A Phase II Study of the Safety and Efficacy of SVN53-67/M57-KLH (SurVaxM) in Survivin-Positive Newly Diagnosed Glioblastoma
Phase: PHASE2
Conditions: Glioblastoma, Gliosarcoma
Sponsor: Roswell Park Cancer Institute

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TITLE: A Phase II Study of the Safety and Efficacy of SVN53-67/M57-KLH (SurVaxM) in 
Survivin-Positive Newly Diagnosed Glioblastoma 
Roswell Park Cancer Institute
Study Number:
I 259614
Initial Date:
Amendment #1:
Amendment #2:
Amendment #3:
Amendment #4:
Amendment #5:
Amendment #6:
Amendment #7:
Amendment #8:
Amendment #9:
Amendment #10:
Amendment #11:
06 February 2015
14 October 2015
10 December 2015
21 December 2015
16 March 2016
26 April  2016
16 February 2017
23 June 2017
19 October 2017
07 November 2017
30 January 2018
06  September 2019
IND Holder:
Roswell Park Cancer Institute
Principal Investigator:
Cleveland Clinic
Manmeet Ahluwalia, MD FACP
Cleveland Clinic
9500 Euclid Avenue, S73
Cleveland, Ohio 44195
216-444-6145
Ahluwam@ccf.org 
Principal Investigator: 
Roswell Park Cancer Institute
Robert Fenstermaker, M.D. 
Roswell Park Cancer Institute
Elm & Carlton Streets
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Buffalo, New York 14263
716-845-3154
Robert.Fenstermaker@RoswellPark.org
Principal Investigator:
Dana Farber
David Reardon, M.D
Dana Farber
450 Brookline Avenue
Boston, MA 02215
617-632-2166
Dreardon3@partners.org 
Principal Investigator:
Beth Israel
Eric Wong, MD
Beth Israel
330 Brookline Avenue
Boston, MA 02215
617-667-1665
Ewong@bidmc.harvard.edu  
Principal Investigator:
Mass General
William Curry, MD
Mass General
55 Fruit Street
Boston, MA 02114
617-726-3779
wcurry@partners.org
Sponsor:
Roswell Park Cancer Institute
Confidentiality Statement
Any and all information presented in this document shall be treated as confidential and 
shall remain the exclusive property of the party (ies) mentioned above. The use of such 
confidential information must be restricted to the recipient for the agreed purpose and 
must not be disclosed, published, or otherwise communicated to any unauthorized persons, 
for any reason, in any form whatsoever without the prior written consent of the party (ies) 
above.
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SYNOPSIS
Title
A Phase II Study of the Safety and Efficacy of SVN53-67/M57-
KLH (SurVaxM) in Survivin-Positive Newly Diagnosed 
Glioblastoma 
Roswell Park Cancer Institute Study 
Number
I 259614
Roswell Park Cancer Institute Investigator
Robert Fenstermaker, M.D. 
Sponsor
Roswell Park Cancer Institute
Study Drugs
•
SVN53-67/M57-KLH 
•
Montanide ISA 51
•
Sargramostim (GM-CSF)
•
Temozolomide (Temodar®)
Objectives
Primary Objective: 
•
To evaluate 6-month progression-free survival (PFS6) in 
patients with survivin positive newly diagnosed glioblastoma 
multiforme (GBM) treated with at least 4 doses of SurVaxM 
and standard of care temozolomide. PFS6 is defined as the 
percentage of patients without tumor progression or death from 
any cause 6 months after the date of diagnosis by biopsy.
Secondary Objectives: 
•
To determine the safety and tolerability of SurVaxM in patients 
receiving standard care adjuvant temozolomide.
•
To evaluate overall survival (OS) in patients with survivin 
positive newly diagnosed GBM treated with SurVaxM and 
adjuvant temozolomide. 
•
To describe the immune response in patients treated with 
SurVaxM and predictors of response.
•
To evaluate objective tumor response rate (applicable only for 
patients with evaluable disease at study entry, as defined by 
RANO criteria) and predictors of response.
Study Design
This is a multi-center, open-label, single arm, phase II trial in adult 
patients with newly diagnosed GBM, evaluating the efficacy and 
safety of SurVaxM and adjuvant temozolomide after patients have 
received concurrent radiation and temozolomide.
Target Accrual and Study Duration
Sample Size: Approximately 50 eligible patients with survivin 
positive newly diagnosed GBM will be enrolled over a 25-month 
period. Subjects will be followed to determine progression free 
survival and overall survival. The study duration will be at least 37 
months.
