Conditions: Breastcancer Breast Neoplasm
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 24
Healthy volunteers: no

Brief summary:
This is a single arm, open label study of SV-BR-1-GM, a targeted immunotherapy for breast cancer. Eligible patients will have histological confirmation of breast cancer with recurrent and/or metastatic lesions. The treatment regimen includes a pre-treatment with low-dose cyclophosphamide 2-3 days before the inoculation; inoculation in 4 sites on the thighs and upper back; and post-treatment inoculation of Interferon-alpha-2b into the sites of inoculation \~2 and \~4 days after the inoculation. These is repeated every 2 weeks for one month (3 treatments), then monthly for up to one year. Standard tumor assessments are performed at baseline and then every 2-3 months.

Detailed description:
This is a single arm, open label study of SV-BR-1-GM in recurrent and/or metastatic breast cancer. The detailed treatment regimen follows:

Pre-Inoculation Regimen:

Cyclophosphamide (Cytoxan) 300 mg/m\^2 I.V., 1x only, will be given 48-72 hours before each SV-BR-1-GM inoculation, with an antiemetic of the provider's choice (steroids prohibited). If the patient is not tolerating the cyclophosphamide, a lower dose may be used (e.g. 200 or 150 mg/m\^2) or it may be withheld, with the Sponsor's approval.

Innoculation Day Standard Operating Procedures:

1. Inquire regarding events of past weeks, change in medications, pain scale, ECOG scale, and review of systems.
2. Check injection sites.
3. Perform DTH skin test intra-dermally with the SV-BR-1 parent cell line (\~1 x 10\^6 irradiated tumor cells). Observe about 20 minutes for acute hypersensitivity. Grade III or higher acute hypersensitivity will abort therapy.
4. Inject SV-BR-1-GM intra-dermally into 4 sites in thighs and upper back (0.5 mL each). Monitor patients for 60 minutes. Vital signs will be assessed and medical attention will be warranted if unstable.

SV-BR-1-GM Preparation \& Inoculation Regimen:

Each inoculation will be administered via intra-dermal injection at the investigational sites. Subjects will receive 15-25 x 10\^6 viable, irradiated transfected breast tumor cells in a total volume of 2.0 ml Ringer's lactate. SV-BR-1-GM cells will be irradiated to ensure cell replication incompetency.

SV-BR-1-GM will be divided into four aliquots of 0.5 mL each and injected intra-dermally; one each into the anterior skin of the subject's right and left thighs and over the right and left upper back . Application of anesthetic lidocaine crème may be used if necessary for control of local pain before inoculation. Subjects will be monitored for 60 minutes.

After at least 10 subjects have been treated safely with this regimen, the dose of SV-BR-1-GM may be escalated or decreased in subsequent patients based on the emerging data.

Post-Inoculation Regimen:

2 days (± 1 day) after inoculation, and again 4 days (± 1 day) later after inoculation, the patient will return to the principal investigator's office to receive Interferon-alpha-2b (Merck) in 0.1 mL saline, prepared as follows: These will also be provided by the sponsor and injected intra-dermally to each inoculation site, beneath the thickest area. Again, subjects will be observed about 20 minutes. The DTH response will also be recorded at the 2 days (± 1 day) visit.

This cycle will be performed every 2 weeks for the first month of treatment (3 inoculations), and then every month for up to one year.

Arms:
arm 1: Pretreatment with low dose cyclophosphamide 2-3 days prior to SV-BR-1-GM inoculation; SV-BR-1-GM inoculation intradermally in 4 sites on the upper back (x2) and thighs (x2); Post-inoculation low dose Interferon-alpha-2b into the vaccination sites \~2 and \~4 days after SV-BR-1-GM inoculation

Interventions: intervention 1: SV-BR-1-GM intervention 2: Cyclophosphamide intervention 3: Interferon-alpha-2b
Intervention descriptions: intervention 1: See above intervention 2: Low dose pre-treatment to reduce regulatory T cells intervention 3: Low dose given in the vaccine site to boost the immune response

Protocol document:
Prot_SAP_000.pdf: 
 
TITLE PAGE:  
 
Study Title:         
A Phase I/IIa Study of SV-BR-1-GM in Metastatic or Locally 
Recurrent Breast Cancer Patients 
 
Study Sponsor:   
BriaCell Therapeutics Corp 
    
820 Heinz Ave. 
 
Berkeley, CA  94710 
 
Tel: 888-485-6340          FAX: 424-245-3719    
 
Test Article: 
SV-BR-1-GM 
                            
 
IND Number: 
BB-IND-10312 
 
ClinicalTrials.gov Identifier: 
NCT03066947 
 
Study ID Number: 
WRI-GEV-007 
 
Intended use: 
Treatment of Stage IV Breast Cancer with special 
consideration to CNS metastases 
 
 
 
 
Version 8.4, rev. July 11, 2018 
 
 
 
 
 
CONFIDENTIALITY STATEMENT 
 
  
This document is a confidential communication of BriaCell Therapeutics Corp.  Acceptance of 
this document constitutes agreement by recipient that no unpublished information contained 
within will be published or disclosed to a third party without prior written authorization from the 
sponsor, except disclosure to applicable Institutional Review Board/ Independent Ethics 
Committee under the same confidentiality conditions. 
 
 
 
 
 


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TABLE OF CONTENTS 
1. 
INTRODUCTION 
7 
1.1. 
BACKGROUND 
9 
1.1.1. 
General Background of the Experimental Product 
9 
1.1.2. 
Background of the Target Condition - Cancer 
9 
1.1.2.1. 
Clinical Immunology and Immunotherapy 
10 
1.1.2.2. 
Work done by Dr. Charles Wiseman & Colleagues 
11 
1.1.3. 
Alternative Treatments for Cancer 
12 
1.1.3.1. 
Strategies for tumor therapy 
12 
1.1.4. 
Previous Studies 
13 
1.1.5. 
Evaluation of Previous Studies 
15 
1.1.6. 
Plans for This Study 
16 
1.2. 
STUDY DESIGN 
17 
1.2.1. 
Study Purpose 
17 
1.2.2. 
Study Objectives 
17 
1.2.2.1. 
Primary Objectives 
17 
1.2.2.2. 
Secondary Objectives 
17 
1.2.2.3. 
Exploratory Objectives 
17 
1.2.3. 
Rationale 
18 
1.2.4. 
Hypothesis 
18 
1.2.4.1. 
Success Measures 
18 
2. 
STUDY PLAN 
20 
2.1. 
TRIAL SITES 
20 
2.2. 
STUDY POPULATION 
20 
2.2.1. 
Subjects 
20 
2.2.2. 
Source of Subjects 
20 
2.2.3. 
Recruitment of Subjects 
20 
2.3. 
ELIGIBILITY CRITERIA 
20 
2.3.1. 
Inclusion Criteria 
20 
2.3.2. 
Exclusion Criteria 
21 
2.4. 
DURATION OF PARTICIPATION 
22 
3. 
EXPERIMENTAL TREATMENT REGIMEN 
24 
3.1. 
GENERAL INFORMATION 
24 


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3.2. 
SUBJECT SCREENING 
24 
3.3. 
SV-BR-1-GM CYCLES 
24 
4. 
RISKS, BENEFITS, & RISK MANAGEMENT 
30 
4.1. 
PHYSICAL RISKS 
30 
4.2. 
NONPHYSICAL RISKS 
30 
4.3. 
ADVERSE EVENTS 
30 
4.3.1. 
Definitions and Reporting 
30 
4.4. 
LABORATORY TEST ABNORMALITES 
32 
4.4.1. 
Definitions and Reporting 
32 
4.5. 
SERIOUS ADVERSE EVENTS 
32 
4.5.1. 
Definitions and Reporting 
32 
4.6. 
RESPONSE TO ADVERSE EVENTS 
34 
4.6.1. 
During SV-BR-1-GM Administration 
34 
4.6.2. 
After the SV-BR-1-GM Administration 
34 
4.6.3. 
In Case of Injury 
34 
4.6.4. 
Adverse Events of Special Interest 
35 
4.7. 
BENEFIT TO SUBJECTS & OTHERS 
35 
5. 
STUDY PROCEDURES, METHODS, AND MATERIALS 
36 
5.1. 
RECRUITMENT 
36 
5.2. 
CONSENT PROCESS 
36 
5.3. 
SCREENING PROCESS 
36 
5.4. 
WITHDRAWAL and TERMINATION CRITERIA 
37 
5.4.1. 
Individual Subject Withdrawal Criteria 
37 
5.4.2. 
Study Termination Criteria 
37 
5.5. 
STUDY TESTS & PROCEDURES 
38 
5.5.1. 
General Considerations 
38 
5.5.2. 
Study Tests & Evaluations 
38 
5.5.2.1. 
Pre-Study Testing and Ongoing Monitoring 
38 
5.5.2.2. 
Immunological/Allergy Monitoring 
39 
5.5.2.3. 
Cutaneous Monitoring Criteria 
39 
5.5.2.4. 
Tumor and SV-BR-1-GM Specific Immunological Response 
40 
5.5.2.5. 
Collection of Biological Specimens for Ongoing Research 
40 
5.5.3. 
Goals of Immunological/Allergy Monitoring 
41 
5.5.4. 
Study Observation & Response Criteria 
41 


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5.5.4.1. 
Measurability 
41 
5.5.4.2. 
Responses 
42 
5.5.4.3. 
Toxicity and Evaluation for Adverse Events 
42 
5.5.5. 
Study Visits 
42 
5.6. 
STUDY VISITS & PROCEDURES 
43 
5.7. 
DATA COLLECTION 
43 
5.8. 
CONFIDENTIALITY& RECORDS 
44 
5.8.1. 
General Precautions 
44 
5.8.2. 
Study Information Leaving the Offices of the Investigator 
44 
5.9. 
COMPENSATION 
45 
5.10. SPECIMEN LABELING INFORMATION 
45 
6. 
MONITORING PROCEDURES 
46 
6.1. 
GENERAL PROCEDURES 
46 
6.1.1. 
Data Monitoring and Auditing of Data 
46 
6.2. 
AFTER COMPLETION OF THE STUDY 
46 
7. 
STATISTICAL CONSIDERATIONS 
48 
7.1. 
DATA of SPECIAL INTEREST 
48 
7.2. 
REVIEW of STUDY DESIGN 
48 
7.3. 
RESPONSE DEFINITIONS 
49 
7.4. 
DATA ANALYSIS 
49 
8. 
PROCEDURE and FORM ITEMIZATION 
50 
9. 
FORMS and REFERENCES 
55 
9.1. 
CONSENT, SCREENING & ENROLLMENT FORMS 
55 
9.1.1. 
Primary Consent Form 
56 
9.1.2. 
HIPAA Authorization Form 
70 
9.1.3. 
Consent for Use of Blood or Tissue for Research 
72 
9.1.4. 
Study Information Sheet 
74 
9.1.5. 
Screening Evaluation Form 
77 
9.1.6. 
Screening and Enrollment Log 
80 
9.2. 
SUBJECT MANAGEMENT FORMS 
81 
9.2.1. 
Subject Withdrawal Form 
81 
9.2.2. 
Telephone Contact Log 
82 
9.3. 
CLINICAL and DATA COLLECTION FORMS 
83 
9.4. 
REFERENCES 
83 


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9.4.1. 
Cited Literature 
83 
9.4.2. 
Pharmaceutical Descriptions of Study Substances 
90 
9.4.3. 
SV-BR-1-GM Preparation 
92 
9.4.4. 
CTCAE v4.03 Toxicity Criteria 
98 
9.4.5. 
Positive Culture Action Plan 
98 
 
 
LIST OF TABLES 
Table 1:  
 
8 
Table 2:  
 
28 
 
LIST OF FIGURES 
Figure 1: 
 
6 
Figure 2: 
 
12 
Figure 3: 
 
14 
 
 
 
 


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Figure 1: 
STUDY SUMMARY & PROGRAM SCHEMA 
 
 
 
SV-BR-1-GM 1,2,3
(week 1, 3, 5)
SV-BR-1-GM 4,5
(month 2,3)
SV-BR-1-GM 6,7,8
(month 4,5,6)
Non-progressive response
Progression
Progression
Non-progressive response
†SV-BR-1-GM 12,13,14
(month 10,11,12)
†SV-BR-1-GM 9,10,11
(month 7,8,9)
OFF 
TREATMENT
Restage: Imaging, labs, clinical evaluation*
Restage: Imaging, labs, clinical evaluation
(before month 10 and cycle 12)
Restage: Imaging, labs, clinical evaluation
Baseline: Imaging, labs, clinical evaluation
Restage: Imaging, labs, clinical evaluation
(before month 7 and cycle 9)
* Restaging to occur between Treatment 4 and 6. Patients with rapid progression may go off-study per PI.
†Continuation to Treatment 8 is mandatory unless rapidly progressive in opinion of PI; Treatments 9-14 are optional and the 
patients must fullfill the criteria of non-progressive disease and desire to continue treatments.
NOTE: Grade III hypersensitivity or IV toxicity at ANY step will warrant special review; see Toxicity
Flexibility between cycles can be +/- within one week under special circumstances as approved by PI.


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1. 
INTRODUCTION 
This Phase I/IIa study is designed to evaluate the safety and efficacy of, using SV-BR-1-GM, a 
breast cancer cll line genetically engineered to secrete GM-CSF and consequently augments 
dendritic cell activity [1-4].  A breast cancer cell line is expected to contain one or more putative 
tumor rejection antigens; for non-breast cancer cases, eligibility requires the subject’s tumor also 
to have evidence of HER2/neu positivity, which is commonly reported as 20-30% of cases in the 
published literature [5].   
 
Previous work with this program demonstrated prompt and near-complete regression of multiple 
sites of metastatic breast cancer involving brain, and therefore special consideration is given to 
allow protocol entry to selected patients with central nervous system (CNS) involvement.   
 
Each experimental administration cycle comprises of 4 intra-dermal injections.  This will be 
given 3 times as a cycle: once every 2 weeks during the initial phase.   
 
Each cycle will be comprised of 4 study events (and location) 
1. Pre-SV-BR-1-GM cyclophosphamide (physician’s office)            
2. SV-BR-1-GM inoculation (physician’s office)  
3. Interferon-alpha-2b (Merck) at 2 days post- SV-BR-1-GM (physician’s office)                                 
4. Interferon-alpha-2b (Merck) at 4 days post- SV-BR-1-GM (physician’s office) 
 
A Quality of Life questionnaire (SF-36) will be administered at the start of each cycle.  The 
evaluation of safety and clinical developments will be assessed at every study visit after starting 
the SV-BR-1-GM therapy cycles.  The first three cycles will occur over one month at Weeks 1, 
3, and 5. This will be followed by monthly cycles for a total of 6 months; with optional 
treatments out to a year. Imaging and restaging will occur between the 4th and 6th inoculations 
(e.g. about month 2-3).  In the absence of progressive disease (defined below) or major safety 
issues, the patient will continue with additional SV-BR-1-GM therapy cycles to complete 6 
months of experimental SV-BR-1-GM administration, with restaging every 3 months at 
approximately 3 weeks following the last treatment. If the patient remains non-progressive and 
desires to continue treatment after six months they will be offered an additional three months of 
treatment followed with restaging at nine months. Again, if the patient has non-progressive 
disease and desires to continue treatment, they will be offered an additional 3 months of 
treatment, with completion at 12 months. 
 
 
 


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Table 1:  
SV-BR-1-GM CYCLES 
Week # 
Cycle 
Comments 
1, 3, 5 
1, 2, 3 
 
Month # 
 
 
2, 3 
4, 5 
Restaging about 1-2 weeks prior to initiation of next cycle (#6) 
4, 5, 6, 
6, 7, 8 
Restaging about 1-2 weeks prior to initiation of next cycle (#9) 
Optional Treatment Cycles Patient may continue if they show non-progressive response 
7, 8, 9 
9, 10, 11 
Restaging about 1-2 weeks prior to initiation of next cycle (#12) 
Optional Treatment Cycles Patient may continue if they show non-progressive response 
10, 11, 12 
12, 13, 14 
Off-treatment evaluation about 6-8 weeks after last inoculation 
cycle 
Flexibility between cycles can be +/- within one week under special circumstances as approved by PI. 
 
 
 
The schedule is also provided graphically in Figure 1, “Program Schema.” 
To boost the immune response, patients will be pretreated with low-dose cyclophosphamide that 
has been shown to down-regulate T regulatory-cell mechanisms [6-9] 2-3 days prior to each SV-
BR-1-GM inoculation.  Low-dose Interferon-alpha-2b (Merck) serves as an adjuvant [10,11] and 
is given by intradermal injection to the inoculation site 2 days and 4 days after SV-BR-1-GM 
inoculation.  Biological specimens will be collected at regular intervals per protocol, and stored 
in a repository (with subject permission) pending future research by the sponsor.  Collection, 
labeling, and storage of these specimens will follow the procedures outlined in a separate 
Laboratory Manual. Study procedures involving subjects (e.g. screening, inoculation, follow-up 
visits, etc.) will take place at trial sites.  SV-BR-1-GM manufacturing, quality control, 
preparation, and study laboratory tests will take place at the sponsor’s research facility.  SV-BR-
1-GM and specimens will be transported to the sites using appropriate procedures summarized in 
Section 9.4.5. 
Study participants will be closely monitored for adverse events (toxicity) using the common 
terminology criteria for adverse events (CTCAE v 4.03) scale.  Development of Grade IV 
toxicity in any subject will truncate accrual until further review by the medical monitor, IRB and 
FDA as appropriate.  Development of a new or progressive tumor, or treatment-related Grade III 
allergy/hypersensitivity, will truncate further inoculations to any particular subject. We have 
previously reported results on 4 patients included remarkable responses and positive 
improvement of survival [12]. Given the initial development of even minimal evidence of host 
responses, and absence of toxicity, we plan to test 10 patients and plan to perform a safety 
analysis. Once deemed safe, an additional cohort of 15-30 patients (up to total of 25-40) will be 
enrolled. Patients who do not reach the initial post-dose tumor assessments may be replaced at 
the discretion of the Sponsor. 
Each patient will be on treatment for 6-12 months and no extended follow up. Any future 
research on specimens collected during this study will be controlled by a separate, IRB-approved 
protocol; to be developed as the need arises. 


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1.1. 
BACKGROUND 
1.1.1. 
General Background of the Experimental Product 
 
SV-BR-1-GM is an experimental, HER-2/neu positive, allogeneic, whole cell breast tumor cell 
line transfected with the GM-CSF gene to secrete GM-CSF in situ and consequently augment 
dendritic cell activity [15-18].  This biological product has been previously granted an IND by 
the FDA for investigational use only under BB-IND-10312, under the designation SV-BR-1-
GM.  Documentation of initial tumor regression has been published [19].  This preliminary data 
is especially notable for demonstrating regression of brain metastases and for the reinduction of 
response with retreatment.  Regression of brain metastases has not been commonly reported in 
such studies.  However, we observed regression in a patient on this protocol.  To note, such 
regression was also seen in another patient, previously treated by our group under another 
protocol, BB-IND-2749 [20]. 
1.1.2. 
Background of the Target Condition - Cancer 
 
Cancer of all types is one of the biggest medical public health problems in the world.  This study 
can provide a template for looking at the effects of the investigational product known as SV-BR-
1-GM on various types of cancer.  For the current protocol, we emphasize that HER2/neu 
antigens on SV-BR-1-GM are strongly over-expressed and that similar over-expression is a 
feature not unique to breast cancer.  Approximately 20-30% of prostate, lung, ovary, gastric, 
pancreatic, colon, bladder, and other categories of human malignancy may display HER2/neu 
antigenic over-expression, albeit not necessarily having similar molecular biology or prognostic 
features as breast cancer.  The possibility certainly exists that SV-BR-1-GM with over-
expression of known and defined antigen, might have applications for other tumor types.   
  
But to consider only breast cancer, we address a public health problem of enormous magnitude. 
Worldwide, an estimated 500,000 women will die from this disease each year.  In the US, 1 in 8 
women will contract the disease, and, despite some progress in therapy, the majority of patients 
with metastatic breast cancer will ultimately die within 3 years [21] (See also 
http://www.cancer.gov/cancerinfo).  
 
While complete responses are certainly not uncommon in general clinical practice, an analysis by 
Greenberg, et al. of 1581 patients at the M.D. Anderson Hospital and Tumor Institute 
demonstrated this outcome occurred in only 16.6%, and by 5 years, only 3.1% were still in 
complete remission [22]. The natural history of metastatic breast cancer in 2003 can still be 
appropriately compared to studies 25 years ago [23].  Fossati’s review of published randomized 
trials, involving 31,510 metastatic breast cancer patients [21] did indicate progress, but certainly 
new and more effective therapies are needed.  There is a possibility that targeted 
immunotherapies (also known as therapeutic cancer vaccines) will be useful, and the Physicians 
Data Query (PDQ) compilation describes such clinical trials in progress throughout the United 
States.  
 
 


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1.1.2.1. 
Clinical Immunology and Immunotherapy 
 
The efforts of many researchers have suggested the presence of breast cancer-associated 
antigens, including CEA, T/Tn, MAGE, MUC-1, and others [24].  A comprehensive review is 
beyond the scope of this protocol.  Previously, Renkvist et al. [25] made a catalog of tumor-
associated antigens recognized by T-cells, of which breast-cancer related antigens are frequently 
noted.  A more recent compilation has been published in the open journal Cancer Immunity by 
van der Bruggen [26]. 
 
Previously, the establishment of a large library of breast cancer cell lines, together with available 
autologous serum, supported the sponsor’s earlier studies of tumor-specific host immune 
responses [27].  These cell lines included the often studied MDA-MB-231, -435, -156, and 
others.  Indirect immunofluorescent antibody assays detected autologous reactivity to established 
breast cancer cell lines in 8 of 10 patients; reactivity remained present after absorption with 
heterophile antigens, normal breast tissue, and AB+ human red cells.  These reactions occurred 
in 40-66% of allogeneic sera samples from breast cancer patients, and were not explainable as 
reactions to CEA. Additional work indicated both humoral and cell-mediated reactivity [28, 29] 
to antigens related to mouse mammary tumor virus.  There has been renewed interest [30] in the 
possibility that human breast cancer may involve an agent similar to mouse mammary tumor 
virus. Those early serological studies as well as in vitro studies of cell-mediated immunity were 
consistent with this still-unresolved hypothesis. 
Breast cancer may have antigens related to the Thompson-Friedenreich blood group antigen [31].  
The sponsor has had an interest in these antigens, and performed a small survey of cellular and 
humoral responses to a commercial “T-antigen” preparation (Wiseman et al, unpublished).  To 
note, others have pursued this area, even to the point of very large Phase III clinical trials [32].  
Given the existence of known and putative breast-cancer associated antigens, there are many 
options for creating cancer targeted immunotherapies [7]. Questions persist regarding the use of 
whole-cell vs. tumor lysates, autologous antigens vs. chemically defined antigens, and other 
treatment variables Issues on dose, route, schedule and duration of therapy require much further 
investigation, especially in the absence of a commonly-accepted surrogate marker of immune 
response [33, 34].  Even if available, the evaluation of disease-free and overall survival is the 
ultimate, practical outcome measure, in conjunction with toxicity and impairment (or lack 
thereof) of one’s quality of life. 
Targeted immunotherapy has been associated with regression of bulky, macroscopic tumors.  
Our group described such results, notably, in a melanoma patient, involving a change in tumor 
volume on the order of 800 cc [35].  Others have also reported tumor regressions in advanced 
cancer, and in particular, breast cancer.  Jiang et al. reported using subcutaneous injections of 
autologous and allogeneic MCF-7 breast cancer cells, together with CA15-3, CEA, CA125 plus 
IL-2 and GM-CSF in 42 patients with advanced breast cancer, and observed clinical regression 
in 2 patients, one of whom had complete disappearance of hepatic metastases [36].  Krause et al. 
have been applying a dendritic cell immunotherapy program to breast cancer as well as 
melanoma [37] and have observed several breast cancer patients with major regression of 
advanced, metastatic tumor, one of whom had a response of such intensity as to precipitate tumor 
lysis syndrome [38]. The early reports on sialyl-Tn immunotherapy identified partial responses 
in 3 of 12 patients [39] although, as mentioned, a Phase III clinical trial by the Biomira Corp. 


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failed to achieve the predetermined statistical endpoints of improvement in time to disease 
progression and overall survival. 
 
Disis et al. have demonstrated that frequent and durable immune responses to HER2/neu can be 
generated [40].  This study also employed GM-CSF in conjunction with peptides of the 
HER2/neu receptor antigen.  Of 64 patients with over-expression of HER2/neu (including 
ovarian and non-small cell lung cancer), 92% demonstrated immune responses to the 
immunizing antigen, and persistence of same for at least 12 months.  Moreover, the phenomenon 
of epitope-spreading was documented as well.  The overall implications for clinical outcome 
remain inconclusive, however. 
Whole cell preparations continue to hold appeal for targeted cancer immunotherapy studies, 
especially given the report of 3 of 33 complete remissions in lung cancer with a whole-cell 
preparation transfected with GM-CSF [41].  We note that the plasmid-transfection methodology 
used here has the potential to provide a more stable and more sustained level of GM-CSF 
production than other transfection techniques.  Given our current lack of knowledge of the 
presence and distribution of the relevant tumor-associated antigen(s) [42], whole cells may have 
the advantage of providing a large repertoire of both membrane and cytoplasmic antigens, and, 
while some antigens have been characterized, it is likely many more remain to be identified.  
1.1.2.2. 
Work done by Dr. Charles Wiseman & Colleagues 
 
The research program of the sponsor, Dr. Wiseman, has used whole-cell targeted 
immunotherapies in a variety of human malignancies, including melanoma and pancreatic 
cancer. More recently, he has evaluated a cohort of breast cancer patients treated with a cell line 
established in his laboratory and administered in conjunction with GM-CSF. This particular cell 
line, designated SV-BR-1 is fast growing and has strong expression of the HER2/neu antigen, an 
immunogenic neoantigen that has been shown to be overexpressed by a high number of breast 
tumors [43].  
 
