Conditions: Stage III Fallopian Tube Cancer Stage III Ovarian Cancer Stage III Primary Peritoneal Cancer Stage IIIA Fallopian Tube Cancer Stage IIIA Ovarian Cancer Stage IIIA Primary Peritoneal Cancer Stage IIIB Fallopian Tube Cancer Stage IIIB Ovarian Cancer Stage IIIB Primary Peritoneal Cancer Stage IIIC Fallopian Tube Cancer Stage IIIC Ovarian Cancer Stage IIIC Primary Peritoneal Cancer Stage IV Fallopian Tube Cancer Stage IV Ovarian Cancer Stage IV Primary Peritoneal Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 11
Healthy volunteers: no

Brief summary:
This phase II trial studies how well pUMVC3-IGFBP2 plasmid deoxyribonucleic acid (DNA) vaccine (IGFBP-2 vaccine) and combination chemotherapy work in treating patients with stage III-IV ovarian, fallopian tube, or primary peritoneal cancer undergoing surgery. IGFBP-2 is a protein found in the blood and tumor cells of most who have been diagnosed with ovarian cancer. Too much IGFBP-2 has been associated with more invasive disease. Vaccines made from DNA may help the body build an effective immune response to kill tumor cells that express IGFBP-2. Drugs used in chemotherapy, such as paclitaxel and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving IGFBP-2 vaccine and combination chemotherapy may work better in treating patients with stage III-IV ovarian, fallopian tube, or primary peritoneal cancer undergoing surgery.

Detailed description:
PRIMARY OBJECTIVES:

I. Determine whether the addition of an IGFBP-2 vaccine to neoadjuvant chemotherapy increases the rate of complete pathologic response (CR).

SECONDARY OBJECTIVES:

I. Determine whether the addition of an IGFBP-2 vaccine to neoadjuvant chemotherapy increases progression free survival at 12 months.

II. Determine whether the addition of an IGFBP-2 vaccine to neoadjuvant chemotherapy improves overall survival.

III. To determine whether IGFBP-2 vaccination in combination with chemotherapy increases the level of tumor infiltrating lymphocytes (TIL) in the tumor.

IV. To assess the level of IGFBP-2 type 1 helper cells (Th1) elicited with vaccination concurrent with chemotherapy.

EXPLORATORY OBJECTIVES:

I. To explore whether there is a predictive genomic signature for CR induction when IGFBP-2 vaccination is used in combination with chemotherapy.

OUTLINE:

Patients receive paclitaxel intravenously (IV) over 3 hours and carboplatin IV over 1 hour followed by IGFBP-2 vaccine intradermally (ID) 2 weeks later. Treatment repeats every 3 weeks for up to 3 cycles in the absence of disease progression or unacceptable toxicity. After completion of 3 cycles, patients then undergo cytoreductive surgery.

After completion of study treatment, patients are followed up at 6 months and then once a year for 5 years.

Arms:
arm 1: Patients receive paclitaxel IV over 3 hours and carboplatin IV over 1 hour followed by IGFBP-2 vaccine ID 2 weeks later. Treatment repeats every 3 weeks for up to 3 cycles in the absence of disease progression or unacceptable toxicity. After completion of 3 cycles, patients then undergo cytoreductive surgery.

Interventions: intervention 1: Carboplatin intervention 2: Gynecological Surgical Procedure intervention 3: Laboratory Biomarker Analysis intervention 4: Paclitaxel intervention 5: pUMVC3-hIGFBP-2 Multi-Epitope Plasmid DNA Vaccine
Intervention descriptions: intervention 1: Given IV intervention 2: Undergo cytoreductive surgery intervention 3: Correlative studies intervention 4: Given IV intervention 5: Given ID

Protocol document:
Prot_SAP_001.pdf: 
Protocol 144, CC Protocol 9760 
 
07/28/2018 
Page 1 of 39 
 
 
UNIVERSITY OF WASHINGTON 
DEPARTMENT OF MEDICINE 
DIVISION OF ONCOLOGY 
Current Version Date:  07/19/2018 
Protocol 144 
A Phase II Study of Concurrent IGFBP-2 Vaccination and Neoadjuvant Chemotherapy to 
Increase the Rate of Pathologic Complete Response at the Time of Cytoreductive 
Surgery 
Researchers: 
 
 
 
John B. Liao, M.D., Ph.D. 
Associate Professor 
Division of Gynecologic 
Oncology, UW 
(206) 543-3669 
Mary L. Disis, M.D. 
Professor  
Division of Oncology, UW 
Member FHCRC 
(206) 616-1823 
William R.Gwin, M.D. 
Acting Instructor 
Division of Oncology 
206-221-5956 
Sasha E. Stanton, M.D., 
PhD 
Assistant Professor 
Division of Oncology 
(206) 685-8949 
Andrew Coveler, M.D. 
Assistant Professor 
Division of Oncology, UW (206) 221-7509 
Doreen Higgins, B.S.N. 
Research Nurse 
Division of Oncology, UW (206) 616-9538 
Jennifer Childs, M.P.H. 
Research Coordinator Division of Oncology, UW (206) 616-2305 
Hania Shakalia, B.S. 
Research Coordinator Division of Oncology, UW (206) 543-3829 
James Dai, Ph.D. 
Associate Member 
Fred Hutchinson Cancer 
Research Center/Public 
Health Sciences Division 
Biomathematics & 
Biostatistics 
 
 
Emergency (24 hour) pager:  John B. Liao, (206) 797-2297 
 
 
 
TABLE OF CONTENTS 
 
IRO received 12/22/20
FHCRC IRB Approval  
01/15/21 
Document Released Date


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Study Synopsis ........................................................................................................................... 3 
List of Appendices ....................................................................................................................... 5 
Abbreviations .............................................................................................................................. 6 
Introduction ................................................................................................................................. 8 
Background ................................................................................................................................. 8 
Objectives ................................................................................................................................. 13 
Drug Information ....................................................................................................................... 13 
Patient Selection ....................................................................................................................... 15 
Experimental Design ................................................................................................................. 16 
Plan of Treatment ..................................................................................................................... 17 
Withdrawal from Study .............................................................................................................. 19  
Evaluation and Management of Toxicity .................................................................................... 20 
Dose and Schedule Modifications ............................................................................................. 22 
Statistical Considerations .......................................................................................................... 22 
Administrative Considerations ................................................................................................... 24 
References ............................................................................................................................... 26 
 


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STUDY SYNOPSIS 
Title  
A Phase II Study of Concurrent IGFBP-2 Vaccination and Neoadjuvant 
Chemotherapy to Increase the Rate of Pathologic Complete Response 
at the Time of Cytoreductive Surgery 
 
Study Population 
Newly diagnosed patients with ovarian/fallopian tube/peritoneal cancer 
recommended for neoadjuvant chemotherapy with carboplatin and 
paclitaxel with subsequent cytoreductive surgery due to extent of 
metastases. 
 
Rationale 
The importance of immunity in ovarian cancer has been well established 
[1].  Most ovarian cancer patients have low levels or no evidence of Type 
I tumor infiltrating lymphocytes (TIL). Integration of vaccine strategies 
designed to elicit tumor specific Type I T-cells early in treatment may 
result in improved clinical outcomes in women with ovarian cancer.  
Patients particularly at risk for poor outcomes are those that are not 
surgically resectable.  An approach to patients with advanced disease 
not thought to be amenable to surgical resection is neoadjuvant 
chemotherapy followed by interval cytoreductive surgery [2]. After 
neoadjuvant chemotherapy and surgery, patients with no residual 
disease have the best chance of survival [3].    The presence of a Type I 
adaptive immune response in the tumor is known to have prognostic 
significance. This effect is most likely due to CD8 cytotoxic T-cells which 
directly kill cancer as well as T-helper 1 (Th1) cells which secrete 
cytokines to activate local antigen presenting cells to expand destructive 
immunity.   
 
Our group has been developing vaccines specifically aimed at stimulating 
Type I immunity for several years. We have recently made several 
advances that could facilitate successful application of selective Th1 
vaccines to the clinic for the treatment of ovarian cancer. First, we have 
identified epitopes within the natural sequence of self-tumor antigens that 
selectively elicit either Th1 or are regulatory and induce antigen specific 
Th2 immune responses [4]. The Th1 selective epitopes, when used in a 
vaccine, can elicit unopposed Type I immunity and are effective in 
inhibiting cancer growth in pre-clinical models. If Th2 inducing epitopes 
are included in a vaccine, Th2 cells elicited via immunization will abrogate 
the anti-tumor response of Th1 cells. The second advance has been the 
identification of biologically relevant antigens associated with the 
development of epithelial to mesenchymal transition (EMT) and drug 
resistance such as IGFBP-2. Type I mediated elimination of cancer cells 
expressing IGFBP-2 may significantly 
enhance 
the 
effect 
of 
chemotherapy in ovarian cancer while immune surveillance stimulated by 
vaccination eliminates micro-metastatic disease. A final advance is the 
strategic use of chemotherapy concurrent with vaccination to augment 
the immune response. Platinum and taxanes have been shown to 
activate cytotoxic T-cells, augment Th1 responses, and inhibit T-
regulatory (Treg) cells and myeloid derived suppressor cells (MDSC) 
which can limit Type I immunity. In addition, we have demonstrated the 
Type I cytokines released by T-cells induced by vaccination can have 
direct anti-proliferative effects on cancer cell growth and will sensitize the 


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tumor to chemotherapy resulting in greater cell kill. Neoadjuvant 
chemotherapy is known to enhance host immune responses and 
sequential chemoimmunotherapy has been suggested to improve 
disease control in advanced ovarian cancer. [5] The combined use of 
chemotherapy and an IGFBP-2 vaccine could be effective in enhancing 
the cytotoxic effects of chemotherapy. The purpose of this study is to 
increase the rate of complete response (CR) at the time of cytoreductive 
surgery in patients with advanced stage ovarian cancer 
Objectives 
Primary: 
1. Determine whether the addition of an IGFBP-2 vaccine to 
neoadjuvant chemotherapy increases the rate of pathologic complete 
response (CR) induction. 
Secondary: 
1. Determine whether the addition of an IGFBP-2 vaccine to neoadjuvant 
chemotherapy increases progression free survival at 12 months. 
 
2. Determine whether the addition of an IGFBP-2 vaccine to neoadjuvant 
chemotherapy improves overall survival. 
 
3. To determine whether IGFBP-2 vaccination in combination with 
chemotherapy increases the level of TIL in the tumor. 
 
4. To assess the level of IGFBP-2 Th1 elicited with vaccination 
concurrent with chemotherapy.  
Exploratory: 
1. To explore whether there is a predictive genomic signature for CR 
induction when IGFBP-2 vaccination is used in combination with 
chemotherapy.  
Study Design 
This will be a Phase II single arm, non-randomized study in patients with 
advanced stage (III/IV) ovarian/fallopian tube/peritoneal cancer that are 
about to start neoadjuvant carboplatin / paclitaxel chemotherapy with 
subsequent cytoreductive surgery. 
 
Number of Patients 
The study will accrue a maximum of 38 patients. 
Outcome Measures 
Primary Endpoints: 
1. Rate 
of 
pathologic 
complete 
response 
after 
neoadjuvant 
chemotherapy.  
Secondary Endpoints: 1.   Progression free survival at 12 months. 
 
2.   Overall survival. 
3. Immunohistochemical staining for tumor infiltrating T cells correlated 
with complete cytoreduction. 
 
4. Th1 antigen specific T cells in peripheral blood correlated with 
surgical outcome. 
Exploratory Endpoint: 1.  Whole exome sequencing of tumor correlated with surgical outcome. 


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List of Appendices 
Appendix A  
ECOG Performance Scale 
Appendix B 
Calendar of Events 
Appendix C 
Data and Safety Monitoring Plan 
Appendix D 
Common Chemotherapy Side Effects 
Appendix E 
NCCN Guidelines for Menopause Status 


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Abbreviations 
APC  
Antigen presenting cells 
CR 
Complete remission 
CRC 
Clinical Research Center 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
CTL 
Cytotoxic T lymphocytes 
DFS 
Disease-free survival 
DLT 
Dose limiting toxicity 
DSMP 
Data and Safety Monitoring Plan 
ECD 
Extracellular domain of HER2 
EMT 
Epithelial to mesenchymal transition 
ES 
Epitope spreading 
FHCRC 
Fred Hutchinson Cancer Research Center 
GMP 
Good manufacturing practice 
HER2 
HER-2/neu 
HLA 
Human leukocyte antigen 
i.d. 
Intradermal 
ICD 
Intracellular domain of HER2 
IDS 
Investigational Drug Services 
IFN-g 
Interferon-gamma 
IGFBP 
Insulin-like growth factor binding protein 
MDSC 
Myeloid derived suppressor cells 
MHC 
Major histocompatibility complex 
NED 
No evidence of disease 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cells 


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PFS 
Progression-free survival 
RFS 
Relapse-free survival 
rhuGM-CSF 
Recombinant human granulocyte-macrophage colony stimulating 
factor; GM-CSF; LEUKINE® (sargramostim) 
SI 
Stimulation index 
TGF-beta 
Transforming growth factor beta 
TIL 
Tumor infiltrating lymphocytes 
Th 
T helper cells 
Treg 
T regulatory cell 
TVG 
Tumor Vaccine Group 
ULN 
Upper limit of normal 
UPN 
Unique patient number 
UW 
University of Washington 


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1. INTRODUCTION 
Ovarian cancer is immunogenic, and immunity may confer a better prognosis.[6, 7]  If immunity 
could be generated in the majority of advanced stage ovarian cancer patients during treatment 
induced remissions, perhaps clinical outcomes could be improved.  A vaccine targeting 
immunogenic biologically relevant proteins in ovarian cancer could offer such a possibility.  
Unfortunately, there are several obstacles to vaccine development such as the lack of identified 
commonly expressed ovarian cancer antigens and the inability of the immune response elicited 
with vaccination to overcome the immunosuppressive ovarian cancer tumor microenvironment.[8]  
IGFBP-2 is a tumor antigen in ovarian cancer patients and an excellent target for active 
immunization.  The protein is overexpressed in most invasive ovarian cancers, is associated with 
invasive potential and the development of metastasis, and has shown to be a predictor of poor 
prognosis.  Moreover, studies in animal models demonstrate that vaccination against IGFBP-2 
significantly inhibits tumor growth without causing any toxicity, as does the infusion of IGFBP-2 
specific T cells.[9] 
We have extensive experience in developing vaccine strategies designed to elicit Type I 
inflammatory CD4+ T helper immunity (Th1).[10]  A focus on eliciting CD4+ tumor specific Th1 
cells with vaccination has several distinct advantages over immunization strategies designed to 
elicit predominantly CD8+ T cells.  First, vaccine stimulated tumor antigen-specific CD4+ Th1 cells 
may home to the tumor and the inflammatory cytokines they secrete, such as IFN-gamma (g), 
may modulate the tumor microenvironment.  Th1 cytokines enhance the function of local antigen 
presenting cells (APCs) and augment endogenous antigen presentation.[11]  Increased 
processing of endogenous tumor cells results in epitope spreading, the development of an 
immune response to the multiple immunogenic proteins expressed in the tumor.[12]  In addition, 
by providing a robust CD4+ Th1 T cell response, tumor-specific CD8+ T cells will be elicited and 
proliferate endogenously.[13]  Finally, antigen specific CD4+ T cells would provide the 
environment needed to enhance and sustain tumor specific T cell immune responses over time.  
We have identified multiple Th epitopes derived from IGFBP-2 which can be exploited in a 
polyepitope vaccine. 
The trial described here is a Phase II, single arm study of a plasmid based DNA vaccine targeting 
IGFBP-2 amino acid (aa) sequence spanning from aa1-163.  Studies from our group, described 
below, have identified this region of the protein as the most immunogenic encoding several native 
MHC class II peptides.  Our primary objective is to assess the clinical efficacy of IGFBP-2 
vaccination given concurrently with platinum-based neoadjuvant chemotherapy in patients with 
newly diagnosed advanced stage ovarian cancer.  Our secondary objectives are to determine the 
immunogenicity of the vaccine, whether the vaccine elicit an IGFBP-2 Th1 immune response, 
increase the level of TILs, and whether administering vaccine with neoadjuvant chemotherapy 
improves progression free survival at 12 months and overall survival in this population.  We will 
also explore whether there is a predictive genomic signature for complete response (CR) with 
IGFBP-2 vaccination given concurrently with neoadjuvant chemotherapy. 
 