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Statistical Analysis
Efficacy Analysis: The primary objective is to evaluate 
progression-free survival at 6 months (PFS6) in patients with newly 
diagnosed GBM treated with 4 priming doses of SurVaxM and 
standard-of-care adjuvant temozolomide as compared to historical 
control. Patients who are alive and disease free at the last study 
assessment will be treated as censored.
Patients in this population defined by the eligibility criteria receive 
standard-of-care which consists of concurrent temozolomide and 
radiation followed by adjuvant temozolomide. Based on provided 
historical information, the 6 month PFS survival fraction is assumed 
to be 0.55. We hypothesize that treatment with SurVaxM and 
adjuvant temozolomide will increase the 6 month PFS survival 
fraction to 0.70. Therefore the PFS survival fraction will be 
measured after all patients have been followed for 6 months.
The 6 month PFS survival fraction is estimated as standard 
binomial proportion. An exact one-sided binomial test will be used 
to test our primary hypothisis. The nominal significance level to be 
used for this test is 0.10. In addition, a Kaplan-Meier curve for PFS 
will be used calculated to generate summary descriptive statistics, 
e.g. median PFS. 
Correlative Data Analysis: Immunologic response to vaccine will 
be used as a secondary measure of vaccine activity. Survivin-
specific CD8+ responses, CD4+ helper support, and anti-survivin 
antibody (humoral) responses will be measured individually by the 
Immunotherapy Immune Analysis Facility and Neuro-oncology 
Laboratory at Roswell Park Cancer Institute.
To assess immunologic responses to SVN53-67/M57-KLH 
(SurVaxM), PBMC will be analyzed using multimer, IFNγ 
ELISPOT and qPCR assays of cytokine expression in CD4+ and 
CD8+ cells. Antibodies to survivin peptides and KLH in serum will 
also be measured by ELISA to assess humoral immune responses.
HLA-A class I typing on blood samples will be performed at each 
study site as a part of screening to determine eligibility. Following 
entry, detailed HLA typing (MHC class I and MHC class II) will be 
performed in an exploratory fashion as part of the analysis of 
immunologic response to vaccination.
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INVESTIGATOR STUDY ELIGIBILITY VERIFICATION FORM
Participant Name: (Network sites use participant initials): ___________________________
Medical Record No.: (Network sites use participant ID): _____________________________
Title: A Phase II Study of the Safety and Efficacy of SVN53-67/M57-KLH (SurVaxM) in 
Survivin-Positive Newly Diagnosed Glioblastoma
INCLUSION CRITERIA
Yes
No
N/A
All answers must be “Yes” or “N/A” for participant enrollment.
Date
1.
Age ≥ 18years of age.
2.
Have a Karnofsky performance status ≥ 70 (i.e. the patient must be able to 
care for himself/herself with occasional help from others; refer to  
Appendix B).
3.
Documented survivin-positive tumor status.
4.
Pathologically confirmed diagnosis of glioblastoma multiforme (GBM).or 
WHO grade IV[gliosarcoma]
5.
Have the following clinical laboratory values obtained within 14 days 
prior to registration:
a.
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
b.
Platelets ≥ 100 x 109/L
c.
Hemoglobin (Hgb) > 9.0 g/dL
d.
Serum total bilirubin: ≤ 1.5 x ULN
e.
ALT and AST ≤ 4.0 x ULN
6.
Patients on full-dose anticoagulants (e.g., warfarin or LMW heparin) must 
meet   the following criteria:
a.
No active bleeding or pathological condition that carries a 
high risk of bleeding (e.g., tumor involving major vessels or 
known varices).
7.
Adequate renal function, as defined below:
•
Creatinine ≤ 1.8 mg/dl
8.
HLA-A*02, HLA-A*03, HLA-A*11 or HLA-A*24 positive patients.
9.
MRI (Ideally completed within 96  hours after surgery) documenting 
gross total resection consisting of no gadolinium enhancement; or subtotal 
resection consisting of linear enhancement with (or without) nodular 
gadolinium enhancement measuring no greater than 1 cm x 1 cm x 1cm 
total volume or 100 mm2 in cross sectional area.
10. No evidence of true progressive disease from the 
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INCLUSION CRITERIA
Yes
No
N/A
All answers must be “Yes” or “N/A” for participant enrollment.