Data have been presented describing a small cohort of patients with very advanced stage IV 
breast cancer inoculated with a targeted immonotherapy consisting of 10-20 x106 irradiated 
tumor cells (SV-BR-1).   SV-BR-1 was administered by lymphangiogram technique, 
intralymphatic technique or intradermally admixed with an equal number of cryopreserved 
peripheral blood lymphocytes obtained by leukapheresis [44].   Patients were pretreated with 
low-dose cyclophosphamide 300mg/m2 2-3 days prior to SV-BR-1 and received subcutaneous 
injections of GM-CSF just prior, and for 8 days after, SV-BR-1 inoculation.  Toxicity included 
one patient with increasing ascites and abdominal discomfort during the GM-CSF injections and 
another patient who developed, following cyclophosphamide, exacerbation of pericardial 
effusion and atrial fibrillation, which spontaneously resolved.  It is unclear if these are really 
adverse effects from the inoculations or natural progression of un-responding breast cancer.  
There were 4 patients surviving more than 12 months.  One patient is alive at 156 months. (See 
Figure 2 below) 
 
 
 


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Figure 2: 
SURVIVAL OF 14 BREAST CANCER PATIENTS TREATED WITH PBL/ID 
TUMOR CELL PREPARATION (SV-BR-1) 
 
 
1.1.3. 
Alternative Treatments for Cancer 
1.1.3.1. 
Strategies for tumor therapy 
An effective therapy for patients with advanced malignancy would produce tumor regression to 
detectable levels, would extend the time to relapse, and would improve survival.  Should 
malignant transformation occur again by whatever mechanism previously involved with the 
initial tumor, host defenses would prevent de novo tumor growth.   
Current thinking about cancer biology asserts that cancer is a clonal population that rapidly 
becomes heterogeneous. Tumor growth follows Gompertzian kinetics and chemotherapy works 
via first order kinetics [45].  Since clinical tumors have been present but undetectable for 90% or 
more of the lifespan of the malignancy, whatever host immune response they might have elicited 
must have been somehow nullified.  Immunotherapy to be effective must reverse this state of 
tolerance [46, 47].  Current understanding of the key mechanism of immune cytotoxicity favors a 
process mediated by CD8+ T-lymphocytes, although important contributions by NK-cells, 
antibody, and other mechanisms are not discounted [48,49].  
While these and other theoretical concepts above are receiving intense reappraisal, the necessary 
and sufficient conditions for effective therapy are not known, and intermediate processes will be 
much better understood if and when reliable surrogate markers of effective immunization have 
been identified [50].  A promising new test, the Cell Search assay, which quantifies circulating 
breast cancer cells, may be useful for the identification of early response (or lack thereof) [51] 
long before there is indication of tumor regression by the usual imaging techniques.  
The kinetics of immune response may also play a very important role.  The sponsor of this study 
has collaborated with a number of mathematicians (Mathematics of Medical Oncology Study 
Group), resulting in a publication [52]. The sponsor also helped organize an international 
meeting sponsored by the American Institute of Mathematics (www.aimath.org) (The Modeling 


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of Cancer Progression and Immunotherapy December 12 to December 16, 2005 at the American 
Institute of Mathematics, Palo Alto, California organized by Lisette de Pillis, Ami Radunskaya, 
and Charles Wiseman). From various studies in the public domain, the publication mentioned 
above describes a computer simulation based on the following differential equations:   
 
  
 
 
 
 
 
 
 
 
 
 
 
  
The model documented the importance of both NK cell and CD8+ cytotoxicity, a difference in 
the dynamics of their response, and the utility of currently available immuno-monitoring 
methods. Sensitivity analysis emphasized a primary role of patient-specific responses.  
Refinements to this model are ongoing, but this study provides an obvious resource for 
generating data useful for hypothesis testing of the computer model. This model was based on 
kinetics of a mouse tumor, but was in part validated using published data from clinical 
immunotherapy investigations in humans.  Clearly strategies do exist with the potential to help 
develop clonal proliferation of tumor-specific effector cells from antigen primed memory T-cells 
[53].  Remarkably, increasing number of reports are appearing which demonstrate up-regulation 
of cytotoxic T-lymphocytes after targeted immunotherapy; a change that occurs despite the 
abundance of antigen that must already be circulating in patients with tumor. 
The immune response begins with antigen presentation, which is believed to be mediated mostly 
by dendritic cells, the most active of the “professional” antigen-presenting cells.  Dendritic cell 
differentiation can be augmented by GM-CSF, a lymphokine currently used for protecting 
marrow during intense chemotherapy [54].  The application of GM-CSF in clinical trials has 
extended from the evaluation of effects as a single agent [55], to combining with targeted tumor 
immunotherapies [56,57] and to use in creating genetically-engineered tumor cell 
immunotherapies that release GM-CSF locally [58,59].  In addition, many of these studies of 
GM-CSF modulated immunotherapy are now including the use of currently-available 
chemotherapy [60, 61].  
1.1.4. 
Previous Studies 
 
The sponsor, Dr.Wiseman, was involved with the Immunotherapy Laboratory at St. Vincent 
Medical Center, Los Angeles, up until 2006.  During that time, he had been involved with 


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establishing a program of investigations of whole-cell tumor preparation through IND BB-2749.  
Initially concerned with preparing single-cell suspensions of tumor cells for application in the 
autologous setting, this research program had evolved to provide off-the-shelf whole tumor cell 
preparations in the event autologous tumor was not available.  Over the years there has been a 
series of different modifications to the original clinical trial program of autologous or allogeneic 
whole cell targeted immunotherapies. Some of the principal changes are shown below: 
 
EVOLUTION OF TARGETED IMMUNOTHERAPY STUDIES 
1. Fresh frozen tumor cells 
2. Pre-treatment of patients enrolled with low-dose Cyclophosphamide 
3. Cholesteryl Hemisuccinate for Antigen Up-regulation 
4. Cy+ CHS/Targeted Immunotherapy +IL-2 
5. IFN-alpha treatment of tumor cells for Antigen Up-regulation 
6. GM-CSF administration 
7. IFN-gamma treatment of tumor cells for Antigen Up-regulation 
8. Tumor cell/PBL Co-inoculum 
9. Genetically-engineered whole tumor cell preparations 
 
More than 250 patients have been studied under this program (BB-IND 2749) in its various 
iterations and modifications.  While melanoma was initially our major concern, changes in 
referral pattern have encouraged study of other tumor types as well. (See Figure 3 below): 
 
Figure 3: 
Types of Cancer Studied Under BB-IND 2749 
 
 
 
 
    
 
 
14% 


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The initial strategy of our program was to evaluate small cohorts in sequential Phase 1 studies:  
 
DESIGN OF CLINICAL TRIALS   
1. Evaluate cohort: 
a. If >1 of 14 objective responses, continue accrual  
b. If Grade IV toxicity, suspend study, consult FDA; redesign as needed 
c. If >30% response, plan for publication and further clinical trial studies 
d. If 10-20%, evaluate possible prognostic factors, review literature, redesign the 
clinical trial  
 
2. Ongoing collection to bank serum, plasma, lymphocytes, tumor tissues (available basis), 
etc. for further correlative study 
 
3. Critical review of clinical and possible surrogate endpoints       
 
More recently, the sponsor has been involved with evaluating the role of subcutaneous GM-CSF 
administered simultaneously with targeted immunotherapies under this previously approved 
IND, BB- IND-10312.  Data has been reported at major meetings for his work with breast cancer 
[62], melanoma [63] pancreatic cancer [64, 65], renal carcinoma [66], and lung cancer [67].  A 
presentation at the Society of Biological Therapy in October 2006 [68] described TWO patients 
with regression of brain metastases during targeted immunotherapy: one patient described in the 
publication above; another treated under a different protocol (BB-IND 2749).  Dr. Wiseman is 
now assuming the role of sponsor -BriaCell Therapeutics- under Part 312 of the Federal 
regulations, and thus, the research in this protocol will be performed by outside principal 
investigators. 
1.1.5. 
Evaluation of Previous Studies 
 
The possibility of 'subclinical regressions' deserves further study as the reliance on imaging 
methods may be insensitive. Leung et al. described a program of neoadjuvant therapy for 
hepatoma, which did not appear to have any efficacy according to CAT scan and radiologic 
imaging [69].  However, some cases proceeded to surgical resection and showed only fibrosis 
and scarring; this complete pathological response would not have been recognized at all by the 
usual radiological techniques.  A similar finding was reported for pancreatic cancer, with 2 of 15 
patients in complete pathological remission identifiable only after surgical resection [70]. 
Clinical use of serum markers may provide an opportunity to identify such 'subclinical 
responses', at least for some malignancies. Our work with pancreatic cancer fits this paradigm of 
possible increased survival associated with targeted immunotherapy in the absence of 
identifiable changes in measurable or evaluable metastatic lesions. 
 
Wiseman and colleagues [71] treated 17 evaluable pancreatic cancer patients with allogeneic 
targeted immunotherapy prepared from culture of the cell line MiaPaca (ATCC).  For 7 of the 17 
patients having a drop in CA 19-9 equal to or greater than 20%, the survival was 8.3 months; for 
those not showing such biological effect, the median survival was 4.0 months. Survival versus 
change in CA 19-9 had correlation-with a statistically significant value: p =0.007 [71]. 


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1.1.6. 
Plans for This Study 
This study will address safety, feasibility and toxicity, and plan for the investigation of clinical 
(or immunological) responses. As mentioned above, we have published results of a study finding 
widespread clinical regressions in breast cancer.  Results from the current study will possibly 
support or preclude expansion to Phase II and Phase III studies under this IND. 
 
At the initiation of dosing in this study, the Food and Drug Administration (FDA) requested that 
the first three patients be dosed sequentially, with at least 2 weeks between patients, to evaluate 
the safety of SV-BR-1-GM.  This phase of the study was completed as of 27 September 2017 
and no safety issues related to SV-BR-1-GM were noted that would limit continued dosing in 
these patients or preclude dosing additional patients.  With this phase of the study completed, the 
second phase of the study commenced where patients can be enrolled and dosed simultaneously.  
This marks the transition from the Phase I to the Phase IIa part of the study. 
 
In addition, one patient developed a fatal serious adverse event on study.  The patient was a 54-
year-old woman with metastatic breast cancer involving one breast, including cutaneous 
metastases, and the pleura with a large pleural effusion.  Prior treatment had included neo-
adjuvant docetaxel, carboplatin, trastuzumab, pertuzumab and capecitabine.  She came in for 
cycle 2 of cyclophosphamide. She had evidence of a clinical response in her cutaneous 
metastases.  She was scheduled to have a pleurex catheter placed for chronic, recurrent pleural 
effusion.  Breathing was at baseline (mild dyspnea).  She received cyclophosphamide.  Two days 
later the patient presented to clinic with complaint of weakness and shortness of breath, 
worsening over the last 2 days. The patient had not had much to eat or drink, this is typical of 
when she has had chemo before, similar to cycle 1 of cyclophosphamide.  Urine appeared very 
concentrated and 1 liter of normal saline was administered in clinic along with oxygen. On exam 
she had a blood pressure of 113/70s, pulse 90s. Her left pleural effusion (on physical exam) was 
~1/2 lung field. She had trace bipedal edema, which she also noted following her cycle 1 dose.  
She was advised to go to the emergency room to have the pleural effusion drained. The patient 
received SV-BR-1-GM following which she was stable with continued dyspnea and sent to the 
emergency room. In the emergency department, the patient was evaluated, and her initial intake 
vital signs showed a temperature of 35.4°C, a pulse of 71, a blood pressure of 97/72, a 
respiratory rate of 14, with 98% oxygen saturation on room air.  On physical exam, she was 
noted to be distressed and tachycardic with decreased breath sounds on her left, consistent with 
the known malignant pleural effusion.   Labs were remarkable for hyperkalemia, lactic acidosis, 
hypoproteinemia, transaminitis and leukocytosis.  An initial chest x-ray was read as “Near 
complete white out of the left hemithorax…Heart size cannot be accurately assessed.”  ECG 
findings included sinus tachycardia and low voltage QRS.  Approximately 3 hours after her 
initial arrival to the emergency department, the subject went into pulseless electrical activity 
(PEA) arrest.  CPR was initiated, the patient was intubated, and a left chest tube was placed.  
During the code, a limited transthoracic echocardiogram was obtained.  With only subcostal 
windows, the patient was noted to have global left ventricular hypokinesis (ejection fraction 
estimated at 10%), “RV collapse during systole in the presence of a circumferential small 
volume pericardial effusion.” The patient had return of circulation with support of an epinephrine 
drip.  A CT scan (without IV contrast) was obtained that was read as having “near complete 
consolidation of both lungs…Moderate to large pericardial effusion.”  The patient remained on 
vasopressor medications in the ICU; however, she continued to decline clinically and ultimately 


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died. No autopsy was performed. The Investigator and the Sponsor both noted the event was 
unlikely related to study drug. 
1.2. 
STUDY DESIGN 
 
This study incorporates elements of Phase I design such as toxicity and immunological/allergy 
monitoring, which will measure the overall tolerability of the experimental therapy.  In addition, 
Phase II elements such as clinical efficacy - determined as RECIST and iRECIST criteria - will 
be studied.  
1.2.1. 
Study Purpose  
 
The purpose of this study is to gather preliminary data to evaluate the safety, tolerability, and 
feasibility of targeted immunotherapy for advanced breast cancer with a special consideration for 
CNS metastasis using allogeneic breast tumor cell line transfected with the GM-CSF gene (SV-
BR-1-GM).  This experimental therapy will be evaluated in a small initial cohort of 25-40 
subjects with qualifying stage IV breast cancer.  SV-BR-1-GM is inoculated by intradermal 
injections with subsequent local injection of low-dose Interferon-alpha-2b (Merck). 
1.2.2. 
Study Objectives 
 
As this design incorporates elements of a preliminary safety/toxicity study, clinical response, 
duration of response, and survival are not primary endpoints of the protocol, but such data will 
be monitored for possible support of further research plans.  Similarly, quality of life (QOL) will 
be assessed using a standardized questionnaire [73, 74] (See SF-36 Health Survey) 
 
To evaluate the performance of the experimental therapy, the following objectives will be 
assessed. 
1.2.2.1. 
Primary Objectives 
 
To evaluate the number, frequency, duration, and relation of toxicity events to SV-BR-1-GM, as 
defined by CTCAE and additional tests as described in section 5.5.2. 
1.2.2.2. 
Secondary Objectives 
 
1.  To evaluate tumor response:  
a. Objective response rate (ORR), defined as complete response (CR) or partial response 
(PR) per RECIST and iRECIST response criteria 
 
b. Non-progressive rate, defined as CR, PR or stable disease (SD) per RECIST and iRECIST 
 
c. Durability of response, by evaluating those patients eligible to complete the optional 
treatments from 9-12 months. 
1.2.2.3. 
Exploratory Objectives 
 
1. To assess immune responses to SV-BR-1-GM, and to recall antigens, if any, as measured 
by DTH skin tests and/or other immunological tests. 


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2. To gather data in support of further investigations blood and urine will be stored in a 
tissue repository for future analysis.  Studies anticipated will include, but are not limited 
to histocompatibility characterization, levels of circulating cytokines antibodies and cell 
mediated immune responses. 
3. To measure the quality of life (QOL) of participants and the effect the biological agent 
may have on the subjective sense of well-being. To measure changes in weight, 
performance status, and pain. 
1.2.3. 
Rationale 
 
A recent review describes a number of studies using cancer cell targeted immunotherapies 
genetically modified to produce various cytokines, including GM-CSF [75].  These reports add 
to the understanding of safety and tolerability for GM-CSF-transfected whole-cell targeted 
immunotherapies and reinforce the notion that the method of GM-CSF introduction appears to 
have several important advantages over subcutaneous injections of the exogenous cytokine: a) it 
is less labor-intensive, b) it is less likely to cause the side-effects associated with systemic GM-
CSF injections, c) local cytokine concentration is more stable and long-lasting, and d) cytokine is 
directly released to activate APC at the site of targeted immunotherapy injection. 
 
Thus, given the current data regarding GM-CSF secreting breast cancer cell line SV-BR-1-GM 
with several desirable features developed in our laboratory, we propose this clinical 
investigation. SV-BR-1-GM will be injected intradermally to potentiate activation of in-situ 
APC.  Interferon-alpha-2b (Merck) will be used subsequently as an adjuvant, since it serves as a 
“danger signal” and has been shown to facilitate the maturation of APC precursors into 
functionally active dendritic cells [11].  Patients will be premedicated with low-dose 
cyclophosphamide because of its effect on T-regulatory cell activity [8, 9, 10, 76] and potential 
synergism with the targeted immunotherapy process by fostering cytokine responses, induction 
of MHC antigens on tumor cells or other mechanisms not yet identified [77]. 
1.2.4. 
Hypothesis   
  
Based on preliminary results of the sponsor’s previous studies of SV-BR-1-GM, it is 
hypothesized that this biological agent will be safe, well-tolerated, and clinically efficacious for 
metastatic breast cancer patients.  
 
1.2.4.1. 
Success Measures 
Success of the study in meeting the above hypothesis will be defined according to traditional 
FDA criteria.  We will investigate the likelihood of objective responses and will apply the 
combined RECIST/iRECIST criteria as recently studied [78].  The key to success at this stage 
will be to compile an adequate pool of data to merit FDA recognition of “proof of principle” 
sufficient to warrant expansion to the next level of study (i.e. traditional Phase II and/or Phase 
III).   
 
To this end, while the core success measure is safety and lack of toxicity, any of the following 
may be applied as Success Measures: 


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1. Objective clinical response as defined by RECIST 1.1 criteria or iRECIST criteria in 25% 
of patients. 
2. Improvement in quality of life in 50% or more patients as evidenced by significant 
change in 1 or more scales in the SF-36 questionnaire. 
3. Prolongation of disease-free and overall survival as compared with historical controls 
from reports of other salvage therapies in the published literature. 
Evidence of development or amplification of immune responses, especially if correlating with 
prolongation of survival.  


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2. 
STUDY PLAN 
2.1. 
TRIAL SITES 
 
The investigational sites will screen patients and enroll within trial. The treatments will be 
administered to patients at the investigational sites. All scans will be obtained at the 
investigational sites and evaluated by the site PI.  All blood tests will be performed at that the 
investigational sites or using major CLIA certified national laboratories. The results will be 
entered into the EDC. 
2.2. 
STUDY POPULATION 
2.2.1. 
Subjects 
 
The subjects will be females age 18 or older, who are diagnosed with metastatic breast cancer 
and qualify via the inclusion and exclusion criteria.  A sufficient number of subjects will be 
enrolled to assure a minimum of 10 for initial safety analysis and then expanded to 25-40 to 
complete the primary, secondary and exploratory end points. Patients who do not reach the initial 
on treatment tumor assessment may be replaced at the Sponsor’s discretion. 
2.2.2. 
Source of Subjects 
 
New subjects may be enrolled into this study from several sources, including but not limited to: 
 
1.  From the investigational treatment sites, as qualifying patients present and are referred. 
2.  From physician referrals to the trial. 
3.  From the NCI-PDQ website. 
4.  From patient advocacy organizations or any other pertinent agencies. 
2.2.3. 
Recruitment of Subjects 
 
(See also section 5.1 for more details.)  IRB-approved recruitment materials may be used to 
approach potential subjects during the screening period, as they present to the investigational 
treatment sites.  These recruitment materials will also be provided to potential referring 
physicians, at their request.  The consent form and attached study calendar; a brochure of 
frequently asked questions and answers; the enrollment forms are included in section 9.    
2.3. 
ELIGIBILITY CRITERIA 
2.3.1. 
Inclusion Criteria 
 
1. Have histological confirmation of breast cancer with recurrent and/or metastatic lesions 
via investigational site. 
**** Patients with new or progressive breast cancer metastatic to brain will be eligible 
provided: 
a. There is no need for steroids and patients have not had steroids at least 2 weeks 
b. No individual tumor size is >50 mm3 


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c. ECOG status <3 
d. Tumor is not impinging on Middle Cerebral Artery/speech-motor strip   
e. If surgically debulked, must be healed from surgery and at least 3 weeks have elapsed 
since general anesthesia 
f. Patients consent to MRI studies at 3-4 week intervals until evidence of tumor 
regression on at least 2 imaging studies.  In no case, will the interval between MRI 
studies be longer than 3 months.  MRI study may be introduced at any time should 
the patients develop new or clearly worsening symptoms and/or introduction of 
steroids 
g. Must have received prior radiation therapy for brain metastases or be ineligible for 
radiation therapy     
 
2. Have evidence of persistent, recurrent, or progressive disease for which there is no 
known or established treatment available with curative intent, after failing at least one 
course of community standard systemic treatment with chemotherapy (and endocrine 
therapy if appropriate)                                           
3. Be 18 years of age or older and female 
4. Have expected survival of at least 4 months 
5. Have adequate performance status (ECOG 0-2)   
6. Patients may be maintained on hormonal therapy provided there is clear evidence of 
tumor progression 
7. Have provided written informed consent. 
2.3.2. 
Exclusion Criteria 
 
1. Concurrent or recent chemotherapy (within 3 weeks), XRT within 1 week, may have had 
immunotherapy in the past (off within 3 weeks), or general anesthesia/major surgery 
(within 3 weeks).  Patients must have recovered from all known or expected toxicities 
from previous treatment and passed a treatment-free “washout” period of 3 weeks before 
starting this program (8 weeks for persons receiving nitrosourea or mitomycin). 
 
2. History of clinical hypersensitivity to GM-CSF, Interferon-alpha-2b (Merck), beef, or to 
any components used in the preparation of the experimental therapy. 
 
3. BUN >30 in conjunction with a creatinine >2. 
 
4. Absolute granulocyte count < 1000; platelets <100,000. 
 
5. Bilirubin >2.0; alkaline phosphatase >5x upper limit of normal (ULN); ALT/AST >2x 
ULN. 
 
6. Proteinuria >1+ on urinalysis or >1 gm/24hr. 
 
7. Left ventricular ejection fraction (LVEF as determined by cardiac echo or MUGA scan) 
below the normal limits of the institutions specific testing range.  This assessment may be 
repeated once at the discretion of the Investigator with the approval of the Sponsor. 
 


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8. New York Heart Association stage 3 or 4 cardiac disease.  
 
9. A pleural or pericardial effusion of moderate severity or worse. 
 
10. Any woman of childbearing potential, unless she: 
a. Agrees to take measures to avoid becoming pregnant during the study and 
b. Has a negative serum pregnancy test within 7 days prior to starting treatment.  
 
11. Women who are pregnant or nursing. 
 
12. Patients with concurrent second malignancy.  Persons with previous malignancies 
effectively treated and not requiring treatment for >24 months are eligible, provided there 
is unambiguous documentation that current local recurrence or metastatic site represents 
recurrence of the primary breast malignancy. 
 
13. Patients who are HIV positive (by self-report) or have clinical or laboratory features 
indicative of AIDS. 
 
14. Patients who require systemic steroids at a dose equivalent of >10 mg/day of prednisone. 
Beta-blocker therapy, while not exclusionary, is discouraged and alternatives should be 
sought if possible. The beta-blocker might compromise use of epinephrine for the rare 
possibility of anaphylaxis. Anticoagulants must be approved by the Investigator with 
notification of the Sponsor. 
 
15. Patients who are on treatment for rheumatological or autoimmune disease unless 
approved by the Investigator in consultation with the Sponsor (e.g., as for replacement 
therapy for autoimmune thyroiditis or diabetes).  
 
16. Patients with severe psychiatric disorders (e.g., schizophrenia, bipolar, or borderline 
personality disorder) or other clinically progressive major medical problems, unless 
approved by the PI. 
 
17. Male breast cancer patients. 
 
18. Patients may not be on a concurrent clinical trial, unless approved by PI. 
 
2.4. 
DURATION OF PARTICIPATION 
 
1. Initial screening and enrollment (approximately 1-4 weeks): The actual time it will take 
for introduction of the study to prospective subjects, the consent process, and screening & 
enrollment procedures is difficult to estimate due to clinical and scheduling 
considerations. 
 
2. Initial phase:  Participants will receive 3 cycles of SV-BR-1-GM at 2-week intervals. 
The initial phase is expected to last about 1 month. 


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3. Monthly maintenance phase: Subjects will receive SV-BR-1-GM cycles monthly for 6 
months (8 total cycles). Initial reimaging, laboratory evaluation and clinical evaluation 
will be performed at 2-3 months from initiation between SV-BR-1-GM cycles 4 and 6. 
Similar imaging re-evaluation will take place after every 3 months to identify progressive 
disease, to evaluate any off-study clinical criteria, and to investigate any possible clinical 
or immunological responses. Imaging may be performed more frequently, at the 
discretion of the Investigator in consultation with the Sponsor.  Copies of all imaging 
reports should be deidentified and provided to the Sponsor or their designate for entry 
into the database. 
 
4. Optional monthly maintenance treatments: Subjects that have completed 8 cycles, 
have a non-progressive response, and desire to continue on treatment have the option to 
receive an additional 6 months of treatment (6 cycles) for a total of 12 months of 
treatment (14 cycles in-total). They will have additional imaging, laboratory evaluation 
and clinical evaluation at month 9 after the 11th cycle. If they continue to have a non-
progressive response and desire to stay on treatment, they may continue out the 12 
months of treatment. 
 
Total duration:  Each subject’s active participation in the above phases combined is 
expected to last a total of approximately 6-12 months, allowing for “real life” variations in 
scheduling.   


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3. 
EXPERIMENTAL TREATMENT REGIMEN 
3.1. 
GENERAL INFORMATION 
 
This is a preliminary safety/toxicity study, clinical response, duration of response, and survival 
data are also being collected. Quality of life is assessed by a standardized questionnaire (SF-36 
Health Survey). The protocol begins with characterization of the patients' clinical and 
immunological status. The experimental part of the study employs intradermal immunization 
with irradiated, GM-CSF-producing breast cancer whole-cell targeted immunotherapy SV-BR-1-
GM, pretreatment with low-dose cyclophosphamide, and boosting with an injection of low-dose 
Interferon-alpha-2b (Merck) to the inoculation site after 2 and 4 days. The study concludes with 
follow-up for restaging after the 6-12 months of treatment.   
3.2. 
SUBJECT SCREENING 
 
Subjects will undergo staging and baseline studies within about 14 days of starting treatment; 
within 28 days for radiographic studies.  The screening window may be extended to 40 days with 
the approval of the Sponsor.  See sections 5.3 and 5.5 for more detailed information. 
3.3. 
SV-BR-1-GM CYCLES 
 
SV-BR-1-GM administration cycle begins when low-dose cyclophosphamide is given via 
intravenous infusion 2-3 days before SV-BR-1-GM. Low-dose cyclophosphamide may have 
multiple modes of action, including the down-regulation of immune regulatory T-cell activity 
[8,9], induction of type 1 Interferon-alpha-2b (Merck) [10], up-regulation of MHC antigens [79], 
reversal of tolerance via up-regulation of tumor-specific CD4+ helper activity [80], and/or by 
other mechanisms not yet studied.  Following injection of SV-BR-1-GM, clinical evaluation and 
Interferon-alpha-2b (Merck) -α booster injection in situ at the inoculation site occurs 2 days and 
4 days later.  Interferon-alpha-2b (Merck) is included particularly because of its effect in 
augmenting dendritic cell maturation [11, 81, 82] 
Pre- SV-BR-1-GM Regimen: 
Cyclophosphamide (Cytoxan) 300 mg/m2 I.V., 1x only, will be given 2-3 days before each SV-
BR-1-GM dose, with an antiemetic of the provider’s choice (steroids prohibited). To simplify, 
this event will also include the phlebotomy, which should occur prior to the cyclophosphamide 
infusion. See Table 2.  If the patient is not tolerating the cyclophosphamide, a lower dose may be 
used (e.g. 200 or 150 mg/m2) or it may be withheld, but only with the Sponsor’s approval. 
 