2. BACKGROUND 
2.A. Rationale for immune therapy in ovarian cancer.  Ovarian cancer, the most lethal of 
gynecologic cancers, is well suited to immunologic approaches to therapy.  The majority of 
patients initially respond well to standard therapies, cytoreductive surgery and chemotherapy, 
obtaining a complete remission or minimal residual disease state.  The time to relapse after 
definitive treatment in advanced stage patients can often be measured in months and years, 
providing a sufficient window of opportunity for the development of a therapeutic immune 
response against this low microscopic tumor burden.  Moreover, ovarian cancer is immunogenic, 
and patients have been found to possess pre-existent immunity to tumor-associated proteins and 


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T cells that recognize autologous tumors.[6, 14-17]  The presence of tumor infiltrating T cells in 
ovarian cancers has also been shown to confer a favorable prognosis while regulatory T cells and 
immunosuppressive B7-H4 expressing macrophages have an inverse association with 
survival.[1, 7, 18-20]  Microarray expression analysis of advanced serous ovarian cancers has 
further demonstrated that the upregulation of immune function genes, particularly those 
associated with Type I immunity (Th1), is strongly correlated with improved survival.[21]  The 
development of an effective therapeutic immune response via active immunization resulting in the 
eradication of minimal residual disease in ovarian cancer patients requires both an immune target 
that is expressed on the majority of ovarian cancers (we propose IGFBP-2) and a method of 
vaccination that can actively modulate the immunosuppressive factors in the ovarian cancer 
microenvironment (we propose plasmid DNA encoding multiple IGFBP-2 Th1 epitopes). 
2.B. IGFBP-2 as a target for ovarian cancer immune therapy. The insulin like growth factor 
(IGF) pathway has become recognized for its role in the growth regulation of ovarian cancer.  IGF 
signaling stimulates proliferation and inhibits apoptosis in cancer cells.[22]  Insulin like growth 
factor binding proteins, such as IGFBP-2, transport IGFs from the circulation into tissues and form 
an important regulatory network controlling cell proliferation, migration, and apoptosis.[23]  
IGFBP-2 is one of six IGFBPs and is found at elevated levels in the sera of ovarian cancer 
patients.[24, 25]  While IGFBP-2 can directly promote tumor growth, the protein is also a regulator 
of PI3K/Akt activation and may facilitate malignant transformation.[26, 27]  Other studies have 
suggested that IGFBP-2 promotes invasion as well as metastasis.[28]  IGFBP-2 upregulation 
measured by immunohistochemical staining with IGFBP-2 specific antibodies is specific for high 
grade invasive tumors as compared to low malignant potential tumors or cysts (p<0.0001).[28]  
IGFBP-2 is widely overexpressed in ovarian cancers.  Quantitative real-time PCR performed on 
113 epithelial ovarian cancers measured a 38-fold higher mean IGFBP-2 expression in epithelial 
ovarian cancers compared to normal ovarian epithelium.[24]  In a large study of over 200 ovarian 
cancers, high levels of IGFBP-2 expression, as assessed by immunohistochemical staining, were 
detected in greater than 80% of serous tumors (n=173) and greater than 70% of endometrioid 
tumors (n=26).[29]  Furthermore, overexpression of IGFBP-2 was preserved across all stages of 
invasive disease (stage I-IV).[29]  In a study of nearly 100 patients with ovarian cancer, 
persistently elevated IGFBP-2 serum levels after cytoreductive surgery were associated with a 
greater rate of disease relapse, regardless of IGFBP-2 level in the tumor.[25]  Taken together, 
these studies establish that IGFBP-2 is both significantly expressed and detected in the vast 
majority of epithelial ovarian cancers and suggest that stimulating immune eradication of IGFBP-
2 expressing ovarian cancer cells may prolong remission or prevent relapse. 
While IGFBP-2 is upregulated in cancer cells, basal levels of IGFBP-2 are found in many normal 
tissues.  In particular, colon, lung, and thyroid tissue weakly express IGFBP-2 in a majority of 
samples tested.  Studies from our group and others have indicated that overexpression or 
abundance of a protein within a cell makes that protein more amenable to immune recognition.  
Indeed, the immunogenicity of the HER-2/neu (HER2) protein is directly related to the level of its 
overexpression in primary breast tumors.30  Theoretically, marked abundance of a protein in the 
cell may alter the peptide repertoire display as compared to peptides presented when the protein 
is at basal levels.  Due to the potential risk of immune reaction directed against normal tissues 
after IGFBP-2 vaccination, however, patients will be monitored frequently by both blood analyses 
and physical exam during the course of this study.   
2.C. IGFBP-2 is a human tumor antigen. We have shown that IGFBP-2 is a tumor antigen in 
patients with ovarian cancer.[9]  Sera from patients with ovarian cancers (n=120) were more likely 
to have antibody immunity to IGFBP-2 than samples from volunteer donors (n=200), p=0.03.  
Moreover, we could identify peptide epitopes derived from IGFBP-2 that had high likelihood of 
binding to human class II MHC molecules.  Previous studies from our group had demonstrated 
that high affinity binding peptides that were responsive across multiple DR alleles were likely to 
be native epitopes of tumor antigens, such as HER2.[30]  We developed a combined scoring 


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system using widely available algorithms for predicting potential human class II binding in an effort 
to rank individual peptides that had a high likelihood of being encompassed in a sequence that 
bound with predicted high affinity across multiple HLA DR alleles, e.g. promiscuous epitopes.  14 
peptides were constructed.  Ten (71%) of the 14 evaluated peptides stimulated significant IFN-g 
ELISPOT responses in volunteer donors and ovarian and breast cancer patients.  In addition, 
IGFBP-2 protein specific T cells could be generated after in vitro priming with the identified 
peptides.[9] 
Human IGFBP-2 has a high degree of homology with murine IGFBP-2 (82%) and for this reason 
we questioned whether immunity to IGFBP-2 would impact tumor growth in mice.  IGFBP-2 
peptides p8-22, p251-265, and p291-305 were studied because they were shown to be native 
epitopes of human IGFBP-2, and all have significant homology with murine IGFBP-2 protein.  We 
chose to evaluate therapeutic efficacy in the neu-transgenic (neu-tg) mouse model.  Although the 
neu-tg mouse develops breast cancer, we hypothesized it would be a reasonable model to adapt 
to the study of ovarian cancer for several reasons; (1) there are few transgenic mouse models of 
ovarian cancer, (2) the immune system of the neu-tg mouse has been extensively characterized 
by our group.  The animals do not mount significant immunity to their tumors via the same 
mechanisms that are in effect in patients with ovarian cancer, e.g. Tregs, (3) the tumors naturally 
up-regulate IGFBP-2, and (4) the mice express murine IGFBP-2 in normal tissues, thus, would 
provide an adequate animal model for toxicity testing prior to a clinical trial.  Animals were 
immunized with a vaccine composed of all three peptides.  Immunized mice developed murine 
IGFBP-2-specific IgG antibody immunity, the level of IGFBP-2 specific IgG was significantly 
higher post- than pre-vaccine in vaccinated mice (p<0.05).  The vaccine generated both peptide 
and murine IGFBP-2 protein-specific IFN-g secreting T cells.  IFN-g ELISPOT responses were 
significantly higher to the peptide mix (p=0.0022) and murine recombinant protein (p=0.002) as 
compared to no antigen wells.  Mice demonstrated no toxicities associated with vaccination.   
Mice were immunized twice, two weeks apart and then challenged with 1x106 tumor cells.  IGFBP-
2 peptide vaccination inhibited tumor growth by approximately 50% compared with control groups.  
To assess the therapeutic efficacy of IGFBP-2-specific T cells, 1x107 of in vitro cultured IGFBP-2 
peptide specific T cells were adoptively transferred to 10-day tumor bearing mice.  A single 
infusion of IGFBP-2 specific T cells inhibited tumor growth by 60%.[9]  To further determine which 
cell subset was the mediator of the anti-tumor effect, mice were selectively depleted of CD4+ and 
CD8+ T cells just prior to and during IGFBP-2 immunization.  The anti-tumor effect of vaccination 
was impacted by CD8+ T cell depletion but not by CD4+ T cell depletion.[9]  Data suggests tumor 
antigen specific CD4+ Th1 cells home to the tumor and secrete inflammatory cytokines, which 
modulate the tumor microenvironment and enhance the function of local APC.  The actions of 
tumor specific Th1 in the tumor microenvironment facilitates cross priming allowing tumor antigen 
specific CD8+ T cells to be elicited endogenously.  This broadening of the immune response, or 
epitope spreading, has also been elicited in our clinical vaccine trials and is associated with 
improved survival. 
In subsequent studies by our group, we screened PBMC derived from 40 donors for IGFBP-2 
epitope specific T cells that preferentially secreted IFN-g or IL-10.  In this population based study 
we identified 6 peptides that were associated with preferential IFN-g secretion and 8 peptides that 
preferentially induced IL-10 secretion in response to antigen.  Peptides that elicited IFN-g 
secretion were clustered in the N terminus of the protein sequence (aa 1-163) whereas peptides 
that elicited IL-10 preferentially were clustered in the C terminus (aa 164-328).  We constructed 
plasmid DNA vaccines using pUMVC3 including sequences 1-328 (whole protein) and the N 
terminus (1-163) and immunized mice.  The vaccine derived from the N terminus elicited both 
IGFBP-2 peptide (p=0.003) and protein (p=0.001) specific immunity as assessed by ELISPOT as 
compared to vector alone controls.  The full length sequence was non immunogenic.  Moreover, 
the N terminus construct significantly inhibited tumor growth in the neu-tg mouse (p<0.0001) as 
compared to vector control or the full length construct which were not significantly different from 


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each other.  Mice demonstrated no untoward effects to vaccination.  These data demonstrate that 
IGFBP-2 is immunogenic in cancer patients, including ovarian cancer, and can mediate anti-tumor 
immunity in a biologically relevant murine model.  Moreover, an extended sequence derived from 
the N terminus of IGFBP-2 contains multiple class II epitopes and elicits Th1 immunity that may 
be therapeutic. 
2.D. Plasmid DNA is an optimal vaccine platform for eliciting long lasting tumor antigen 
specific Th1 immunity.  We propose to deliver IGFBP-2 antigen in a plasmid based DNA 
vaccine.  We have developed an extended Th epitope plasmid DNA based vaccine for HER2 
(pNGVL3-hICD) and determined the optimal dose and route of administration of such a construct.  
The clinical application of plasmid based vaccines has several advantages over the use of 
synthetic peptides.  Plasmid DNA can produce antigen inside a cell, enhancing the generation of 
a CTL response via antigen uptake in the class I processing pathway.  Unlike peptides which are 
quickly degraded in the skin, plasmid DNA can stably transfect skin cells and result in a depot of 
antigen which may generate persistent immunity.[31]  We have recently completed a 66 patient 
dose escalation study of pNGVL3-hICD which targets the HER2 ICD (an extended sequence 
similar to the IGFBP-2 vaccine).  Vaccines were administered intradermally (i.d.) at a 10mcg, 
100mcg or 500mcg/dose (22 patients/arm).  The magnitude of pNGVL3-hICD induced IFN-g 
antigen specific ELISPOT response was significantly higher in the 100mcg vs. 10mcg dose; HER2 
ICD (p=0.001), and ECD (p=0.0005).  As the pNGVL3-hICD vaccine targets the HER2 ICD, the 
ECD responses reflect the development of epitope spreading and occurred in 77% of patients.  
The HER2 specific Th1 responses induced with high-dose pNGVL3-hICD (500mcg dose) were 
statistically identical to those induced with 100mcg pNGVL3-hICD.  Thus, 100mcg was selected 
as the maximum biologic dose for antigen specific plasmid based DNA vaccines using this 
construct.  Simultaneously, and in a similar patient population (optimally treated HER2+ Stage 
III/IV breast cancer), we had an ongoing Phase II study of a HER2 ICD peptide based vaccine.  
The median post-vaccination ICD IFN-g secreting Th1 response after synthetic peptide 
immunization (in the first 25 patients) was shown to be statistically identical to that generated with 
the intermediate and high dose of pNGVL3-hICD vaccine (p=0.400).  Additionally, peptide-
induced epitope spreading immune responses to the ECD were not significantly higher when 
compared to DNA induced responses (p=0.353). 
Studies of plasmid based vaccines in infectious disease have demonstrated that the plasmid can 
stably transfect cells and persist at the site of vaccination for extended periods of time (>1yr).  
Data has suggested that this depot effect can enhance the generation of immunologic 
memory.[32]  We biopsied the vaccine site at 1 and 6 months after plasmid immunization in 52 of 
66 patients and the majority of subjects (75%) demonstrate persistent plasmid expression in skin 
at 6 months.  Moreover, patients immunized with pNGVL3-hICD continue to show persistent 
HER2 ICD immunity of high magnitude post-vaccination.  At 1 year after the end of active 
immunization 80% of subjects still have elevated levels of HER2 ICD immunity.  In contrast, our 
recently published HER2 synthetic peptide vaccine trial reported approximately half of the patients 
had persistent HER2 ICD immunity at 1 year.[12]   
2.E. The plasmid backbone, pNGVL3 (pUMVC3), is associated with minimal side effects 
when used in vaccination.  Two key concerns associated with DNA vaccination are (1) potential 
integration of plasmid DNA into the host chromosomal DNA following direct injection, and (2) the 
potential risk of foreign DNA inducing an autoimmune state.  Both of these theoretical safety 
concerns were addressed as part of the pNGVL3-hICD Phase I study.  First, lymphocytes from 
study patients were evaluated for presence of plasmid vector pre- and 1 month post-vaccination.  
To date, there has been no detection of DNA plasmid in lymphocytes from patients immunized 
with any dose of pNGVL3-hICD.  Additionally, DNA plasmid persistence in the skin (positive skin 
biopsies) as described above has not been associated with any adverse clinical sequelae to date. 
Secondly, ANA, anti-dsDNA and complement levels (C3) were evaluated as markers of 
autoimmune disease as part of eligibility screening and then at each vaccine visit starting at 


