour angiogenesis in ovarian 
carcinomas. Int J Cancer, 1996. 69(3): p. 205-11. 
33. 
Nakanishi, Y., et al., The expression of vascular endothelial growth factor and 
transforming growth factor-beta associates with angiogenesis in epithelial ovarian 
cancer. Int J Gynecol Pathol, 1997. 16(3): p. 256-62. 
34. 
Byrne, A.T., et al., Vascular endothelial growth factor-trap decreases tumor burden, 
inhibits ascites, and causes dramatic vascular remodeling in an ovarian cancer model. 
Clin Cancer Res, 2003. 9(15): p. 5721-8. 
35. 
Hu, L., et al., Vascular endothelial growth factor trap combined with paclitaxel strikingly 
inhibits tumor and ascites, prolonging survival in a human ovarian cancer model. Clin 
Cancer Res, 2005. 11(19 Pt 1): p. 6966-71. 

MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 10-099 A(3) 
Amended: 6/12/12 
Page 48 of 56 
 
 
36. 
Kim, K.J., et al., Inhibition of vascular endothelial growth factor-induced angiogenesis 
suppresses tumour growth in vivo. Nature, 1993. 362(6423): p. 841-4. 
37. 
Willett, C.G., et al., Direct evidence that the VEGF-specific antibody bevacizumab has 
antivascular effects in human rectal cancer. Nat Med, 2004. 10(2): p. 145-7. 
38. 
Shaheen, R.M., et al., Inhibited growth of colon cancer carcinomatosis by antibodies to 
vascular endothelial and epidermal growth factor receptors. Br J Cancer, 2001. 85(4): p. 
584-9. 
39. 
Hurwitz, H., et al., Bevacizumab plus irinotecan, fluorouracil, and leucovorin for 
metastatic colorectal cancer. N Engl J Med, 2004. 350(23): p. 2335-42. 
40. 
Miller, K.D., et al., Randomized phase III trial of capecitabine compared with 
bevacizumab plus capecitabine in patients with previously treated metastatic breast 
cancer. J Clin Oncol, 2005. 23(4): p. 792-9. 
41. 
Burger, R.A., et al., 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(33): p. 5165-71. 
42. 
Cannistra, S.A., et al., Phase II Study of Bevacizumab in Patients With Platinum- 
Resistant Ovarian Cancer or Peritoneal Serous Cancer. J Clin Oncol, 2007. 25(33): p. 
5180-5186. 
43. 
Garcia, A.A., et al., Phase II Clinical Trial of Bevacizumab  and Low-Dose Metronomic 
Oral Cyclophosphamide in Recurrent Ovarian Cancer: A Trial of the California, Chicago, 
and Princess Margaret Hospital Phase II Consortia. J Clin Oncol, 2008. 26(1): p. 76-82. 
44. 
Monk, B.J., et al., Activity of bevacizumab (rhuMAB VEGF) in advanced refractory 
epithelial ovarian cancer. Gynecol Oncol, 2005. 96(3): p. 902-5. 
45. 
Garcia, A.A., et al., Phase II clinical trial of bevacizumab and low-dose metronomic oral 
cyclophosphamide in recurrent ovarian cancer: a trial of the California, Chicago, and 
Princess Margaret Hospital phase II consortia. J Clin Oncol, 2008. 26(1): p. 76-82. 
46. 
Burger, R.A., et al., Phase II trial of bevacizumab in persistent or recurrent epithelial 
ovarian cancer (EOC) or primary peritoneal cancer (PPC): A Gynecologic Oncology 
Group (GOG) study. J Clin Oncol (Meeting Abstracts), 2005. 23(16_suppl): p. 5009-. 
47. 
Livingston, P.O., et al., Phase I trial of immunological adjuvant QS-21 with a GM2 
ganglioside-keyhole limpet haemocyanin conjugate vaccine in patients with malignant 
melanoma. Vaccine, 1994. 12(14): p. 1275-1280. 
48. 
Eisenhauer, E.A., et al., New response evaluation criteria in solid tumours: revised 
RECIST guideline (version 1.1). Eur J Cancer, 2009. 45(2): p. 228-47. 
49. 
National Cancer Institute. Common terminology criteria for adverse events (CTCAE) v4.0. 
National Cancer Institute; 2009.http://ctep.cancer.gov/reporting/ctc.html [accessed 5 June 
2009]. 
Available from: .http://ctep.cancer.gov/reporting/ctc.html. 
 