SV-BR-1-GM Day Standard Operating Procedures: 
a)  Inquire regarding events of past weeks, change in medications, pain scale, ECOG scale, and 
review of systems. 
b)  Check SV-BR-1-GM injection sites. 
c)  Perform immediate and delayed-type hypersensitivity (DTH) skin testing by intradermal 
injection of BriaTest™ (irradiated SV-BR-1 parent cells) or with SV-BR-1-GM.  BriaTest™ 
or SV-BR-1-GM will be used to evaluate potential immediate hypersensitivity and DTH. 


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Observe about 20 minutes for acute hypersensitivity to the SV-BR-1 parent cells or SV-BR-
1-GM. Any evidence of immediate hypersensitivity to the SV-BR-1 parent cells or to the test 
dose of SV-BR-1-GM precludes dosing with the full dose of SV-BR-1-GM.   
d) Anergy testing with Candida antigen will also be performed prior to dosing on cycles 1, 3, 6, 
9, 12.  Candida antigen (Candin, 0.1 mL) will be injected intradermally into the forearm and 
evaluated 2 days (±1 day) later to evaluate for anergy.   
e)  Inject SV-BR-1-GM 0.5 ml intra-dermally into thighs and upper back.  Monitor patients for 
60 minutes.  Vital signs will be assessed and medical attention will be warranted if unstable. 
 
SV-BR-1-GM Preparation & Inoculation Regimen: 
     
Each SV-BR-1-GM inoculation will be administered via intra-dermal injection at the 
investigational sites.  Subjects will receive 15-25 x 106 irradiated transfected breast tumor cells 
in a total volume of 2.0 ml Ringer’s lactate.  SV-BR-1-GM cells will be irradiated to 20,000 cGy 
(dose applied previously), or to an alternative dose ensuring cell replication incompetency, with 
an approved Cesium source or alternatively in Varian Linac IX, medically approved for radiation 
therapy. The liquid formulation of SV-BR-1-GM and skin test material (BriaTest™ or SV-BR-1-
GM) should be kept under temperature controlled conditions (2-8° C) until ready for use (i.e. 
when the results of all release testing is available).  If the frozen formulations are used, SV-BR-
1-GM should be thawed at room temperature and then kept under temperature controlled 
conditions (2-8° C) until ready for use.  
 
Prior to SV-BR-1-GM administration, both the skin test and the final SV-BR-1-GM preparations 
will be gram stained and tested for endotoxin at the sponsor’s designated laboratory. The 
remainder will be stored frozen at –80° C for future reference.  No preparations will be injected 
if the gram stain is suspicious for bacterial or other contamination or if the endotoxin test is 
positive.  Nothing will be administered unless and until there is review that there is nothing 
positive on the gram stain and the endotoxin test is negative. 
 
SV-BR-1-GM will be divided into aliquots and prepared with coded study labels "Investigational 
Use Only", and hand-delivered or shipped overnight to the clinical site on the day of the 
scheduled inoculation. At the Investigator’s site, the BriaTest™ and/or SV-BR-1-GM will be 
thawed if frozen.   SV-BR-1-GM is stable up to 24 hours at 2 – 8 °C and should not be used 
more than 24 hours following the conclusion of irradiation for the liquid formulation.  SV-BR-1-
GM will be delivered in cryovials and should be drawn into syringe(s) through a large bore (18 
gauge or larger) needle.  It may be back-filled into 1 mL syringes for injection, or could be 
directly injected following switching to a smaller gauge needle (e.g. 27 gauge).  SV-BR-1-GM 
will be injected intra-dermally; one each into the anterior skin of the subject’s right and left 
thighs and over the right and left upper back.  Application of anesthetic lidocaine crème may be 
used if necessary for control of local pain before inoculation.  Subjects will be monitored for 60 
minutes with vital signs performed at least every 15 minutes, or more frequently if clinically 
indicated.  See the Pharmacy Manual for additional details. 
 
After at least 10 subjects have been treated with this regimen, at the Sponsor’s discretion and in 
consultation with the investigator, the dose of SV-BR-1-GM may be escalated to 30-50 x 106 
irradiated transfected breast tumor cells in a cohort of 6 or more patients.  This dose will not be 


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exceeded without further protocol amendment, FDA notification and IRB approval.  At the 
Sponsor’s discretion and in consultation with the investigator, the dose of SV-BR-1-GM may 
also be decreased to 5-15 x 106 irradiated transfected breast tumor cells in a cohort of 6 or more 
patients.  If, after dosing the first 10 patients at a dose of 15-25 x 106 irradiated transfected breast 
tumor cells, grade 2 or higher toxicity at least possibly related to SV-BR-1-GM inoculation is 
seen in at least 30% of patients, the dose will be decreased to 5-15 x 106 irradiated transfected 
breast tumor cells for subsequent patients. 
 
Post-Inoculation Regimen: 
 
Two days (±1 day) after SV-BR-1-GM, and again 4 days (±1 day) later after SV-BR-1-GM, the 
patient will return to the principal investigator’s office to receive 10,000 U of Interferon-alpha-
2b (Merck) in 0.1 ml saline.  This may be prepared as follows (alternative methods also 
permissible): 
 
1) Retrieve vial of Intron A liquid (conc. = 10 million IU/mL) 
2) Withdraw 0.5 mL (5 million IU) from the vial with a syringe 
3) Dilute with 49.5 mL NS + 0.9% benzyl alcohol in a sterile empty vial (conc. = 100,000 
IU/mL)  
4) Withdraw 0.1 mL (10,000 IU) per syringe (prepare 4 syringes in total per protocol) 
5) Store at 2-8° C.   Stable for up to 28 days. 
 
One alternative method is shown here: 
 
1) Retrieve vial of Intron A powder, 10 million IU/ml in bottle. 
2) Add    1.0 ml NS + 0.9% benzyl alcohol (conc 10 mil IU/ml) 
3) Dilute to 100 ml with NS + 0.9% benzyl alcohol (conc100,000 IU/ml) 
4) Aliquot to syringes 0.10 ml (=10,000 IU) 
5) Store at 2-8° C.    Stable for up to 28 days.  
 
These will also be injected intra-dermally to each SV-BR-1-GM inoculation site, beneath the 
thickest area.  Again, subjects will be observed about 20 minutes. The DTH/anergy response will 
also be recorded in the EDC at the 2 days (±1 day) visit. 
 
General Regimen for Adverse Reactions: 
 
1.  Acute - Contingent on clinical features, the following protocol will inform the  
 
management of any acute hypersensitivity rxn., to be adhered to or modified according      
 
to the treating physician.  
 
 
--Fever, chills, rigors:            acetaminophen 1000 mg po 
 
--Urticaria (hives), itching, facial flushing:          IV diphenhydramine 50 mg. 
 
       if no improvement within 5 minutes, IV hydrocortisone 100 mg. 
 
       repeat IV diphenhydramine 50 mg, 0.2 – 0.5 mL epinephrine 1:1000 subcutaneous 
            --Hypotension, wheezing, shortness of breath, lip, tongue swelling 


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      Place pulse oximeter; if O2 saturation <92%, start O2 by nasal cannula     
 
 
            2 l/min 
 
      NS 150ml/min, 
                  Rx    0.2 – 0.5 mL epinephrine 1:1000 subcutaneous, IV diphenhydramine 50mg, 
  
 
100 mg hydrocortisone 
 
2. Chronic – treatment as determined by the treating physician. 
 
 
In the case of grade 3 or greater localized toxicity (e.g., ulcer formation) further dose inoculation 
will not occur.  
 
It is expected that all experimental treatment procedures will be performed in the principal 
investigator’s office, and hospitalization is not expected unless complications develop. Treatment 
will be administered with appropriate medical supervision and the close availability of support 
measures. 
 
Subsequent SV-BR-1-GM Cycles: 
  
SV-BR-1-GM Cycles 2 and 3 will occur at 2-week intervals from initiation of treatment for a 
total of 3 cycles.  Cycle 4 will be initiated one month later, provided there has not been undue 
toxicity (defined under Treatment Plan, Toxicity). Subsequent cycles will then occur monthly; 
with restaging every 3 months.  
 
For example, restaging would occur at month 3, after completion of 5 SV-BR-1-GM cycles. 
Patients with progressive disease should go off treatment after 5 SV-BR-1-GM cycles, or earlier 
if needed as per the PI. Patients without progressive disease may remain on treatment and will be 
restaged after completion of SV-BR-1-GM cycles 6, 7, 8 after 6 months. If they remain non-
progressive they continue for another 3 cycles (1 per month), followed by restaging at 9 months 
(cycles 9, 10, 11). Again, if they remain non-progressive they may continue for another 3 months 
(cycles 12, 13, 14) followed by final staging. Thus, the program totals 12 months of SV-BR-1-
GM inoculations. Refer to the study calendar below (Table 2) for a complete schedule. 
 
 
 


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Table 2:  
Study Calendar (SV-BR-1-GM Cycles) 
STUDY EVENT 
Eval 
Inj 
Inj 
Inj 
Inj 
Inj 
Eval 
Inj 
Inj 
Inj 
Eval 
Eval 
Visits 
Baseline 
Eval. 
Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Initial Treatment 
Eval. 
Cycle 
6 
9 
12 
Cycle 
7 
10 
13 
Cycle 
8 
11 
14 
Re-Eval  
(after every 3 
cycles) 
Off Tx Eval  
(after Cycle 
14 
or when off-
study) 
Week/Month of Study 
-2wk 
1 
3wk 5wk 2mon 3mon Between 2-
4mon 
4, 7, 10 
mon 
5, 8, 11 
mon 
6, 9, 12 
mon 
After 6, 9 
mon 
After 12 
mon 
COMPLETE PHYSICAL EXAM (8) 
X 
 
 
 
 
 
X 
 
 
 
X 
X 
Vital Signs & Wt Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review of Systems 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Quality of Life Form 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbrev. Physical Exam (8) 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
 
LABORATORY 
 
 
 
 
 
 
 
 
 
 
 
 
Serum/Plasma (1 red top ~8ml & 1 purple top ~8 
ml) 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
PBL (3 yellow top ~24 ml) 
X 
X 
 
 
 
 
X 
 
 
 
X 
X 
CBC & Diff. 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CMP, GGT, LDH, Uric Acid (2) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PT, aPTT, INR (2) 
X 
X 
 
 
 
 
X 
 
 
 
X 
X 
Serum Pregnancy Test (7) 
X 
 
 
 
 
 
 
 
 
 
 
 
T&B Subsets 
X 
X 
 
 
 
 
X 
 
 
 
X 
X 
Serologic Markers (2) 
X 
X 
 
 
 
 
X 
 
 
 
X 
X 
Urinalysis (6) 
X 
X 
 
 
 
 
X 
 
 
 
X 
X 
2 CellSave Preservation Tubes (~10 ml 
each) 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
HLA Typing (buccal swab) 
X 
 
 
 
 
 
 
 
 
 
 
 
DTH Skin Test (4) 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
 
Anergy (Candin) (4) 
 
X 
 
X 
 
 
 
X 
 
 
 
 
Cardiac Assessments (9) 
X 
 
 
 
 
 
X 
 
 
 
X 
X 
TUMOR ASSESSMENT RADIOLOGY (1)  
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
TREATMENT 
 
 
 
 
 
 
 
 
 
 
 
 
Cyclophosphamide 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
 
SV-BR-1-GM Inject (4) 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
 
nterferon Injection #1 (5) 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
 
nterferon Injection #2 (5) 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
 
DATA SAFETY & EVALS FOR AEs 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
  
Notes:  
1. Radiology Procedures:  Baseline studies to be performed within 28 days of beginning clinical 
trial (as clinically indicated for staging).  CT of: chest, abdomen, pelvis; isotope bone scan; 
other X-Rays; PET scan; mammogram; (ultrasound/MRI scans as needed for disease 
assessment and/or at the discretion of the investigator).  These will be repeated between SV-
BR-1-GM cycles 4 and 6, and then every 3 months or more frequently at the discretion of the 
Investigator in consultation with the Sponsor. Patients with disease progression should 
progress to the Off Tx Evaluation. 
2. All blood to be drawn on arrival for cyclophosphamide infusion; if overlooked, may draw 
before skin tests, but must be annotated clearly. Comprehensive Metabolic Profile (CMP), 
GGT, LDH, and Uric Acid to be done each visit.  Coagulation studies (PT, aPTT, INR) 
should be performed every 3 months as noted.  These or other laboratory evaluations may 
occur more frequently for responsible patient care at the discretion of the investigator.  
Serological markers include: CEA; CA 27.29 (or CA 15-3 if preferred by the Investigator).    
3. Day 1 of each cycle is the day of SV-BR-1-GM injection. 
4. DTH skin test will be with 1.0 ± 0.2 x 106 irradiated BriaTest™ (SV-BR-1) cells or 1.0 ± 0.2 


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x 106 irradiated SV-BR-1-GM cells intradermally in the forearm. See Sec. 3.3. 
5. Interferon-alpha-2b (Merck) injection is done 2 (±1) days and 4 (±1) days after SV-BR-1-
GM injection. 
6. Aliquot of urine to be archived with each U/A 
7. For women of childbearing potential, a pregnancy test will be done within 7 days of starting 
SV-BR-1-GM. 
8. Complete physical exam will include the following organ or body system assessments:  skin; 
head, eyes, ears, nose, and throat; thyroid; lungs; cardiovascular system; abdomen (liver, 
spleen); extremities; lymph nodes; and a brief neurological examination.  Brief physical 
exam will include assessment(s) of the body systems or organs, as indicated by subject 
symptoms, AEs, or other findings.  Abbreviated physical exam is needed for Cycle 1 only if 
not performed within the past 2 weeks. 
9. Cardiac assessments will include baseline ECG, cardiac troponin (cTn), NT-proBNP and an 
estimation of left ventricular ejection fraction (LVEF) by either cardiac echo or MUGA scan.  
The ECG and estimate of LVEF (by the same method) will be performed after 3, 6 and 12 
months on study if the subject remains asymptomatic, or earlier if a patient becomes 
symptomatic. LVEF assessment may be repeated once at the discretion of the Investigator 
with the approval of the Sponsor. 
 


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4. 
 RISKS, BENEFITS, & RISK MANAGEMENT 
Trial subjects will be monitored closely for any side effects and will be encouraged and expected 
to report any new symptoms or developments to the principal investigator.  
4.1. 
PHYSICAL RISKS 
 
SV-BR-1-GM:  Allergic reactions, local pain, redness, or itch, local infection or other infections; 
tumor enhancement; allergy to the SV-BR-1-GM, cross-reactive allergy to food or medicines; 
autoimmune disease.  
 
Cyclophosphamide:  Low-dose cyclophosphamide (Cytoxan) is sometimes associated with 
nausea, loss of appetite, or vomiting, constipation.  Side effects of the higher, conventional doses 
include hair loss, fall in blood counts (which can lead to fatigue, increased risk of infection), and 
bladder irritation. 
 
Interferon-alpha-2b (Merck):  The dose of Interferon-alpha-2b (Merck) used here (10,000 U) 
is a tiny fraction of the usual amount used clinically (1 million U or more).  Possible side effects 
include itching, inflammation, pain, or local infection at the injection puncture site.  
 
GM-CSF: Since only small amounts of GM-CSF are released at the SV-BR-1-GM inoculation 
site, side effects reported in other studies with much larger doses are not expected.  Larger 
clinical doses have produced flu-like symptoms or local reaction such as redness or itching at the 
site of the injection, acute allergic reactions to the lymphokine, and exacerbation of underlying 
heart, lung, or liver problems.  
 
Combinations of Agents: SV-BR-1-GM has been safely administered in combination with pre-
treatment cyclophosphamide and post-treatment interferon alpha as noted above.  No adverse 
events outside of those expected from the individual agents were seen.  Additional, unexpected 
side effects may be seen. 
4.2. 
NONPHYSICAL RISKS 
 
Non-physical risks may include increased time commitments and travel considerations, financial 
implications, loss of privacy, or problems with insurability.  Participation on this protocol 
requires termination of previous treatments and excludes concomitant treatments by other 
standard or investigational programs. 
 
4.3. 
ADVERSE EVENTS 
4.3.1. 
Definitions and Reporting 
For the purposes of this Protocol, an adverse event (AE) is defined as the appearance of (or 
worsening of any pre-existing) undesirable sign(s), symptom(s), or medical condition(s) that 
occur after a subject provides informed consent.  Abnormal laboratory values or test results 
occurring after informed consent constitute AEs only if they induce clinical signs or symptoms, 


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are considered clinically meaningful, require therapy (e.g., hematologic abnormality that requires 
transfusion), or require changes in the study drug(s). 
Adverse events that begin or worsen after informed consent should be recorded on the Adverse 
Events page of the CRF.  Conditions that were already present at the time of informed consent 
should be recorded on the Medical History page of the CRF.  Adverse event monitoring should 
be continued for at least 30 days after the last dose of study drug.  Adverse events (including 
laboratory abnormalities that constitute AEs) should be described using a diagnosis whenever 
possible rather than by individual underlying signs and symptoms.  When a clear diagnosis 
cannot be identified, each sign or symptom should be reported as a separate AE. 
Adverse events will be assessed according to the CTCAE version 4.03.  The occurrence of AEs 
should be sought by nondirective questioning of the subject during the screening process after 
signing the ICF and at each visit during the study.  Adverse events may also be detected when 
they are volunteered by the subject during the screening process or between visits, or through 
physical examination, laboratory test, or other assessments.  As far as possible, each AE should 
be evaluated to determine: 
• The severity grade (CTCAE Grade 1 to 5). 
• Reasonable possibility that the AE is related to the study treatment:  unrelated (no) or 
related (yes). 
− Note that when SV-BR-1-GM is used in combination with other agents (e.g. 
cyclophosphamide, interferon-α), the relationship to study drug can be assessed 
for SV-BR-1-GM alone, the other study medications alone, or the combination of 
agents. 
• Start and end dates, unless unresolved at final examination. 
• Action taken with respect to study drug (e.g., none, dose adjusted, temporarily 
interrupted, permanently discontinued, unknown, not applicable). 
• Outcome (e.g., not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequelae, fatal, unknown). 
• Whether it is serious, as per serious adverse event (SAE) definition provided in 
Section 8.3.1. 
Unlike routine safety assessments, SAEs are monitored continuously and have special reporting 
requirements, see Section 8.3.2. 
All AEs should be treated appropriately.  If a concomitant medication or nondrug therapy is 
given, this action should be recorded on the AE and Prior/Concomitant medications pages of the 
CRF. 
Once an AE is detected, it should be followed until it has resolved or until it is judged to be 
permanent; assessment should be made at each visit (or more frequently if necessary) of any 
changes in severity, the suspected relationship to the study drug, the interventions required to 
treat it, and the outcome. 
Disease progression should not be regarded or reported as an AE itself, unless it is associated 
with a separate AE. 


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4.4. 
LABORATORY TEST ABNORMALITES 
4.4.1. 
Definitions and Reporting 
Laboratory abnormalities that constitute an AE in their own right (are considered clinically 
meaningful, induce clinical signs or symptoms, require concomitant therapy, or require changes 
in study drug), should be recorded on the AE page of the CRF.  Whenever possible, a diagnosis 
rather than a symptom should be provided (e.g., anemia instead of low hemoglobin).  Laboratory 
abnormalities that meet the criteria for AEs should be followed until they have returned to 
normal or an adequate explanation of the abnormality is found.  When an abnormal laboratory 
test result corresponds to a sign or symptom of a previously reported AE, it is not necessary to 
separately record the laboratory test result as an additional event. 
Laboratory abnormalities that do not meet the definition of an AE should not be reported as AEs.  
A Grade 3 or 4 (severe) AE, as per CTCAE, does not automatically indicate an SAE unless it 
meets the definition of serious, as defined in Section 8.3.1, and/or per the investigator's 
discretion.  A dose interruption or adjustment for the laboratory abnormality may be required 
(see Section 5.6) and should not contribute to the designation of a laboratory test abnormality as 
an SAE. 
4.5. 
SERIOUS ADVERSE EVENTS 
4.5.1. 
Definitions and Reporting 
A SAE is defined as an event that meets 1 of the following criteria: 
• Is fatal or life-threatening (i.e., immediate risk of dying). 
• Results in persistent or significant disability or incapacity. 
• Constitutes a congenital anomaly or birth defect. 
• Is clinically meaningful (i.e., defined as an event that jeopardizes the subject or 
requires potential medical or surgical intervention to prevent 1 of the outcomes listed 
above). Considered meaningful by the investigator as an important medical event that 
may not result in death, be life-threatening, or require hospitalization, but may be 
considered a SAE when, based upon appropriate medical judgment, it may jeopardize 
the subject or may require medical or surgical intervention to prevent 1 of the 
outcomes listed in this definition. 
• Requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is a result of: 
− Routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition. Elective or preplanned treatment for a pre-existing 
condition that is unrelated to the indication under study and has not worsened 
since signing the ICF. 
− Treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission. 


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− Social reasons and respite care, in the absence of any deterioration in the subject's 
general condition. 
− Any SAEs that are expected due to the condition being treated, including if the 
SAE is a primary outcome measure, or where there has been a clear agreement 
with regulators not to consider these as SAEs, provided the information is 
collected elsewhere. 
The Sponsor will notify FDA and all participating investigators in an IND safety report of 
potential serious risks identified, from clinical trials or any other source, as soon as possible, but 
in no case later than 15 calendar days after determination that the information qualifies for 
reporting, as delineated in CFR 312.32 (available at 
https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=312.32).  
Unexpected fatal or life-threatening suspected adverse reaction reports. The Sponsor will also 
notify FDA of any unexpected fatal or life-threatening suspected adverse reaction as soon as 
possible but in no case later than 7 calendar days after the Sponsor's initial receipt of the 
information. To ensure subject safety, every SAE, regardless of suspected causality, occurring 
after the subject has signed the ICF and up to the last study visit, or up to 30 days after the 
subject has stopped study treatment, whichever is later, must be reported to the sponsor (or 
designee) within 24 hours of learning of its occurrence.  Any SAEs experienced after this period 
should be reported to the sponsor (or designee) only if the investigator suspects a causal 
relationship to the study drug.  Recurrent episodes, complications, or progression of the initial 
SAE must be reported as the follow-up to the original episode within 24 hours of the investigator 
receiving the follow-up information.  An SAE occurring at a different time interval or otherwise 
considered completely unrelated to a previously reported one should be reported separately as a 
new event.  Previously planned (before providing informed consent) surgeries should not be 
reported as SAEs unless the underlying medical condition worsens over the course of the study. 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form.  The investigator must assess and record the relationship of each SAE to each specific 
study drug (if there is more than 1), complete the SAE Report Form in English, and send the 
completed, signed form by fax within 24 hours to the sponsor or its designee.  The investigator 
must assess if there is a reasonable possibility that the SAE is related to the study treatment:  
unrelated (no) or related (yes). 
Note that when SV-BR-1-GM is used in combination with other agents (e.g. cyclophosphamide, 
interferon-α, ipilimumab, pembrolizumab), the relationship to study drug can be assessed for SV-
BR-1-GM alone, the other study medications alone, or the combination of agents. 
Serious AEs related to unblinded comparator drugs or concomitant medications/drug delivery 
systems are reported directly to the manufacturers of those drugs/devices in accordance with the 
package insert. 
The telephone and facsimile number of the sponsor's contact persons, specific to the study, are 
listed in the investigator folder provided to each site.  The original copy of the SAE Report Form 
and the fax confirmation sheet must be kept with the CRF documentation at the study site. 
Follow-up information is sent to the same person to whom the original SAE Report Form was 
sent, using a new SAE Report Form stating that this is a follow-up to the previously reported 
SAE and giving the date of the original report.  Each recurrence, complication, or progression of 


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the original event should be reported as a follow-up to that event regardless of when it occurs.  
The follow-up information should describe whether the event has resolved or continues, if and 
how it was treated, and whether the subject continued or withdrew from study participation, or if 
study drug was interrupted or discontinued. 
If the SAE is not previously documented in the IB for the study drug (new occurrence) and is 
thought to be related to the sponsor's study drug, a sponsor's associate may urgently require 
further information from the investigator for reporting to health authorities. 
The sponsor or its designee may need to issue an Investigator Notification (IN) to inform all 
investigators involved in any study with the same drug that this SAE has been reported.  
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with Directive 
2001/20/EC, or as per national regulatory requirements in participating countries. 
4.6. 
RESPONSE TO ADVERSE EVENTS 
 
All adverse events will be recorded on the Adverse Event Form.  Development of treatment 
related Grade IV toxicity will truncate all new subject accrual until further review by the medical 
monitor, IRB and FDA as appropriate.  Treatment-related Grade III allergy/hypersensitivity will 
truncate further inoculations to any particular subject.  The first three patients will be enrolled 
sequentially, with at least 2 weeks between patients.  After 10 patients are enrolled a safety 
analysis will be performed.  If no significant toxicity has been reported, an additional cohort of 
15-30 participants (to a total of 25-40) may be enrolled to evaluate the primary, secondary and 
exploratory end points.  
 