Date
postoperative period to the post-chemoradiation period, 
based on changes in the neurologic exam, steroid use, or 
evident radiographic progression, according to RANO 
criteria (see Appendix C). Patients with increased or new 
gadolinium enhancement may continue on protocol if in the 
investigator’s judgment that enhancement is likely due to 
pseuodoprogression. The use of correlative imaging studies 
(including PWI) or diffusion weighted imaging (DWI), and 
repeat  imaging after an interval of 2-4 weeks is strongly 
encouraged to help distinguish between pseudoprogression 
and true progression.  
11. Participants of child-bearing potential must agree to use adequate 
contraceptive methods (e.g., hormonal or barrier method of birth control; 
abstinence) prior to study entry, and have a negative pregnancy test prior 
to starting study treatment. Should a woman become pregnant or suspect 
she is pregnant while she or her partner is participating in this study, she 
should inform her treating physician immediately.
12. Dexamethasone dose less than or equal to 4 mg daily at time of study 
enrollment.
13. Patients must have completed initial radiation therapy (RT) and 
temozolomide (TMZ) for the treatment of their glioblastoma (i.e., 
completed 6-week course of RT and, completed ≥ 75% of 6-week course 
of induction TMZ chemotherapy).
14. Participant or legal representative must understand the investigational 
nature of this study and sign an Independent Ethics 
Committee/Institutional Review Board approved written informed 
consent form prior to receiving any study related procedure.
Investigator Signature: ___________________________________
Date: ___________
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INVESTIGATOR STUDY ELIGIBILITY VERIFICATION FORM
Participant Name: (Network sites use participant initials): ___________________________
Medical Record No.: (Network sites use participant ID): _____________________________
Title: A Phase II Study of the Safety and Efficacy of SVN53-67/M57-KLH (SurVaxM) in 
Survivin-Positive Newly Diagnosed Glioblastoma
EXCLUSION CRITERIA
Yes
No
N/A
All answers must be “No” or “N/A” for participant enrollment.
Date
1.
The patient must not have received any immunotherapy for their brain 
tumor.
2.
Patients with serious concurrent infection or medical illness, which in the 
treating physicians opinion would jeopardize the ability of the patient to 
receive the treatment outlined in this protocol with reasonable safety.
3.
Patients who are pregnant or breast-feeding.
4.
Patients receiving concurrent therapy for their tumor (i.e. 
chemotherapeutics or investigational agents) other than temozolomide.
5.
Patients with a concurrent or prior malignancy are ineligible unless they 
are patients with curatively treated carcinoma-in-situ or basal cell 
carcinoma of the skin. Patients who have been free of disease (any prior 
malignancy) for at least 3 years are eligible for this study.
6.
Patients who have had repeat craniotomy for tumor therapy after 
receiving RT and TMZ treatment.
7.
Patients who received other chemotherapeutics or investigational agents 
in addition to their radiation therapy and concomitant temozolomide 
treatment.
8.
Patients who have received Gliadel wafers or alternating electrical field 
therapy (ETTF) are not eligible for this study.
9.
Known history of an autoimmune disorder.
10. Known human immunodeficiency virus (HIV) positivity or acquired 
immunodeficiency syndrome (AIDS) related illness or other serious 
medical illness.
11. Patients who have contraindication to MRI.
12. Unwilling or unable to follow protocol requirements.
13. Any condition which in the Investigator’s opinion deems the participant 
an unsuitable candidate to receive study drug.
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EXCLUSION CRITERIA
Yes
No
N/A
All answers must be “No” or “N/A” for participant enrollment.
Date
14. Received an investigational agent within 30 days prior to registration.
Participant meets all entry criteria:
  Yes
  No
If “NO”, do not enroll participant in study.