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baseline and up to 12 months post vaccine.  While a few patients developed positive ANA titers, 
the titers were low level and had resolved by the end of vaccination.  Moreover, no patients 
developed anti-dsDNA antibodies, abnormal C3 levels and/or any clinical signs/symptoms 
suggestive of autoimmune disease.  Thus, similar to published pre-clinical animal data our phase 
I findings have demonstrated only non-significant increases in autoimmune markers and no 
evidence of autoimmune disease induction or acceleration after plasmid DNA administration.29   
Based on this phase I pNGVL3-hICD data, we expect minimal if any autoimmune toxicity.  Yet, 
given that the administration of pUMVC3-hIGFBP-2 is the first-in-man, autoimmune parameters 
including ANA, C3, thyroid function, and anti-dsDNA will be evaluated prior to the first vaccine 
(baseline), prior to the third vaccine, and one, six and twelve months after the last vaccine.  
However, eligibility pre-screening for autoimmunity with ANA, anti-dsDNA, and C3 will not be 
done.  Rationale for this is based on our phase I pNGVL3-hICD findings in which extensive 
screening of these autoimmune markers was conducted as part of eligibility.  Specifically, 83 
patients were screened for ANA, anti-dsDNA, and C3.  All patients screened with this autoimmune 
panel had to pass the first criteria of not having an “active autoimmune process”.  Of the 83 
patients who were screened based on a negative history of an “active autoimmune process” only 
5 patients (6%) had positive ANAs which were non-specific and very low titer.  None of these 
patients had a positive anti-dsDNA or abnormal complement levels on screening.  These findings 
corroborate current recommendations for the use of autoimmune markers including ANA and anti-
dsDNA as initial screens of autoimmune disorders in that these markers are most useful only in 
patients with known or suspected autoimmune disease.  Thus, in the absence of a known or 
suspected autoimmune disorder, these laboratory markers are non-specific and do not signify the 
presence of autoimmune illness. 
These data suggest that plasmid based DNA vaccination, using sequences derived from tumor 
associated proteins such as IGFBP-2, which contain numerous Th1 epitopes, can be safely 
administered and result in long lived immunity. 
2.F.  Neoadjuvant chemotherapy and modulation of the tumor immune microenvironment 
The approach to patients with advanced disease not thought to be amenable to optimal surgical 
resection is often neoadjuvant chemotherapy followed by interval cytoreductive surgery.[2] While 
this approach is considered not inferior to primary surgery, its use has important implications for 
surgical milestones and the immune response to ovarian cancer.  With the neoadjuvant approach, 
only complete cytoreductive surgery to no residual disease improves survival; the common 
definition of optimal cytoreduction to largest residual tumor diameter of less than 1 cm, which 
offers less precision in assessing total tumor burden, no longer does.[3]  Furthermore, when 
neoadjuvant chemotherapy is used, tumor infiltrating T cells, the immune measure that has been 
associated with improved prognosis, is also no longer significant.[3]   
Although cytotoxic chemotherapy has traditionally been viewed as being immunosuppressive, 
recent studies have shown that specific agents may possess significant immune stimulatory 
effects.[33] Platinum-based chemotherapies, the most widely used in the primary treatment of 
ovarian cancer, are now also being appreciated for their immune potentiating effects.[34] The use 
of therapeutic cancer vaccines in conjunction with platinum-based chemotherapy has also been 
shown to successfully augment antitumor responses in phase 2 clinical trials for lung cancer.[35]  
There is further evidence of T-cell activation in omental biopsies after neoadjuvant chemotherapy, 
specifically CD4+ T cells with enhanced interferon gamma production and antitumor Th1 gene 
signatures.[36] 
We hypothesize that vaccination against IGFBP-2 can synergize with neoadjuvant chemotherapy 
to improve the rate of complete pathologic complete response at time of surgery.  We further 
hypothesize that this will be accomplished through induction of a Th1 immune response, antigen 
specific T cells, and tumor infiltrating lymphocytes.   
 


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3. OBJECTIVES 
3.A. Primary objectives 
1. Determine whether the addition of an IGFBP-2 vaccine to neoadjuvant chemotherapy 
increases the rate of pathologic complete response (CR). 
3.B. Secondary objectives 
1. Determine whether the addition of an IGFBP-2 vaccine to neoadjuvant chemotherapy 
increases progression free survival at 12 months. 
2. Determine whether the addition of an IGFBP-2 vaccine to neoadjuvant chemotherapy 
improves overall survival. 
3. To determine whether IGFBP-2 vaccination in combination with chemotherapy increases 
the level of TIL in the tumor. 
4. To assess the level of IGFBP-2 Th1 elicited with vaccination concurrent with 
chemotherapy.  
3.C. Exploratory 
 
To explore whether there is a predictive genomic signature for CR induction when 
IGFBP-2 vaccination is used in combination with chemotherapy.  
 
4. DRUG INFORMATION 
4.A. Chemotherapy (this will be performed per standard of care) 
The accepted concurrent chemotherapy regimen under this clinical trial is paclitaxel (175 mg per 
square meter of body surface) administered as a 3-hour infusion immediately followed by an 
intravenous infusion of carboplatin (area under the curve of 6) [37] over 1 hour per Vergote et al 
[2]. However, carboplatin at an area under the curve of at least 5 are allowed [2]. 
 
4.B. IGFBP-2 Vaccine 
The IGFBP-2 plasmid-based DNA vaccine, which contains the IGFBP-2 N terminus sequence (1-
163), can be used clinically (BB-IND 14906, Sponsor Mary L. Disis).  
We recently completed a Phase I study with the IGFBP-2 vaccine in 25 patients with ovarian 
cancer. Vaccination was safe and 90% of patients developed IGFBP-2 immunity. 
4.C. Synthesis and characterization 
Plasmid DNA (pUMVC3-hIGFBP-2) for clinical use will be amplified, quantified and vialed by the 
Biologics Production Facility at the Fred Hutchinson Cancer Research Center under GMP 
laboratory conditions. 
 
4.D. Formulation and stability 
The vaccine will be vialed as single doses containing DNA suspended in tromethamine/EDTA 
(TE) as a stabilizing buffer.  The vaccine formulation is labeled to accurately reflect the product 
identity, concentration, lot number and fill date.  These labels are attached to vials immediately 
post-fill.  Vials will be subjected to microbial, sterility and stability testing to ensure safety and 
stored at -20ºC ± 5ºC until use. 
 


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4.E. GM-CSF 
Recombinant human GM-CSF (rhuGM-CSF; Sargramostatin, LEUKINE) will be used as adjuvant 
admixed with IGFBP-2 DNA plasmid based vaccine.  GM-CSF is a growth factor that supports 
the survival, clonal expansion, and differentiation of hematopoietic progenitor cells including 
dendritic APCs.  In general, the use of GM-CSF is associated with little toxicity and rhuGM-CSF, 
when administered IV or SC, is generally well tolerated at doses ranging from 50-500 mcg/m2/day.  
Severe toxicity is extremely rare in patients treated with rhuGM-CSF.  For the current study, 
rhuGM-CSF will be used at a total injection dose of 100 mcg. 
Administration of rhuGM-CSF may aggravate fluid retention in patients with pre-existent edema, 
capillary leak syndrome, or pleural or pericardial effusions.  In some patients with pre-existing 
renal or hepatic dysfunction, elevation of the serum creatinine or bilirubin and hepatic enzymes 
has occurred during rhuGM-CSF administration.  Dose reduction or interruption of rhuGM-CSF 
administration has resulted in a decrease to pretreatment values.  Occasional transient and 
reversible supraventricular arrhythmia has been reported in uncontrolled studies, particularly in 
patients with a previous history of cardiac arrhythmia.  Stimulation of marrow precursors with 
rhuGM-CSF may result in a rapid rise in white blood cell count.  If rhuGM-CSF is being used for 
the purpose of hematopoietic reconstitution, dosing should be stopped if the ANC exceeds 
20,000/cm3.  The dose being used in this study should not have an effect on ANC levels.  RhuGM-
CSF may stimulate the growth of myeloid malignancies; therefore caution must be exercised in its 
use in these malignancies or myelodysplastic syndromes. Our group has given over 1100 vaccine 
injections mixed with 100 mcg GM-CSF to patients on previous studies.  During those studies 
patients sometimes complained of mild to moderate flu like symptoms (fever, chills, achy, fatigue) 
for 1 – 2 days following vaccination which may be related to the use of GM-CSF. 
Patients with contraindications to receiving rhuGM-CSF will not be eligible for study as noted in 
Section 5.B.4.  Contraindications will include: (1) previous allergic reactions to GM-CSF, (2) 
laboratory values outside of an adequate range as described in Section 5.A.4 and (3) cardiac 
conditions as described in Section 5.B.1. 
RhuGM-CSF is a sterile, white, preservative-free lyophilized powder in 250 mcg vials.  
Reconstituted rhuGM-CSF will be admixed and administered with IGFBP-2 DNA plasmid based 
vaccine. 
 
4.F. Final vaccine preparation 
The pUMVC3-hIGFBP-2 vaccine is supplied in single-use vials as a sterile, frozen solution.  Each 
single-use vial has a volume of 1.2 mls.  The pUMVC3-hIGFBP-2 vaccine will be supplied as 
frozen vials and each vial will carry a label bearing the drug identification and conditions for 
storage.  Investigational Drug Services (IDS) pharmacy at the University of Washington (UW) will 
prepare and dispense the drug for administration per their standard operating procedure as 
follows: 
• 
170mcg DNA / 1 ml TE.  Total DNA per vial is 200mcg.  0.6 ml (100mcg) of vaccine will 
be delivered to patients enrolled at this dose-level. 
 
4.G. Vaccine product accountability 
The IGFBP-2 DNA plasmid based vaccine and rhuGM-CSF will be managed by the UW IDS.  UW 
IDS will be responsible for the study drug disposition (drug receipt, dispensing, transfer or return) 
and shall be documented on the Investigational Drug Accountability Record. 
 


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5. PATIENT SELECTION 
5.A. Inclusion criteria 
1. Patients with newly diagnosed advanced stage (III/IV) ovarian cancer (ovarian/fallopian 
tube/peritoneal cancer) who have been recommended to receive neoadjuvant carboplatin / 
paclitaxel chemotherapy with subsequent cytoreductive surgery. 
2. Patients must have ECOG Performance Status Score of ≤ 2 (Appendix A). 
3. Patients must have recovered from major infections and/or surgical procedures, and in the 
opinion of the investigator, not have any significant active concurrent medical illnesses 
precluding protocol treatment. 
4. Estimated life expectancy of more than 6 months. 
5. Adequate laboratory values within 30 days of enrollment to study defined as follows: 
a. WBC ≥ 3000/mm3 
b. Hgb ≥ 10 g/dl  
c. Hct ≥ 28%  
d. Serum creatinine ≤ 2.0 mg/dl or creatinine clearance > 60 ml/min 
e. Total bilirubin  ≤ 2.5 mg/dl 
f. AST/SGOT ≤ 3 times ULN 
g. Blood glucose <1.5 ULN 
6. All patients who are having sex that can lead to pregnancy must agree to contraception for 
the duration of the study. 
7. Patients must be at least 18 years of age. 
 
5.B. Exclusion criteria 
1. Patients with any of the following cardiac conditions: 
1. Symptomatic restrictive cardiomyopathy 
2. Unstable angina within 4 months prior to enrollment 
3. New York Heart Association functional class III-IV heart failure on active treatment  
4. Symptomatic pericardial effusion 
2. Uncontrolled diabetes 
3. History of (non-infectious) pneumonitis that required steroids or current pneumonitis 
4. Patients with any contraindication to receiving rhuGM-CSF based products 
5. Patients with any clinically significant autoimmune disease uncontrolled with treatment 
6. Patients who are currently receiving an anti-IGF-IR monoclonal antibody as part of their 
treatment regimen  
7. Patients who are simultaneously enrolled in any other treatment study 
8. Patients who are pregnant of breastfeeding 
 
 


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6. EXPERIMENTAL DESIGN 
6.A. Study design  
This will be a phase II, single arm, non-randomized study.  A total of 38 patients will be enrolled. 
 
6.B. Sample size 
To test the primary hypothesis on the pathological complete response induction rate, we will enroll 
38 patients to treat with IGFBP-2 vaccine with neoadjuvant chemotherapy.   This target sample 
size will provide 80% power to detect significance increase in pathological complete response 
with the one-sided type I error rate 0.05, when compared to the average historical pathological 
response rate at 0.075 with neoadjuvant chemotherapy alone.[38, 39]  7.5% is a fixed benchmark 
and this is a single arm trial.   
 
6.C. Outcome measures 
A. Primary endpoints:  
1. The increased rate of pathologic complete response (CR) will be assessed.  
B. Secondary and exploratory endpoints:  
1. Evaluation of PFS will be followed through 12 months. Though not statistically powered 
to this endpoint, large differences in PFS if observed between the treatment groups 
will be noted and described. 
 
2. Evaluation of OS will be followed and compared between the treatment arms. Though 
not statistically powered to this endpoint, large differences in OS if observed between 
the treatment groups will be noted and described. 
 
3. Relate the response to the level of IGFBP-2 Type I T-cells elicited with vaccine by IFN-
g ELISPOT assay to evaluate for the presence of Th1 and Th2 T cells responsive to 
IGFBP-2 epitopes.  
The level of IGFBP-2 Type 1 T-cells elicited will also be correlated to tumor burden at 
definitive surgery.   
4. Increase level of TIL in the tumor will be evaluated by Immunohistochemical staining 
from tumor blocks obtained from cytoreductive surgery post neoadjuvant 
chemotherapy and vaccination.  Immunohistochemical staining for CD3, CD4, CD8, 
and CD27 will be performed and quantitated using published methods and will be 
correlated with surgical CR [3, 40]. 
C. Exploratory endpoints: 
1. Predictive signature of CR induction when vaccinated with an IGFBP-2 vaccine in 
combination with neoadjuvant chemotherapy.   
 