If any subjects show an unanticipated abnormality on any lab assay or screening procedure, 
clinical management of their condition will take precedent.  Results of testing will be provided to 
their physician(s) with appropriate medical release. 
4.6.1. 
During SV-BR-1-GM Administration  
 
1. Pain and/or anxiety: Subjects will be closely monitored for their reaction to SV-BR-1-GM 
administration, including any pain at the injection site, general anxiety or discomfort.  
Appropriate rest periods will be offered, and subjects always have the right to withdraw from 
the study at any time and/or refuse an injection. 
2. Other adverse events: Unanticipated adverse events should be managed as clinically 
appropriate, and recorded on the Adverse Event Form. 
4.6.2. 
After the SV-BR-1-GM Administration 
 
After SV-BR-1-GM inoculation, the subject will be monitored for 60 minutes for any adverse 
reaction to the SV-BR-1-GM.  Unanticipated adverse events should be managed as clinically 
appropriate, and recorded on the Adverse Event Form.   
4.6.3. 
In Case of Injury 
 


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No funds have been provided or set aside in case of injury to a subject.  Each subject (primarily 
their insurance or Medicare) will be responsible for usual and customary fees regarding the 
procedures, supplies used in this study, and office visits, with the exception of the experimental 
therapy.  There will be no charges for preparation or administration of SV-BR-1-GM, but there 
will be routine charges for an office visit, imaging, laboratory tests, etc. 
4.6.4. 
Adverse Events of Special Interest 
 
An Adverse Event of Special Interest (AESI) is to be reported on the SAE form and timelines for 
submission and processing are expected to be the same as a reported SAE.  Adverse Events of 
Special Interest include the following:  
  
● New or worsening Autoimmune Disease 
● Major cutaneous reactions at the inoculation sites (e.g., ulcers, necrosis) 
● Allergic reactions to SV-BR-1-GM 
● Cardiac events 
4.7. 
BENEFIT TO SUBJECTS & OTHERS 
 
This is a Phase I/IIa safety and efficacy study of an experimental treatment that has not yet been 
proven.  No direct benefits to subjects can be anticipated.  Even though this experimental 
treatment is based on current medical science theories, it is not possible to predict the outcome in 
advance. Possible benefits may include improvement in immune function or possible tumor 
regression, or possible improvement in time to progression or survival after treatment.  However, 
each person is unique and results are not predictable. 


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5. 
STUDY PROCEDURES, METHODS, AND MATERIALS 
5.1. 
RECRUITMENT  
 
It is expected that patients will sometimes be referred by clinicians who know the sponsor or 
affiliated investigators, or they may self-refer after an internet search.  The sponsor will refer all 
patient inquiries to an appropriate principal investigator. 
 
Potential participants will be informed that this program is experimental and that an evaluation 
on site is necessary to make the final decision on whether a patient qualifies for the program.  In 
addition, each potential participant is to be clearly informed that travel costs and other expenses 
associated with the screening, eligibility, and study procedures will not be compensated without 
pre-approval of the Sponsor.  Prospective participants will be denied participation if all eligibility 
criteria are not met or, if after screening and evaluation the principal investigator or the patient's 
personal physician feels some other therapy is more appropriate.  
5.2. 
CONSENT PROCESS 
 
a)  The investigational trial site staff will explain the study, its procedures, and the consent 
documents to patients. 
b)  Potential participants will be given an opportunity to read the consent documents, to have 
their questions answered to their satisfaction, and to defer a decision, perhaps to discuss study 
participation with their physician or significant others. 
c)  It will be carefully explained to participants that they may withdraw from participation at any 
time, without prejudice or jeopardy to their standard medical care. 
d)  In all cases, prior to initiation of treatment, participants are again queried regarding their 
understanding of the program, or any unresolved issues.  A copy of the consent form will be 
provided to the participant, and this is to be noted within the electronic case report form (eCRF). 
5.3. 
SCREENING PROCESS 
 
Written informed consent will be obtained before any screening procedures are initiated. Study 
staff may explain the study to participants and ascertain presumptive eligibility.  Multiple visits 
may be conducted to complete all required procedures if necessary.  Due to the delay in 
receiving the results of tests, the final eligibility decision cannot be made during the participant’s 
initial screening visit. 
 
a)  After review of all screening information, an entry will be made in the Screening & 
Enrollment Log for all participants who consent to be in the study, whether or not they qualify 
after the screening procedures. 
 
b)  If any participant is determined to meet preliminary eligibility criteria, and expresses 
willingness to continue with the study, she will proceed.  Detailed instructions, study-specific 
procedures and study calendar will again be explained to qualified participant. 
 


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c)  If any participant is determined to be ineligible, she will be informed by the study staff of the 
reason(s) for ineligibility.  
 
5.4. 
WITHDRAWAL and TERMINATION CRITERIA 
5.4.1. 
Individual Subject Withdrawal Criteria 
1. Criteria - Any individual subject can be withdrawn from the study if any of the following 
occurs: 
a) The subject may request at any time to withdraw from the study, with no prejudice to her 
medical care at the principal investigator’s practice. 
b) The subject is unable to reliably adhere to the study procedures. 
c) The subject exhibits extreme anxiety during the treatment.  
d) Staff members are unable to contact the subject or proxy to collect post-procedure 
information will account as withdrawal. 
 
2. After providing 'adequate trial' with sufficient time and doses, experimental therapy will be 
terminated in a subject with significantly progressive disease.  
 
3. In addition, experimental therapy will be terminated in a subject at the discretion of the 
sponsor or principal investigator if:  
a) The patient/subject demonstrates evidence of progressive disease as per RECIST and 
iRECIST criteria.  
b) Grade III or IV toxicity of any kind occurs, or 
c) Autoimmune disease (validated) of any toxicity level. 
 
4. Subjects MUST be withdrawn from dosing for any of the following: 
a) Any grade 3 or greater NCI CTC v. 4.03 toxicity at least possibly related to study agent. 
b) Any grade 2 or greater hypersensitivity reaction. 
c) If LVEF drops >20% or is below facility limits of normal or the patient becomes 
symptomatic of CHF and requires treatment. LVEF assessment may be repeated once at 
the discretion of the Investigator with the approval of the Sponsor. 
5.4.2. 
Study Termination Criteria 
 
The study will be terminated if any of the following occur: 
a) Any death at least possibly related to the study drug. 
b) 2 or more grade 4 events at least possibly related to the study drug. 
If either of these occur, recruitment will be halted and dosing of all subjects paused while the 
case(s) are investigated.  Following discussions with the IRB/Ethics Committee and with 
regulatory authorities, the protocol may be amended.  The study may be restarted only with the 
approval of the IRB/Ethics Committee and regulatory authorities.  


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5.5. 
STUDY TESTS & PROCEDURES 
5.5.1. 
General Considerations 
 
The pre-study tests (see section 5.5.2.1) should be obtained prior to enrollment in accordance 
with good medical practice.  Results do not necessarily determine eligibility and minor 
deviations would be acceptable if they do not impact on patient safety in the clinical judgment of 
the treating physician after consultation with the Medical Monitor.  Further review and 
consultation with the Institutional Review Board is anticipated if there are significant deviations 
from the values of these tests, from ongoing monitoring, and/or changes in clinical status. 
 
1. Subject safety and comfort are of first priority and unexpected events may occur, to be 
responded to according to the physician’s judgment and community standards of clinical 
practice. 
 
2. Subjects will undergo imaging studies within 28 days of starting treatment; baseline 
laboratory studies within 14 days. (See also Study Calendar.) 
5.5.2. 
Study Tests & Evaluations 
5.5.2.1. 
Pre-Study Testing and Ongoing Monitoring 
 
1. Focused medical & social history (screening). 
2. Complete physical exam, including vital signs.  
3. Cardiac assessments will include baseline ECG, cardiac troponin (cTn), NT-proBNP and 
an estimation of left ventricular ejection fraction (LVEF) by either cardiac echo or 
MUGA scan.  LVEF assessment may be repeated once at the discretion of the 
Investigator with the approval of the Sponsor. 
4. CBC, differential, platelets, T and B subsets, comprehensive metabolic biochemical 
profile, LDH, GGT, and uric acid, at each visit, or as clinically indicated.  Coagulation 
studies (PT, aPTT and INR) and urinalysis at baseline, Cycle 1, and then every 3 months.  
All labs during treatment should be drawn prior to administration of cyclophosphamide.  
Additional blood samples will be collected during the same phlebotomy procedures, for 
storage in the repository. (See Laboratory Manual) 
5. HLA profile – to be obtained from a buccal swab.  Patients should gargle with water and 
then fast until the buccal swab is collected approximately 30 minutes later.  Please handle 
with gloves to avoid contamination. 
6. Quality of Life Questionnaire SF-36. 
7. ECOG scale. 
8. CT scan chest, abdomen and pelvis (or PET scan at the discretion of the PI) at baseline 
(within 28 days of initiation of treatment), at initial treatment evaluation, after 3 monthly 
maintenance inoculations, and after study conclusion. Chest X-ray at baseline is desirable 
but not required if patient is getting CT study.  
9. Isotope bone scan, and/or selected MRI if clinical suspicion of bone metastases. 
10. MRI or mammogram of the breast at baseline; if positive repeated at 3-months and 
subsequent evaluations; PET is desirable but not required. (This is not applicable if the 
patient has had a complete mastectomy). 


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11. CEA and CA 27.29 (or CA 15-3 if preferred by the Investigator). 
12. Brain scan MRI or CT technique if clinical indication of neurological symptoms. 
13. Serum beta-HCG pregnancy test within 7 days before starting treatment for women of 
childbearing potential. 
14. Immunohistological and FISH evaluation, if not already performed by a referring 
physician, of HER2/neu expression from whatever previous biopsy was diagnostic of 
cancer metastases.  
15. If tumor tissue is available for additional testing, it may be sent for evaluation of 
additional markers such as PDL1, PRAME, HLA-A, HLA-B, HLA-C, HLA-DR, HLA-
DP, and/or HLA-DQ.   
16. If malignant fluids (e.g. pleural fluid, ascites) or tumor tissue (e.g. from biopsies) are 
available, unused or unneeded portions may be collected and archived for future research, 
provided nothing is done to compromise good clinical practice for the intended diagnostic 
evaluation.  Possible research may involve characterization studies (e.g. antigenicity, 
genomic evaluations, transcriptome or proteome analyses) or establishment of cell lines. 
 
During the initial phase of experimental therapy, participants will get SV-BR-1-GM injected and 
closely observed about every 2 weeks at the investigational sites.  Subsequent inoculations occur 
at monthly intervals. Data will be recorded on eCRF for safety monitoring and/or relevant 
toxicity evaluation.   
5.5.2.2. 
Immunological/Allergy Monitoring 
 
Anergy Evaluation: Antigen preparations and suppliers as determined by availability: Candida 
0.10 ml (Candin: Niesen Biosciences, San Diego, CA. nielsenbio.com).  The erythema and 
induration reaction will be measured and captured in the EDC at approximately 2 days (to 
coincide with the Interferon-alpha-2b injection appointment). 
 
Delayed-type hypersensitivity (DTH) reaction - tumor-specific: An aliquot of 1.0 (± 0.2) x 
106 non-transfected irradiated SV-BR-1 tumor cells or 1.0 (± 0.2) x 106 irradiated SV-BR-1-GM 
cells, and, if available, irradiated autologous tumor cells, prepared identically as original source 
of SV-BR-1 (BriaTest™), each in 0.1ml of LRS will be injected intra-dermally into the patient’s 
arm on the day of SV-BR-1-GM injection. 
 
At the time of testing, the cutaneous tumor-cell injection will be observed for the possibility of 
immediate hypersensitivity reactions, and the patient will be monitored for 20 minutes or more 
before proceeding with full dose SV-BR-1-GM injection. Any evidence of immediate 
hypersensitivity, such a urticaria, will preclude administration of full dose SV-BR-1-GM.  The 
erythema and induration reaction will also be measured approximately 2 days later (to coincide 
with the Interferon-alpha-2b (Merck) injection appointment) and captured in the EDC. 
5.5.2.3. 
Cutaneous Monitoring Criteria 
 
Immediate hypersensitivity is defined as a 2x increase of the two largest measured diameters of 
the initial injection wheal, occurring within 20 minutes, or the development of systemic 
symptoms of wheezing, additional zones of urticaria remote from the injection site, or 
generalized pruritus.  Immediate hypersensitivity precludes further SV-BR-1-GM treatment on 


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that visit, will be treated as appropriate in the clinical judgment of the clinician, and evaluation 
by an allergist will be encouraged.  Further SV-BR-1-GM inoculations are still permissible 
contingent on recommendations by a board-certified allergist  
 
The presence of an immediate reaction to tumor SV-BR-1-GM may not imply absence of desired 
delayed-type cell-mediated immune responses.  It is not known whether further tumor SV-BR-1-
GM immunization might or might not down-regulate the Type I hypersensitivity, analogous to 
clinical allergy desensitization. 
 
Delayed type hypersensitivity will be assessed at about 2 days after injection. The two largest 
diameters of induration and erythema will be measured in our clinic by the PI, nurse, or other 
clinical staff, and each type of response will be evaluated independently.  While most 
investigators consider induration as the relevant response, a recent paper involving melanoma 
demonstrated improved survival was highly correlated to skin test responses as measured by 
erythema [84] 
5.5.2.4. 
Tumor and SV-BR-1-GM Specific Immunological Response 
 
Serum antibodies to SV-BR-I whole cell antigens, and to HER2/ neu:  The antibody titers 
will be determined by ELISA according to methods described in laboratory SOPs. 
 
Peripheral blood antigen-reactive T cells to SV-BR-I cell:  The antigen reactive T cells will 
be determined by flow cytometry or by other tests (e.g. ELISpot). 
5.5.2.5. 
Collection of Biological Specimens for Ongoing Research 
 
Biological specimens will be collected from patients who provide additional consent using the 
form in section 9.1.3.  Collection will take place during study visits according to the schedule in 
Table 2 and will take place in the offices of investigational institutions.  Whenever possible, 
specimen collection will take place during the same venipuncture procedures as for the toxicity 
studies, so that only one blood draw procedure need be performed during any visit. Urine will be 
collected via urine specimen cup using the clean catch method. 
 
Specimens to be collected include: 
 
● 1 red top (~8ml), 1 purple top (~8 ml), and 3 yellow top (citrate) vacutainer tubes (3x 
~8 ml). 
● 2 CellSave Preservative Tubes (https://www.cellsearchctc.com/product-systems-
overview/cellsave-preservative-tubes) (~10 ml each) – One tube may be collected at the 
Investigator’s discretion if necessary to protect patient safety. 
● Urine specimen cup (~100ml or larger). 
 
Phlebotomy of peripheral blood will be collected by credentialed staff (RN, LVN, etc.) according 
to community practice.  Serum (approximately 8 ml) will be collected in commercially available 
vacuum tubes (red top) used for serum collection, purple top tube (approximately 8ml) used for 
plasma and an additional amount will be collected in commercially available citrate vacuum 
tubes for harvest of peripheral blood lymphocytes (approximately 24ml) and for evaluation of 


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circulating tumor cells and related markers (approximately 20ml, or 10 ml at the discretion of the 
investigator). Malignant fluids (if available) will be placed in heparinized tubes or other suitable 
vessels for harvest of malignant cells. 
 
Handling of the specimens after collection will follow the procedures found in the separate 
Laboratory Manual for future research protocols. 
5.5.3. 
Goals of Immunological/Allergy Monitoring 
 
Tumor-specific immunological response: ERBB2 (HER-2/neu) and the cancer/testis antigen 
PRAME are expressed in the SV-BR-1-GM cell line (M. Lacher and C. Wiseman; American 
Association for Cancer Research annual meeting, 2016, New Orleans).  While it is expected that 
other relevant antigens may be present as well, the presence of at least these antigens will 
provide the study with candidate antigens to correlate with clinical benefit.  We will try to 
evaluate the generation of immune responses against the tumor cell-line, and, if such responses 
are present, identify if directed against HER-2/neu or non-HER-2/neu epitopes. Clinical 
immunotherapy studies using purified HER-2/neu antigens have reported up-regulation of T-cell 
responses to antigens quite unrelated to those used for immunization, the phenomenon of 
“epitope spreading,” [56] and this phenomenon may or may not be identified in this trial. We 
will collect information regarding subjects’ HER-2/neu status and treatment with trastuzumab for 
data analysis, but do not exclude or stratify otherwise qualified breast cancer subjects by these 
criteria. 
5.5.4. 
Study Observation & Response Criteria 
 
The following is a capsule summary of these response criteria.  Please see Therasse et al. for full 
description [85]. 
5.5.4.1. 
Measurability 
 
Measurable disease:  require such features so as to be accurately measurable (+/- 10%) in at least 
one dimension on CT (</= 1.0 cm cuts), MRI, plain X-ray, or medical photographs AND have a 
major axis of 2.0 cm or more.  Tumor lesions seen on images obtained by spiral CT must be 1.0 
cm or greater. Ultrasound imaging will be permitted only for superficial lesions.  Bone lesions 
will not be considered under these criteria.  
 
Non-measurable disease:  includes bone lesions, effusions, poorly-demarcated pulmonary 
infiltrates, and lesions <1.0 cm by radiological imaging.  
 
Objective status at examination:  Target lesions are to be defined as measurable lesions, up to 5 
sites per patient and no more than 2 sites in any one organ. 
 
1. Measurements of target lesions must be provided at evaluations pre-treatment, at 2-3 
months, and at 3 month intervals throughout treatment.  Nothing in this protocol precludes 
additional imaging, not explicitly scheduled, via CT, MRI, ultrasound, PET or other 
modalities if the clinical judgement of the treating physician indicates such would provide 
significant insight to more accurately aid evaluating CR or PR status.   


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2. Development of new lesions must be documented. 
5.5.4.2. 
Responses 
 
Responses are to be defined according to the RECIST/iRECIST criteria [78]  
5.5.4.3. 
Toxicity and Evaluation for Adverse Events 
 
Subjects will be queried at each visit regarding: 
1. Local reactions to SV-BR-1-GM injections and skin tests. 
2. Allergic symptoms such as rhinitis, skin rash, or itching.  
3. Performance status, ECOG scale.  
4. Inter-current infections 
5. Changes in medications (especially pain medications) 
6. Subjective sense of well-being or lack thereof 
7. Review of systems 
 
Safety/Tolerability responses will be evaluated.  Toxicity responses will be characterized and 
graded according to the new NIH Common Toxicity Criteria, CTCAE Version 4.03 which may be 
downloaded at http://www.hrc.govt.nz/sites/default/files/CTCAE%20manual%20-
%20DMCC.pdf 
 
Unexpected or early death or life-threatening toxicity (such as myocardial infarction, renal failure 
or thrombo-embolic disease) will be reported immediately to the sponsor, the Institutional Review 
Board, and to the FDA. The Study site will be responsible for notifying the Sponsor and the IRB.  
The Sponsor, or their designate, will be responsible for notifying regulatory authorities. 
 
Grade IV toxicity at least possibly related to the experimental therapy will terminate patient 
accrual until additional review and approval by the IRB and FDA of any necessary changes in the 
protocol may be indicated.  
 
Grade III toxicity at least possibly related to the experimental therapy will terminate further 
inoculations in that patient. 
 
A recent publication [61] has summarized the experience with other GM-CSF secreting tumor 
targeted immunotherapies.  In over 450 inoculations, severe toxicity was rare and no treatment-
related deaths were described.  The most serious toxicities were local allergic/inflammatory 
responses which were manageable by usual clinical measures. 
 
Adverse events will be responded to and recorded according to section 4.3. 
5.5.5. 
Study Visits 
 
Subjects will be asked to return to the principal investigator’s office according to the visit 
schedule in section 3.3 (Table 2 “Study Calendar”). 
 


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Because immunological therapies may sometimes require a lengthy time interval to observe 
response, our concept emphasizes observation over a period of several months.  The key 
evaluation is that which occurs two weeks after the last SV-BR-1-GM in the initial treatment 
phase.  This evaluation, which occurs at month 3, is to identify if there is progressive tumor 
growth refractory to current treatment. Patients will continue 6 months of treatment, the decision 
to cease or continue treatment occurs after the 6-month re-evaluation. 
 
Measurable lesions (together with immunological indices) will be evaluated after about 3 months 
from initiation of therapy and every 3 months of treatment. Performance status and quality of life 
will be documented regularly using the ECOG/WHO performance scale and the widely used, 
validated [74] SF-36 questionnaire. 
 
For a list of potential procedures to be performed, see the Procedure and Form Itemization in 
section 8.  
 
The final visit will be the off-treatment visit, (at the conclusion of approximately 6-12 months of 
experimental treatment or whenever the patient comes off study). 
 
5.6. 
STUDY VISITS & PROCEDURES 
 
For a detailed itemization of study visits and procedures, see section 8, “Procedure Itemization” 
5.7. 
DATA COLLECTION 
 
Relevant study data will be collected on each subject and entered into an Electronic Data Capture 
(EDC) system.  The URL for the EDC system is https://login.medrio.com.  Supported operating 
systems are Microsoft Windows XP, Microsoft Windows 2000, Microsoft Windows 7 and 8, 
Microsoft Vista, and Mac OS X.  Microsoft Internet Explorer (version 9 and later), Firefox 
(version 27 and later), Chrome (version 30 and later), and Safari (version 9.0 and later) are 
acceptable web browsers.   
 
Medrio software supports compliance with regulations such as 21 CFR Part 11, Annex 11, EU 
Safe Harbor, Good Clinical Practice, and HIPAA.  Procedural controls include electronic audit 
trails of all changes to study data, electronic signatures, data encryption, and access restrictions 
to Protected Health Information (PHI).   Access to the Medrio EDC system will only be granted 
to study personnel after training is conducted.  User accounts are permission based which grants 
limited access and functionalities dependent upon permissions granted by study administrator.   
All data that goes into and out of the server is encrypted using 128-bit Secure Sockets Layer 
(SSL) and 1024-bit RSA public keys.  The servers, hosted by Medrio, are housed in a fully 
redundant N+1 data center with redundant power, cooling, and network connectivity.  All servers 
reside behind Cisco firewalls and advanced intrusion detection/prevention systems.  Medrio 
performs nightly backups to locations both on-site and off-site and maintains redundant 
hardware. 
Data collection will begin at the signing of informed consent. All data must be submitted within 
72 working hours of the visit in which data was collected.   Edit checks (often called queries) 


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will fire in real time as data is being entered to ensure quality data is provided.  In addition to 
edit checks, manual queries will be generated by Data Managers and Monitors.  Sites will have 
10 working days to address all edit checks and manually created queries. Source Data 
Verification (SDV), Data Management Review and electronic signature by site PI will all take 
place prior to locking data.   
5.8. 
CONFIDENTIALITY& RECORDS 
5.8.1. 
General Precautions 
 
The confidentiality of subjects will be protected.  Names and other identifying information will 
not appear on any study forms, except the Informed Consent, HIPAA Authorization and the 
Enrollment Log, where subject names will be matched to their unique Study Number. 
 
Subsequent study forms and any laboratory tests will be identified only by a unique Study 
Number assigned to each subject, which is recorded on the EDC (see section 9.1.6).   
 
The source documents (which meet the record-keeping requirements of §312) are maintained and 
protected in a fireproof file cabinet in a locked room. Written research records will be kept in a 
locked room, in a locked file cabinet accessible only to the principal investigator and only those 
members of staff with specific project responsibilities. Research charts will not be labeled by 
patient name but rather by unique identification code. Records will be maintained for at least 7 
years after completion of the drug investigation. 
 
Research data will be stored and analyzed by computer. The research team members will be the 
only people to have access to the computer file, which is protected with a confidential password.  
Computer records are not totally immune to review by unauthorized persons, (hackers), but will 
be protected by password and unique ID of each patient. 
 
Research records may be also be reviewed by government organizations such as the Food and 
Drug Administration, the Institutional Review Board, and other persons who are required to 
watch over the safety and effectiveness of medical products and therapies or the conduct of 
research. If the research record is reviewed by any of these groups, there may be a need to 
examine the entire medical record and/or hospital charts. Under certain circumstances, Congress 
or a court order could obtain research records.  While every effort will be taken to keep 
information confidential, under special circumstances, this could mean public disclosure.  
5.8.2. 
Study Information Leaving the Offices of the Investigator 
 
All identifying information will be stripped from study records provided to the Study Monitor.  
Data on a subject generated by other physicians and by the Principal Investigator will be provided 
to the Study Monitor only after being de-identified.  No consent forms or other documents 
identifying the subjects in any way will be provided to the Study Monitor, except to be provided 
at the site during a monitoring visit. The Study Monitor will have access to all study records to 
verify proper conduct of the study. 


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5.9. 
COMPENSATION 
 
Subjects will not be paid for their participation.  Compensation for travel or other expenses 
associated with study procedures require pre-approval from the Sponsor.  Patients (or their 
insurance, e.g. Medicare) are expected to be responsible for all usual and customary fees 
associated with office visits, study tests and procedures, and follow-up costs, as is customary for 
national cancer trials. 
There will be no fee attached to the preparation or quality control testing of the SV-BR-1-GM, but 
standard fees for doctor visits and nurse visits will apply.   
5.10. 
SPECIMEN LABELING INFORMATION 
 
Laboratory specimens and test results will be coded only with a unique identifying number (i.e. 
“Study Number”), date of collection, and the protocol number.  The Consent Forms and 
Enrollment Log will be the only places on which subject names will be linked to their Study 
Number.  (Names and other identifying information of screening failures will not be recorded.). 
Biological specimens will be stored according to the sponsor’s laboratory SOPs, and used for 
ongoing research only as specified in the supplemental enrollment form, “Consent for the Use of 
Blood or Tissue.” (See section 9) 


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6. 
MONITORING PROCEDURES 
6.1. 
GENERAL PROCEDURES 
 
On-site study monitoring will be performed in accordance with 21 C.F.R. §312.60 obligations.  
The Study Monitor will perform in accordance with 21 C.F.R. §312.50. 
 
Study monitors will visit the site to: 
● Verify compliance with human subjects and other applicable research regulatory 
guidelines and requirements. 
● Assess adherence to the study protocol, study specific procedures and Standard Operating 
Procedures. 
● Confirm the quality and accuracy of trial conduct, recording and reporting by clinical site. 
 
Site investigators will allow study monitor to inspect study facilities and documentation (e.g., 
informed consent forms, clinic and laboratory records, other source documents, electronic case 
report forms), as well as observe the performance of study procedures.  Investigators will allow 
inspection of all study-related documentation by sponsor's and regulatory authorized 
representatives.  A site visit log will be maintained at the study site to document all visits. 
 