Investigator Signature: ___________________________________
Date: __________
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TABLE OF CONTENTS
1
Background ............................................................................................................................15
1.1
Glioblastoma.......................................................................................................................15
1.2
Survivin Expression in Gliomas .........................................................................................15
1.3
Immunization......................................................................................................................15
1.4
Study Drugs ........................................................................................................................16
1.4.1
SVN53-67/M57-KLH (SurVaxM)..................................................................................16
1.4.2
Montanide ISA 51...........................................................................................................17
1.4.3
Sargramostim ..................................................................................................................17
1.4.4
Temozolomide ................................................................................................................18
1.5
Pharmacodynamics of SVN53-67/M57..............................................................................18
1.5.1
Peptide Binding Analysis................................................................................................18
1.5.2
Murine CTL studies of SurVaxM ...................................................................................19
1.5.3
Pre-clinical Human CTL studies of SurVaxM................................................................20
1.5.4
Pre-clinical survivin reactive IgG antibodies in human serum.......................................22
1.6
Safety Pharmacology..........................................................................................................23
1.7
Pharmacokinetics................................................................................................................24
1.8
Efficacy...............................................................................................................................24
1.8.1
Pre-clinical Data..............................................................................................................24
1.8.2
Clinical Data ...................................................................................................................25
1.9
Risks and/or Benefits..........................................................................................................26
1.9.1
SVN53-67/M57-KLH .....................................................................................................26
1.9.2
Risks Associated with Montanide...................................................................................26
1.9.3
Risks Associated with Sargramostim..............................................................................27
2
Rationale.................................................................................................................................29
3
Objectives...............................................................................................................................29
3.1
Primary Objective...............................................................................................................29
3.2
Secondary Objectives .........................................................................................................30
4
Methodology ..........................................................................................................................30
4.1
Study Design.......................................................................................................................30
4.2
Target Accrual and Study Duration....................................................................................31
5
Participant Selection...............................................................................................................32
5.1
Inclusion Criteria ................................................................................................................32
5.2
Exclusion Criteria ...............................................................................................................33
5.3
Inclusion of Women and Minorities...................................................................................34
6
Treatment Plan .......................................................................................................................34
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6.1
Dosing and Administration.................................................................................................34
6.1.1
Administration of SurVaxM ...........................................................................................35
6.1.2
Administration of Temozolomide...................................................................................35
6.2
Dose Modifications.............................................................................................................36
6.2.1
SurVaxM Dose Omission or Discontinuation ................................................................36
6.2.2
Temozolomide Dose Adjustments..................................................................................36
6.3
General Concomitant Medication and Supportive Care.....................................................37
6.3.1
Guidance for Management of Expected Toxicity...........................................................38
6.4
Duration of Treatment ........................................................................................................39
6.5
Duration of Follow-Up .......................................................................................................39
6.6
Treatment Discontinuation .................................................................................................39
7
Investigational ProductS.........................................................................................................40
7.1
SVN53-67/M57-KLH (SurVaxM) .....................................................................................40
7.1.1
Pharmacological Class ....................................................................................................40
7.1.2
Structural Formula ..........................................................................................................40
7.1.3
All Active Ingredients.....................................................................................................40
7.1.4
Drug Shipment ................................................................................................................40
7.1.5
Preparation ......................................................................................................................41
7.1.6
Storage and Stability .......................................................................................................41
7.1.7
Handling and Disposal....................................................................................................41
7.2
Vaccine Preparation: SVN53-67/M57-KLH, Montanide® ISA 51 and Sargramostim .....41
7.2.1
Interaction with Other Medicinal Products and Other Forms of Interaction ..................42
7.2.2
Overdose .........................................................................................................................42
7.2.3
Pregnancy, Lactation, and Pediatric Use ........................................................................42
7.3
Adjuvant Temozolomide ....................................................................................................42
8
Study Procedures....................................................................................................................42
8.1
Schedule of Investigations and Data Collection.................................................................42
8.1.1
Screening Period .............................................................................................................43
8.1.2
Treatment Phase..............................................................................................................43
8.1.3
Treatment Completion/Discontinuation..........................................................................43
8.1.4
Post-Treatment Follow-up Phase....................................................................................43
8.2
Blood Draws for Humoral and Cellular Immune Response...............................................47
8.3.1  Pathology .............................................................................................................................48
9
Efficacy Evaluations...............................................................................................................50
9.1
Objective Tumor Response.................................................................................................50
9.2
Evaluation of Response ......................................................................................................51
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9.2.1
Survival ...........................................................................................................................51