 
 
 


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7. PLAN OF TREATMENT (SEE APPENDIX B)  
7.A.  Active Treatment – Period (7A-7C): Initial Evaluation (may be performed within 2 
weeks prior to initial vaccine visit) 
1. Sign consent form before initiation of study treatment. 
2. Medical history and complete physical examination which includes weight, vital signs, 
baseline symptom assessment and ECOG scoring (Appendix A).   
3. Clinical labs used for determination of eligibility as defined above in (Section 5.A.4) may be 
used as baseline labs prior to vaccine 1 if < 30 days from enrollment.  These include: 
a. Complete blood count with differential and platelet count.  
b. Comprehensive metabolic panel which includes electrolytes, glucose, creatinine, blood 
urea nitrogen, AST, ALT, alkaline phosphatase, and total bilirubin. 
c. CA-125. 
4. Baseline ANA, C3, thyroid function tests, and anti-dsDNA. 
5. Research blood:  
a. Approximately 200 mls for immunologic monitoring as described in Section 7.F. below.  
6. Collect archived tissue from the primary diagnosis, if available. We plan to compare pre and 
post treatment samples to understand how the addition of IGFBP-2 vaccine alters the study 
responses. 
 
7.B. Immunizations (approximately 2 weeks after each chemotherapy visit) 
1. A physical examination will be done prior to each vaccination which will include weight, 
vital signs, medication review, symptom/toxicity assessment. 
2. Patients who are having sex that can lead to pregnancy must have a negative urine 
pregnancy test.  This excludes patients who have undergone permanent sterilization (i.e., 
tubal ligation, hysterectomy or menopause as defined per the NCCN Guidelines.  See 
Appendix E).  
3. Collection of lab results from their oncologist prior to their chemotherapy. 
4. Tetanus diphtheria (Td) immunization if one has not been administered within six months 
(prior to first vaccine only). 
5. Vaccinations will be given during neoadjuvant chemotherapy of combination carboplatin 
and paclitaxel and prior to interval cytoreductive surgery. 
a. Carboplatin and paclitaxel will be given IV every three weeks per standard of care 
by the patient’s primary Gynecology Oncology or Medical Oncology physician. 
i. 3 chemotherapy cycles will be completed prior to surgery 
1. Additional chemotherapy cycles may be given but no additional 
vaccines 
ii. Clinical labs obtained at the beginning of each chemotherapy cycle will be 
reviewed prior to each vaccination. 
b. Vaccinations will be given intradermally approximately two weeks after each 
combination chemotherapy for 3 doses.  


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i. A total of three vaccines will be given on the arm or leg 
ii. As much as possible, each vaccine will be administered within the same 
draining lymph node site 
iii. All vaccines will be administered in the outpatient setting at the UW Clinical 
Research Center. 
 
6. Post-immunization monitoring:  Patients will be observed for a minimum of 60 minutes post 
immunization and post-vaccine vital signs will be documented (See Section 7.F. below).   
 
 
7.C. Evaluation after the final vaccine 
1. Approximately one to two weeks after the final vaccination: 
a. A physical examination will be performed which will include weight, vital signs, 
symptom/toxicity assessment.  
• Complete blood count with differential and platelet count. 
• Comprehensive metabolic panel which includes electrolytes, glucose, creatinine, 
blood urea nitrogen, AST, ALT, alkaline phosphatase, and total bilirubin. 
• CA-125. 
• ANA, C3, thyroid function tests, and anti-dsDNA. 
b. Research blood. 
• 
Up to 200 mls for immunologic monitoring as described in Section 7.F. below. 
2. Collect pathology report, operative report, and tissue from surgery after neoadjuvant 
chemotherapy and vaccination.  Immunohistochemical staining for CD3, CD4, CD8, and 
CD27 will be performed and quantitated and will be correlated with surgical CR. In addition, 
whole exome sequencing on vaccinated patients’ tumors and we will correlate expression 
profiles with primary platinum sensitive, resistance and refractory outcomes to determine 
differences induced by vaccination. 
 
7.D. Follow-Up (approximately 6 months after the last vaccine) 
1. A physical examination will be performed which will include weight, vital signs, 
symptom/toxicity assessment as well as: 
a. Complete blood count with differential and platelet count. 
b. Comprehensive metabolic panel which includes electrolytes, glucose, creatinine, blood 
urea nitrogen, AST, ALT, alkaline phosphatase, and total bilirubin. 
c. CA-125. 
d. ANA, C3, thyroid function tests, and anti-dsDNA. 
2. Research blood 
a. Up to 200 mls of blood will for immunologic monitoring as described in Section 7.F. below.  
• 
 
 
7.E. Long-Term Follow-Up 


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Once a year for five years the patient’s primary oncologist will be contacted for recent laboratory 
evaluation of toxicity, CA-125, and the patient’s disease free and overall survival status.  Clinical 
notes and/or laboratory values will be requested directly from the primary care physician.  
 
7.F. Management of potential study risks 
Although patients have a small chance of experiencing an allergic-type reaction to the vaccine, if 
a reaction were to happen, it would usually occur within one hour of the vaccination.  For this 
reason, all patients will undergo observation and monitoring of vital signs for a minimum of 60 
minutes post-vaccination.  
Large volume blood draws (up to 200 mls) are required at designated study visits for immunologic 
monitoring.  The amount of blood obtained for immunologic monitoring assays at designated time 
points is in strict adherence with guidelines set by the Bloodworks Northwest and are associated 
with minimal risks.  However, as with any large volume blood draw patients should be well 
hydrated prior to the blood draw.  Thus, during the consent process, and at subsequent visits, 
patients will be instructed to hydrate sufficiently prior to visits requiring large volume blood draws. 
Study physician will review recent hematocrit and hemoglobin values to determine a safe amount 
of blood to be drawn (not to exceed 200 mls for immunologic monitoring). 
 
7.G. Storing samples for future testing  
If any research blood or tumor tissue is left over after the study’s immunologic monitoring, it may 
be stored for future research related to the development of other immunotherapies.  The choice 
to store any leftover samples is up to the patient and whatever their decision, it will not affect their 
participation in this study. 
 
8. Subject Withdrawal/Study Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator. 
 
If a subject withdraws from the study, we will discuss with the subject participating in LTFU and 
post vaccine blood as outlined in 7.C and 7.D. If the subject agrees to participate in the LTFU and 
post-vaccine blood draws we will proceed with these as described above in 7.C., 7.D., and If the 
subject declines any further involvement in the follow-up of the study then they will not be 
contacted for LTFU and post-vaccine blood draws.    
 
A subject must be discontinued from the trial for any of the following reasons: 
• 
The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
• 
Unacceptable adverse experiences as described in Section 9 
• 
Concurrent illness that prevents further administration of treatment 
• 
Investigator’s decision to withdraw the subject 
• 
Noncompliance with trial treatment or procedure requirements 
• 
Administrative reasons 


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We will continue to monitor clinically significant toxicity until the toxicity resolves or returns to an 
individual’s baseline.   
If patients are willing, we will continue to follow them for disease status and/or research blood to 
follow immunity as described in Section 7.D. above.  We will report the study termination to the 
Fred Hutchinson Cancer Research Center Cancer Consortium Institutional Review Board at the 
time we become aware of the study termination (with 10 days).  
 
9. EVALUATION AND MANAGEMENT OF TOXICITY 
Patients will be asked to report local injection site reactions; and systemic reactions post vaccine 
visit. Toxicity will be evaluated after each vaccine visit.  Toxicity grading will be evaluated 
according to the CTEP CTCAE v. 4.0 and the Data and Safety Monitoring Plan (DSMP) described 
in Appendix C. 
 
9.A.  IGFBP-2 Vaccine 
For grade 1 or 2 vaccine-related reactions, patients may be treated with acetaminophen or 
Benadryl as clinically indicated at the discretion of the study clinician. 
Table 1. Expected and Allowable Grade 3 and 4 toxicities (CTCAE v4.0) that are not DLT and felt to be related to 
vaccination 
Category 
Toxicity/Adverse Event 
Allowable Duration 
General disorders and administration 
Flu-like symptoms 
2 weeks 
 
Fever 
2 weeks 
 
Malaise 
2 weeks 
Musculoskeletal and connective tissue 
disorders 
Arthralgia 
2 weeks 
 
Myalgia 
2 weeks 
Investigations 
Lymphocyte count 
decreased 
2 weeks 
 
Hemoglobin decrease 
2 weeks 
 
White blood cells decreased 
2 weeks 
Gastrointestinal Disorders 
Constipation 
2 weeks 
 
Diarrhea 
2 weeks 
 
Ascites 
2 weeks 
 
Nausea/vomiting 
2 weeks 
Metabolism and Nutritional Disorders 
Dehydration 
2 weeks 
If grade 3 or 4 toxicity at least possibly related to the vaccination (except as described above in 
Table 1) is observed, treatment if indicated, will be initiated per standard of care and that patient 
will be permanently removed from the study treatment.  Additionally, if grade 3 or 4 toxicity at least 
possibly related to vaccine-induced immune responses is observed, a regimen of corticosteroids 
will be administered.  The following dose schedule will be used: 
 
 
Day 1:  
Intravenous Solu-Medrol at 1 mg/kg 
 
Day 2:  
Intravenous Solu-Medrol at 1 mg/kg 


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Day 3-4: 
Prednisone at 30 mg BID PO q day 
 
Day 4-5: 
Prednisone at 15 mg BID PO q day 
 
Day 5-6: 
Prednisone at 10 mg BID PO q day 
 
Day 6-7: 
Prednisone at 10 mg PO q day 
 
Day 8-9: 
Prednisone at 5 mg PO q day 
 
 
9.B. Chemotherapy – Carboplatin and Paclitaxel 
Table 2. Expected and Allowable Grade 3 and 4 toxicities (CTCAE v4.0) that are not DLT and felt to be related to 
chemotherapy [2].  
Category 
Toxicity/Adverse Event 
Allowable Duration 
Blood and Lymphatic System Disorders 
Anemia 
2 weeks 
Neutropenia 
2 weeks 
Gastrointestinal Disorder 
Abdominal Ascites 
2 weeks 
Abdominal Pain 
2 weeks 
Constipation 
2 weeks 
Diarrhea 
2 weeks 
Nausea/Vomiting 
2 weeks 
Fatigue/General Weakness 
2 weeks 
General Disorders and Administration Site 
Conditions 
Fever 
2 weeks 
Dehydration 
2 weeks 
Appendix D provides a description of the common side effects of carboplatin/ paclitaxel that can 
serve as a reference when trying to determine attribution of vaccine reactions. 
 
9.C.  Dose Limiting Toxicity 
DLT is defined as any incidence of Grade 3 or greater toxicities (other than those listed above in 
Tables 1 and 2) using the CTCAE v 4.0. Specifically, we will consider any Grade 3 or greater non-
hematologic toxicity events a DLT with the only exceptions listed in Tables 1 and 2.   Furthermore, 
any of the following adverse events that is at least possibly related to vaccines will be regarded 
as a DLT. 
 
1 Any Grade 3 or higher non-hematologic adverse events with the exceptions of transient 
nausea, vomiting and diarrhea, responding to supportive care.  
2 Any Grade 3 or higher allergic reaction 
3 Any Grade 2 or higher autoimmune reaction 
4 All Grade 2 or higher hypersensitivity reactions 
5 Grade 3 or higher thrombocytopenia 
6.   Any Grade 4 or higher hematologic adverse events lasting more than 7 days 
 
Any patient who develops a DLT will be permanently removed from the study and will not be 
replaced. 
 


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When recording adverse events we will be making every attempt to distinguish which treatment 
contributes to the adverse event: (1) IGFBP-2 vaccine, (2) chemotherapy, (3) both IGFBP-2 
vaccine and chemotherapy or (4) neither of the treatments. 
 
10. DOSE AND SCHEDULE MODIFICATIONS 
There will not be any modifications of vaccine dose.  There may be allowances for the timing of 
the administration of vaccine to accommodate for special circumstances and must be approved 
by the Principal Investigator and documented.   
Neoadjuvant chemotherapy dose reduction or dose delay will be allowed under this study if dose 
reduction or delay are managed in accordance with published neoadjuvant chemotherapy reports 
and guidelines [2, 41]. Neoadjuvant dose reductions or delays will be managed by the patient’s 
primary treating Gyn. Oncologist or Medical Oncologist. If a dose of neoadjuvant chemotherapy 
is delayed then subsequent vaccination will be delayed for 2 weeks +/- 2 days after neoadjuvant 
chemotherapy is reinitiated, in order to maintain the two week window between chemotherapy 
and vaccination. 
 
11. STATISTICAL CONSIDERATIONS 
11.A. Study hypotheses  
We hypothesize that the addition of an IGFBP-2 vaccine to neoadjuvant chemotherapy will  
• 
Increase the rate of pathological complete response induction (primary) 
• 
Increase progression free survival at 12 months (secondary) 
• 
Improve overall survival (secondary) 
• 
Increase the level of TIL in the tumor (secondary) 
• 
Elicit IGFBP-2 Th1 (secondary) 
 
11.B. Power and sample size calculation 
To test the primary hypothesis on the pathological complete response induction rate, we will enroll 
38 patients to treat with IGFBP-2 vaccine with neoadjuvant chemotherapy.   This target sample 
size will provide 80% power to detect significance increase in pathological complete response to 
20% with the one-sided type I error rate 0.05, when compared to the average historical 
pathological response rate of 7.5% with neoadjuvant chemotherapy alone.[38, 39]  7.5% is a fixed 
benchmark and this is a single arm trial.   
 
11.C. Projected gender and ethnic distribution 
The ethnic and gender distribution chart below (Table 3) reflects estimates of race and gender of 
the population to be included in this study.  Men do not develop ovarian cancer, thus, the study 
population will be female.  These estimates are based on the following general statistics of the 
population in Washington State based on the recent 2010 US Census data.  The population pool 
from which patients will be drawn is 83.8% Caucasian, 7.0% Asian American, 3.9% African 
American, 1.8% American Indian or Alaska Native and 0.5% Native Hawaiian or Other Pacific 
Islander. 
Table 3.  Distribution of ethnicity and gender. 