20.0 
APPENDICES 
 
Appendix A: Laboratory Standard Operating Procedures 
 
Appendix B: FIGO Stage Grouping for Primary Carcinoma of the Ovary (1985) 
Appendix C: New York Heart Association 
Appendix D: Procedure for Obtaining a Urine Protein / Creatinine Ratio 

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APPENDIX A: Laboratory Standard Operating Procedures 
 
A.1 Correlative Studies 
A.1.A 10-plex Angiogenesis Immunoassay 
Summary and Principle 
Dec ision Biomar kers, Inc ( DBI) has developed a novel, automated immunoassay platform to simultaneously evaluate 
multiple biomarkers in a single reaction device, the MAX BIOCHIP®. The MA X BIOCHIP® is a polycarbonate cartr idge 
with a sample chamber, tw o self-contained reagent chambers, and a reaction chamber, all connected by a series of 
channels interspersed w ith sensors and valves to detect and direct fluid flow . The reaction chamber of the 
MAXBIOCHIP® cons ists of a microarray of specific antibodies spotted onto a glass slide pre-coated w ith an ultra-thin 
film of nitrocellulose. To perform an analysis, the MAXBIOCHIP® is inserted into the AVANTRA® Biomarker 
Workstation. Sample is injected and the instrument automatically directs, in sequence, the flow of sample, solublized 
biotinylated detection antibodies, labeled streptav idin, and w ash buffer across the microarray. Spent reagents then 
flow into tw o w aste receptacles. All liquid is self-contained w ithin the BIOCHIP. The resulting fluorescently labeled 
complexes are then imaged by an internal CCD camera. Instrument softw are correlates spot intensity w ith analyte 
concentration. 
 
Materials Required: MAX BIOC HIP® Angio-10 Blocking Reagent (PN 00-0015) buffer with detergent, 
preservative and blocking factors, DBI Pipette Tip (PN 00-0004): 96 custom loading tips, Optional Components 
Available: MAX BIOC HIP® Angio-10 High control ( PN 00-00 19), MAX BIOC HIP® Angio-10 Low control ( PN 00-0020) 
Controls consist of a mixture of all 10 recombinant proteins. 
 
PRECAUTIONS AND WARNINGS: Reagents are harmful if sw allow ed. Avoid contact w ith skin and eyes. 
Wear suitable protective clothing. Some reagents contain trace amounts of sodium azide w hich is potentially reactive 
with copper or lead plumbing. Flush plumbing w ith large amoun ts of w ater during disposal. All samples of a 
potentially infectious or hazardous origin should be handled in the manner outlined by the Center for Disease Control 
and the Occupational Health and Safety Administration for blood-borne pathogens and human and animal-source 
materials. 
 
Reagent storage and stability: Unopened BIOCHIPs are stable until the expiration date show n on the label 
w hen stored at 2 - 8C. Keep the MAX BIOCHIP® Angio-10 Blocking Reagent at -20C prior to first time use. Thaw at 
room temperature and maintain at 2-8C for up to one month. Do not re-freeze. 
 
Quality Control: Controls are recommended for a complete quality control program. Each laboratory should 
establish its ow n control means and ranges as w ell as a quality control program to monitor laboratory testing. In 
addition, each BIOCHIP contains negative and positive control spots w hich monitor instrument and BIOCHIP 
performance. Please refer to the Lot Specific Control BIOCHIP Values. Positive and negative control spots on each 
BIOCHIP may assist the investigator with identifying potential instrument or BIOCHIP problems. 
 