Any amendments, revisions, or updates to the research activities will be submitted to the IRB and 
FDA, in accordance with 21 C.F.R. §312.30, §312.66, and §50.27.  Such modifications may 
include, but not limited to, changes to the protocol, informed consent documents, investigators, 
sources of funding, etc. A change may be implemented prior to approval by the IRB or FDA only 
when it is necessary to eliminate apparent immediate hazards to the research subjects in 
accordance with 21 C.F.R. §312.66.  In such an instance, the IRB (21 CFR 312.53.c.1.vii) and 
FDA will be notified 5-10 days following its implementation. 
6.1.1. 
Data Monitoring and Auditing of Data 
 
The monitors and study coordinator will verify accuracy of data, regularly review source 
documents and compare these to ongoing study data input. Data collecting and reporting will 
proceed in accordance with the protocol.  All data correction notes are corrected within the eCRF.  
This procedure maintains the original record and identifies the dates of correction. Individual 
making the correction sign and date, and give the reason for any changes.  The data monitors 
review the eCRFs weekly and query the investigational sites for missing or incomplete data. The 
site visit monitor will compare source documents to the eCRF to verify for completeness and 
accuracy.   
All eCRF documents, forms, lab results, hospital records, x-rays, billings, etc. will be reviewed 
and used as comparison, to verify the accuracy of the electronic case report forms.   
6.2. 
AFTER COMPLETION OF THE STUDY 
 
The conduct of the study termination or “End of Study Visit” will follow all GCPs and FDA 
guidelines.  The monitor will conduct the study termination visit to: 
 


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1. Review all regulatory files for completeness; 
2. Compete the verification of all data in eCRFs with source documentation;  
3. Ensure that any equipment on loan is returned; 
4. Meet with the research team to discuss the results of: 
● The final audit of the regulatory files, 
● The final source data verification, 
● The possibility of a quality assurance and /or FDA audit, 
● The requirement for data storage. 
 
The study monitor will discuss with the principal investigator regarding any follow up for serious 
adverse events after formal termination from study.  
 
At the completion of the investigators’ participation, a final report will be reviewed by the 
monitors and submitted to the FDA, in compliance with 21 CFR 312.64(c) within two weeks.  To 
ensure timely preparation and delivery of this document, time and resources will be allocated to 
complete the final document as part of the budget and planned timeline.  
 
The study monitor will discuss with the principal investigator the next phase of the trial, the 
possibility of future studies, etc. and will ensure that:  
 
1. All study drug is accounted for 
2. Any study materials not used for this study are returned or destroyed 
3. Study files are prepared for long-term storage 
 


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7. 
STATISTICAL CONSIDERATIONS 
The primary endpoint is safety, which does not require statistical analysis, nor does the decision 
to expand the patient cohort from 10 subjects to 25-40.  Subjects who do not reach the first post-
dose tumor assessments may be replaced at the discretion of the Sponsor.  However, for scientific 
data review, de-identified data will be entered onto CRFs and from there into a computer database 
for possible statistical analysis.  
 
In addition to those variables specifically mentioned in this protocol, which are related to the 
current treatment and assessments, information on a variety of patient characteristics will also be 
entered, including but not limited to demographics (age, sex, race/ethnicity), medical history 
(stage at diagnosis, ER/PR/HER2neu, genomic analysis per community practice, prior cancer 
treatments, time from diagnosis to first metastases, sites of disease, etc.), physical exam 
characteristics, and date of death for computing survival time from first SV-BR-1-GM 
inoculation.   
7.1. 
DATA of SPECIAL INTEREST 
 
In addition to the above expected demographic variables and endpoints, several other 
characteristics will be addressed, including: 
 
1. Changes in weight, performance status, pain; 
2. Quality of life (as measured by the SF-36);  
3. Delayed type hypersensitivity to SV-BR-1 or SV-BR-1-GM and to recall antigens; 
4. Immunological responses (if feasible, to perform in real time); 
5. CEA, CA 27.29 (or CA 15-3 if preferred by the Investigator) 
 
The HLA phenotype will be tested before beginning the program, as many consider the presence 
of HLA A2 a necessary condition for developing an immune response to peptide antigens 
displayed to the T-cell receptor.  This locus is present in about 45% of patients, about 10% higher 
in Chinese and about 15% lower in African-Americans.  The absence of HLA-A2 has not been an 
exclusion criterion for our previous work, but given its frequency, data gathering seems warranted 
as it may show some correlation.  While not present on SV-BR-1-GM it was present on the 
patient described in our case report [19]. Of 8 HLA alleles phenotypically identified on SV-BR-1, 
5 were held in common with this responder case (2 of which, HLA-A*11:01 and HLA-
DRB3*02:02, were recently confirmed at the allele level; presented at the annual American 
Association for Cancer Research meeting, 2016, New Orleans); the significance of this is not 
known but subject to further study.  HLA data will be accessible only to the medical monitor and 
BriaCell personnel; no HLA data is to be released to any investigator or associated staff.   
7.2. 
REVIEW of STUDY DESIGN 
 
This is a phase I/IIa safety analysis. The initial 10 patients will be enrolled, which will trigger a 
pure safety analysis of the treatment. Once deemed safe an additional 15-30 patients will be 
enrolled to complete the primary, secondary and exploratory end points.  
 


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7.3. 
RESPONSE DEFINITIONS 
 
Both objective tumor response (CR or PR) and immunological response will be considered as 
evidence of activity.  Criteria for clinical response have been described in detail in the discussion 
of RECIST and iRECIST.  Three tests will be used for evaluation of SV-BR-1-specific 
immunological response.  Serum antibody levels against live SV-BR-1 cells will be measured by 
cell suspension ELISA.  T-cell mediated response will be measured by delayed type 
hypersensitivity (DTH) skin test and by flow cytometry.  The latter test is designed to calculate 
the frequency of peripheral blood T cells producing interferon-gamma in response to stimulation 
with monocytes pulsed with SV-BR-1 cell lysate.  For cell suspension ELISA and flow cytometry 
assay, a 1.5-fold increase from pre-SV-BR-1-GM to post-SV-BR-1-GM level is considered 
evidence of response [87].  For DTH, an induration of >5mm in diameter is commonly considered 
evidence of reaction [83], although erythema has been considered informative in one recent report 
[88]. If a patient has either a clinical response or an immunological response on any of the three 
measures, he/she will be considered to have a biological response. In addition, data may later be 
analyzed using the recently published iRECIST criteria [89]. 
 
These criteria for response (as well as an alpha error rate of 0.10) are being used because this is an 
early trial of a new regimen that is expected to be well tolerated and is being used in patients who 
have failed the standard therapeutic approaches.  Their survival time is expected to be limited 
under any circumstances, and it is important not to miss a possibly active treatment regimen.  
Insofar as the patients for this regimen will have very advanced cancer, the absence of toxicity 
will be considered very significant and will encourage consultation with the FDA for advice for 
planning further investigations in patients with more favorable prognoses and more robust 
immune capabilities. 
 
Also, early termination can occur based on toxicity, as described earlier in the toxicity section.  
7.4. 
DATA ANALYSIS 
 
A variety of statistical analyses will be performed to assess the relationship between clinical 
response, immunological response, and possible prognostic factors.  The appropriate statistical 
test will be determined by the bio-statistician. 
 
Multiple regression and/or Cox regression will be performed to identify factors predictive of 
response if the number of subjects entered into the study so permits.  This may include logistic 
regression when using response as the endpoint and Cox regression when using survival time.  
Other parametric and nonparametric tests will be used as appropriate to evaluate relationships of 
interest.  For all tests, criterion for statistical significance will be set at p <0.05, two-tailed test. 
  
The principal investigator will review clinical and laboratory data at the times of reimaging and 
restaging or earlier as needed.  Protocol deviations will be entered onto a form to be included in 
the regulatory binder.  Missing data, patient absence or other non-compliance will be documented 
in a Note to File, copied to the IRB, and included in the annual report unless safety concerns 
warrant prompt FDA filing as per the criteria for Serious Adverse Events. 


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8. 
PROCEDURE AND FORM ITEMIZATION 
Cycle I 
 
Day 
Procedure 
Within 2-4 
weeks before 
starting   
Initial 
Treatment 
Phase (ITP) 
Get blood tests and imaging tests.  HLA profile if not done already; Serologic 
Markers; Urinalysis. 
Blood /specimens for research.   
Baseline physical and medical history. 
Decision about eligibility. 
SF-36 “Quality of Life” form.  
Explanation of program, questions answered, study enrollment forms reviewed 
and signed.  (Section 9 for forms) 
Cardiac assessments: baseline ECG, cardiac troponin (cTn), NT-proBNP and 
an estimation of left ventricular ejection fraction (LVEF) by either cardiac echo 
or MUGA scan.   
 
2-3 days 
before 
starting ITP 
Get routine blood tests. Serologic Markers; Urinalysis. 
Blood/specimens for research.  
Abbreviated physical exam (only if not performed within the past 2 weeks). 
Beta-HCG serum pregnancy test for women of childbearing potential within 7 
days of first SV-BR-1-GM.   
SF-36 “Quality of Life” form.  
Have low-dose cyclophosphamide (Cytoxan) premedication (to possibly 
enhance immune response).  
 
Day 0 
Start of Initial Treatment Phase (ITP) 
Anergy  test. (to occur with cycles 1, 3, 6, 9, 12) 
Have DTH (~106 BriaTest™ or SV-BR-1-GM) and anergy (Candin) skin test 
injections in forearm.  Evaluate for immediate hypersensitivity to BriaTest™ or 
SV-BR-1-GM.  
Receive injections of full dose SV-BR-1-GM into skin of right and left thighs 
and two places on upper back (unless allergy to skin test is seen).  
 
 
Day 2 & 4 
(±1) 
Evaluation of skin tests (anergy to Candin and DTH to BriaTest™ or SV-BR-1-
GM) and of SV-BR-1-GM injection sites. 
Interferon-alpha-2b (Merck) injection into SV-BR-1-GM sites on day 2 (± 1 
day) and 4 (± 1 day) to possibly enhance immune response.  
 
Cycle 2 
 
Day 
Procedures 
Day 11 or 12 
Brief physical and update of medical history. 


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Get routine blood tests. 
SF-36 “Quality of Life” form. 
Low-dose cyclophosphamide (Cytoxan)  
Day 14 
Have DTH (~106 BriaTest™ or SV-BR-1-GM) skin test injections in forearm. 
Evaluate for immediate hypersensitivity.  Any evidence of immediate 
hypersensitivity precludes dosing with SV-BR-1-GM. 
Receive injections of SV-BR-1-GM into skin of right and left thighs and two 
places on the upper back. 
Day 16 & 18 
(±1) 
Evaluation of skin tests (DTH to BriaTest™ or SV-BR-1-GM). Evaluation of 
SV-BR-1-GM injection sites.  
Interferon-alpha-2b (Merck) injection into SV-BR-1-GM sites on 2 days (± 1 
day) and 4 days (± 1 day) after SV-BR-1-GM to possibly enhance immune 
response.  
 
Cycle 3 
 
Day 
Procedures 
Day 25 or 26 
Brief physical and update of medical history.  
Get routine blood tests.  
SF-36 “Quality of Life” form.  
Low-dose cyclophosphamide (Cytoxan).  
Day 28 
Have DTH (~106 BriaTest™ or SV-BR-1-GM) and anergy (Candin) skin test 
injections in forearm.  Evaluate for immediate hypersensitivity to BriaTest™ or 
SV-BR-1-GM. Any evidence of immediate hypersensitivity to BriaTest™ or 
SV-BR-1-GM precludes dosing with full dose SV-BR-1-GM. 
Anergy test (Candin) is to occur with cycles 1, 3, 6, 9, and 12. 
Receive injections of SV-BR-1-GM into skin of right and left thighs and two 
places on the upper back.  
Day 30 & 32 
(±1) 
Evaluation skin tests (anergy to Candin and DTH to BriaTest™ or SV-BR-1-
GM) and of SV-BR-1-GM injection sites  
Interferon-alpha-2b (Merck) injection into SV-BR-1-GM sites on 2 days (± 1 
day) and 4 days (± 1 day) after SV-BR-1-GM to possibly enhance immune 
response.  
 
Cycle 4 
 
Day 
Procedures 
Day 53 or 54 
Brief physical and update of medical history.  
Get routine blood tests.  
SF-36 “Quality of Life” form. 
Low-dose cyclophosphamide (Cytoxan).  
Day 56 
Have DTH (~106 BriaTest™ or SV-BR-1-GM) skin test injections in forearm. 
Evaluate for immediate hypersensitivity. Any evidence of immediate 
hypersensitivity precludes dosing with full dose SV-BR-1-GM. 


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Receive injections of SV-BR-1-GM into skin of right and left thighs and two 
places on the upper back.  
Day 58 & 60 
(±1) 
Evaluation of skin tests (DTH to BriaTest™ or SV-BR-1-GM). Evaluation of 
SV-BR-1-GM injection sites.  
Interferon-alpha-2b (Merck) injection into SV-BR-1-GM sites on 2 days (± 1 
day) and 4 days (± 1 day) after SV-BR-1-GM to possibly enhance immune 
response.  
Cycle 5 
 
Day 
Procedures 
Day 81 or 82 
Brief physical and update of medical history.  
Get routine blood tests 
SF-36 “Quality of Life” form.  
Low-dose cyclophosphamide (Cytoxan).  
Day 84 
Have DTH (~106 BriaTest™ or SV-BR-1-GM) skin test injections in forearm. 
Receive injections of SV-BR-1-GM into skin of right and left thighs and two 
places on upper back.  
Day 86 & 88 
(±1) 
Evaluation of skin tests (DTH to BriaTest™ or SV-BR-1-GM). Evaluation of 
SV-BR-1-GM injection sites. Evaluate for immediate hypersensitivity. Any 
evidence of immediate hypersensitivity precludes dosing with SV-BR-1-GM. 
Interferon-alpha-2b (Merck) injection into SV-BR-1-GM sites on 2 days (± 1 
day) and 4 days (± 1 day) after SV-BR-1-GM to possibly enhance immune 
response.   
 
Clinical Evaluation Visit 
 
Day 
Procedures 
Day 110 
(approx.) 
Get routine blood tests and imaging tests. Serologic Markers; Urinalysis.  
Blood and urine for research.  
Physical exam and update of medical history.  
SF-36 “Quality of Life” form. 
Cardiac assessments: An ECG and estimate of LVEF (by the same method) 
will be performed after 3, 6 and 12 months on study if the subject remains 
asymptomatic, or earlier if a patient becomes symptomatic.   
 
Cycle 6, 7, 8 - Refer to procedure as cycle 3, 4 and 5. 
Re-Evaluation Visit - Refer to procedure for Clinical Evaluation Visit. If patient has a non-
progressive response and desires to continue treatment, may proceed for 3 additional cycles with 
re-evaluation after the 3 cycles. If patient progresses or choses to stop treatment they will be 
considered off-treatment. 
 
Optional Cycle 9, 10, 11 - Refer to procedure as cycle 3, 4 and 5. 


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Re-Evaluation Visit - Refer to procedure for Clinical Evaluation Visit. If patient has a non-
progressive response and desires to continue treatment, may proceed for 3 additional cycles with 
re-evaluation after the 3 cycles. If patient progresses or choses to stop treatment they will be 
considered off-treatment. 
 
Optional Cycle 12, 13, 14 - Refer to procedure as cycle 3, 4 and 5. 
Off-Treatment Visit 
   
Day 
Procedures 
Day will vary Get routine blood tests and imaging tests. Serologic Markers, Urinalysis.   
Blood and for research. 
Physical exam and update of medical history. 
SF-36 “Quality of Life” form. 
  
Flexibility within cycles 
-Pretreatment: IV low-dose cyclophosphamide (300 mg/m2 or a lower dose with the Sponsor’s 
approval) C 2-3 days before SV-BR-1-GM inoculation 
-Treatment: intradermal injection of SV-BR-1-GM (5-50 x 106 cells) in 4 divided doses into the upper 
back and upper thighs 
-Posttreatment: intradermal Interferon-alpha-2b (Merck) alpha (10,000 U) into each SV-BR-1-GM 
inoculation site at 2 and 4 days ± 1 day. 
 
Flexibility between cycles can be +/- within one week under special circumstances as approved 
by PI. 


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9. 
FORMS AND REFERENCES 
9.1. 
CONSENT, SCREENING & ENROLLMENT FORMS 
 
9.1.1 Primary Informed Consent Form 
9.1.1A Attachment - Study Calendar 
9.1.2 HIPAA Authorization Form 
9.1.3 Consent for Use of Blood or Tissue for Research 
9.1.4 Study Information Sheet (FAQs) 
9.1.5 Screening Evaluation Form 
9.1.6 Screening & Enrollment Log 
 
 
 
 
 
 
 
 
 
 
 


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9.1.1. 
Primary Consent Form 
 
A Phase I/IIa Study of the SV-BR-1-GM in Metastatic or Locally Recurrent Breast Cancer 
Patients 
 
                         Principal Investigator (Study Doctor):  [Name of Investigator] 
                           CONSENT TO BE A RESEARCH PARTICIPANT  
 
This is a clinical trial, a type of research study.  A description of this clinical trial will be 
available on http://www.ClinicalTrials.gov, as required by U.S. Law. This Website 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 study doctor will explain the clinical trial to you. Clinical trials include only people who 
choose to take part. Please take your time to make your decision about participating.  You don’t 
have to make this decision now.  You may also take this consent form and other materials and 
discuss your decision with your friends and family.  You can also discuss it with your own 
doctor, and health care team.  If you have any questions, you can always ask the study doctor or 
their designate for more explanation.  
 
You are being asked to consider taking part in this study because you have recurrent breast 
cancer that has not responded to traditional treatments.  
 
Why is this study being done? 
The purpose of this research program is to study the safety and effectiveness of an experimental 
immunotherapy for advanced cancer.  In this study, we want to see whether SV-BR-1-GM 
injections help boost your immune system and/or help control or help improve your cancer.  The 
researchers will also be studying the safety of SV-BR-1-GM to investigate what effects good 
and/or bad the injections have on you and your cancer.  Initially, ten patients will take part in the 
study.  If there are no serious side effects, an additional 15 patients may be treated to evaluate the 
same effects. 
 
What is the experimental therapy? 
The therapy is called SV-BR-1-GM.  This is created with a human breast cancer cell line that has 
been genetically engineered to produce a substance called “GM-CSF,” which occurs naturally in 
the body. We would like to see if injecting the investigational agent into your body in 
combination with other drugs will have an effect on your cancer.  Before injection the tumor 
cells in the SV-BR-1-GM are given a treatment similar to x-ray therapy so they do not spread or 
grow.  
 
SV-BR-1-GM has been under study for many years, to bring it to this stage for evaluation in 
additional research participants. The prior results in this program have shown some preliminary 
effect on their brain tumor metastases in the one patient affected.  The intended study will further 
explore the activity of the product.  
 
What is required to be part of this study?  


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To fully consider whether you want to take part in this study, you will be asked to read many 
forms, and sign them if you choose to take part.  These include: 
1. This consent form. 
2. A separate consent form for future use of your blood and/or tissue samples. 
3. An information sheet with frequently asked questions about this type of research. 
 
After considering all the information carefully, and if you choose to take part in this study, you 
will first be evaluated for qualifying medical conditions.  
 
To be considered eligible for the study, you will need to have the following conditions: 
 
● You must have a qualifying type of stage four (Stage IV) breast.   
● You must also have evidence that surgery, radiation, or other medical therapies have not 
helped you. 
● You must have received chemotherapy (and/or hormonal therapy, if appropriate) in the 
past. 
● You must be expected to live for at least another 4 months. 
● You must be in charge of your own health care decisions. 
● You must have acceptable blood and other test results that will be done to see if you are 
eligible. 
 
 You may not participate in this study if any of the following apply: 
 
● You are not eligible if you are a woman who is pregnant or nursing. 
● If you are a woman of childbearing age, you must also be careful not to BECOME 
pregnant or nurse a child while you are in this study because the researchers don’t know 
how the SV-BR-1-GM may affect a developing baby. If you are a woman of potential 
childbearing age, you must have a negative pregnancy test within 7 days before starting 
this study. You must then take appropriate measures to keep from becoming pregnant. If 
you become pregnant during the study, you should report this to the study doctor or their 
designate. 
● If you have recently had chemotherapy, hormonal therapy, XRT, Immunotherapy, or 
general anesthesia/major surgery, you must have complete recovery from expected side 
effects of the last treatment (usually a period of 3 weeks).  
● If you have another cancer in any other part of your body, other than the primary breast, 
you usually will not qualify. However, you may still take part in the study if the other 
cancer has not needed treatment in the past 24 months. 
● If you have cancer spread to the brain, you understand that it will be necessary to monitor 
the tumor with MRI imaging about every 3-4 weeks.  You understand that the standard of 
practice in the community is to initiate radiation therapy and that delaying radiation 
therapy to see SV-BR-1-GM effect is experimental.   
● You must not be taking Coumadin or similar anti-clotting medicine, or systemic steroids 
(at a dose greater than 10 mg a day of prednisone), or “beta-blockers” (a blood pressure 
medicine). 


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● You must not have certain rheumatologic (Lupus), psychiatric (unpredictable to major 
psychosis), immune disorder (such as HIV or AIDS), or any other major medical 
problems. 
 
If you decide to take part, the Study Doctor or their designate will discuss with you your complete 
health history (and social history as it relates to your health). 
 
What will be done to see if I am eligible? 
There will be many tests to see if you are eligible, and to provide data that can be compared at the 
end of the study to see how SV-BR-1-GM worked.  Because there are so many tests, and the 
timing of when these tests is important, it might take several visits to this office to get them all 
done in the order required for this study. 
 
I.  Procedures that will be done at the treatment office. (Most of these will be done today if you 
agree to take part and sign the consent forms): 
1. Questions about your medical & social history (screening only). 
2. A complete physical exam, including vital signs. 
3. About 40 ml of blood will be collected from your arm using a needle and small tubes for 
future research purpose, and other blood tests will be done in about 14 days of receiving 
the first SV-BR-1-GM injection.  
a. Tests will be done including CBC, differential, platelets, T and B subsets, 
comprehensive metabolic biochemical profile, LDH, GGT, uric acid, HLA profile. 
(The study doctor or their designate will explain to you what all these tests mean). 
b.   Cancer blood tests will also be done, for example, CEA and CA 27.29 (or CA 15-3) 
serology.  
4. For women of childbearing potential, a pregnancy test will also be done from the same 
blood samples in about 7 days before receiving the first SV-BR-1-GM injection. 
5. This office will collect urine for a routine urine test and for possible future research. 
6. You will be asked to fill out a questionnaire that gathers information about your quality of 
life. 
7. Tests will also be done to see if you are allergic to SV-BR-1-GM or its ingredients.  These 
tests, called “immunohistological” or “anergy” tests, will be done by using a needle to 
inject a small amount of BriaTest™ (which is closely related to SV-BR-1-GM) or SV-BR-
1-GM just under the skin of your forearm, and observing the results over several days. 
8. A buccal swab (getting cells from inside your cheek with a Q-tip) will be collected to 
perform HLA typing (similar to tissue typing for transplantation).  This is a genetic test. 
II. Procedures that need to be scheduled (within 28 days of receiving the first SV-BR-1-GM 
injection): 
1. A regular chest X-ray (if determined necessary by your study doctor). 
2. A CT scan of your chest, abdomen, and hips (or PET scan at the discretion of your study 
doctor). 


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3. A bone scan, and/or selected bone X-rays if there is any clinical suspicion of bone cancer. 
4. A breast MRI or mammogram may done.  Also, a PET test may be required.  If you have 
already had these done you may be asked to share the results with the study doctor or their 
designate. 
5. A brain scan (MRI or CT technique) will be done if you have any neurological symptoms 
related to your cancer. 
6. An electrocardiogram. 
7. An evaluation of heart function either by a cardiac echo or a radioactive tracer scan. 
 
When all your eligibility tests have been done, the study doctor or their designate will make a 
decision about whether you can take part in the study.  You will be notified by the office of test 
results and final decision of the study doctor.  If any test results show anything that could affect 
your health, or might need further testing for your medical care, your own doctor(s) will be 
notified.  You will be asked to sign a release form for this purpose. 
 
What will happen when I receive the SV-BR-1-GM? 
Receiving the experimental therapy is a detailed process that happens in a “cycle”.  Each cycle 
spans 7 to 9 days, and requires 4 different visits to this office; each about 2 days apart.  There will 
be 15 cycles of receiving SV-BR-1-GM over the course of 13 months during the treatment phase 
of this study. A schedule of the cycles is attached to this consent form for your reference. 
 
During each cycle, the following procedures will be done: 
 
Visit 1: 2 days before receiving the SV-BR-1-GM, you will first have lab tests done.  You will 
then receive a medicine to prepare your immune system.  This medicine is called 
cyclophosphamide (Cytoxan).  It is widely used in doses that are 2-3 times more than that used in 
this study.  This drug will be injected into a vein (i.e. given intravenously) over the course of 
about 60 minutes.  You will also receive a drug to reduce nausea. 
 
Starting with the 2nd SV-BR-1-GM cycle, other procedures will be done at this first visit of each 
cycle, including a brief physical exam and update of your medical history.  You will also be asked 
to fill out the quality of life questionnaire again. This visit will take about an hour. 
 
Visit 2:  In a separate office visit 2-3 days later, you will first have the allergy test injections done 
on your forearm.  After 20 minutes, if all is well, you will receive injections of the experimental 
therapy, SV-BR-1-GM.  In this study, the SV-BR-1-GM is injected into four places (two sites:  on 
the upper back and two thighs, right and left).  After the injections, you will be asked to remain in 
the office for 60 minutes to see if there are any side effects.  This entire visit will take about 90 
minutes. 
 
Visit 3:  1-3 days after you receive the SV-BR-1-GM, you will return to this office to receive a 
drug called “Interferon-alpha”.  Interferon-alpha-2b (Merck) is available from drug companies 
and is also widely studied to improve immune function.  At this visit, a very small amount of 
Interferon-alpha-2b (Merck) will be injected into same places as the SV-BR-1-GM, to help boost 
the local immune reaction. 


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Visit 4:  In another office visit 1-3 days later (3-5 days after SV-BR-1-GM), Interferon-alpha-2b 
(Merck) injection will be repeated again.  Each of these visits will take only about 15 minutes. 
During the first month of the study, you will be asked to come in to this office for 3 SV-BR-1-
GM cycles, totaling 12 visits. This is an important time commitment on your part, and you should 
consider the impact it will have on your schedule. 
 