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TARGETED/PLANNED ENROLLMENT: Number of Subjects 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
3 
0 
3 
Not Hispanic or Latino 
35 
0 
35 
Ethnic Category: Total of All Subjects * 
38 
0 
38 
Racial Categories 
 
American Indian/Alaska Native 
1 
0 
1 
Asian 
3 
0 
3 
Native Hawaiian or Other Pacific Islander  
0 
0 
0 
Black or African American  
2 
0 
2 
White 
32 
0 
32 
Racial Categories: Total of All Subjects * 
38 
0 
38 
 
11.D. Patient accrual and study monitoring 
We expect to recruit 2-3 patients per month, therefore accrual will take approximately 13 months 
for the first stage of the study, additional 6 months for follow-up to study termination.  
 
Sequential boundaries will be used to monitor the grade 3 dose-limiting toxicity rate and the grade 
4 DLT rate. The accrual will be halted if excessive numbers of dose-limiting toxicities are seen, 
that is, if the number of dose-limiting toxicities is equal to or exceeds bn out of n patients with full 
follow-up (see Table 4 and 5 below). This is a Pocock-type stopping boundary that yields the 
probability of crossing the boundary at most 5% when the rate of dose-limiting toxicity is equal to 
the acceptable rate of grade 3 DLT rate at 15%, and the grade 4 DLT rate at 5%.[42]  In addition, 
the study will stop if there is any fatality not attributed to disease progression, surgery and 
complications from surgery, or chemotherapy. 
  
Table 4. Stopping boundary for grade 3 DLT rate 15% 
  
Number of 
Patients, n 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 
12 13 
14 15 
16 17 
18 19 
20 
Boundry,bn 
- 
- 
3 
3 
4 
4 
4 
5 
5 
5 
6 
6 
6 
6 
7 
7 
7 
7 
8 
8 
Number of 
Patients, n 
21 
22 23 
24 25 
26 27 
28 29 
30 31 
32 33 
34 35 
36 37 
38 39 
40 
Boundary,bn 
8 
8 
8 
9 
9 
9 
9 
10 10 
10 10 
10 11 
11 11 
11 12 
12 - 
- 
  
  
Table 5. Stopping boundary for grade 4 DLT rate 5% 
  


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Number of 
Patients, n 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 
12 13 
14 15 
16 17 
18 19 
20 
Boundry,bn 
- 
2 
2 
2 
3 
3 
3 
3 
3 
3 
3 
3 
4 
4 
4 
4 
4 
4 
4 
4 
Number of 
Patients, n 
21 
22 23 
24 25 
26 27 
28 29 
30 31 
32 33 
34 35 
36 37 
38 39 
40 
Boundary,bn 
4 
4 
5 
5 
5 
5 
5 
5 
5 
5 
5 
5 
6 
6 
6 
6 
6 
6 
- 
- 
 
 
11.E. Data analysis plan 
The clinical and pathologic characteristics, including age, stage, surgical outcome, progression 
free survival and overall survival will be tabulated for the first and if recruited, the second set of 
patients, as well as the combined set. The rate of pathological complete response (CR) induction 
will be compared to the historical control rate by a binomial test; the progression free survival and 
overall survival will be plotted by Kaplan-Meier curve, and compared to the survival data reported 
by Vergote et al which reported median PFS of 12 months and median OS of 30 months for 
patients treated with neoadjuvant chemotherapy by a log-rank test.[43] Immunohistochemical 
staining for CD3, CD4, CD8, and CD27 will be performed and quantitated using published 
methods and will be correlated with surgical CR by the Man–Whitney U or one-way ANOVA test 
were used, depending on the distribution of TIL outcomes. The level of IGFBP-2 Type 1 T-cells 
elicited will be evaluated by IFN-g ELISPOT assay and correlated to tumor burden at definitive 
surgery.  
 
For the exploratory signature study endpoint, we hypothesize that we can selectively eliminate 
cancer cells destined to become chemoresistant by vaccinating against EMT associated proteins. 
We will perform whole exome sequencing on vaccinated patients’ tumors.  We will interrogate the 
data set for genes that predict an ordinal chemo-response variable (sensitive, resistant, 
refractory). We will use the LASSO regularized regression method to generate preliminary data 
for a predictive signature. We will correlate mutational profiles with primary platinum sensitive, 
resistance and refractory outcomes, leveraging the TCGA data publicly available, to determine 
differences induced by vaccination.  
 
 
12. ADMINISTRATIVE CONSIDERATIONS 
12.A. Institutional review board 
In accordance with federal regulations, an Institutional Review Board that complies with the 
regulations in 21 CFR 56 must review and approve this protocol and the informed consent form 
prior to initiation of the study. 
12.B. Consent 
The P.I., study physician or their designated physician extender must explain verbally and in 
writing the nature and duration of the study and possible consequences of the treatment.  Patients 
must also be informed that they may withdraw from the study at any time and for any reason 
without jeopardizing their future treatment.  At the initiation of eligibility screening and prior to 
enrollment, the investigators or their associates will obtain permission from the patient to access 
medical records for research purposes.   
12.C. Reporting adverse events  
Adverse events will be reported using the NCI’s CTEP CTCAE v 4.0.  A copy of the CTCAE v 4.0 
can be downloaded from the CTEP homepage (http://ctep.info.nih.gov).  Guidelines for adverse 
event reporting to the FDA and the NCI are described in the DSMP, Appendix C. The Monitoring 


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Plan (as mandated by the NIH/NCI) Policy and Procedure for this phase I study is described in 
Appendix C.   
All serious adverse events are communicated to the Principal Investigator, FDA, NIH Office of 
Science Policy (OSP) formally NIH OBA, Medical Monitor, FHCRC/UW CC IRB, UW IBC, Clinical 
Research Center (CRC)..  In addition, the study will be monitored by Clinical Research Services 
(CRS) according to the FHCRC – Cancer Consortium monitoring plan. 
 
12.D. Confidentiality of patient records 
All eligible patients will be assigned a unique study ID number that will not contain any personally 
identifying information, such as name, initials, medical record number, social security number, 
etc.  The study ID number will be used on all specimens, research study records and associated 
documents collected in the research record.  To maintain confidentiality, we protect the link 
between the patients’ personal identifying information and study ID number by limiting who has 
access to the patients’ chart documentation.  Only specified clinical research staff has access to 
the data, which remain locked at all times when not in use. 
All hard copy research records collected on potential and enrolled patients are stored in a locked 
filing cabinet that can only be accessed by approved clinical research staff when not in use.  This 
staff includes: Principal Investigator, study physician(s), and designated clinical research staff.  
These are also the only people that have access to the link between the patients’ personal 
identifying information and their assigned UPN codes. 
In terms of the protections and security of electronic clinical data it is being performed by the 
University of Washington Medicine Information Technology (IT) Services.  The UW Medicine IT 
information security policy is to protect UW Medicine information and information systems.  It also 
ensures compliance with University of Washington policy and state and federal regulations.   
 
12.E. Study team roles and responsibilities 
Dr. Liao, the Principal Investigator, will be responsible for the oversight of the research.  Dr. Liao 
is responsible for ensuring that all information and documentation related to the conduct and safety 
of the study is disseminated to the proper agencies in the proper timeframe. 
Research physicians/physician extenders will be responsible for conducting consent conferences 
at the initial visit as well as performing monthly assessments prior to vaccination.  
Research Nurse(s)/Coordinator(s) will be responsible for initial screening and scheduling patient 
visits.  The Research Nurse(s)/Coordinator(s) will ensure that the clinical data is entered into the 
database in a timely manner, so as to have real time data to review and report any safety concerns 
trends.  They will also be responsible for maintaining regulatory documentation to the various 
agencies involved with this research and ensure that all research team members are following the 
protocol and all regulations.   


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1. 
Sato, E., et al., Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell 
ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci U S A, 2005. 102(51): 
p. 18538-43. 
2. 
Vergote, I., et al., Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N 
Engl J Med, 2010. 363(10): p. 943-53. 
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Wouters, M.C., et al., Treatment Regimen, Surgical Outcome, and T-cell Differentiation Influence 
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Cecil, D.L., et al., Elimination of IL-10-inducing T-helper epitopes from an IGFBP-2 vaccine ensures 
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Tucker, S.L., et al., Molecular biomarkers of residual disease after surgical debulking of high-grade serous 
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Goodell, V., et al., Antibody immunity to the p53 oncogenic protein is a prognostic indicator in ovarian 
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Knutson, K.L., W. Wagner, and M.L. Disis, Adoptive T cell therapy of solid cancers. Cancer Immunol 
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Le Bon, A., et al., Cross-priming of CD8+ T cells stimulated by virus-induced type I interferon. Nat 
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Castellino, F. and R.N. Germain, Cooperation between CD4+ and CD8+ T cells: when, where, and how. 
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Peoples, G.E., et al., Breast and ovarian cancer-specific cytotoxic T lymphocytes recognize the same 
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Hayashi, K., et al., Clonal expansion of T cells that are specific for autologous ovarian tumor among 
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Dadmarz, R.D., et al., Tumor-infiltrating lymphocytes from human ovarian cancer patients recognize 
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17. 
Fisk, B., et al., Identification of an immunodominant peptide of HER-2/neu protooncogene recognized by 
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Shah, C.A., et al., Intratumoral T cells, tumor-associated macrophages, and regulatory T cells: association 
with p53 mutations, circulating tumor DNA and survival in women with ovarian cancer. Gynecol Oncol, 
2008. 109(2): p. 215-9. 
19. 
Hamanishi, J., et al., Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are 
prognostic factors of human ovarian cancer. Proc Natl Acad Sci U S A, 2007. 104(9): p. 3360-5. 
20. 
Kryczek, I., et al., Relationship between B7-H4, regulatory T cells, and patient outcome in human ovarian 
carcinoma. Cancer Res, 2007. 67(18): p. 8900-5. 
21. 
Lancaster, J.M., et al., Gene expression patterns that characterize advanced stage serous ovarian cancers. 
J Soc Gynecol Investig, 2004. 11(1): p. 51-9. 
22. 
Pollak, M.N., E.S. Schernhammer, and S.E. Hankinson, Insulin-like growth factors and neoplasia. Nat Rev 
Cancer, 2004. 4(7): p. 505-18. 
23. 
Samani, A.A., et al., The role of the IGF system in cancer growth and metastasis: overview and recent 
insights. Endocr Rev, 2007. 28(1): p. 20-47. 
24. 
Lancaster, J.M., et al., High expression of insulin-like growth factor binding protein-2 messenger RNA in 
epithelial ovarian cancers produces elevated preoperative serum levels. Int J Gynecol Cancer, 2006. 16(4): 
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25. 
Baron-Hay, S., et al., Elevated serum insulin-like growth factor binding protein-2 as a prognostic marker 
in patients with ovarian cancer. Clin Cancer Res, 2004. 10(5): p. 1796-806. 


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26. 
Mehrian-Shai, R., et al., Insulin growth factor-binding protein 2 is a candidate biomarker for PTEN status 
and PI3K/Akt pathway activation in glioblastoma and prostate cancer. Proc Natl Acad Sci U S A, 2007. 
104(13): p. 5563-8. 
27. 
Perks, C.M., et al., IGF-II and IGFBP-2 differentially regulate PTEN in human breast cancer cells. 
Oncogene, 2007. 26(40): p. 5966-72. 
28. 
Lee, E.J., et al., Insulin-like growth factor binding protein 2 promotes ovarian cancer cell invasion. Mol 
Cancer, 2005. 4(1): p. 7. 
29. 
Wang, H., et al., Insulin-like growth factor-binding protein 2 and 5 are differentially regulated in ovarian 
cancer of different histologic types. Mod Pathol, 2006. 19(9): p. 1149-56. 
30. 
Salazar, L.G., et al., Immunization of cancer patients with HER-2/neu-derived peptides demonstrating high-
affinity binding to multiple class II alleles. Clin Cancer Res, 2003. 9(15): p. 5559-65. 
31. 
Davis, H.L., et al., DNA-mediated immunization to hepatitis B surface antigen: longevity of primary 
response and effect of boost. Vaccine, 1996. 14(9): p. 910-5. 
32. 
Watson, B., et al., Persistence of immunologic memory for 13 years in recipients of a recombinant hepatitis 
B vaccine. Vaccine, 2001. 19(23-24): p. 3164-8. 
33. 
Kandalaft, L.E., et al., The emergence of immunomodulation: combinatorial immunochemotherapy 
opportunities for the next decade. Gynecologic oncology, 2010. 116(2): p. 222-33. 
34. 
Hato, S.V., et al., Molecular pathways: the immunogenic effects of platinum-based chemotherapeutics. 
Clinical cancer research : an official journal of the American Association for Cancer Research, 2014. 
20(11): p. 2831-7. 
35. 
Quoix, E., et al., Therapeutic vaccination with TG4010 and first-line chemotherapy in advanced non-small-
cell lung cancer: a controlled phase 2B trial. The Lancet. Oncology, 2011. 12(12): p. 1125-33. 
36. 
Bohm, S., et al., Neoadjuvant Chemotherapy Modulates the Immune Microenvironment in Metastases of 
Tubo-Ovarian High-Grade Serous Carcinoma. Clin Cancer Res, 2016. 22(12): p. 3025-36. 
37. 
Calvert, A.H., et al., Carboplatin dosage: prospective evaluation of a simple formula based on renal 
function. J Clin Oncol, 1989. 7(11): p. 1748-56. 
38. 
Muraji, M., et al., Histopathology predicts clinical outcome in advanced epithelial ovarian cancer patients 
treated with neoadjuvant chemotherapy and debulking surgery. Gynecol Oncol, 2013. 131(3): p. 531-4. 
39. 
Petrillo, M., et al., Prognostic role and predictors of complete pathologic response to neoadjuvant 
chemotherapy in primary unresectable ovarian cancer. Am J Obstet Gynecol, 2014. 211(6): p. 632 e1-8. 
40. 
Sato, E., et al., Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell 
ratio are associated with favorable prognosis in ovarian cancer. Proceedings of the National Academy of 
Sciences of the United States of America, 2005. 102(51): p. 18538-43. 
41. 
Network., N.C.C. Ovarian Cancer.  August 30, 2016]; Available from: 
https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf. 
42. 
Ivanova, A., B.F. Qaqish, and M.J. Schell, Continuous toxicity monitoring in phase II trials in oncology. 
Biometrics, 2005. 61(2): p. 540-5. 
 
 


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Appendix A. ECOG Performance Scale 
 
Performance status: Patients will be assessed according to the current ECOG performance 
scale. 
 
ECOG performance scale 
Grade Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up 
and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
 
As published in Am. J. Clin. Oncol: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, 
T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative 
Oncology Group. Am J Clin Oncol 5:649-655, 1982.  
The ECOG/Zubrod Performance Status is in the public domain therefore available for public use.  
To duplicate the scale, please cite the reference above and credit the Eastern Cooperative 
Oncology Group, Robert Comis M.D., Group Chair.  