Suggested Ranges for Lot:20090304 Positive Control Range: 33049-61377 RFU, Upper Lim it Negative 
Control: 200 RFU 
 
Calibration: Replicate measurements of standards containing all 10 biomarkers are used to generate master curves 
for all analytes. These are provided on the lot specific CD supplied w ith each shipment of BIOCHIPs. 
Results: Refer to the Assay Results tab in the AVANTRA® Express Softw are. An individual sample result may be 
view ed by single or double c licking on the + next to each BIOCHIP ID. Results below the analytical sensitivity (see 
Table 8 below ) or above the upper limit of the dynamic range w ill not be quantified. Results may be exported to MS 
Excel by highlighting the result(s) then selecting the Export Data icon in the AVANTRA® Express toolbar. 

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Performance Characteristics 
Precision: Spot-to-Spot, or intra-assay precision (six spots per analyte from four biochips) and BIOCHIP-to- 
BIOCHIP, or inter-assay precision (14 BIOCHIPs run over 2 days) w ere calculated for a low-level control for each 
marker. The data show n in Table 9 below meet the % CV BIOCHIP to BIOCHIP specification of <20%. 
Analytical Sensitivity: Analytical sensitivity w as ascertained by evaluating replicates of the zero standard, 
calculating the mean and SD of those values, and determining the concentration equivalent to 2 SD’s above the 
mean. Representative results are show n in Table 10. Results show n are the mean sens itivities of 7 BIOCHIP lots. 
 
Table 9 - Precision 
 
Spot-to-Spot 
BIOC HIP to BIOC HIP 
Table 10 – Representative Results 
 
Biom arker 
%CV 
Biom arker 
%CVD  
ICA M-1 
7 
ICA M-1 
5 
E- Selectin 
11 
E- Selectin 
11 
TIMP- 1 
4 
TIMP- 1 
6 
IL-8 
5 
IL-8 
3 
TIE-2 
5 
TIE-2 
9 
HGF 
8 
HGF 
7 
FGF- basic 
6 
FGF- basic 
5 
PLGF 
5 
PLGF 
5 
VEGF-R2 
7 
VEGF-R2 
12 
VEGF 
12 
VEGF 
13 
BIOC HIP handling: Remove appropriate number of foiled pouches from 
the refrigerated kit. Allow to equilibrate at room temperature for at least 
30 minutes prior to opening pouch. Do not open individual pouches 
until ready to run the BIOC HIP. 
BIOC HIP Injection Instructions: Please use the Eppendorf pipette provided along w ith the Dec ision Biomar kers 
pipette tips (w ith w hite collar) for injecting the sample into the BIOCHIP. The BIOC HIP must be inserted into the 
AVANT RA® Biom arker Workstation prior to injecting the sam ple. 
 
Control / Sample Handling and Preparation: Safe laboratory pr actices and personal protective equipment such as 
gloves, lab coat, and safety glasses should be used w hen handling any samples. EDTA plas ma is the recommended 
sample type. Avoid multiple freeze-thaw cycles.Warm DBI Angio-10 Blocking Reagent to room temperature. Ensure 
that the solution is completely thaw ed. 
 
a. 
Thaw controls or patient samples at room temperature and mix gently; avoid prolonged storage at room 
temperature. 
b. 
Any solid material observed in a sample should be spun dow n by centrifugation. Spin sample at 500xg 
for five minutes. Transfer supernatant to fresh tube. 
c. 
Gently pulse vortex both the bloc king buffer and the sample. 
d. 
Combine 125 L of control / sample w ith 125 L of DBI Angio-10 Blocking Reagent. 
e. 
Mix thoroughly, either by pipett ing up and dow n at least 5X or vortexing gently. 
Biomarker 
ICAM-1 
E-Selectin 
TIMP-1 
IL-8 
TIE-2 
HGF 
FGF-basic 
PLGF 
VEGF-R2 
VEGF 
Sensitivity 
7 ng/mL 
6 ng/mL 
13 
ng/mL 
3 pg/mL 
0.3 
ng/mL 
93 
pg/mL 
497 
pg/mL 
8 pg/mL 
150 
pg/mL 
244 
pg/mL 
Specification 
<20  ng/mL 
<30  ng/mL 
<55  ng/mL 
<10  pg/mL 
< 1  ng/mL 
<410 pg/mL 
<1500 pg/mL 
<20 pg/mL 
<540  pg/mL 
<350  pg/mL 

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f. 
Immediately inject the treated sample into the BIOCHIP follow ing the directions provided. 
 