Evaluation Periods 
After the first 3 cycles, you will start monthly cycles for a total of 8 cycles over 6 months. After 4 
or 5 cycles (2-3 months) blood and imaging tests will be done, so that the results can be compared 
to baseline.  After 8 cycles (6 months) blood and imaging tests will be done, to evaluate the 
results over time. Some extra blood will be drawn at some visits to measure cancer cells that may 
be in your blood.  The study doctor or their designate will explain exactly which tests will need to 
be done in your case.  Based on the results of the 6 month tests, you and your doctor will make a 
decision whether you are eligible to proceed for the optional 3 months of treatment (3 more 
cycles). If you are eligible and chose to proceed with the optional treatments, another re-
evaluation of imaging and labs will be performed after cycle 11 (month 9). If you are still eligible 
(based on the 9 month tests) for continued optional treatments and you chose to proceed you will 
have a total of 12 months of treatment and 14 cycles of treatment. Imaging tests may be 
performed more frequently if your doctor thinks this is advisable.  The electrocardiogram and the 
evaluation of heart function will be repeated after 3, 6 and 12 months or more frequently if you 
develop symptoms like chest pain, shortness of breath or weakness. 
 
Monthly Maintenance Cycles 
After the first month, if you continue in the study, you may be scheduled to complete 5 additional 
SV-BR-1-GM cycles, each about a month apart.  There will be one SV-BR-1-GM cycle each 
month, with the similar visits, timing, and procedures described above.  After each 3 SV-BR-1-
GM cycles (about 3 months apart), there will be another Evaluation Period to see if you should 
continue on the study.  This will involve the similar tests and evaluations described above. 
 
After the last SV-BR-1-GM treatment (about 6-12 months into the study), you will again have 
blood and imaging tests for a final comparison.  You will not participate in more than 14 SV-BR-
1-GM cycles during the entire study.  The total length of your participation in the “treatment 
phase” of this study depends on many scheduling factors, but is expected to last about 6-12 
months.   
Should your doctors decide that SV-BR-1-GM is not helping, you will be taken off protocol.  
You will not be able to receive further SV-BR-1-GM and you may receive whatever treatments 
that are recommended by your doctor. 
 
The attached Study Calendar details the timing of all these visits, procedures, and follow-up.  You 
will be asked to stick with this study schedule as closely as possible, and to tell the study doctors 
or their designate about any good or bad changes to your health. 
 
What happens after the study ends? 


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Two weeks after you are finished with the last SV-BR-1-GM cycle, the study doctor or their 
designate will ask you to visit the office for follow-up blood and imaging tests, and a final physical 
exam.   
 
If you are not coming to our office for other reasons, we would like to call you, your doctor, or the 
person you may choose, on the telephone every 6 months to see how you are doing.  This will help 
us look at the long-term effects of the SV-BR-1-GM. 
 
We would like to keep track of your medical condition for the rest of your life. (You can decide to 
stop the phone calls at any time.)  A special form is on hand (“Designation of Proxy”) for you to 
provide us with the contact people you wish to designate.  
The results of the study may be published in medical journals or other media.  Your identity will 
not be disclosed in any of the publications, presentations, or articles that result from this study.  
 
Can I stop being in the study? 
Yes.  You can decide to stop at any time.  Simply tell the study doctor or their designate if you are 
thinking about stopping or decide to stop.  He or she will tell you how to stop safely.  
 
It is important to tell the study doctor if you are thinking about stopping so any risks from the SV-
BR-1-GM can be evaluated for your safety.  Another reason to tell your doctor that you are 
thinking about stopping is to discuss what follow-up care and testing could be most helpful for 
you, and what information (if any) you would like to share with your other doctors. 
 
The study doctor may stop you from taking part in this study at any time if he/she believes it is in 
your best interest, if you do not follow the study rules, or if the study is stopped for any reason. 
 
RISKS AND BENFITS OF BEING IN THIS STUDY 
 
What side effects or risks can I expect from being in the study?  
You may have side effects while on the study.  Everyone taking part in the study will be watched 
carefully for any side effects.  However, doctors don’t know all the side effects that may happen.  
Side effects may be mild or very serious. Your health care team may give you medicines to help 
lessen side effects, as part of your regular medical care outside of the study.  Many side effects go 
away soon after you stop taking the SV-BR-1-GM.   In some cases, side effects such as allergic 
reactions could be serious long-lasting, or even produce risk of death. One patient on this study 
died.  She was a 54-year-old woman with breast cancer which had spread throughout one breast 
and the outside of the lungs.  In her second cycle of treatment, she received the cyclophosphamide 
and came in 2 days later feeling weak and short of breath.  She received the SV-BR-1-GM and was 
sent to the emergency room for the shortness of breath.  Her heart stopped and attempts to revive 
her were not successful.  No autopsy was performed.  The Investigator thought this death was 
unlikely related to SV-BR-1-GM. 
 
You should always notify your study doctor right away of any side effects that you have while 
taking part in the study.    
 
Risks and side effects related to the experimental treatment include: 


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Likely 
● Pain from injection 
 
 
● Redness, swelling, itch developing at the injection sites 
 
 
Less likely   
● Flu-like symptoms such as fever, chills, aches, tiredness   
● Rash and/or itch on body, away from injection  
Rare but serious 
● Wheezing, hives (allergic reaction), which could be recurrent in the future. 
● Food allergy to beef or yeast products such as bread, pasta (transient) 
 
Risks and side effects related to low-dose cyclophosphamide (Cytoxan) include: 
● Nausea (manageable with medication) 
● Lack of appetite, and less commonly vomiting, and a decrease in blood counts 
 
Risks and side effects related to the low-dose Interferon-alpha-2b (Merck) include:  
● Local pain  
● Redness, swelling, itch  
● Flu-like symptoms  
Risks and side effects related to skin tests include:  
● Pain  
● Allergy 
● Redness, swelling 
 
For more information about risks and side effects of the study treatment and drugs, ask your study 
doctor. 
 
Are there other non-medical risks if I take part in the study? 
Yes.  You have already been provided with papers describing our office privacy precautions, and 
although we will try our best, we cannot guarantee total privacy.  We will do all we can to make 
sure that the personal information in your research records will be kept private. Your personal 
information may be given out if required by law.  If information from this study is published or 
presented at scientific meetings, or in the media your name and other personal information will not 
be used.  
 
Organizations that may look at and/or copy your research records for quality assurance, and data 
analysis include: 
● The Institutional Review Board (a group that watches the study to protect you and your 
rights) 
● The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA) 
 
As you take part in the study, you may require travel, finding accommodations, and restaurants if 
you do not live nearby.  SV-BR-1-GM cannot be mailed or transported to your community 


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physician.  These arrangements will be your own financial responsibility, and there may be risks 
involved. 
 
Another risk is that you will not be allowed to receive other chemotherapy during the study and 
participating in this study could possibly disqualify you from entering future research studies. 
Although SV-BR-1-GM is considered safe, regulatory bodies may be interested in carrying out 
autopsy, at the time of death of the patient.  You and/or your family are under no obligation to 
approve an autopsy.  If there are personal, religious, or any other objections, it is your right not to 
give permission.  
 
Are there benefits to taking part in the study? 
Taking part in this study may or may not make your health better.  While doctors hope SV-BR-1-
GM will be more useful against cancer compared to the usual treatment, there is no proof of this 
yet.  We do know that the information from this study will help doctors learn more about these 
therapies as a treatment for cancer.  This information could help future cancer patients. 
 
What other choices do I have if I do not take part in this study? 
Your other choices may include: 
● Getting treatment or care for your cancer without being in a study. 
● Taking part in another study. 
● Getting no treatment. 
● Getting comfort care also called palliative care.  This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer.  It does not treat the 
cancer directly, but instead tries to improve how you feel.  Comfort care tries to keep you 
as active and comfortable as possible.   
 
Talk to your doctor about your choices before you decide if you will take part in this study. 
 
What are the costs of taking part in this study? 
There is no fee for the SV-BR-1-GM, but your study doctor, the laboratories, and imaging centers 
performing study procedures and tests will require payment for goods and services (for example, 
office visits, medicines such as cyclophosphamide, and Interferon-alpha-2b (Merck), IV tubing 
and syringes used for injections, etc.) according to customary fee schedules. 
 
You and/or your health plan or insurance company will need to pay for some or all of the costs of 
treating your cancer in this study.  Some health plans will not pay these costs for people taking part 
in research studies.  Check with your health plan or insurance company to find out what they will 
pay for.  Taking part in this study may or may not cost your insurance company more than the cost 
of getting regular cancer treatment.  
 
You will not be paid or compensated in any way for taking part in this study. Travel, lodging and 
other reasonable expenses may be reimbursed by the Sponsor when requested by the Investigator 
but must be pre-approved by the Sponsor. 
 
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute’s Web site www.cancer.gov 


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Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) 
 
What happens if I am injured because I took part in this study? 
It is important that you tell your study doctor if you feel that you are having a side effect or have 
been injured because of taking part in this study.  You can tell him in person or call him/her. 
You will get medical treatment if you are injured as a result of taking part in this study.  You 
and/or your health plan will be charged for this treatment.  No arrangements have been made, or 
funds set aside, for the treatment of injuries resulting from taking part in this study.   
 
What are my rights if I take part in this study? 
Taking part in this study is your choice.  You may choose either to take part or not to take part in 
the study.  If you decide to take part in this study, you may leave the study at any time.   No matter 
what decision you make, there will be no penalty to you and you will not lose any of your regular 
benefits.  Leaving the study will not affect your medical care.  You can still get your medical care 
from our institution, or any other of your choice. 
 
We will tell you about new information or changes in the study that may affect your health or your 
willingness to continue in the study. 
 
In the case of injury resulting from this study, you do not lose any of your legal rights to seek 
payment by signing this form.  Any questions regarding rights as a patient may be referred to the 
Institutional Review Board at: Western IRB (1-800- 562- 4789). 
 
Who can answer my questions about the study? 
You can contact your study doctor about any questions or concerns you have about this study.  If 
there are any questions or concerns that you don’t feel comfortable discussing with him, you can 
ask the sponsor, your own doctors, trusted persons, or the Institutional Review Board listed above. 
 
Please note:  There will be several other forms given to you about this study, including one that 
informs you about research studies that could be done with biological specimens collected from 
people who are taking part in the main study.  You can give permission for your biological 
specimens to be used in these additional studies if you want to, or you can refuse.  You may 
withdraw your specimens from further study at any time if you change your mind.  You can still be 
a part of the main study even if you say ‘no’ to take part in any of these additional studies. 
 
Where can I get more information? 
The study doctor is available to answer questions: 
[Name of Investigator] 
Phone: (XXX) XXX-XXXX. 
 
You may call the National Cancer Institute's Cancer Information Service at:  
● 1-800-4-CANCER (1-800-422-6237) or TTY: 1-800-332-8615 
 
You may also visit the NCI Web site at http://cancer.gov/ 
● For NCI’s clinical trials information, go to: http://cancer.gov/clinicaltrials/ 


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● For NCI’s general information about cancer, go to http://cancer.gov/cancerinfo/ 
 
 
 
 


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SIGNATURES 
 
 
Participant:  I have been told about 
this study and have taken time to ask 
questions and think about my 
decision.  I agree to participate. 
Person obtaining consent:  I have 
talked with the participant about the 
study and answered all of his/her 
questions.  I accept his/her consent. 
 
Printed Names 
 
 
 
Signatures 
 
 
 
 
 
Date / Time 
 
 
 
 
Study Number: _________________________________________________________. 
 
 


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9.1.1(A) – Study Calendar (Attachment to the Consent Form) 
 
STUDY CALENDAR 
 
 
Screening and Eligibility Procedures 
Within 2-4 weeks 
before starting 
Initial Treatment 
Phase (ITP) 
FIRST:  Explanation of study, questions answered, enrollment forms 
reviewed and signed  
Get screening blood tests, heart evaluation and imaging tests.  (The 
study doctor or their designate will help you schedule these.) 
Fill out the “Quality of Life” questionnaire. 
Initial physical and medical history done. 
Decision about eligibility 
 
  Initial Treatment Phase (ITP) - Cycle #1 
2-3 days before 
receiving SV-BR-
1-GM 
Brief physical and update of medical history (only if not performed 
within the past 2 weeks). 
Get routine, research blood tests and urine tests. 
Fill out the “Quality of Life” questionnaire. 
Receive low-dose cyclophosphamide (Cytoxan) pre-medication to 
possibly enhance immune response. 
Day 1 
Receive first SV-BR-1-GM injections 
Have Anergy and DTH skin test injections in forearm. 
Receive injections of SV-BR-1-GM into skin of right and left thighs and 
two places on the upper back (unless allergy to skin test is seen). 
Day 3 (±1) and  
Evaluation of skin tests, SV-BR-1-GM injection sites. 
Receive Interferon-alpha-2b (Merck) injection into SV-BR-1-GM sites 
on day 2 (± 1 day) and 4 (± 1 day) to possibly enhance immune response. 
Day 5 (±1) 
Evaluation of skin tests, SV-BR-1-GM injection sites. 
Receive Interferon-alpha-2b (Merck) injection into SV-BR-1-GM sites 
on 2 days (± 1 day) and 4 days (± 1 day) after SV-BR-1-GM. 
 
  ITP - Cycle #2 
Day 12 or 13 
Brief physical and update of medical history. 
Get routine blood tests. 
Fill out the “Quality of Life” questionnaire. 
Receive low-dose cyclophosphamide (Cytoxan) pre-medication. 
Day 15 
Receive DTH skin test injections in forearm. 
Receive injections of SV-BR-1-GM into skin of right and left thighs and 
two places on the upper back. 
Day 17 (±1) 
Evaluation of skin tests, SV-BR-1-GM injection sites. 


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Receive Interferon-alpha-2b (Merck) injection into SV-BR-1-GM sites 
on 2 days (± 1 day) and 4 days (± 1 day) after SV-BR-1-GM. 
Day 19 (±1) 
Evaluation of skin tests, SV-BR-1-GM injection sites. 
Receive Interferon-alpha-2b (Merck) injection into SV-BR-1-GM sites 
on 2 days (± 1 day) and 4 days (± 1 day) after SV-BR-1-GM. 
 
  ITP - Cycle #3 
Day 26 or 27 
Brief physical and update of medical history. 
Get routine blood tests and research tests. 
Fill out the “Quality of Life” questionnaire. 
Receive low-dose cyclophosphamide (Cytoxan). 
Day 29 
Have Anergy and DTH skin test injections in forearm. 
Receive injections of SV-BR-1-GM into skin of right and left thighs and 
two places on the upper back. 
Day 31 (±1) 
Evaluation of skin tests, SV-BR-1-GM injection sites. 
Receive Interferon-alpha-2b (Merck) injection into SV-BR-1-GM sites 
on 2 days (±1) and 4 days (±1) after SV-BR-1-GM. 
Day 33 (±1) 
Evaluation of skin tests, SV-BR-1-GM injection sites. 
Receive Interferon-alpha-2b (Merck) injection into SV-BR-1-GM sites 
on 2 days (± 1 day) and 4 days (± 1 day) after SV-BR-1-GM. 
 
  Monthly Maintenance Phase - Cycles 4 through 8 (1 month apart) 
Visit 1 
Brief physical and update of medical history. 
Get routine blood tests. 
Fill out the “Quality of Life” questionnaire. 
Receive low-dose cyclophosphamide (Cytoxan). 
Visit 2 
Have skin test injections in forearm. 
* Cycle # 6 only - Have Anergy test injections. 
Receive injections of SV-BR-1-GM into skin of right and left thighs and 
two places on the upper back. 
Visit 3,4 
Evaluation of SV-BR-1-GM injection sites. 
Receive Interferon-alpha-2b (Merck) injection into SV-BR-1-GM sites 
on 2 days (±1) and 4 days (±1) after SV-BR-1-GM. 
 
    Evaluation Period – Collected After Cycle 4, Before Cycle 6 
Approx. 2 wks 
later  
 
After every 3 
Cycles 
 
Get routine blood tests, research tests, urinalysis, heart tests and imaging 
tests; Serologic markers. 
Brief physical and update of medical history. 
Fill out the “Quality of Life” questionnaire. 
 
 


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Repeat Evaluation Period – Collected After Cycles 8 & 11– 
Decision about eligibility for additional 
optional treatment 
Approx. 2 wks 
later 
 
After every  
3 Cycles 
 
Get routine blood tests, research tests, urinalysis and imaging tests; 
Serologic markers.  
Brief physical and update of medical history. 
Fill out the “Quality of Life” questionnaire. 
 
 
  Optional Monthly Additional Phase - Cycles 9 through 14 (1 month apart) 
Visit 1 
Brief physical and update of medical history. 
Get routine blood tests. 
Fill out the “Quality of Life” questionnaire. 
Receive low-dose cyclophosphamide (Cytoxan). 
Visit 2 
Have DTH skin test injections in forearm. 
* Cycle # 9 and 12 only - Have Anergy test injections. 
Receive injections of SV-BR-1-GM into skin of right and left thighs and 
two places on the upper back. 
Visit 3,4 
Evaluation of SV-BR-1-GM injection sites. 
Receive Interferon-alpha-2b (Merck) injection into SV-BR-1-GM sites 
on 2 days (±1) and 4 days (±1) after SV-BR-1-GM. 
 
 Off-Treatment Evaluation Visit 
 
About 6-12 
months after 1st 
SV-BR-1-GM 
Get routine blood tests, research tests, urinalysis and imaging tests; 
Serologic markers.   
Brief physical and update of medical history. 
Fill out the “Quality of Life” questionnaire. 
 
  
 
 
 
 


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9.1.2. 
HIPAA Authorization Form 
 
RESEARCH CONSENT FORM ADDENDUM 
 
DISCLOSURE OF YOUR PERSONAL HEALTH INFORMATION 
You are being invited to be in a research study.  As part of that study lots of data will be 
generated.  Some of it will be your personal health information.  If you don’t authorize use or 
disclosure of your health information, you cannot participate in the study as it would not 
contribute to the outcome. 
 
1. WHO can give out the information? 
 
Principal Investigator or “Study Doctor" 
[Investigators name] 
Phone: (XXX) XXX-XXXX. 
 
2. WHAT information may be disclosed?  
● Results of the experimental procedure 
● Laboratory results of tests done for the study 
● Study-related medical information 
 
3. TO WHOM and WHY will the information above will be disclosed? 
● BriaCell Therapeutics Corp (Study Sponsor) 
● Cancer Insight (Clinical Research Organization running the trial) 
● The National Cancer Institute (NCI) and U.S. Food and Drug Administration (FDA), to 
audit. 
● The Institutional Review Board responsible for oversight of this research is entitled to 
inspect the above information. 
 
Your personal health information may no longer be protected by the Privacy Rule if any of these 
groups re-disclose it to somebody else.  (There could be other rules they must follow, however.) 
 
4. REVOCATION: You may cancel this authorization at any time, by notifying the following 
person in writing to your study doctor 
 
If you cancel this authorization, your health information collected during the study will only be 
used to make administrative or safety reports required by the study.  You will also have to be 
withdrawn from the study. 
 
5. EXPIRATION: This authorization will expire automatically at the end of the study. 
 
6. REFUSAL: If you decline to sign this authorization, it will not affect regular, non-research 
treatment by your doctor, payment from your insurance, enrollment in any health plan, or 
eligibility for their benefits.  However, you cannot participate in the study if you do not sign. 
 


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7. ACCESS TO INFORMATION:  You may inspect and get a copy of the information 
disclosed under this Authorization. 
8. COMPENSATION:  There is no additional compensation provided to study doctor for the 
cost of obtaining this Authorization. 
 
Participant's Signature and Investigator/Coordinator Signature: 
 
 
Participant:  I am authorizing 
use of my health information in 
the way it is described above.  
After we sign this, I will get a 
copy. 
Person obtaining consent:  We 
will allow participant's information 
to be used only as described above. 
After we sign this, we will keep the 
original.  
Printed Names 
 
 
 
 
 
Signatures 
 
 
 
 
 
Date / Time 
 
 
 
 
 
 
 
  
 
 
 
 


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9.1.3. 
Consent for Use of Blood or Tissue for Research 
 
CONSENT FOR THE USE OF BIOLOGICAL SPECIMENS FOR RESEARCH 
 
                        Study Sponsor: BriaCell Therapeutics Corp. 
 
PURPOSE 
BriaCell would like your permission to use your tissue and/or other 
biological specimens for ongoing research in developing cancer 
treatments.  The specimens will be collected from you by the study 
doctor or his/her staff, during your participation on this research 
study sponsored by BriaCell Therapeutics Corp. 
PROCEDURES 
The specimens will be collected during routine blood draws or urine 
collections.  They will be stored in a deep freeze liquid nitrogen 
storage tank or freezer.  The specimens will remain in the 
possession of BriaCell Therapeutics Corp and will not be transferred 
to any other researcher without your specific permission below. 
CONFIDEN-
TIALITY 
The specimens will be stripped of all information that could identify 
you, and a code number assigned.  The code number may link to 
certain clinical or other information about you that will be protected 
as best as possible by BriaCell Therapeutics Corp. 
RISKS 
There are no physical risks to you or anyone else.  There is a remote 
possibility that information about you could be inadvertently 
disclosed in the process of conducting research.  However, the risk 
is very small because your name and other identifying information 
will no longer be associated with the biological specimens. 
BENEFITS 
There will be no benefit to you. The knowledge gained by BriaCell 
could help cancer patients in the future.  Your specimens and 
information will be combined with other specimens and used by 
scientists.  You will not share in any profits that might result. 
ALTERNATIVES 
You can refuse to allow your specimens to be used by BriaCell for 
its own or outside research purposes.  Please designate “yes” or 
“no” in the space provided below. 
QUESTIONS 
If you have any questions about the storage or use of your 
specimens, please contact your Study Site. 
RIGHTS 
You have the right to refuse to participate. If you agree, you have 
the right to withdraw your samples at any time.  Simply contact your 
Study Site at the numbers above, and your samples will be re-
identified and destroyed.  If you refuse or withdraw there will be no 
penalty to you. 
 
 
 
 
 
 
 


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  Participant's Signature - Please sign and date ONE section below: 
 
YES - I agree to allow BriaCell 
Therapeutics Corp to conduct ongoing 
research on my biological specimens as 
explained on this form, including possible 
transfer to outside researchers. 
NO - I do not want any more research done 
on my specimens than necessary for this 
study.  Please destroy them after the tests are 
completed for the main study. 
 
Your Signature: 
 
 
Your Signature: 
 
 
Your Printed Name: 
 
 
Your Printed Name: 
 
 
Today’s Date: 
 
 
Today’s Date: 
 
 
If you choose YES, to allow BriaCell Therapeutics Corp to conduct ongoing research on your 
biological specimens; please designate your decisions below, then sign and date. 
 
Decisions for you to tell us about: (Check one answer per question) 
 
1. □ Yes □ No  Do you agree to donate specimens for this repository to be used for ongoing 
research by BriaCell Therapeutics Corp.?  
 
2. □ Yes □ No  Do you give permission for your biological specimens to be connected to your 
medical information by a code?  
 
3. □ Yes □ No  Is it OK for your biological specimens to be given by BriaCell Therapeutics 
Corp. to other researchers for further investigations?  
 
4. □ Yes □ No  Is it OK if the study site contacts you in the future about clinical information 
discovered as part of its ongoing research? 
 
 
Your Signature: 
 
 
Your Printed Name: 
 
 
Today’s Date: 
 
 
 


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9.1.4. 
Study Information Sheet 
FREQUENTLY ASKED QUESTIONS ABOUT 
SV-BR-1-GM  
                
                           Principal Investigator (Study Doctor): As per the Study Site 
                                 Study Sponsor: BriaCell Therapeutics Corp 
 
1. How is the SV-BR-1-GM made? 
Tumor cells are collected from cancer patients.  The cells are modified to produce GM-CSF, a 
biological medication widely used to stimulate the bone marrow production of white blood cells.  
The tumor cells are grown in special flasks and frozen.  Just before use, the cells are thawed; the cell 
preparation is diluted, and then given a treatment with x-rays to nullify any further cell growth. 
 
2. How is the SV-BR-1-GM given? 
The SV-BR-1-GM is injected into the skin in four places, two places on the upper back and two 
places on the thighs (left and right).  
 
3. How often is it given? 
SV-BR-1-GM is given every 2 weeks for 3 times.  Then the participant has repeat scans and/or x-
rays to see any possible effect.  Depending on the tumor response, the participant may then go onto a 
monthly booster schedule for more injections. 
 
4. Do I have to be in the hospital? 
No, the SV-BR-1-GM is designed to be given in a doctor’s office. 
 
5. What is GM-CSF and why is it needed? 
GM-CSF is a biological medication widely used to stimulate the bone marrow production of white 
blood cells.  There is, however, new data that this agent can also help generate a more effective 
immune response. 
 
6. What are the side-effects of SV-BR-1-GM? 
Side effects are uncommon.  We have had no life-threatening events and have only rarely seen 
allergic reactions or incision infections. These have been mild and self-limited. You will not lose 
your hair or have vomiting from the SV-BR-1-GM. Nausea after the priming medicine, if it is 
occurs, is manageable with some of the newest anti-vomiting medicines. The SV-BR-1-GM is 
checked carefully for contamination, viruses, or infectious microbes. In theory, there is always a 
slight chance of some undiscovered or unpredicted side-effects. 
 
7. 
Am I being experimented on?  
Yes.  As a research participant, you should know that this study was reviewed by a registered 
Institutional Review Board for compliance with medical ethics, safety, and scientific justification.  
The programs are then reviewed by the FDA and listed in the National Cancer Institute website. You 
should understand clearly that this program is a research investigation.  We are trying to develop a 
new treatment, learn as much as possible, and hopefully help the patients who come to us.  But this 


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is a research program, we cannot guarantee it will benefit you, and we must always be on the lookout 
for unpredicted or unexpected effects. 
 
8. 
What is “informed consent?” 
Before you decide to be in the study or begin any study procedures you will be given a document 
which explains in detail the program and any known or theoretical side effects as mentioned above.  
The document must be signed to indicate that you have been told the details of the program that you 
enter into it freely without pressure or deception, that you have been informed you can at any time 
ask further questions, and that you also have been informed about your rights and responsibilities as 
a research participant. 
 