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Appendix B. Calendar of Events 
 
Visit Time Point 
Procedures 
Baseline Visit 
Some procedures 
may be done up to 
two weeks prior to 
initial vaccine visit 
• 
Consent 
• 
Medical history and complete physical examination 
• 
Vitals signs-including weight 
• 
ECOG scoring 
• 
Baseline symptom assessment 
• 
Clinical labs if greater than 30 days old: complete blood counts (with 
differential and platelet count), serum chemistries (electrolytes, glucose, AST, 
ALT, alkaline phosphatase, bilirubin, creatinine, blood urea nitrogen), ANA, 
C3 and anti-ds-DNA, thyroid function tests 
• 
CA125 
• 
Research blood: approximately 200 mls*  
• 
Archived tissue collection, if available 
First Vaccine: 
2 weeks after 
chemotherapy  
• 
Medical history and complete physical examination 
• 
Vitals signs-including weight 
• 
ECOG scoring 
• 
Baseline symptom/toxicity assessment (if not collected previously) 
• 
Urine pregnancy test (if applicable) 
• 
Tetanus diphtheria immunization 
• 
pUMVC3-hIGFBP-2 vaccine 
• 
Post vaccine monitoring 
Second Vaccine: 
2 weeks after 
chemotherapy 
• 
Medical history and complete physical examination 
• 
Review of pre chemotherapy lab results 
• 
Vitals signs-including weight 
• 
Symptom/toxicity assessment 
• 
Urine pregnancy test (if applicable) 
• 
pUMVC3-hIGFBP-2 vaccine 
• 
Post vaccine monitoring 
Third Vaccine: 
2 weeks after 
chemotherapy 
• 
Medical history and complete physical examination 
• 
Review of pre chemotherapy lab results 
• 
Vitals signs-including weight 
• 
Symptom/toxicity assessment 
• 
Urine pregnancy test if applicable) 
• 
pUMVC3-hIGFBP-2 vaccine 
• 
Post vaccine monitoring 
Evaluation after 
the final 
vaccine   
(Approx. 1 week 
after final vaccine 
Prior to surgery 
• 
Medical history and complete physical examination 
• 
Vitals signs-including weight 
• 
Symptom/toxicity assessment 
• 
Clinical labs: complete blood counts, serum chemistries, ANA, C3 and 
anti_ds-DNA, CA125, thyroid function tests 
• 
Research blood: approximately 200 mls*  
Month 6  
• 
Medical history and complete physical examination 
• 
Vitals signs-including weight 
• 
Symptom/toxicity assessment 


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Visit Time Point 
Procedures 
Post the last 
vaccine 
• 
Clinical labs: complete blood counts, serum chemistries, ANA, C3 and anti-
ds-DNA, CA125, thyroid function tests 
• 
Research blood: approximately 200 mls* 
Once 
yearly 
follow-up for 5 
years 
• 
Collection of physician notes to review toxicity and clinical status 
* During the consent process, and at subsequent visits, patients will be instructed to hydrate 
sufficiently prior to visits requiring large volume blood draws. 
 
 


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Appendix C. Data and Safety Monitoring Plan 
 
A. Purpose 
To ensure that the Tumor Vaccine Group (TVG) follows NIH/NCI/CTEP/FDA guidelines with 
respect to: (1) accurate assessment and timely reporting of adverse drug reactions associated 
with investigational drugs, (2) adherence to protocol, and (3) accurate reporting of data.  The 
DSMP will be approved by Fred Hutchinson Cancer Research Center (FHCRC) /University of 
Washington (UW) – Cancer Consortium IRB (FHCRC/UW – CC IRB) in Seattle, Washington. 
The Principal Investigator (PI), for this project, is responsible for the conduct of the study.  The PI 
will be involved in the study design, delegating responsibility/authority and will be involved with 
final analysis.  The Sponsor of the study is responsible for study design, , monitoring of the study 
conduct and final analysis of the study data.  Regulations defining the responsibilities for 
assessment and reporting of all adverse events (AE), serious AE (SAE), and unexpected AEs are 
defined by the Code of Federal Regulations:  21 CFR 312.32 and Common Terminology Criteria 
for Adverse Events (CTCAE) Version 4.0 published by the Cancer Therapy Evaluation Program 
(CTEP), a division of the NCI/NIH.  
This clinical study will rely upon the monitoring of the trial by the IND Sponsor, Principal 
Investigator (P.I.) in conjunction with a Research Nurse, research staff, Statistician, an 
Independent Medical Monitor and an Independent Study Monitor assigned by the Clinical 
Research Support (CRS) of the FHCRC/UW–CC IRB. 
The Independent Medical Monitor for this study is Ron Swensen, M.D., Gynecologic Oncology 
Physician at the Valley Medical Center.  Dr. Swensen has conducted research in gynecologic 
oncology and immune therapy.  The Medical Monitor will be notified that the study is open prior 
to patients being recruited in order to orient committee participants to the study.  The Medical 
Monitor will then discuss the study every 6 months throughout the study treatment period with the 
P.I., Research MD(s), Research Nurse(s), Research Coordinator(s), and/or other related clinical 
research staff.  The Medical Monitor will review patient recruitment and retention, adherence to 
protocol, follow-up, data quality, and participant risk versus benefit. 
If a SAE occurs the PI will be notified along with the IND Sponsor, FDA, NIH OSP, Medical 
Monitor, FHCRC/UW CC-IRB, UW IBC, and UW CRC. 
 
B. Objectives 
1. To ensure that the PI and Clinical Research Staff follow federal and institutional regulatory 
guidelines with respect to timely reporting of adverse reactions associated with investigational 
drugs.  
2. To define classification of adverse drug reactions as expected or unexpected. 
3. To define classification of adverse drug reactions as serious or non-serious. 
4. To ensure compliance and accuracy of documentation of SAE reactions reportable to: (1) FDA 
(2) NIH OSP, (3) Medical Monitor, (4) FHCRC/UW CC-IRB,, (5) UW IBC, (6) UW CRC and 
(7) IND Sponsor. 
 


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C. Adverse event reporting policy and procedures 
1. Evaluation of adverse events: Patients are monitored for the development of toxicities by 
assessing adverse events lab values throughout the study.  The development of  laboratory 
autoantibody responses will also be clinically assessed at baseline visit, and approximately 1 
week and 6 months after the last vaccine for the development of anti-DNA antibodies (ANA, 
C3, thyroid function tests, and anti-dsDNA).   All adverse events for all systems are graded 
on a scale of 1-5 and attribution is assigned, using the Common Terminology Criteria for 
Adverse Events Version 4.0 (CTCAE v4.0).   
2. Definitions of adverse events (AEs): 
a. AE - any unfavorable and unintended sign (including abnormal laboratory finding), 
symptom or disease temporally associated with the use of a medical treatment or 
procedure regardless of whether it is considered related to the medical treatment or 
procedure. 
An adverse event may include  
• 
an exacerbation of a pre-existing illness that would stop treatment of a standard  
chemotherapy treatment.  
• 
an increase in frequency or intensity of a pre-existing episodic event or condition. 
• 
a condition detected or diagnosed after study drug administration.  
• 
continuously symptoms that were present at baseline and worsen following the start 
of the study.  
An adverse event does not include:  
• 
medical or surgical procedures unrelated to the treatment of the disease (e.g., surgery, 
endoscopy, tooth extraction, or transfusion); however, the condition that leads to the 
procedure may be an adverse event.  
• 
pre-existing diseases, conditions, or laboratory abnormalities present or detected at 
the start of the study that do not worsen.  
• 
hospitalizations or procedures that are done for elective purposes not related to an 
untoward medical occurrence (e.g., hospitalizations for cosmetic or elective surgery or 
social/convenience admissions).  
• 
the disease being studied or signs/symptoms associated with the disease unless more 
severe than expected for the patient's condition.  
• 
overdose of study drug without any clinical signs or symptoms. 
b. Expected AE - an event that may be reasonably anticipated to occur as a result of the 
study procedure and is described in the IND 14906 and/or consent form. 
c. Unexpected Adverse Event - an AE that is not described in the IND 14906 and/or consent 
form and is unanticipated.  An event that might have been anticipated but is more serious 
than expected or occurs more frequently than expected, would be considered an 
unexpected adverse event. 
d. Life-threatening AE - the patient was at substantial risk of dying at the time of the adverse 
event or it is suspected that the use or continued use of the product would have resulted 
in the patient’s death. 
e. Serious AE - grade 4 or 5 toxicity or any AE occurring at any dose that results in any of 
the following outcomes: death, a life threatening AE, inpatient hospitalization or 


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prolongation of existing hospitalization due to the AE, a persistent or significant 
disability/incapacity or a congenital anomaly/birth defect that is expected and related. 
f. Hospitalizations that do not meet these criteria are:  
• 
reasons described in the protocol, e.g., drug administration, protocol-required testing.  
• 
social reason in the absence of an AE.  
Note: Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations; for example, important medical events may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the patient or 
may require intervention to prevent one of the outcomes listed in the definition above. Any adverse 
event is considered a serious adverse event if it is associated with clinical signs or symptoms 
judged by the investigator to have a significant clinical impact.  
3. Scale of scoring adverse events  
a. Grade 1 = mild adverse event 
b. Grade 2 = moderate adverse event 
c. Grade 3 = severe adverse event 
d. Grade 4 = life-threatening or disabling adverse event 
e. Grade 5 = death related to adverse event. 
4. Attribution of adverse event 
a. 5 (definite): the adverse event is clearly related to the investigational agent.   
b. 4 (probable): the adverse event is likely related to the investigational agent. 
c. 3 (possible): the adverse event may be related to the investigational agent. 
d. 2 (unlikely): the adverse event is doubtfully related to the investigational agent. 
e. 1 (unrelated): the adverse event is clearly NOT related to the investigational agent. 
5. SAE event reporting 
This procedure is outlined below by regulatory agency (Table 3). 
FDA (for trials using an Investigational New Drug (IND) – Serious adverse events will be 
reported in accordance with the requirements under 21 CFR 312.32. 
NIH Office of Biotechnology Activities (NIH OSP) - any serious adverse event that is fatal or 
life-threatening that is unexpected and associated with the use of a gene transfer product must 
be reported as soon as possible but no later than 7 days after the sponsor’s initial receipt of the 
information.  Unexpected serious adverse events that are associated with the gene transfer 
product, but are not fatal or life-threatening must be reported as soon as possible but no later than 
15 calendar days from the sponsor’s initial receipt of the information.  An adverse event that is 
initially considered not associated with the use of the gene transfer product but is subsequently 
determined to be associated must be reported within 15 calendar days of the determination.  All 
other adverse events will be reported to NIH OSP in the annual report.  The NIH Office of 
Biotechnology Activities will accept the report in either a narrative format.  We will send a copy of 
the MedWatch Form 3500A.   . 
Independent Medical Monitor - At a minimum, the medical monitor should comment on the 
outcomes of serious adverse event(s) to the vaccine or prepare an unbiased written report of the 
event.  They should also indicate whether they agree with the details of the report provided by the 
study investigator. 


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Fred Hutchinson Cancer Research Center/UW Cancer Consortium IRB - We will follow the 
current AE reporting policy of the FHCRC – CC IRB. 
University of Washington IBC - We will follow the current AE reporting policy of the UW IBC. 
University of Washington Clinical Research Center (UW CRC) - The CRC will receive copies 
of the documents submitted to the FHCRC/UW CC-IRB within 7-10 calendar days. 
IND Sponsor – Will be notified within 24 hours of the event occurring in order to report to the FDA 
if needed. 


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Table 3. Adverse event reporting 
 
Expected 
Expected 
Unexpected 
Unexpected 
 
Non-Serious 
Serious 
Non-Serious 
Serious (including 
grade 4 & 5 toxicity) 
 
Attribution * 
(Possible, 
Probable, 
Definite) 
Attribution * 
(Possible, 
Probable, 
Definite) 
Attribution * 
(Possible, 
Probable, 
Definite) 
Attribution * (Possible, 
Probable, Definite) 
FDA 
Annual 
Progress 
Report 
Annual 
Progress 
Report 
Annual 
Progress 
Report 
FDA Form 3500A or 
Narrative Format – 
ASAP but within 7-15 
days )  
NIH OSP 
Annual Report 
Annual Report 
Annual Report 
FDA Form 3500A or 
Narrative Format – 
ASAP but within 7-15 
days)  
Medical 
Monitor 
Bi-annual 
Meeting (twice 
a year) 
Bi-annual 
Meeting (twice 
a year) 
Bi-annual 
Meeting (twice 
a year) 
FHCRC Adverse 
Event Expedited 
Reporting Form –
Following the 
FHCRC/UW CC-IRB 
policy 
FHCRC/UW – 
Consortium 
IRB 
Continuation 
Review Report 
Continuation 
Review Report 
Continuation 
Review Report 
FHCRC Adverse 
Event Expedited 
Reporting Form – 
Following the 
FHCRC/UW CC-IRB 
policy 
UW IBC 
Routine Report, 
as appropriate 
Routine 
Report, as 
appropriate 
Routine Report, 
as appropriate 
Follow UW IBC 
reporting policy 
UW CRC 
Copy of 
Continuation 
Review Report 
Copy of 
Continuation 
Review Report 
Copy of 
Continuation 
Review Report 
Copy of FHCRC/UW 
CC-IRB Adverse 
Event Expedited 
Reporting Form 
 
6. Procedure for reporting SAEs: 
a. Identify the classification/attribution of the adverse event as defined above using the 
Modified Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE v4.0). 
b. After appropriate medical intervention has been instituted, the Principal Investigator or 
his/her designee will be notified within 24 hours. 


Protocol 144, CC Protocol 9760 
 
07/28/2018 
Page 36 of 39 
 
 
c. File appropriate reports immediately by phone/fax with appropriate agencies, as described 
in Table 3. 
d. Notify the patient’s primary physician or referring physician within a medically appropriate 
timeframe, depending on the classification of the adverse event. 
e. Submit written reports to appropriate agencies. 
f. Document the adverse event in the patient’s research file, using a progress note to 
describe the event and treatment, if appropriate.   
g. File copies of all forms/correspondence relating to the adverse event in the patient’s 
research file. 
 