Directions: 
 
a. 
Pow er on the instrument by pressing the green pow er button on the front of the instrument. 
b. 
On the computer, open the AVANTRA® Express Softw are 
c. 
The instrument is ready for use w hen the front panel indicates “ Ready for BIOCHIP Insert BIOCHIP”. 
d. 
Remove protective red tape, including paper backing, from BIOCHIP and insert BIOCHIP into the 
AVANTRA® Biomarker Workstation until it snaps into place 
e. 
Enter an optional new Study name, or select a previously used Study name. The St udy name w ill be 
retained for subsequent samples until changed by the user or the softw are is restarted. Optional 
information may be entered into the Operator Comments field. 
f. 
Scan or enter a Control/Sample ID and click “SEND ID” - The sample must be then loaded w ithin 10 
minutes of sending an ID 
g. 
Set your DBI prov ided Eppendorf pipette to 200 L 
h. 
Place a DBI pipette tip (w ith w hite collar) onto the pipette and slow ly aspirate 200 L of treated 
control/sample 
i. 
While holding the BIOCHIP in place, insert the DBI pipette tip into the sample septum of the BIOCHIP 
until the collar touches the septum. 
j. 
Slow ly depress the plunger to the first stop to inject the sample. 
k. 
Continue holding the BIOCHIP and remove the pipette w ithout releasing the pipette plunger. 
Dispose of tip appropriately 
l. 
Close and latch the door to the AVANTRA® 
m. Push the Start Button. 
n. 
The assay w ill take approximately one (1) hour to run. Upon completion, the AVANTRA® w ill signal that 
the assay is complete. The front panel w ill indicate “Assay Complete Discard BIOCHIP”. 
 
Removing the BIOC HIP: Once the assay is complete, the BIOCHIP can be removed by opening the door and 
pressing on the tw o side release tabs. Discard the BIOCHIP in a biohazard w aste container. Results may be view ed 
under the Assay Results tab on the AVANTRA® Express software 
A.1.b 
8-plex Cytokine Immunoassay 
 
Summ ary and Principle 
 
Dec ision Biomar kers, Inc ( DBI) has developed a novel, automated immunoassay platform to simultaneously evaluate 
multiple biomarkers in a single reaction device, the MAX BIOCHIP®. The MAX BIOCHIP® is a polycarbonate 
cartridge w ith a sample chamber, tw o self-contained reagent chambers, and a reaction chamber, all connected by a 
series of channels interspersed w ith sensors and valves to detect and direct fluid flow . The reaction chamber of the 
MAX BIOCHIP® consists of a microarray of specific antibodies spotted onto a glass slide pre-coated w ith an ultra-thin 
film of nitrocellulose. To perform an analysis, the MAX BIOCHIP® is inserted into the AVANTRA® Biomar ker 
Workstation. Sample is injected and the instrument automatically directs, in sequence, the flow of sample, solublized 
biotinylated detection antibodies, labeled streptav idin, and w ash buffer across the microarray. Spent reagents then 
flow into tw o w aste receptacles. All liquid is self-contained w ithin the BIOCHIP. The resulting fluorescently labeled 
complexes are then imaged by an internal CCD camera. Instrument softw are correlates spot intensity w ith analyte 
concentration. 
Materials Required : MAXBIOC HIP® Cyto-8 Blo ck ing Reagent (PN 00-0014): Buffer w ith detergent, preservative 
and blocking factors, DBI Pipette Tip (PN 00-0004): 96 custom loading tips, Optional Components Available: MAX 
BIOC HIP® Cyto-8 High control ( PN 00-0016) MAX BIOC HIP® Cyto-8 Mid control ( PN 00-0017) MAX BIOC HIP® 
Cyto-8 Low control (PN 00-0018) Controls consist of a mixture of all eight recombinant cytokines. 
 