Signing the consent form does not take away any of your rights, including the right to change your 
mind.  The consent process actually helps protect your rights and it also protects the ethical intent of 
our research. 
 
9. How much does the SV-BR-1-GM cost? 
We do not charge for the SV-BR-1-GM.  You should be aware that there will be costs and charges, 
according to standard fees, for most study procedures including medical visits, for the doctor’s visits 
where the SV-BR-1-GM and other study drugs are given, for laboratory and imaging tests, and for 
the supplies, needles and syringes, medications, etc. used in the study. 
 
10. 
Will my insurance or Medicare cover these fees? 
Generally, third-party payers routinely cover doctors’ visits and routine charges.  Depending on 
circumstances, some carriers will reimburse for expenses associated with the experimental treatment, 
but we cannot predict or guarantee you will be covered for all or part of the expenses.  The sponsor 
and your doctors are committed to minimizing costs and to providing care and working with all 
eligible patients.  The SV-BR-1-GM study is NOT subsidized by Federal funds.  If you have special 
circumstances please be sure to discuss these with your doctors.  Travel, lodging and other 
reasonable expenses may be reimbursed by the Sponsor when requested by the Investigator but must 
be pre-approved by the Sponsor. 
 
11. 
I’d like to be part of this study.  What do I do next? 
Notify our office and information will be provided.  We will need medical records, pathology 
reports, x-rays and scans, etc.  We frequently like to discuss your medical situation with your 
personal physician.  In evaluating your case we will try to make our recommendations as responsibly 
as possible. 
 
USEFUL CONTACT INFORMATION: 
 
Principal Investigator: [Investigator’s name] 
Phone: (XXX) XXX-XXXX. 
 
 
 


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You may also call the National Cancer Institute's Cancer Information Service at:  
 
● 1-800-4-CANCER (1-800-422-6237) or TTY: 1-800-332-8615 
 
You may also visit the NCI Web site at http://cancer.gov/ 
 
● For NCI’s clinical trials information, go to: http://cancer.gov/clinicaltrials/ 
 
● For NCI’s general information about cancer, go to http://cancer.gov/cancerinfo/ 
 
 


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9.1.5. 
Screening Evaluation Form 
 
SUGGESTED FORM TO DETERMINE FINAL ELIGIBILITY OF PARTICIPANT 
 
Do not write participant's name or other identifying information on this form. 
 
Step 1:  Consent & Enrollment Procedure  
                            Date: 
□ Consent form signed by subject and PI. 
 
□ All the subject’s questions answered. 
□ HIPAA form signed by subject and PI. 
 
□ CA Bill of Rights signed by subject and PI. 
□ Proxy form signed by subject.  
□ Medical Release form signed by subject.  
 
□ Supplement consent form regarding biological specimens signed by subject. 
 
□ Privacy Notice provided to subject. 
 
□ Copies of all signed forms provided to subject. 
 
 
Step 2:  Assign Study ID Number 
 
Participant’s Study ID Number:  __________________________________________ 
 
 
Step 3:  Inclusion /Exclusion Criteria                                                  Date: 
□ Yes           □ No 
Are all inclusion criteria met? 
 
□ Yes           □ No 
Does the participant meet any exclusion criteria? 
 
□ Yes           □ No 
In the investigator’s determination, does this participant qualify 
to be in this study? 
 
Explain any exceptions or deviations from protocol (notify the IRB): 
 
 
 
 
 
 
 
 
 
 
 


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Step 4: Screening Tests & Procedures 
 
 Is the subject eligible to be in this study, based on the results of: 
Focused medical & social history 
 
□ Yes  □ No   □ N/A 
 
Date done: 
 
CA 125 
 
□ Yes  □ No   □ N/A 
 
Date done: 
 
Complete history physical exam & ECOG 
scale  
 
□ Yes  □ No   □ N/A 
 
Date done: 
 
CEA, CA 27.29 (or CA 15-3) 
 
□ Yes  □ No   □ N/A 
 
Date done: 
 
Blood tests 
 
□ Yes  □ No   □ N/A 
 
Date done: 
 
Urinalysis 
 
□ Yes  □ No   □ N/A 
 
Date done: 
Serum beta-HCG pregnancy test  
(within 7 days of SV-BR-1-GM  start date) 
 
□ Yes  □ No   □ N/A 
 
Date done: 
 
HL-A profile 
 
□ Yes  □ No   □ N/A 
 
Date done: 
 
Immunohistological evaluation 
 
□ Yes  □ No   □ N/A 
 
Date done: 
  
SF-36 Questionnaire 
 
□ Yes  □ No   □ N/A 
 
Date done: 
 
 MRI or mammogram of the breast 
 
□ Yes  □ No   □ N/A 
 
Date done: 
 
Chest X-ray 
 
□ Yes  □ No   □ N/A 
 
Date done: 
CT scan chest, abdomen and pelvis 
 
□ Yes  □ No   □ N/A 
 
Date done: 
 


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Isotope bone scan, and/or selected  
bone X-rays    
 
□ Yes  □ No   □ N/A 
 
Date done: 
 
Brain scan MRI or CT technique 
 
□ Yes  □ No   □ N/A 
 
Date done: 
 
Explain any non-eligibility factors, exceptions, or deviations from protocol (notify the IRB): 
 
 
 
 
 
 
 
Step 5: Eligibility Status 
□ Eligible  
           
□ Ineligible 
Final eligibility status 
 
 
 
If ineligible, what was the reason? 
 
 
 
 
 
 
Step 6: Signatures 
 
Principal Investigator 
Person who collected information 
on this form. 
Printed Names 
 
 
 
 
 
Signatures 
 
 
 
 
 
Date / Time 
 
 
 
 
 
Step 7: FILE the original form in the study files for this participant. 
 
 


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9.1.6. 
Screening and Enrollment Log 
 
This is a confidential form; to be used ONLY by the Principal Investigator, or his/her authorized 
designee.  Keep this form in a locked filing cabinet when not in use.  Enter information for all 
participants who are screened; whether or not they are eligible. 
 
If Eligible:  Write a sequential number, the Subject ID #, and status “Enrolled" 
If Ineligible: Do NOT number.  Provide the reason for ineligibility 
Do not write participant's name or other identifying information on this form. 
No. 
Screening 
Date 
Participant 
ID # 
Status 
Ineligible 
Reason 
End Date 
Reason 
Initial 
 
 
 
□ Enrolled            
□ Ineligible        
□ Withdrawn 
 
_________  
 
 
 
□ Enrolled          
□ Ineligible        
□ Withdrawn 
 
_________  
 
 
 
□ Enrolled          
□ Ineligible        
□ Withdrawn 
 
_________  
 
 
 
□ Enrolled          
□ Ineligible        
□ Withdrawn 
 
_________  
 
 
 
□ Enrolled          
□ Ineligible        
□ Withdrawn 
 
_________  
 
 
 
□ Enrolled          
□ Ineligible        
□ Withdrawn 
 
_________  
 
 
 
□ Enrolled          
□ Ineligible        
□ Withdrawn 
 
_________  
 
 
 
□ Enrolled          
□ Ineligible        
□ Withdrawn 
 
_________  
 
 
 
□ Enrolled          
□ Ineligible        
□ Withdrawn 
 
_________  
 
Principal Investigator:  __________________________________ Date: ___________  
 
Checked by Monitor: ____________________________________ Date: ___________ 
 
 


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9.2. 
SUBJECT MANAGEMENT FORMS 
 
 
9.2.1. 
Subject Withdrawal Form 
 
Participant’s ID Number:  _______________________ Withdrawal Date: ________ 
 
□ Participant's Decision  
           
□ Investigator's Decision 
Withdrawal reason(s): 
Other comments: 
 
 
 
 
□ NOTE:  Inform participant that this is the end of the study. 
 
 
Principal Investigator 
Person who collected information 
on this form. 
Printed Names 
 
 
 
Signatures 
 
 
 
Date / Time 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 


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9.2.2. 
Telephone Contact Log 
All telephone calls to/from the Principal Investigator’s office regarding this study, the date, time, 
and reason for the contact should be recorded, as well as who initiated the contact.  Write a brief 
explanation of the resolution of the event, and follow the procedures for reporting any adverse 
events as needed. 
 
Do not write participant's name or other identifying information on this form. 
Date/ 
Time 
Participant 
ID Number 
Reason for Call / Resolution 
Staff 
Initial
s 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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9.3. 
CLINICAL and DATA COLLECTION FORMS  
   
Clinical and data collection forms record the protocol required information to be reported.  The 
primary data collection instrument for the study is the eCRF.  Essential eCRFs are listed: 
 
● Medical and Surgical History CRF 
● Physical Exam with Vitals and ECOG Performance Status CRF 
● SF-36 QOL Questionnaire  
● Demographics and Clinical Information CRF 
● Concomitant Medications CRF 
● Adverse Events CRF 
● Full Labs CRF (includes CBC, CMP, Urinalysis, T&B subsets, Serological markers) 
● CBS Lab CRF (CBC diff only) 
● Baseline Tumor Assessment (RECIST and iRECIST criteria) CRF 
● 3/6/9/12 Month Tumor Assessment (RECIST and iRECIST criteria) CRF 
● Treatment Cycle Encounter CRF  
 
 
 
9.4. 
REFERENCES 
 
9.4.1. 
Cited Literature 
 
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pathogenesis, prebiopsy carcinoma-detection, and long-term breast carcinoma immunotherapy. 
Critical Reviews in Oncogenesis. 1995; 6:57-85. 
32. Holmberg LA, Sandmaier BM. Theratope vaccine (STn-KLH). Expert Opin Biol Ther. 2001; 
1(5):881-91. 
33. Wolchok JD, Chapman PB. How can we tell when cancer vaccines vaccinate? J Clin Oncol. 
2003; 21(4):586-7. 
34. Lyerly HK, Morse MA, Clay TM. Surrogate markers of effective anti-tumor immunity. Ann 
Surg Oncol. 2001 Apr;8(3):190-1. 
35. Wiseman CL, Kharazi AI, et al. Interferon-modified whole cell intralymphatic vaccine in stage 
IV melanoma: results for allogeneic vs. autologous preparations. in Development of 
Therapeutic Cancer Vaccines 2003 organized by John Wayne Cancer Institute, Santa Monica, 
CA  
36. Jiang XP, Yang DC, Elliott RL, Head JF. Vaccination with a mixed vaccine of autogenous and 
allogeneic breast cancer cells and tumor associated antigens CA15-3, CEA and CA125--results 
in immune and clinical responses in breast cancer patients. Cancer Biotherapy & 
Radiopharmaceuticals. 2000; 15:495-505. 
37. Krause SW, Neumann C, Soruri A, Mayer S, Peters JH, Andreesen R. The treatment of 
patients with disseminated malignant melanoma by vaccination with autologous cell hybrids of 
tumor cells and dendritic cells. J Immunother. 2002; 25(5):421-8. 
38. Peters JH. Therapeutic tumor vaccination with autologous dendritic cells. LTBH Medical 
Research Institute Cutting Edge Seminar May 30, 2003. 
39. MacLean GD, Miles DW, Rubens RD, Reddish MA, Longenecker BM. Enhancing the effect 
of THERATOPE STn-KLH cancer vaccine in patients with metastatic breast cancer by 
pretreatment with low-dose intravenous cyclophosphamide. Journal of Immunotherapy with 
Emphasis on Tumor Immunology. 1996; 19:309-16. 
40. Disis ML, GK, Lleath PR, et al. Therapeutic vaccines: targetting the Future of Cancer 
Treatment: Medsacpe, 2002. 
41. Nemunaitis J, Sterman D, Jablons D, et al. Granulocyte-Macrophage Colony-Stimulating 
Factor Gene-Modified Autologous Tumor Vaccines in Non-Small-Cell Lung Cancer. J Natl 
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42. Couch M, Saunders JK, O'Malley BW, Jr., Pardoll D, Jaffee E. Spatial distribution of tumor 
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43. Szollosi J, Balazs M, Feuerstein BG, Benz CC, Waldman FM. ERBB-2 (HER2/neu) gene copy 
number, p185HER-2 overexpression, and intratumor heterogeneity in human breast cancer. 
Cancer Res. 1995; 55:5400-7. 


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44. Wiseman C, Kharazi A, Cuevas A and Berliner K. Whole-cell breast cancer vaccine/GM-CSF: 
Clinical experience in 13 patients with cell line SV-R-1.  Int. Soc. Bio. Ther. Annual Meeting. 
2004. 
45. Yarbro, J. (1997). The scientific basis of cancer chemotherapy. The Chemotherapy 
Sourcebook. J. W. Perry. Baltimore, MD., Williams and Wilkins: Pages 3-18.  
46. Anderson CC, Matzinger P. Danger: the view from the bottom of the cliff. Semin Immunol. 
2000; 12(3):231-8; discussion 257-344. 
47. Brown BD and Lillicrap D. "Dangerous liaisons: the role of "danger" signals in the immune 
response to gene therapy." Blood. 2002; 100(4):1133-40. 
48. Morse MA, Lyerly HK, Clay TM, Abdel-Wahab O, Chui SY, Garst J, Gollob J,Grossi PM, 
Kalady M, Mosca PJ, Onaitis M, Sampson JH, Seigler HF, Toloza EM, Tyler D, Vieweg J, 
Yang Y. Immunotherapy of surgical malignancies. Curr Probl Surg. 2004;41(1):15-132.  
49. Hicks AM, Willingham MC, Du W, Pang CS, Old LJ, Cui Z. Effector mechanisms of the anti-
cancer immune responses of macrophages in SR/CR mice. Cancer Immun. 2006; 6:11.  
50. Wolchok JD, Chapman PB. How can we tell when cancer vaccines vaccinate? J Clin Oncol. 
2003; 21(4):586-7. 
51. Hayes DF, Smerage J. Is there a role for circulating tumor cells in the management of breast 
cancer? Clin Cancer Res. 2008 Jun 15;14(12):3646-50. 
52. diPillis LG, Radunskaya AE, Wiseman CL. 2005.  A validated mathematical model of cell-
mediated immune response to tumor growth.  Cancer Research 65 (17): 7950-80. 
53. Ahmed R, Gray D. Immunological memory and protective immunity: understanding their 
relation. Science. 1996; 272(5258):54-60.  
54. Huang AY, Golumbek P, Ahmadzadeh M, Jaffee E, Pardoll D, Levitsky H. Bone marrow-
derived cells present MHC class I-restricted tumour antigens in priming of antitumour immune 
responses. Ciba Found Symp. 1994;187:229-40; discussion 240-4. Review 
55. Brooks S, Takita H, Shin K, Fang Y, Vaughan M, Sharma S, Karakousis CP. Intratumoral 
injection of GM-CSF in perspective - a review. J Med. 2003; 34(1-6):149-53. 
56. Disis M. L. G K, Lleath P R et al. Generation of immunity to the Her2/neu oncogenic protein 
in patients with breast and ovarian cancer using a peptide-based vaccine. Clin Cancer Res 
1999; 5:1289-97. 
57. Greten TF and Jaffee EM. Cancer vaccines. Journal of Clinical Oncology. 1999; 17(3): 1047-
60. 
58. Borrello I, Pardoll D. GM-CSF-based cellular vaccines: a review of the clinical experience. 
Cytokine Growth Factor Rev. 2002; 13(2):185-93. 
59. Dranoff, G. GM-CSF-based cancer vaccines. Immunological Reviews. 2002; 188:147-54. 
60. Machiels JP, Reilly RT, Emens LA, Ercolini AM, Lei RY, Weintraub D, Okoye FI, Jaffee EM. 
Cyclophosphamide, doxorubicin, and paclitaxel enhance the antitumor immune response of 
granulocyte/macrophage-colony stimulating factor-secreting whole-cell vaccines in HER-2/neu 
tolerized mice. Cancer Res. 2001; 61(9):3689-97.  
61. Emens LA, Armstrong D, Biedrzycki B, Davidson N, Davis-Sproul J, Fetting J, Jaffee E, 
Onners B, Piantadosi S, Reilly RT, Stearns V, Tartakovsky I, Visvanathan K, Wolff A. A 
phase I vaccine safety and chemotherapy dose-finding trial of an allogeneic GM-CSF-secreting 
breast cancer vaccine given in a specifically timed sequence with immunomodulatory doses of 
cyclophosphamide and doxorubicin. Hum Gene Ther. 2004 Mar;15(3):313-37. 


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62. Wiseman C, Kharazi A, Cuevas A and Berliner K. Whole-cell based breast cancer 
vaccine/GM-CSF: Clinical experience in 13 patients with cell line SV-BR1. SBT 2004 Annual 
Meeting.  J Immunother. 2004; 27:S34.  
63. Wiseman C, Kharazi A, Cuevas A, McMonigle M and Berliner K. Interferon-modified whole-
cell intralymphatic vaccine in Stage IV melanoma: Results for allogeneic vs. autologous 
preparations.  In: Conference on Development of Therapeutic Cancer Vaccines at John Wayne 
Cancer Institute, Santa Monica, CA, 2003.  
64. Wiseman CL, Kharazi A, Kudinov YG, et al. Whole-cell/a-IFN-modulated pancreas cancer 
vaccine with GM-CSF and low dose cyclophosphamide: initial results in 13 patients.  J 
Immunother. 2000; 23:591. 
65. Wiseman CL, Kharazi AI, Kudinov YG, et al. Improvement in CA 19-9 strongly correlated 
with survival in pancreas patients treated with whole-cell tumor vaccine and subcutaneous 
GM-CSF. ASCO Annual Meeting. Proc Am Soc Clin Oncol. 2001;20 Abstract 2640.  
66. Wiseman, CL, Kharazi, A, and Kudinov, Y. Whole-Cell Tumor Vaccine for Human Renal 
Carcinoma: Preliminary Results in 14 Cases. SBT Annual Meeting, J. of Immunotherapy. 
2002; S24. 
67. Wiseman C, Kharazi A, Cuevas A, Berliner K and Zagalskaya D.  Whole-cell lung cancer 
vaccine: Clinical experience with 27 patients.  Proceedings of AACR 2005 Annual Meeting, 
Anaheim, CA, Abstract 3462.  
68. Wiseman CL, and Kharazi A.  Regression of brain metastases in two breast cancer patients 
with irradiated allogeneic whole-cell vaccines, low dose cyclophosphamide, and GM-CSF.  
International Society for Biological Therapy of Cancer (iSBT) Annual Meeting.  J 
Immunother. 2006 
69. Leung TW, Patt YZ, Lau WY, Ho SK, Yu SC, Chan AT, Mok TS, Yeo W, Liew CT, Leung 
NW, Tang AM, Johnson PJ. Complete pathological remission is possible with systemic 
combination chemotherapy for inoperable hepatocellular carcinoma. Clin Cancer Res. 1999; 
5(7):1676-81. 
70. Aristu J, Cañón R, Pardo F, Martínez-Monge R, Martin-Algarra S, Manuel Ordoñez J, 
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chemoradiotherapy benefits selected patients with unresectable pancreatic cancer. Am J Clin 
Oncol. 2003;26(1) :30-6. 
71. Wiseman, C.L., et al. Whole-Cell/alpha-IFN-modulated pancreas cancer vaccine with GM-
CSF and low-dose cyclophosphamide: initial results in 13 patients. SBT Annual Meeting; J of 
Immunotherapy. 2000, Berlin, Germany. 
72. Hayes DF, Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Miller MC, Matera J, Allard WJ, 
Doyle GV, Terstappen LW. Circulating tumor cells at each follow-up time point during 
therapy of metastatic breast cancer patients predict progression-free and overall survival. Clin 
Cancer Res. 2006; 12(14 Pt 1):4218-24. 
73. Presant CA, Wiseman C, Blayney D, Kennedy P, Gala K, King M. Proposed criteria for serial 
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Erratum in: J Natl Cancer Inst 1990 May 2;82(9):796. 
74. Findler M, Cantor J, Haddad L, Gordon W, Ashman T. The reliability and validity of the SF-36 
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76. Wiseman C, Hood Y, Presant C, Kennedy P. OKT-3/cyclophosphamide up-regulation of 
peripheral blood killer-lymphocyte subsets in human cancer patients. Mol Biother. 1991; 3:63-
7. 
77. Schiavoni G, Mattei F, Di Pucchio T, et al. Cyclophosphamide induces type I interferon and 
augments the number of CD44hi T lymphocytes in mice: implications for strategies of 
chemoimmunotherapy of cancer. Blood 2000; 95:2024-2030. 
78. Wolchok JD, Hoos A, O'Day S, Weber JS, Hamid O, Lebbé C, Maio M, Binder M, Bohnsack 
O, Nichol G, Humphrey R, Hodi FS. Guidelines for the evaluation of immune therapy activity 
in solid tumors: immune-related response criteria. Clin Cancer Res. 2009 Dec 1;15(23):7412-
20. 
79. Boyer CM, Dawson DV, Neal SE, et al. Differential induction by interferons of major 
histocompatibility complex-encoded and non-major histocompatibility complex-encoded 
antigens in human breast and ovarian carcinoma cell lines. Cancer Research. 1989; 49:2928-
34. 
80. Machiels JP, Reilly RT, Emens LA, et al. Cyclophosphamide, doxorubicin, and paclitaxel 
enhance the antitumor immune response of granulocyte/macrophage-colony stimulating factor-
secreting whole-cell vaccines in HER-2/neu tolerized mice. Cancer Research. 2001; 61:3689-
97. 
81. Kharazi A, Kudinov Y, Cuevas A, Wiseman, CL.  Effect of interferon-alpha on the phenotype 
of human monocyte-derived dendritic cells generated in the presence of GM-CSF in vitro.  
European Congress of Immunology, Rhodes, Greece; 87:69, 2003. 
82. Paquette R, Hsu N, Kiertscher S, et al. Interferon-alpha and granulocyte-macrophage colony-
stimulating factor differentiate peripheral blood monocytes into potent antigen-presenting cells. 
J Leukoc Biol. 1998; 64:358-67. 
83. Matsumura T, Kuroume T, Tsukagoshi H. The specificity of the immediate reaction in 
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23. 
84. Baars A, Claessen AME, van den Eertwegh AJM, et al. Skin tests predict survival after 
autologous tumor cell vaccination in metastatic melanoma: Experience in 81 patients. [Article]. 
Annals of Oncology August 2000; 11:965-70. 
85. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to 
treatment in solid tumors (RECIST guidelines). J Natl Cancer Inst. 2000; 92(3): 205-216. 
86. Amin AS, Holmes JP, Storrer CE, Smith AM, Jama YH, Craig, D, Ponniah S, Peoples GE. 
Assessment of circulating tumor cell (CTC) patterns among disease-free breast cancer patients 
vaccinated with a preventive HER2/neu E75-peptide vaccine. J Clin Oncol (Meeting Abstracts) 
25:3059-3059, 2007.  
87. Kammula US MF, Rosenberg SA. Real-time quantitative polymerase chain reaction 
assessment of immune reactivity in melanoma patients after tumor peptie vaccination. J Nat 
Cancer Inst. 2000; 92:1336-44. 
88. Lotem M, Peretz T, Drize O, Gimmon Z, Ad El D, Weitzen R, Goldberg H, Ben David I, Prus 
D, Hamburger T, Shiloni E. Autologous cell vaccine as a post-operative adjuvant treatment for 
high-risk melanoma patients (AJCC stages III and IV). The new American Joint Committee on 
Cancer. Br J Cancer. 2002; 86(10):1534-9. 
89. Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S, Lin NU, Litière S, 
Dancey J, Chen A, Hodi FS, Therasse P, Hoekstra OS, Shankar LK, Wolchok JD, Ballinger M, 
Caramella C, de Vries EG; RECIST working group. iRECIST: guidelines for response criteria 


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for use in trials testing immunotherapeutics. Lancet Oncol. 2017 Mar;18(3):e143-e152. doi: 
10.1016/S1470-2045(17)30074-8. Epub 2017 Mar 2.  
 