D.  Clinical trials monitoring operational procedures  
1. Clinical data documentation 
a. Internal study monitoring: 
All patients actively enrolled in the study are seen every 3 weeks during the treatment 
period. Clinical labs are evaluated (1) during eligibility, within 2 weeks prior to vaccines 1, 
2, and 3 as well as 1 week and 6 months after the last vaccine, for the development of 
toxicity (adverse events) related to the vaccine.    Any clinically significant abnormal lab 
values may be faxed to the patient’s physician.   
A Research Physician, physician extender or P.I. sees each study participant at each visit 
with the following evaluations being completed: physical assessment and adverse events 
summary (these evaluations are part of the source documentation that is filled out at each 
visit).  Grade 1 and 2 non-serious and expected adverse events will be reviewed with the 
P.I. or designee regularly.  All other adverse events will be reported to the P.I. or designee 
at the time they become known and reported as outlined above in Section C.  Clinical 
research staff member(s) will review patient research files for patient recruitment and 
retention, protocol adherence, follow-up, data quality, and participant risk versus benefit. 
b. Biannual review by the independent Medical Monitor: 
The Medical Monitor will review data with the P.I., designee, and/or other members of the 
clinical team, approximately every 6 months.  All patients are reviewed for adverse events.  
Conduct of the study is reviewed and changes/clarifications can be requested/discussed 
with the Medical Monitor  
c. Biannual study audit:  
Institutional support of trial monitoring will be in accordance with the FHCRC/UW Cancer 
Consortium Institutional Data and Safety Monitoring Plan.  Under the provisions of this 
plan, FHCRC Clinical Research Support (CRS) coordinates data and compliance 
monitoring conducted by consultants, contract research organizations, or Fred Hutch 
employees unaffiliated with the conduct of the study.  Independent monitoring visits occur 
at specified intervals determined by the assessed risk level of the study and the findings 
of previous visits per the institutional DSMP.  
In addition, protocols are reviewed at least annually and as needed by the Consortium 
Data and Safety Monitoring Committee (DSMC), FHCRC Scientific Review Committee 
(SRC) and the FHCRC/UW Cancer Consortium Institutional Review Board (IRB).  The 
review committees evaluate accrual, adverse events, stopping rules, and adherence to 
the applicable data and safety monitoring plan for studies actively enrolling or treating 
patients.  The IRB reviews the study progress and safety information to assess continued 


Protocol 144, CC Protocol 9760 
 
07/28/2018 
Page 37 of 39 
 
 
acceptability of the risk-benefit ratio for human subjects.  Approval of committees as 
applicable is necessary to continue the study. 
The trial will comply with the standard guidelines set forth by these regulatory committees 
and other institutional, state and federal guidelines. 
 
2. Data validity/integrity 
Systems to insure data integrity have been put into place to provide multiple checks to data entry.  
Patient eligibility is initially reviewed by the Research Coordinator/Research Nurse and the PI or 
designee during the screening portion of the study.  The chart is then reviewed by a study 
physician after the consent conference and before study procedures start.  It is then ultimately 
signed off on by the PI or designee. 
Clinical laboratory monitoring data is reviewed by a qualified clinician (Research MD, physician 
extender, Research Nurse and/or P.I.) and any abnormalities are assessed.  Patient records are 
kept in the patient’s research file and reviewed at biannual monitoring visits. Data is taken from 
the patient’s source documentation, the patient’s research file, and entered into a database which 
links data to patient by a Unique Patient Identifier and is accessible by password code only.  Data 
entry is made by the Research Clinical Research Staff members. A percentage of all data entry 
is reviewed by a member of the clinical research team and/or the Independent Study Monitor.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol 144, CC Protocol 9760 
 
07/28/2018 
Page 38 of 39 
 
 
Appendix D. Common Side Effects of Carboplatin/ Paclitaxel 
 
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Carboplatin and Paclitaxel, more than 20 and up to 100 may 
have: 
• Hair loss 
• Infection, especially when white blood cell count is low 
• Anemia which may cause tiredness, or may require blood transfusions 
• Bruising, bleeding 
• Diarrhea, nausea, vomiting, constipation 
• Sores in mouth which may cause difficulty swallowing 
• Changes in taste 
• Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of 
breath, swelling of the face or throat 
• Pain 
• Muscle weakness 
• Numbness and tingling in fingers and toes 
 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Carboplatin and Paclitaxel, from 4 to 20 may have: 
• Heart attack or heart failure which may cause shortness of breath, swelling of 
ankles, and tiredness 
• Abnormal heartbeat 
• A tear or a hole in the stomach which may cause belly pain or that may require 
surgery 
• Damage to the lungs which may cause shortness of breath 
• Blood clot which may cause swelling, pain, shortness of breath 
 
 
RARE, AND SERIOUS 
In 100 people receiving Carboplatin and Paclitaxel, 3 or fewer may have: 
• Changes in vision 
• Damage to organs which may cause hearing and balance problems 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol 144, CC Protocol 9760 
 
07/28/2018 
Page 39 of 39 
 
 
 
Appendix E. NCCN Guidelines for Menopause Status 
 
The National Comprehensive Cancer Network (NCCN) defines menopause as “generally the 
permanent cessation of menses, includes a profound and permanent decrease in ovarian 
estrogen synthesis.”  According to their guideline, the criteria for determining menopause are: 
• 
Prior bilateral oophorectomy 
• 
60 or older 
• 
Age less than 60 years; amenorrheic for 12 or more months in the absence of 
chemotherapy, tamoxifen, toremifene, or ovarian suppression; and follicle-stimulating 
hormone (FSH) and plasma estradiol in the postmenopausal range. 
• 
If taking tamoxifen or toremifene, and age is under 60 years, then FSH and plasma 
estradiol level should be in the postmenopausal range. 
• 
It is not possible to assign menopausal status to women who are receiving a leuteinizing 
hormone-releasing hormone agonist or antagonist. In women premenopausal at the time 
of adjuvant chemotherapy, amenorrhea is not a reliable indicator of menopausal status. 
  

ICF_002.pdf: 
9760/144 
 
 
Page 1 of 16 
 
 
UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE 
DEPARTMENT OF MEDICINE 
DIVISION OF ONCOLOGY 
TUMOR VACCINE GROUP (TVG) 
Consent to take part in a research study: 
 
A Phase II Study of Concurrent IGFBP-2 Vaccination and Neoadjuvant 
Chemotherapy to Increase the Rate of Pathologic Complete Response at 
the Time of Cytoreductive Surgery 
 
 
PRINCIPAL INVESTIGATOR: John B. Liao, MD, PhD, University of Washington 
 
EMERGENCY NUMBER: 
206-797-2297 (pager), John B. Liao, M.D., PhD 
 
 
                  
 
        
Your doctors are inviting you to participate in a research study. The purpose of 
this research is to determine if adding a cancer specific vaccine (IGFBP-2 
plasmid based vaccine), that works with your immune system, to your standard 
neoadjuvant chemotherapy (carboplatin/paclitaxel/) will help the chemotherapy 
fight your cancer better. 
If you agree to join the study, you will begin receiving chemotherapy with your 
own oncologist.  Approximately two weeks after each chemotherapy you will 
receive a cancer vaccine under your skin in your arm or leg for up to 3 vaccines. 
Before each vaccine you will have a physical exam, blood draw, and review of 
any side effects from the vaccine.  We do not know if adding this vaccine with 
your chemotherapy will help treat your cancer and it may cause side effects.  
You do not have to join this study. You could choose to receive standard 
methods to treat your cancer without the addition of the IGFBP-2 vaccine. In this 
consent we will give you details about the purposes, procedures, risks and 
possible benefits related to this study. We will explain other choices that you 
have. We will also give you any other information that you need in order to make 
an informed decision about joining this study.   
Following is a more complete description of this study. Please read this 
description carefully. Afterwards, you can ask questions that will help you decide 
whether to join the study. If you join this study, we will give you a signed copy of 
this form to keep for future reference.  
We invite you to join this research study. 
We invite you to join this research study because you have just been diagnosed 
with ovarian cancer and have not received chemotherapy or surgery yet.  Up to 
38 people may join this study 
IRO received 12/22/20


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Page 2 of 16 
 
Research is not the same as treatment or medical care. The purpose of a 
research study is to answer scientific questions.  
You do not have to be in the study. You are free to say “yes” or “no”, or to drop 
out after joining. If you say “no,” you would have no penalty or loss of benefits. 
Whatever you decide, your regular medical care would not change.  
Why are we doing this study? 
We are doing this study to examine if giving the vaccine along with your 
chemotherapy enhances the effectiveness of the chemotherapy. The vaccine 
targets IGFBP-2.  IGFBP-2 is a protein found in the blood and tumor cells of most 
women who have been diagnosed with ovarian cancer. Too much IGFBP-2 has 
been associated with more invasive disease. One possible way to get rid of 
IGFBP-2 on tumor cells is simply to encourage your own immune system to 
generate an immune response against the tumor cells expressing IGFBP-2. 
Immunizing you with a vaccine against IGFBP-2 may do this.  
 
The vaccine is made up of DNA which is a natural substance in every living 
organism that helps make the proteins that cause cells in your body to function. 
The DNA we use is isolated from a bacteria and a portion of the IGFBP-2 protein 
code (DNA) is inserted.  The IGFBP-2 vaccine has previously been tested as a 
vaccine alone.   
The vaccine used in this study is not approved by the Food and Drug 
Administration (FDA) for commercial use; however, the FDA has permitted its 
use in this research study.  
What research tests, procedures, and treatments are done in this study? 
If you join this study, we would do these tests and procedures: 
Initial visit (prior to the start of your chemotherapy) 
• Informed consent conference. Review consent, have all your questions 
answered so you can make an informed decision to join the study or 
not. 
• Review your medical history and ensure you meet the eligibility criteria. 
• Physical exam which includes vital signs, medication review, and 
weight. 
• Clinical blood draw: 
o Routine blood tests to evaluate kidney, liver, and blood system 
function 
o ANA, C3, anti-dsDNA to screen for any autoimmune disorders 


9760/144 
 
 
Page 3 of 16 
 
o Thyroid function tests to monitor for any autoimmunity specific 
to your thyroid 
o CA-125 a tumor marker for ovarian cancer 
• Research blood draw 
o Up to one cup of blood will be collected for research testing so 
we can measure your immunity. 
• Archive Tissue Collection 
o If available, we would collect tissue from your primary diagnosis 
to be able to compare it to your tissue from your surgery after 
your complete the study treatment. 
Vaccinations 
Vaccinations will be approximately given two weeks after each chemotherapy 
visit for a total of 3 vaccine visits. Before each vaccine you will have: 
• Physical exam which includes vital signs, weight and a urine 
pregnancy test (if applicable) 
o If you are pregnant you will not be able to receive the study 
vaccine.. 
• Medication review 
• Side effect(s) review 
You must stay in the clinic for at least one hour after each vaccine to monitor 
you for any allergic reaction. 
 
Prior to the first vaccine you will have a tetanus vaccination if you haven’t had 
one in the last 6 months. This will help us measure your overall immune 
response. 
After completion of vaccinations 
After you have finished the vaccines you will enter the follow up part of the 
study. 
About one to two weeks after your last vaccine and before your surgery: 
  
Physical exam which includes vital signs, and weight. 
• Clinical blood draw: 


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Page 4 of 16 
 
o Routine blood tests to evaluate kidney, liver, and blood system 
function 
o  ANA, C3, anti-dsDNA  
o Thyroid function tests  
o CA-125  
• Research blood draw 
o Up to one cup of blood (depending on your blood counts) will be 
collected for research testing so we can measure your 
immunity. 
• After your surgery we will collect a piece of your tissue not needed for 
your clinical care for biomarker research.  The tumor tissue sample 
we collect will only be used for research. 
Approximately six months after your last vaccine, you will come back again 
for the following procedures: 
• Physical exam which includes vital signs, and weight. 
• Clinical blood draw: 
o Routine blood tests to evaluate kidney, liver, and blood system 
function 
o  ANA, C3, anti-dsDNA  
o Thyroid function tests  
o  CA-125  
• Research blood draw 
o Up to one cup of blood (depending on your blood counts) will be 
collected for research testing so we can measure your 
immunity. 
Long-Term Follow-Up 
Long-term follow-up means keeping track of someone’s medical condition for 
a long time.  If you join this study we would check with your oncologist to see 
how you are doing by collecting notes, labs, and imaging reports.  This would 
occur once a year for 5 years.  This information will help us learn about the 
long term effects of the IGFBP-2 plasmid based vaccine in combination with 
carboplatin/paclitaxel. 


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Page 5 of 16 
 
How long would you stay in this study? 
If you join this study, there will be 5 research visits to the University of 
Washington (UW) Clinical Research Center over a period of approximately 10 
weeks for study treatment and an additional follow-up, non-treatment visit, 6 
months after your last vaccine. 
Doctors could take you out of this study at any time. This would happen if: 
• 
Unacceptable side effects. 
• 
Another illness that prevents further infusions. 
• 
They think it is in your best interest not to continue in the study. 
• 
You not able or willing to follow study procedures. 
• 
You want to enroll in another treatment trial. 
• 
You become pregnant. 
• 
The whole study is stopped.  
If you withdraw from the study for any reason, previously collected information 
would remain in the study records and would be included in the analysis of 
results. This information could not be removed from the study records. We may 
ask you to undergo one final physical exam, which includes weight, vital signs, 
symptom assessment and blood collection, if applicable.  
What are the side effects (risks)? 
In this part of the consent form, we describe the side effects we expect from the 
tests and treatments in this study. Although we have given the IGFBP-2 vaccine 
to 25 women with a history of ovarian cancer and didn’t see any serious side 
effects we have never given this vaccine with chemotherapy.  We gave a total of 
86 vaccines. 
If you join this study, we would tell you if we discover new side effects that could 
affect you.  
 
Risks of Blood Tests 
Likely 
Less likely 
Rare but serious 
Pain 
Bruising 
Light-headedness 
Fatigue 
Fainting 
Infection 
 
Risks of Tetanus Diphtheria* Immunization  


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Page 6 of 16 
 
Likely 
Less likely 
Rare but serious 
Redness, pain 
and swelling at 
site 
Mild fever 
Decreased 
appetite 
 
Hard lump at the site 
Allergic reactions 
such as: hives, rash, 
and itching 
 
Fever > 102°F 
Allergic reaction, including shortness of breath, dizziness, 
a feeling of fainting, hives, and difficulty breathing caused 
by swelling of the mouth, face, tongue or throat 
Severe allergic reaction to the vaccine may require 
medication or lead to hospitalization or death 
 
Swelling, severe pain, bleeding and/or redness in the arm 
where the shot was given 
*If you have a history of an allergic reaction to the tetanus immunization, we will not give 
you one and you can still continue to be in the study. 
 
Risks of IGFBP-2 Vaccination(s) 
 
Risk of Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF, 
Sargramostim) 
GM-CSF is a natural substance that will be mixed and injected in very small 
amounts with the vaccine also known as an adjuvant.  In our previous vaccine 
studies that used GM-CSF, patients sometimes complained of mild to moderate 
flu like symptoms (fever, chills, achiness, and fatigue) for 1 – 2 days after 
vaccination which may be related to the use of GM-CSF.  The possible risks 
listed below are for a larger dose of GM-CSF than you will receive in this study; 
you will be getting a fraction of the regular GM-CSF dose. 
 