PRECA UTIONS AND WARNINGS: Reagents are har mful if sw allow ed. Avoid contact w ith skin and eyes. Wear 
suitable protective clothing. Some reagents contain trace amounts of sodium az ide w hich is potentially reactive w ith 
copper or lead plumbing. Flush plumbing w ith large amounts of w ater during disposal. All samples of a potentially 

MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 10-099 A(3) 
Amended: 6/12/12 
Page 52 of 56 
 
 
infectious or hazardous origin should be handled in the manner outlined by the Center for Disease Control and the 
Occupational Health and Safety Administration for blood-borne pathogens and human and animal-source materials. 
 
Reagent storage and stability: Unopened BIOCHIPs are stable until the expiration date show n on the label w hen 
stored at 2 - 8C. Keep the MAX BIOCHIP® Cyto-8 Blocking Reagent at -20C prior to first time use. Thaw at room 
temperature and maintain at 2-8C for up to one month. Do not re-freeze. 
 
Quality Control: Controls are recommended for a complete quality control program. Each laboratory should 
establish its ow n control means and ranges as w ell as a quality control program to monitor laboratory testing. In 
addition, each BIOCHIP contains negative and positive control spots w hich monitor instrument and BIOCHIP 
performance. Please refer to the Lot Specific Control BIOCHIP Values. Positive and negative control spots on each 
BIOCHIP may assist the investigator with identifying potential instrument or BIOCHIP problems. 
 
Suggested Ranges for Lot: 20090113 Positive Control Range: 1256-8669 RFU, Upper Lim it Negative Control: 
50 RFU 
 
Calibration: Replicate measurements of standards containing all 8 cytokines are used to generate master curves for 
all analytes. These are provided on the lot specific CD supplied w ith each shipment of BIOCHIPs. 
Results: Refer to the Assay Results tab in the AVANTRA® Express Softw are. An individual sample result may be 
view ed by single or double clic king on the + next to each BIOCHIP ID. Results below the analytical sensitivity (see 
Table 12) or above 5000 pg/ mL w ill not be quantified. Results may be exported to MS Excel by highlighting the 
result(s) then selecting the Ex port Data icon in the AVANTRA® Express toolbar. 
Perform ance Characteristics 
 
Precision: Spot-to-Spot, or intra-assay precision (six spots per analyte from 12 BIOCHIPs) and BIOCHIP-to- 
BIOCHIP, or inter-assay precision (12 BIOCHIPs run over 3 days) w ere calculated for a mid-level control of 150 
pg/ mL for each cytokine. The data show n in Table 11 below meet the % CV BIOCHIP to BIOCHIP spec ification of 
<20%. 
 
Table 11– Precision 
Table 12 –Representative Results 
Spot-to- Spot 
BIOC HIP-to-BIOC HIP 
Cytokine 
IL-1
%CV 
4 
Cytokine 
IL-1
%CVD  
4 
IL-2 
7 
IL-2 
10 
IL-5 
4 
IL-5 
7 
IL-6 
6 
IL-6 
6 
IL-8 
5 
IL-8 
9 
IL- 10 
6 
IL- 10 
7 
IL- 12 
9 
IL- 12 
9 
TNF
5 
TNF
8 
Cytokine 
Sensitiv 
Specification 
ity 
(pg/mL) 
(pg/mL) 
IL-1
7 
<13 
IL-2 
9 
<20 
IL-5 
4 
<13 
IL-6 
8 
<18 
IL-8 
3 
<5 
IL- 10 
4 
<10 
IL- 12 
9 
<15 
TNF
4 
<12 

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Amended: 6/12/12 
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Analytical Sensitivity: Analytical sensitivity w as ascertained by evaluating replicates of the zero standard, 
calculating the mean and SD of those values, and determining the concentration equivalent to 2 SD’s above the 
mean. Representative results are show n in Table 12. Results show n are the mean sens itivities of 6 BIOCHIP lots. 
 
BIOCHIP handling: Remove appropriate number of foiled pouches from the refrigerated kit. Allow to 
equilibrate at room temperature for at least 30 minutes prior to opening pouch. 
 
Do not open individual pouches until ready to run the BIOC HIP. 
 