 
 


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9.4.2. 
Pharmaceutical Descriptions of Study Substances 
 
Cyclophosphamide (Cytoxan®, CTX, CPM, Neosar®)  
Classification:  Alkylating agent  
Mode of Action:  Cyclophosphamide prevents cell division primarily by cross-linking DNA 
strands.  The cell continues to synthesize other cell constituents (RNA and protein), an imbalance 
occurs and the cell dies.  Cyclophosphamide is considered cell cycle, phase nonspecific.  
Storage and Stability:  Injectable forms are stable at room temperature for storage.  It is 
recommended that temperature for storage not exceed 90oF.  Reconstituted solution is stable 24 
hours at room temperature or 14 days if refrigerated when paraben-preserved diluent is used for 
reconstitution. Unused diluted drug should be discarded.  Shake vials vigorously and warm 
slightly to facilitate dissolving of cyclophosphamide crystals.  Vials may be immersed in 
lukewarm water to facilitate solution without risk of decomposition. 
Dose and Administration:  Cyclophosphamide 300 mg/m2 (or a lower dose with the Sponsor’s 
approval) given as a single dose over 1-2 hours by intravenous infusion.  Premedication with 
antiemetics is permitted, provided no corticosteroids are included.  
Interferon-alpha-2b (Merck)  
Drug Information For: INTRON A 10 MIL IU SOLN SDV 
Ingredient Name:  INTERFERON (in-ter-FEER-on) ALFA-2b  
Drug Manufacturer: MERCK  
Common Uses:  This medicine is an interferon used to treat certain types of leukemia, certain 
AIDS-related illnesses, and certain forms of hepatitis. It may also be used to treat other 
conditions as determined by your doctor.  
Before Using This Medicine:  WARNING: This medicine can cause or worsen some serious 
medical conditions including psychiatric conditions (e.g., depression), immune system problems 
(autoimmune conditions such as lupus or rheumatoid arthritis), and circulation problems (e.g., 
cardiovascular disease/blood clots), or infections (bone marrow suppression). If your medical 
history includes any of these conditions, inform your doctor promptly. Also, tell your doctor 
immediately if any serious symptoms or side effects occur (see Possible Side Effects section). 
These conditions occur infrequently, but some can be fatal. Some medicines or medical 
conditions may interact with this medicine. INFORM YOUR DOCTOR OR PHARMACIST of 
all prescription and over-the-counter medicine that you are taking. ADDITIONAL 
MONITORING OF YOUR DOSE OR CONDITION may be needed if you are taking 
fluorouracil, zidovudine, barbiturates (e.g., phenobarbital), theophylline, vidarabine, other drugs 
that depress the immune system (e.g., anti-cancer type). Tell your doctor if you take any drugs 
that make you drowsy, such as: medicine for sleep (e.g., sedatives), tranquilizers, anti-anxiety 
drugs (e.g., diazepam), narcotic pain relievers (e.g., codeine), psychiatric medicines (e.g., 


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phenothiazines such as chlorpromazine, or tricyclics such as amitriptyline), anti-seizure drugs 
(e.g., carbamazepine), muscle relaxants, and certain antihistamines (e.g., diphenhydramine). USE 
OF THIS MEDICINE IS NOT RECOMMENDED if you have a history of other severe liver 
conditions (e.g., autoimmune hepatitis, decompensated liver disease), or immune system 
suppression for organ transplants. Inform your doctor of any other medical conditions, including 
psychiatric conditions (e.g., depression), low blood cell counts (e.g., red cells, white cells, or 
platelets), heart problems, thyroid problems, lung diseases (e.g., COPD, asthma, pneumonia), 
intestinal disease (e.g., colitis), pancreatitis, immune system diseases (e.g.,  
lupus, rheumatoid arthritis), eye problems, diabetes, kidney disease, high blood pressure, brain 
tumors, seizures, allergies, pregnancy, or breast-feeding. Contact your doctor or pharmacist if 
you have any questions or concerns about taking this medicine.  
How to Use This Medicine:  Follow the directions for using this medicine provided by your 
doctor. This medicine comes with a medication guide. Read it carefully. Ask your doctor, nurse, 
or pharmacist any questions that you may have about this medicine. This medicine is sometimes 
used at home as an injection. Before using this medicine, a healthcare professional will provide 
detailed instructions for its appropriate use. This medicine comes with a patient information 
leaflet. Read it carefully. Ask your doctor, nurse, or pharmacist any questions that you may have 
about this medicine or giving injections. USE THIS MEDICINE AT BEDTIME unless directed 
otherwise. DRINKING EXTRA FLUIDS while you are taking this medicine is recommended. 
Check with your doctor or nurse for instructions. STORE THIS MEDICINE as directed on the 
prescription label. Do not use this medicine if it is cloudy or discolored. ANY LEFTOVER 
MEDICINE or supplies used with this medicine should be placed in a plastic bag and disposed of 
as instructed by your doctor, nurse, or pharmacist. IF YOU MISS A DOSE OF THIS 
MEDICINE, check with your doctor for further instructions. Do not use 2 doses at once. 
Cautions:  KEEP ALL DOCTOR AND LABORATORY APPOINTMENTS while you are 
taking this medicine. DO NOT CHANGE BRANDS OF THIS MEDICINE without discussing it 
with your doctor. THIS MEDICINE MAY CAUSE dizziness. Do not drive, operate machinery, 
or do anything else that could be dangerous until you know how you react to this medicine. THIS 
MEDICINE WILL ADD TO THE EFFECTS of alcohol and other depressants. Ask your 
pharmacist if you have questions about which medicines are depressants. BEFORE YOU HAVE 
DENTAL WORK, check with your doctor. IF YOU EXPERIENCE difficulty breathing; 
tightness of chest; swelling of eyelids, face, or lips; or if you develop a rash or hives, tell your 
doctor immediately. Do not take any more doses of this medicine unless your doctor tells you to 
do so. FOR WOMEN: IF YOU PLAN ON BECOMING PREGNANT, discuss with your doctor 
the benefits and risks of using this medicine during pregnancy. IT IS UNKNOWN IF THIS 
MEDICINE IS EXCRETED in breast milk. DO NOT BREAST-FEED while taking this 
medicine.  
Possible Side Effects:  SIDE EFFECTS, that may go away during treatment, include flu-like 
symptoms of fever, chills, headache, fatigue, muscle/joint aches, loss of appetite, nausea or 
vomiting, diarrhea, or stomach pain; temporary hair loss; or change in taste. If they continue or 
are bothersome, check with your doctor. CONTACT YOUR DOCTOR IMMEDIATELY if you 
experience drowsiness, dizziness, difficulty sleeping, one-sided weakness (arm/leg), vision 
changes, poor coordination, irregular heartbeat, intolerance to heat or cold, black stools, 


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persistent sore throat, chest tightness, unusual bleeding/bruising, tingling hands or feet, 
yellowing of the eyes or skin, dark urine, seizures, change in amount of urine, unusual increase 
in thirst, or severe stomach/abdominal pain. CONTACT YOUR DOCTOR IMMEDIATELY 
AND STOP YOUR TREATMENT with interferon if you experience any of the following: 
unusual or severe mental/mood changes (e.g., suicidal thoughts or severe depression), or bloody 
diarrhea. IF YOU EXPERIENCE difficulty breathing; tightness of chest; swelling of eyelids, 
face, or lips; or if you develop a rash or hives, tell your doctor immediately. Do not use any more 
doses of this medicine unless your doctor tells you to do so. If you notice other effects not listed 
above, contact your doctor, nurse, or pharmacist. 
9.4.3. 
SV-BR-1-GM Preparation 
 
1. Establishment and characteristics of parental breast carcinoma cell line (SV-BR-1): 
The parental cell line was established in 1999 from a chest wall mass occurring in a 36-year old 
woman, married, a mother of 2 children, with no known history of or risk factors for sexually 
transmitted disease.  The patient had previously-diagnosed breast cancer metastatic to brain, 
bone, lung, and skin.  A single-cell suspension was created by collagenase digestion and the cells 
grown in tissue culture according to standard techniques.  Both the cell line and the biopsy from 
which the cell line was derived were consistent with metastatic breast cancer by pathology and 
grew in soft agar. The cells grew as an epithelial, adherent monolayer culture, were passaged 
over 50 times with doubling time of 48 hours. The cell line is negative for estrogen receptors as 
was the original metastatic tumor specimen, and has a human female karyotype. Histochemical 
stains show reactivity with anti-keratin antibodies and strong expression of the HER-2/neu 
antigen. The cell line grew readily in the nude mouse and the resultant tumors had the 
histological appearance of human breast cancer and showed positivity for human beta-actin by 
PCR1. The original Master Cell Bank (MCB) for the SV-BR-1 cell line has been established and 
tested for sterility, mycoplasma, T. pallidum, and human pathogens.  Source documents for all 
the above have previously been submitted for the approved clinical trial, BB-IND 10312, and 
may be provided upon request. 
 
2. Transformation of E. coli with GM-CSF Plasmid: 
Transformation of Ready Made Competent Top 10 E.coli bacteria with pcDNA 3.1 /GS/GM-
CSF Plasmid. The Genestorm hORF (human open reading frame) Expression Vector pcDNA 
3.1/GS kit that includes competent Top 10 E.coli bacteria was purchased from Invitrogen 
(Catalog #H-M13207M). The bacteria were transformed with supplied pcDNA 3.1/GS plasmid 
containing a human GM-CSF ORF (open reading frame) and a zeocin-resistance gene. The GM-
CSF ORF was sequenced and insertion of the GM-CSF ORF was confirmed. However, also 2 
variations from the NCBI Reference Sequence of GM-CSF (NP_000749.2) were detected, one at 
position 53 (Thr instead of Met) and the other at position 117 (Thr instead of Ile). Whereas 
position 53 mapped between the first beta-pleated sheet (amino acids 39-43) and the second 
alpha helix (amino acids 55-64), and was not implicated in binding of GM-CSF to the receptor 
alpha subunit, position 117 mapped to a region associated with receptor binding (Eur J Biochem. 
1994;225(3):873-80), thus raising the question of whether receptor binding and thereby signaling 
can still occur with the threonine at position 117. In agreement with signaling activity and thus 
 
1 Medical Diagnostic Laboratories LLC, Mt. Laurel, NJ 


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GM-CSF bioactivity, cell culture supernatant from irradiated SV-BR-1-GM cells supported the 
proliferation of MUTZ-3 cells, a cell line reported to depend on cytokines such as GM-CSF 
(Leukemia. 1996;10(6):1025-40), whereas supernatant from parental SV-BR-1 cells (not 
engineered to express GM-CSF) had at most a minimal effect (data not shown). 
The map of the pcDNA3.1/GS plasmid indicates that the GM-CSF ORF in mammalian cells is 
driven by a CMV promoter. The bacteriophage T7 promoter upstream of the GM-CSF ORF is 
not expected to be functional in mammalian cells. In addition to the GM-CSF coding sequence 
(CSF2 gene), the GM-CSF ORF also contains, at the 3’ end, a sequence encoding a V5 epitope 
tag and a polyhistidine (6xHis) tag. The entire GM-CSF ORF is thus expressed as a fusion 
protein in mammalian cells. The map also shows that the plasmid is expected to be safe as it does 
not have a replication origin or coding sequences for nuclear antigen to permit 
extrachromosomal replication in human. 
3. Selection of transformed E. coli: 
The transformed bacteria were selected on Zeocin agar plates (Invitrogen; Q621-20), expanded 
in liquid Zeocin media (Invitrogen; Q620-20), mixed with equal amount of glycerol (Gibco, 
15514-011)-SOB Media (Sigma H8032), aliquoted and stored in the -70°C freezer. 
4. Extraction of pcDNA 3.1 /GS/GM-CSF from transformed E. coli: 
The frozen transformed E. coli was expanded in Zeocin Liquid media. The extraction of the 
pcDNA3.1/GS plasmid was carried out using Invitrogen’s S.N.A.P. Miniprep Kit (Cat #K1900-
25) following the manufactures instructions. The extracted plasmid was aliquoted and stored in 
the -70°C freezer. 
5. Evaluation of quantity and purity of the extracted plasmid: 
The quantity and purity of the extracted plasmid was determined by spectrophotometer. The 
plasmid sample was analyzed at 260 nm to determine the total yield of plasmid DNA and at 280 
nm to assess the amount of contaminating proteins. The 260/280 ratio for the plasmid lot used 
for transfection was 1.7 (1.5 ratio is commonly accepted as a “cut-off” level of DNA purity).  
6. Evaluation of integrity of the extracted plasmid: 
The integrity of the extracted plasmid DNA was analyzed by gel electrophoresis. The samples 
were serially diluted 1:2 with sterile distilled water. For each lot of plasmid seven serial dilutions 
were prepared and ran along with 1 kb DNA ladder (Promega, Cat # G5711). The gel was 
stained with SYBR Gold Nuclei Acid Gel Stain and viewed using VisiBlue Transilluminator. 
The plasmid lot used for transfection of SV-BR-1 cells appeared as a single band of 
approximately 3,000 bp and no lighter bands have been detected suggesting integrity of a tested 
plasmid. The anticipated size of the plasmid according to manufacture (Invitrogen) is 4,000 bp. 
The difference can be explained by the circular shape of the plasmid compared to the linear DNA 
present in the ladder that may result in changed gel motility. The additional heavy bands can be 
explained by multiple plasmid DNA particles present in the sample. 
7. Assessment of parental SV-BR-1 cell line sensitivity to Zeocin: 
For selection of successfully transfected tumor cells the parental breast carcinoma (SV-BR-1) 
cells were cultured in the presence of various concentrations of Zeocin to determine the minimal 
concentration that kills most of the nontransfected cells. 


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8. Transfection of SV-BR-1 with pcDNA 3.1/GS/GM-CSF plasmid: 
SV-BR-1 (passage 27) cells were harvested using 0.25% Trypsin – 0.53 mM EDTA (Gibco, Cat 
# 25200, lot 1059547). The cells were seeded in a 12-well plate and incubated for forty-eight 
hours. Following incubation the cells were transfected with the pcDNA 3.1/GS/GM-CSF 
plasmid using LipofectAMINE 2000 reagent (Gibco, Cat #18292-011) according to the 
manufacturer’s directions. The cells were incubated with the transfection solution in the 
antibiotic free RPMI-10% FBS (Fetal Bovine Serum) (FBS, Irvine Scientific #3003, lot 
300390135; RPMI, Irvine Scientific #9160, lot 916081255) for 24 hours 
9. Selection of permanently transfected SV-BR-1-GM clones and establishment of the SV-
BR-1-GM cell line: 
The permanently transfected tumor cells were selected by culturing in the RPMI-10% FCS 
containing 10 g/ml Zeocin (selective media) for approximately one month. The surviving 
colonies were propagated in T-12, T-25, and T-75 flasks using selective mediator to establish a 
permanently transfected cell line (SV-BR-1-GM). After a few successful passages, the 
concentration of Zeocin in the media was decreased by roughly 50% to 4 g/ml (maintenance 
media). The supernatant of cultured transfected tumor cells was tested for GM-CSF production 
by ELISA assay and found positive. The early passages of the SV-BR-1-GM cell line were 
frozen by staged freezing in a controlled rate device via –70º C freezer for 24h prior to final 
storage in a liquid nitrogen freezer.  
10. Preparation and validation of the original SV-BR-1-GM Master Cell Bank (MCB): 
SV-BR-1-GM cells (passage 4) was propagated in T-25, T-75, and T150 flasks using 
maintenance media (FBS, Irvine Scientific #3003, lot 300390135A; RPMI, Irvine Scientific 
#9160, lot 916010673). To confirm the production of GM-CSF, randomly selected flasks were 
incubated with the antibiotic-free RPMI-10% FBS for 72 hours. The supernatant was collected 
and the concentration of GM-CSF was determined by ELISA. The results showed that the GM-
CSF is produced by cultured SV-BR-GM cells at the average concentration of 305.57 ng/ml.  
Biological activity of the released GM-CSF was established by evaluating proliferation of 
MUTZ-2 cells as assessed by 5-bromo-deoxyuridine incorporation, using flow cytometry. This 
leukemic line has sensitive growth-dependence on GM-CSF or other factors. Serial dilutions of 
supernatant of SV-BR-1-GM cells, with appropriate positive and negative controls, demonstrated 
mitotic activity comparable to positive controls. 
The propagated cells were harvested using 0.25% porcine Trypsin – 1 mM EDTA (Gibco 
#25200, lot 1128850). The total yield was 115x106 cells at a viability of 97%. The cells were 
resuspended in the freezing medium (10% Dimethyl Sulfoxide, Sigma, #D2650, lot 111K2340 in 
the antibiotic-free RPMI-5% Human Albumin) aliquoted into 77 cryovials at the concentration of 
1.5x106 viable cells/vial. The aliquots of a final product (before the freezing) were submitted for 
safety testing described next.    
11. Safety and Sterility: 
General sterility testing of the original SV-BR-1-GM master cell bank did not show evidence of 
contamination (testing according to 21CFR 610.12 performed by the Pathology Department of 


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St. Vincent Medical Center).  Endotoxin testing performed in our laboratory was within 
acceptable limits.  
Mycoplasma testing performed by culture at Specialty Laboratories, Santa Monica, CA did not 
show evidence of contamination, nor did parallel immunofluorescence testing done in our 
laboratory.  
No mycoplasma, trypanosomes, or other pathogens were identified by electron microscopy 
performed by Dr. Linda Kelly, Diagnostic Laboratory, USC.   
Treponema pallidum testing, performed on the cell line by qualitative PCR by Medical 
Diagnostic Laboratories LLC, Mt. Laurel, NJ, did not show evidence of contamination.   
Also, one vial of MCB was taken for expansion in the antibiotic-free RPMI-10% FCS media for 
testing of HIV, HBV, HCV, and Human Parvo-virus performed by National Genetics Institute 
(Los Angeles, CA), HTLV, EBV, CMV, in vitro and in vivo adventitious agents performed by 
Apptec Laboratory Services (Camden, NJ). The results of all tests were negative and the level of 
endotoxin in the MCB sample was 0.0176 ng/ml, which is much less than the commonly 
accepted “cut-off” level of 1 ng/ml.  
12. SV-BR-1-GM lot release preparation and validation: 
Each lot of SV-BR-1-GM will be prepared by expansion of cells from one or several vials of a 
frozen SV-BR-1-GM Master Cell Bank (MCB). Expansion and other cell processing steps will 
be conducted under GMP conditions at the University of California, Davis (UC Davis) GMP 
facility at the Institute for Regenerative Cures (Sacramento, CA).   
13. Product Shipping Conditions: 
Tested and released lots of SV-BR-1-GM will be adequately packed with proper temperature 
controls and shipped via courier from the UC Davis GMP facility (Sacramento, CA) to the 
clinical sites. A data logger recording the temperature during transport will accompany each 
shipment. SV-BR-1-GM formulations will either be transported to the clinical sites as “liquid” 
product or as cryopreserved product in dry ice. For the former product, SV-BR-1-GM cells will 
be irradiated and resuspended in lactated Ringer’s solution (LRS) and shipped on wet ice or 
other established temperature condition(s).  For the latter product, SV-BR-1-GM cells will be 
irradiated and resuspended in biocompatible freeze medium then cryopreserved. Whereas SV-
BR-1-GM transported as liquid product will need to be formulated hours before the inoculation, 
SV-BR-1-GM transported as frozen product will be provided to the investigator sites (clinical 
sites) at least 2-3 days in advance of the inoculation. For such frozen product, upon delivery via 
courier to the clinical site, the vials of SV-BR-1-GM will be inspected and transferred to an 
appropriate LN2 storage dewar at the site. For shipments of liquid or frozen product, minimum 
and maximum transport temperatures will be retrieved from the data logger. Thereafter, the data 
logger will be returned to the UC Davis GMP facility and additional temperature data will be 
reviewed. In the event that the minimum and/or maximum temperature(s) deviate(s) from the 
specified range, the SV-BR-1-GM formulation will not be used and will be returned to the UC 
Davis GMP facility or destroyed at the clinical site. SV-BR-1-GM transported as liquid product 
will be shipped via same-day courier to the clinical sites on wet ice or under other established 
temperature condition(s). All steps will be performed in accordance with approved UC Davis and 
BriaCell Therapeutics SOPs. 
 


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14. Product Tracking: 
SV-BR-1-GM is tracked during the manufacturing process according to approved procedures 
and maintained in dedicated liquid nitrogen storage tank(s) during quarantine. Upon receipt of 
acceptable test results consistent with product release, SV-BR-1-GM is maintained at locations 
in the vapor phase of liquid nitrogen storage tank(s) dedicated to approved and released SV-BR-
1-GM. The required number of vials will be removed upon request and prepared at UC Davis for 
in-house formulation or shipment to the clinical site as already formulated product, and verified 
by both qualified manufacturing and quality assurance personnel. Shipping and Quality 
Assurance documentation will be completed and forwarded to the site together with the vials of 
SV-BR-1-GM. Upon receipt and inspection of the SV-BR-1-GM vials, the number of vials and 
corresponding identification numbers will be verified prior to storage or immediate use. The 
recipient will complete the UC Davis chain of custody form as verification of receipt. At the 
completion of enrollment, unopened vials of SV-BR-1-GM will be returned to BriaCell or UC 
Davis for reconciliation, use for research projects, and/or destruction according to approved 
procedures. BriaCell and/or UC Davis will track vials of SV-BR-1-GM, according to lot number 
and other identifiers, from the initiation of manufacture through return to the GMP facility or to 
BriaCell, and to release for research projects or destruction. 
 
15. SV-BR-1-GM formulation: 
 
15.1 SV-BR-1-GM cryopreserved before irradiation 
 
Process 1 (for SV-BR-1-GM not serum-starved prior to cryopreservation) 
In summary, a suitable number of validated SV-BR-1-GM cells (at least approx. 30 million cells) 
vials will be removed from liquid nitrogen storage, thawed, cultured for 2-4 days in full medium 
(RPMI-1640, 10% FBS, GlutaMAX™), serum-starved for 24 hours, enzymatically detached 
using trypsin, and resuspended in phosphate-buffered saline (PBS).  
Process 2 (for SV-BR-1-GM serum-starved prior to cryopreservation) 
In summary, a suitable number of validated SV-BR-1-GM cells (at least approx. 30 million cells) 
vials will be removed from liquid nitrogen storage, thawed, and washed/resuspended in PBS. 
For both Process 1 and 2, total cell counts and viability will be determined.  For preparations 
with a viability of >70%, cells, in PBS, will be irradiated to 20,000 cGy (200 Gy) (dose applied 
previously), or to an alternative dose ensuring cell replication-incompetency, with an approved 
Cesium-source or alternatively in Varian Linac IX, medically approved for radiation therapy. 
Processing will be performed at UC Davis using aseptic GLP and GMP practice. 
Irradiated SV-BR-1-GM cells will be resuspended to a concentration of ~10 x 106/mL in 
Lactated Ringer’s Solution (LRS) solution and aliquoted into 2 mL cryovials (between ~0.5 and 
~1.5 mLs per cryovial) which will be placed in a plastic specimen bag. The remaining cell 
suspensions will be retained at the manufacturing facility and used for Gram staining, endotoxin, 
and 14-day sterility testing.  The Gram staining and endotoxin assessments will be performed 
prior to SV-BR-1-GM administration.  Only lots that pass both the Gram stain and endotoxin 
tests will be injected.  “14-day” sterility cultures will be observed on several days after SV-BR-1-
GM injection and will be continued until about 14 days after SV-BR-1-GM injection to confirm 
sterility.  Each case of SV-BR-1-GM contamination will be reported to the investigator and the 


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IRB/FDA. A positive culture action plan has been established to mitigate the risk to patients 
injected with SV-BR-1-GM that failed the sterility test.  
For the transport to the clinical site, the vials will be labeled with information to include the 
nature of the contents [(SV-BR-1-GM or the parental cell line, BriaTest™ (SV-BR-1)] as well as 
the patient identification number, date of birth, the name of the investigator and that this is for 
investigational use only.  In addition, the specimen bag will be labeled with information to 
include the nature of the contents (SV-BR-1-GM or the parental cell line, BriaTest™), the study 
identification number (ID), subject ID, the subject’s date of birth, Lot Number, Date of 
Manufacture, Expiration date, the investigator’s name and a statement, “Caution: New Drug 
Limited by Federal Law to Investigational Use”.  This will then be transported to the 
investigational treatment site in a Styrofoam box with cold packs to obtain a temperature of 2-8° 
C or under other established temperature condition(s) and utilized within 24 hours.  At the 
investigative site, the SV-BR-1-GM will be distributed into syringes for injection as per Section 
3.3 of this protocol.    
 
15.2 Off-the-shelf product (SV-BR-1-GM cryopreserved following irradiation) 
 
Cells from one or several vials of a Master Cell Bank (MCB) or a Working Cell Bank (WCB) of 
SV-BR-1-GM will be expanded to a lot of Clinical Product (CP), serum-starved for 24 hours, 
irradiated with 20,000 cGy (200 Gy) (dose applied previously), or to alternative dose ensuring 
cell replication-incompetency, and cryopreserved in a biocompatible freeze medium. Vials of 
this CP will be shipped from the UC Davis GMP facility to the clinical site(s) as described 
above. After thawing and prior to inoculation, the content of the CP vials will either be diluted 
with LRS or another suitable medium to reduce the concentration of the cryopreservative (e.g., 
DMSO) or injected undiluted. CP will be handled aseptically, including mixing to dissolve 
potential loosely adherent cells (“clumps”).  The final concentration of cells will be adjusted so 
that no more than 2 mLs (4 x 0.5 mL) are inoculated. 
 
15.3 Parental Cells (SV-BR-1) 
 
“Parental Cells” (SV-BR-1), i.e., cells not stably transfected with CSF2, the gene encoding GM-
CSF, needed for hypersensitivity testing, will be formulated following, in essence, the same 
procedure as for SV-BR-1-GM described above. 
 
16. Formulation Laboratory SV-BR-1-GM Accountability: 
Each SV-BR-1-GM preparation will be documented on the SV-BR-1-GM preparation form. The 
record will include the date, the number of vials thawed, SV-BR-1-GM lot number, and the 
number of cells per vial. All SV-BR-1-GM vials will be kept in a secure cryopreservation tank in 
a locked room with access limited to only authorized personnel. Each SV-BR-1-GM vial used 
will be documented in the liquid nitrogen tank log. The record will include the date, purpose of 
using, and the initials of the person removing the vial. In addition, the used SV-BR-1-GM 
description and location in the tank will be documented on the SV-BR-1-GM formulation form. 
A copy of this form will be filed in the sponsor’s research files. The discarded SV-BR-1-GM lots 
will be documented on the discard form. 


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SV-BR-1-GM preparation (formulation) is initiated only after receipt of a written request by the 
sponsor, their designate, or the investigator for SV-BR-1-GM administration for one or several 
specific, qualifying, consented patient(s).   
 
17. Clinical Site SV-BR-1-GM Accountability: 
With the submission of the vials containing cryopreserved or liquid SV-BR-1-GM or Parental 
Cells (for hypersensitivity testing) to the investigator for injection, the person transferring the 
vials will sign a SV-BR-1-GM Accountability form indicating time, place, and date of the 
transfer.  The receiving person will counter-sign this transfer procedure.     
No SV-BR-1-GM will be provided to any clinician or scientist not involved with the study, and 
no patients except those formally enrolled in this protocol will receive SV-BR-1-GM.  All 
personnel involved in the study will receive in-service training regarding these and other aspects 
of Good Clinical Practice.   Only trained clinical personnel (MD, PA, RN, or others trained by 
them) will perform the injections. 
 
9.4.4. 
CTCAE v4.03 Toxicity Criteria 
 
(Standard reference – not provided) 
 
http://www.hrc.govt.nz/sites/default/files/CTCAE%20manual%20-%20DMCC.pdf   
 
9.4.5. 
Positive Culture Action Plan 
In the case of a positive culture on drug product, the following steps will be taken: 
1. The testing laboratory will notify the medical monitor or, if unavailable, their designate. 
2. The medical monitor or their designate will contact the investigator and notify them of 
the positive culture result.  The investigator will be requested to contact the patient 
immediately and ask whether there have been any signs of infection (local or systemic). 
3. If the patient is not reporting any signs or symptoms of infection, an unscheduled visit to 
the clinical site will be performed as rapidly as feasible and the patient will be evaluated 
by the investigator.  This evaluation will include, at the minimum, vital signs, physical 
examination (with close attention to the inoculation sites), Heme profile and differential, 
metabolic panel, blood and urine cultures. 
4. If the patient is reporting any signs or symptoms of infection, appropriate treatment will 
be instituted immediately under the supervision of the investigator.  The event will be 
written up as a Serious Adverse Event for reporting to regulatory agencies. 
5. In parallel, the testing laboratory or another CLIA-certified laboratory will perform 
identification of the organism and antibiotic sensitivity analyses.  These results will be 
communicated back to the medical monitor, or their designate, and to the investigator.