Likely 
Less likely 
Rare but serious 
Local reactions at the site of 
injection 
Low grade fever (Less than 
100.5° F) 
Chills 
Pain in the bones, muscles, 
chest, abdomen, or joints 
Nausea 
Kidney and liver problems 
Rashes 
Liver enlargement 
Low blood pressure 
Fluid retention (including fluid in 
lungs or around the heart)  
Blood clotting, including blood 
clots in the leg veins that can 
break loose and go to the lung 
Increased platelets, low albumin 
(a protein found in your blood), 
increase of liver enzymes 
Rapid or irregular heartbeat or 
Likely 
Less likely 
Rare but serious 
Pain and discomfort during 
vaccine administration 
Redness and tenderness 
at injection site (this 
usually goes away in 1-2 
days) 
Itching at vaccine site 
Fatigue 
Headache 
Flu-like syndrome 
Muscle pain 
Nausea 
Chills 
Diarrhea 
Allergic reaction, including shortness of breath, 
dizziness, a feeling of fainting, hives, and difficulty 
breathing caused by swelling of the mouth, face, 
tongue or throat 
Severe allergic reaction to the vaccine may require 
medication or hospitalization or death 


9760/144 
 
 
Page 7 of 16 
 
Likely 
Less likely 
Rare but serious 
Vomiting 
Diarrhea 
Flu-like symptoms including 
fatigue, weakness, headache 
Decreased appetite 
Increased white blood cell count 
other heart problems 
Allergic 
reaction, 
including 
shortness of breath, dizziness, a 
feeling of fainting, hives, and 
difficulty breathing caused by 
swelling of the mouth, face, 
tongue or throat 
Worsening of pre-existing fluid 
accumulation in arms and legs, in 
the lungs and around the heart 
that may result in breathing 
problems and heart failure 
Neurologic 
syndrome 
called 
Guillain-Barré syndrome, where a 
person’s own immune system 
damages 
their 
nerve 
cells, 
causing muscle weakness and 
sometimes paralysis 
Temporary loss of consciousness 
 
Risk of Generation of an Immune Response to Normal Cells  
It is unknown whether generating an immune response to this specific protein on 
your cells will have any effect on normal cells. 
 We will be monitoring you closely for signs of immune damage to normal 
cells.  We will be looking for diarrhea, development of any unusual rashes 
and changes in your liver, kidney, and blood function through blood tests.  
 Medicine may be administered if you develop any autoimmune symptoms.  
A severe autoimmune reaction could cause death. 
 
Likely 
Less likely 
Rare but serious 
None 
Skin rashes 
Diarrhea 
A severe autoimmune reaction 
could cause death 
 
Allergic Reaction Monitoring 
Severe allergic reactions are not common, but they do occur.  If they occur, they 
tend to happen within an hour or so of exposure to the substance causing the 
allergy.  Because of this rare risk, we will watch you in the clinic for a minimum of 
one hour after you receive each vaccine and booster vaccine to make sure you 
have no immediate side effects or allergic reactions.  Please allow time in your 
schedule for this 60 minute monitoring.  
Side effects may be mild or very serious. Medicines could be given to help lessen 
side effects. In some cases, side effects can last a long time or never go away. 
There also is a risk of death. 


9760/144 
 
 
Page 8 of 16 
 
 
Chemotherapy 
You will be receiving Carboplatin and Paclitaxel from your own oncologist per 
standard of care. Your oncologist’s team can help you deal with these effects 
should they occur. 
Reproductive Risks 
• Patients should not become pregnant while in this study 
• You should not nurse a baby after enrolling into this study 
• For patients who are having sex that could lead to pregnancy, you must 
agree to use contraception for the duration of the study 
o Check with a study doctor about birth control methods, some 
common methods might not be appropriate 
• There may be long term effects on fetal tissue that we are not aware of 
 
Non-physical risks 
If you join this study, non-physical risks are: 
• 
You might not be able to work. 
• 
Results of genetic tests might be released by accident. This risk is very 
low, because we keep personal information private. If these results 
became known, you could have problems with family members or 
insurance. 
What are the benefits? 
We do not know if the combination of a vaccine (IGFBP-2) in combination with 
chemotherapy will help treat your cancer. We hope the information we learn will 
help people with ovarian cancer in the future. 
We do not know if this study would help you. You might get better if you receive 
this treatment but your condition could stay the same or even get worse. We 
hope the information from this study will help other people with ovarian cancer in 
the future. 
You have other choices besides this study. 
You do not have to join this study. You are free to say “yes” or “no”. Your regular 
medical care would not change if you decide to say “no”.  
You have other choices for treatment.  Each of these choices has risks and 
benefits. You should talk to your doctor or healthcare provider about these 
choices.   
Other choices include: 
• Standard Treatment 


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Page 9 of 16 
 
• Another Research Study 
• No Treatment 
• Comfort Care 
Enrollment in this study may exclude you from other research studies.  
Protecting Privacy as an Individual and the Confidentiality of Personal 
Information  
If you join this study, some people or organizations might need to look at your 
medical records and research records for quality assurance or data analysis. 
They include: 
• 
Researchers involved with this study. 
• 
Institutional Review Boards (IRB), including the Fred Hutchinson 
Cancer Research Center IRB. An IRB is a group that reviews the study 
to protect the rights and welfare of research participants. 
• 
Fred Hutchinson Cancer Research Center, University of Washington,. 
• 
Food and Drug Administration (FDA). 
• 
Office for Human Research Protections (OHRP).  
• 
Other regulatory agencies as required. 
We will do our best to keep personal information confidential. But we cannot 
guarantee total confidentiality.  Personal information may be given out if required 
by law.  For example, workplace safety rules may require health workers to 
contact you about lab tests. Or a court may order study information to be 
disclosed. Such cases are rare. 
We will not use personal information in any reports about this study, such as 
journal articles or presentations at scientific meetings. 
If you join this study, information about your participation would be made part of 
your permanent medical record. This information would include a copy of this 
consent form. If an insurance company or employer or anyone else were 
authorized to see the medical record, they would see a copy of this consent 
form.  
How is my genetic information protected? 
A federal law called the Genetic Information Nondiscrimination Act (GINA) helps 
protect genetic information about people who join research studies.  
 
GINA restricts access to genetic information so that it cannot be used for health 
insurance coverage decisions. GINA prevent health insurance companies or 
group health plans from  
 


9760/144 
 
 
Page 10 of 16 
 
• Asking for genetic information obtained in research studies, or 
• Using genetic information when making decisions regarding your 
eligibility or premiums  
GINA does not help or protect against genetic discrimination by companies that 
sell life, disability or long term care insurance.  
Would we pay you if you join this study? 
There is no payment for being in this study. You will be given the option of 
receiving pre-paid parking vouchers for your research visits to the University of 
Washington Medical Center. 
Would you have extra costs if you join this study?  
If you join this study, you or your insurance company would have to pay for the 
costs of standard treatment in this study. 
What if you get sick or hurt after you join this study? 
For a life threatening problem, call 911 right away or seek help 
immediately.  Contact your study doctor when the medical emergency is over or 
as soon as you can.    
 
For all other medical problems or illness related to this research, immediately 
contact Dr. John B. Liao. His team will treat you or refer you for treatment.  You 
or your health insurance will have to pay for the treatment. There are no funds to 
pay you for a research-related injury, added medical costs, loss of a job, or other 
costs to you or your family.  State or national law may give you rights to seek 
payment for some of these expenses.  You do not waive any right to seek 
payment by signing this consent form. 
 
You or your insurer will be billed for treatment of problems or complications that 
result from your condition or from standard clinical care. 
You would not lose any legal right to seek payment for treatment if you sign this 
form. 
Future genetic research 
Several generic databases are available to help researchers understand different 
diseases. These databases contain DNA code and medical information from 
participants who have various diseases.  
As part of this study, we would like to release DNA code and information about 
your medical condition into a genetic database in order to help future research. 
The genetic database would not contain names, addresses, or other information 
that could be used to identify you.  


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Page 11 of 16 
 
The DNA code in a genetic database cannot be used by itself to identify any 
specific person. A researcher who already has DNA code about you could use 
information from a genetic database to learn more about you. Once we release 
information to a genetic database, we no longer have any control over the use of 
this information.  
Storing samples for future testing 
After we complete the research procedures on your specimens for this study 
there may be some specimens left over. We would like you to donate any leftover 
specimens for future research to the repository that the Tumor Vaccine Group 
(TVG) has. This future research may relate to immune response tests, or 
development of vaccines or other immunotherapies. You will be asked to sign a 
separate consent form for this purpose. 
Your rights 
• 
You do not have to join this study. You are free to say “yes” or “no”.  
• 
If you get sick or hurt in this study, you do not lose any of your legal rights 
to seek payment by signing this form. 
• 
During the study, we might learn new information that you need to know. 
For example, some information may affect your health or well-being. Other 
information might make you change your mind about being in this study. If 
we learn these kinds of information, we would tell you. 
• 
If you join this study, you would not have to stay in it. You could stop at 
any time (even before you start). Your regular medical care would not 
change. You would have no penalty for stopping, but it would be better not 
to join the study if you think that you would change your mind later.   
• 
If you decide to drop out, we would want you to tell the study doctor. The 
doctor could tell you about the effects of stopping the vaccine. You and 
the doctor could talk about the follow-up care and testing that would help 
the most. 
 
o We would want you to come back for a follow up visit if you leave 
the study. 
o We would like to continue to follow your progress and any side 
effects you may have developed because of the vaccine. 


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Page 12 of 16 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, 
as required by U.S. Law. This Web site will not include information that can 
identify you. At most, the Web site will include a summary of the results. You can 
search this Web site at any time.  
Your responsibilities 
If you join this study, you would have some responsibilities.  
• 
Follow the schedule of study visits and procedures. 
• 
Takes study medications as directed. 
• 
Prevent pregnancy.  
• 
Tell us about side effects.    
For more information 
If you have questions or concerns about this study, you could talk to your doctor 
anytime. Other people you could talk to are listed below. 
 
If you 
have questions about: 
 
Call: 
This study (including 
complaints and requests for 
information) 
 
Doreen Higgins, BSN, RN, OCN 
206-616-9538 
If you get sick or hurt in this 
study 
 
206-797-2297 
 Dr. John Liao 
Your rights as a research 
participant 
 
206-667-4867 (Karen Hansen, Director of 
Institutional Review Office, Fred Hutchinson 
Cancer Research Center) 
206-543-0098 (Human Subjects Division, 
University of Washington) 
Emergency number (24 hours): 206-797-2297 
Read each question and think about your choice. When you decide on each 
question, please circle YES or NO. 
 
 
 


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Page 13 of 16 
 
Is it OK if we send your genetic information to one or more databases for 
future research? 
(circle one) 
YES  
NO  
 
 
Is it OK if someone from the Tumor Vaccine Group contacts you in the future 
regarding this or other TVG research? 
 
(Circle one) 
YES 
NO 
Initials:  
Date: 
 


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Page 14 of 16 
 
Signatures 
If you have read this form (or had it read to you), asked any questions, and agree 
to participate, please sign: 
Participant / Printed Name, Signature, and Date 
 
 
Researcher’s statement 
I have discussed the research study, including procedures and risks, with the 
person signing above. A copy of the signed consent form will be given to the 
participant. 
 
Person obtaining consent signature / Printed Name, Signature, and Date 
 
 
Protocol: 9760/144 
Current version date: 07/19/2018 
Previous version date: 06/28/2017 
Copies to: Research Chart, Research Patient, Clinical Research Center 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FHCRC IRB Approval  
01/15/21 
Document Released Date


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Page 15 of 16 
 
 
Calendar of Events 
Visit Time 
Point 
Procedures 
First Visit-
prior to the 
start of your 
chemotherapy 
Some 
procedures 
may be done 
up to two 
weeks prior to 
initial vaccine 
visit 
• 
Consent 
• 
Medical history and complete physical examination 
• 
Vitals signs-including weight 
• 
Baseline symptom assessment 
• 
Routine blood tests to evaluate kidney, liver, and blood system 
function (CBC, CMP) 
• 
ANA, C3, anti-dsDNA 
• 
Thyroid function tests   
• 
CA-125  
• 
Research blood: approximately 200 mls*  
• 
If available, collect archived tissue from primary diagnosis 
First Vaccine: 
Approx. 2 
weeks after 
chemotherapy  
• 
Medical history and complete physical examination 
• 
Vitals signs-including weight 
• 
Urine pregnancy test (if applicable) 
• 
Baseline symptom assessment (if not previously collected) 
• 
Tetanus diphtheria (Td) immunization 
• 
IGFBP-2 vaccine 
• 
After vaccine monitoring for allergic reaction for a minimum of 60 
minutes 
Second 
Vaccine: 
Approx. 2 
weeks after 
chemotherapy 
• 
Medical history and complete physical examination 
• 
Vitals signs-including weight 
• 
Urine pregnancy test (if applicable) 
• 
Symptom/toxicity assessment 
• 
IGFBP-2 vaccine 
• 
After vaccine monitoring for allergic reaction for a minimum of 60 
minutes 
Third Vaccine: 
Approx. 2 
weeks after 
chemotherapy 
• 
Medical history and complete physical examination 
• 
Vitals signs-including weight 
• 
Urine pregnancy test (if applicable) 
• 
Symptom/toxicity assessment 
• 
IGFBP-2 vaccine 
• 
After vaccine monitoring for allergic reaction for a minimum of 60 
minutes 
 
 


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Page 16 of 16 
 
Visit Time Point 
Procedures 
Approx. 1 week 
after final vaccine 
Prior to surgery 
• 
Medical history and complete physical examination 
• 
Vitals signs-including weight 
• 
Symptom/toxicity assessment 
• 
Routine blood tests to evaluate kidney, liver, and blood system 
function  
• 
ANA, C3, anti-dsDNA 
• 
Thyroid function tests   
• 
CA-125  
• 
Research blood: approximately 200 mls*  
• 
Collect tissue from surgery: After your surgery we will collect a 
piece of your tissue not needed for your clinical care for 
biomarker research.   
Approx. Month 6 
After last vaccine 
• 
Medical history and complete physical examination 
• 
Vitals signs-including weight 
• 
Symptom/toxicity assessment 
• 
Routine blood tests to evaluate kidney, liver, and blood system 
function  
• 
ANA, C3, anti-dsDNA 
• 
Thyroid function tests   
• 
CA-125  
• 
Research blood: approximately 200 mls* 
Long-Term 
Follow-Up 
Once yearly 
follow-up for 5 
years 
• 
Collection of physician notes to review toxicity and clinical 
status 
* Please hydrate sufficiently prior to visits due to a large amount of blood being drawn.