BIOC HIP Injection Instructions: Please use the Eppendorf pipette provided along w ith the DBI pipette tips (w ith 
w hite collar) for injecting the sample into the BIOCHIP. The BIOC HIP must be inserted into the AVANTRA® 
Biom arker Workstation prior to injecting the sam ple. 
 
Control / Sample Handling and Preparation: Safe laboratory practices and personal protective equipment such 
as gloves, lab coat, and safety glasses should be used w hen handling any sam ples. EDTA plas ma is the 
recommended sample type. Avoid multiple freeze-thaw cycles. 
 
a. 
War m DBI Cyto-8 Blocking Reagent to room temperature 
b. 
Thaw controls or patient samples at room temperature and mix gently; avoid prolonged storage at room 
temperature 
c. 
Any solid material observed in a sample should be spun dow n by centrifugation. Spin sample at 500xg 
for five minutes. Transfer supernatant to fresh tube 
d. 
Combine 225 L of control / sample w ith 25 L of DBI Cyto-8 Bloc king Reagent 
e. 
Mix thoroughly, either by pipett ing up and dow n at least 5X or vortexing gently 
f. 
Immediately inject the treated sample into the BIOCHIP follow ing the directions provided 
 
Directions: 
 
a. 
Pow er on the instrument by pressing the green pow er button on the front of the instrument 
b. 
On the computer, open the AVANTRA® Express Softw are 
c. 
The instrument is ready for use w hen the front panel indicates “ Ready for BIOCHIP Insert BIOCHIP” 
d. 
Remove protective red tape, including paper backing, from BIOCHIP and insert BIOCHIP into the 
AVANTRA® Biomarker Workstation until it snaps into place 
e. 
Enter an optional new Study name, or select a previously used Study name. The St udy name w ill be 
retained for subsequent samples until changed by the user or the softw are is restarted. Optional 
information may be entered into the Operator Comments field 
f. 
Scan or enter a Control/Sample ID and click “SEND ID” - The sample must be then loaded w ithin 10 
minutes of sending an ID 
g. 
Set your DBI prov ided Eppendorf pipette to 200 L 
h. 
Place a DBI pipette tip (w ith w hite collar) onto the pipette and slow ly aspirate 200 L of treated 
control/sample 
i. 
While holding the BIOCHIP in place, insert the DBI pipette tip into the sample septum of the BIOCHIP 
until the collar touches the septum 
j. 
Slow ly depress the plunger to the first stop to inject the sample 
k. 
Continue holding the BIOCHIP and remove the pipette w ithout releasing the pipette plunger. Dispose of 
tip appropriately 
l. 
Close and latch the door to the AVANTRA® 
m. Push the Start Button 
n. 
The assay w ill take approximately one hour to run. Upon completion, the AVANTRA® w ill signal that the 
assay is complete. The front panel w ill indicate “Assay Complete Discard BIOCHIP” 
Removing the BIOCHIP: Once the assay is complete, the BIOC HIP can be removed by opening the door and 
press ing on the two side release tabs. Discard the BIOC HIP in a biohazard w aste container. Results may be 
view ed under the Assay Results tab on the AVANT RA® Express softw are 

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IRB PROTOCOL 
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Amended: 6/12/12 
Page 54 of 56 
 
 
APPENDIX B: FIGO Stage Grouping for Primary Carcinoma of the Ovary (1985) 
 
These categories are based on findings at clinical examination and/or surgical exploration. The 
histologic characteristics are to be considered in  the staging,  as are results of  cytologic testing  
as far as effusions are concerned. It is desirable  that  a  biopsy be  performed  on suspicious 
areas outside the pelvis. 
Stage I 
Growth limited to the ovaries. 
 
Stage IA 
Growth limited to one ovary; no ascites. 
 
No tumor on the external surface; capsule intact. 
 
Stage IB 
Growth limited to both ovaries; no ascites. 
 
No tumor on the external surfaces; capsules intact. 
 
Stage IC*    Tumor either  Stage  IA  or  IB  but  with  tumor on  the  surface of one 
or both ovaries; or with capsule ruptured; or with ascites present 
containing malignant cells or with positive peritoneal washings. 
Stage II 
Growth involving one or both ovaries with pelvic extension. 
 
Stage IIA 
Extension and/or metastases to the uterus and/or tubes. 
Stage IIB 
Extension to other pelvic tissues. 
Stage IIC* 
 Tumor either Stage IIA or IIB but with tumor on the surface of one 
or both ovaries; or with capsule(s)  ruptured; or with ascites 
present containing malignant cells or with positive peritoneal 
washings. 
Stage III 
 Tumor involving one or both ovaries with peritoneal implants outside the pelvis 
and/or positive retroperitoneal or inguinal nodes. Superficial liver metastasis 
equals Stage III. Tumor is limited to the true pelvis but with histologically verified 
malignant extensions to small bowel or omentum. 
Stage IIIA  Tumor  grossly limited  to  the  true  pelvis  with  negative nodes but  
with histologically confirmed microscopic seeding of abdominal 
peritoneal surfaces. 
Stage IIIB Tumor  of  one or both   ovaries  with   histologically   confirmed 
implants of abdominal peritoneal surfaces, none  exceeding 2  cm  
in diameter. Nodes negative. 
Stage IIIC 
Abdominal implants >2 cm in diameter and/or positive 
retroperitoneal or inguinal nodes. 

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Stage IV 
 Growth involving one or  both ovaries with  distant metastasis.  If  pleural effusion 
is present there must be positive cytologic test results to allot a case to Stage IV. 
Parenchymal liver metastasis equals Stage IV. 
*   In  order  to evaluate  the  impact on prognosis of the different  criteria  for allotting cases to 
Stage IC or IIC, it would be of value to know if rupture of the capsule was  (1)  
spontaneous or (2) caused by the surgeon and if the source of  malignant cells detected 
was (1) peritoneal washings or (2) ascites. 

Amended: 6/12/12 
Page 56 of 56 
MEMORIAL SLOAN-KETTERING CANCER CENTER 
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IRB#: 10-099 A(3) 
 
 
 
APPENDIX C: New York Heart Association 
 
Class 
Patient Symptoms 
Class I (Mild) 
No limitation of physical activity. Ordinary physical activity does not 
cause undue fatigue, palpitation, or dyspnea (shortness of breath). 
Class II (Mild) 
Slight limitation of physical activity. Comfortable at rest, but ordinary 
physical activity results in fatigue, palpitation, or dyspnea. 
Class III (Moderate) 
Marked limitation of physical activity. Comfortable at rest, but less than 
ordinary activity causes fatigue, palpitation, or dyspnea. 
Class IV (Severe) 
Unable to carry out any physical activity without discomfort. Symptoms 
of cardiac insufficiency at rest. If any physical activity is undertaken, 
discomfort is increased. 
 
 
APPENDIX D: Procedure for Obtaining a Urine Protein / Creatinine Ratio 
 
1) Obtain at least 4 ml of a random urine sample (does not have to be a 24-hour urine) 
 
2) Determine protein concentration (mg/dL) 
 
3) Determine creatinine concentration (mg/dL) 
 
4) Divide #2 by #3 above: urine protein / creatinine ratio = protein concentration (mg /dL) / 
creatinine concentration (mg /dL) 
The UPC directly correlates with the amount of protein excreted in the urine per 24 hrs (i.e. a 
UPC of 1 should be equivalent to 1g protein in a 24hr urine collection) 
 
Protein and creatinine concentrations should be available on standard reports of urinalyses, 
not dipsticks. If protein and creatinine concentrations are not routinely reported at an 
Institution, their measurements and reports may need to be requested. 
UPC ratio is calculated using one of the following formulas: 
 
1. [urine protein]/[urine creatinine] – if both protein and creatinine are reported in mg/dL 
 
2. [(urine protein) x0.088]/[urine creatinine] – if urine creatinine is reported in mmol/L 
 
The UPCR has been found to correlate directly with the amount of protein excreted  in a 
24 hour urine collection. Specifically, a UPCR of 1.0  is equivalent to 1.0 gram of protein  
in a 24 hour urine collection. The UPCR is derived as follows: protein concentration 
(mg/dL)/creatinine (mg/dL). Patients must have a UPCR <1.0 to allow participation in the 
study.