10
Safety Evaluation................................................................................................................52
10.1
Adverse Events ...................................................................................................................52
10.1.1
Definition ........................................................................................................................52
10.1.1.1
Diagnosis Versus Signs and Symptoms ......................................................................53
10.1.1.2  Adverse Events Occurring Secondary to Other Events………………………………  52
10.1.1.3
Abnormal Laboratory Values......................................................................................53
10.1.1.4
Preexisting Medical Conditions (Baseline Signs and Symptoms) ..............................54
10.1.2
Grading and Relationship to Drug ..................................................................................54
10.1.3
Reporting Adverse Events ..............................................................................................55
10.2
Serious Adverse Events ......................................................................................................56
10.2.1
Definition ........................................................................................................................56
10.2.2
Reporting Serious Adverse Events .................................................................................56
10.3
Follow-Up for Serious Adverse Events..............................................................................56
10.4
Unanticipated Problems......................................................................................................56
10.4.1
Definition ........................................................................................................................56
10.4.2
Reporting Unanticipated Problems .................................................................................57
10.5
FDA Reporting ...................................................................................................................57
11
Data and Safety Monitoring................................................................................................58
12
Statistical Methodology......................................................................................................58
12.1
Study Design.......................................................................................................................58
12.1.1
Missing Data ...................................................................................................................59
12.2
Study Objectives.................................................................................................................59
12.3
Study Endpoints..................................................................................................................59
12.4
Sample Size Determination ................................................................................................60
12.5
Demographics and Baseline Characteristics: Descriptive Analyses ..................................60
12.6
Safety Analysis ...................................................................................................................60
12.7
Efficacy Analysis................................................................................................................60
12.7.1
Primary Analysis.............................................................................................................60
12.8
Adverse Event.....................................................................................................................62
12.9
Replacement .......................................................................................................................62
12.10
Interim Analysis and Criteria for Early Termination of the Study .................................62
13
Correlative Data Analysis...................................................................................................63
13.1
Immunological Assessments and HLA Typing..................................................................63
13.2
Survivin Expression Status.................................................................................................64
14
Ethical and Regulatory Standards.......................................................................................64
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14.1
Ethical Principles................................................................................................................64
14.2
Informed Consent ...............................................................................................................64
15
Study Responsibilities ........................................................................................................65
15.1
Data Collection ...................................................................................................................65
15.2
Maintenance of Study Documents......................................................................................65
16
Administrative Rules ..........................................................................................................65
16.1
Revisions to the Protocol....................................................................................................65
16.2
Termination of the Study....................................................................................................66
16.3
Confidentiality ....................................................................................................................66
17
Appendices .........................................................................................................................67
18
References...........................................................................................................................86
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IN-TEXT TABLES
Table 1
Temozolomide Dose Levels for Maintenance Treatment ...........................................36
Table 2
Temozolomide Dose Levels for Maintenance Treatment ...........................................37
Table 3
Schedule of Procedures and Observations ..................................................................44
Table 4
Guidelines for Routine Adverse Event Reporting for Phase 2 Studies (Regardless of 
Expectedness) ................................................................................................................................55
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APPENDICES
Appendix A
Instructions for Network Sites .............................................................................68
Appendix B
Karnofsky and ECOG Performance Status Scales...............................................71
Appendix C
Response Assessment in Neuro-Oncology (RANO) ...........................................72
Appendix D
Preparation of Peptide Vaccine Emulsion ...........................................................73
Appendix E
Isolation of Peripheral Blood Mononuclear Cells for Immuno-Monitoring........79
Appendix F
 MMSE Mini-Mental State Examination (Standard Version)…………………...84
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1
BACKGROUND
1.1
Glioblastoma
Although the addition of temozolomide to radiation therapy for the treatment of glioblastoma 
multiforme (GBM) has resulted in improved outcomes, the estimated 2-year survival with 
maximal therapy remains only 27% (1). In a randomized phase 3 multicenter trial(1), patients with 
newly diagnosed GBM received 60 Gy of radiation over 6 weeks with temozolomide 75mg/m2 
for 42 days, followed by adjuvant temozolomide 150mg to 200mg/m2 for 5 consecutive days 
each month for 6 months, vs. radiation alone. The median overall survival for the combined 
radiation and temozolomide group was 14.6 months compared to 12.1 months for radiation 
alone. Since this study was reported, no major improvements in therapy for GBM have been 
shown to be significantly better for the initial treatment of glioblastoma patients. Therefore new 
and improved treatment strategies are greatly needed.
1.2
Survivin Expression in Gliomas
Survivin is a 16.5 kDa intracellular protein that belongs to the inhibitor of apoptosis protein 
(IAP) family. It acts in concert with the mitotic spindle apparatus to regulate cell division and 
localizes to the spindle microtubule organizing center (MTOC) during the G2/M phase of cell 
cycle progression(2, 3). Survivin has also been shown to modulate the function of a number of 
terminal effector cell death proteases (caspases) leading to an inhibition of apoptosis (4, 5). 
Although expressed during fetal development, survivin is rarely detectable in the normal tissues 
of adult organisms (6). Malignant gliomas express survivin at high levels; whereas, low grade 
gliomas and normal glial cells do not (7). In fact, survivin is considered to be one of the most 
specific cancer molecules yet identified (3), despite the fact that it may also be seen in 
hematopoietic progenitor cells, some lymphocytes, neutrophils and vascular endothelial cells (8). 
High-level survivin expression is associated with a poor prognosis (9, 10). Survivin expression in 
tumors is also associated with a high rate of disease recurrence and resistance to therapy (11). 
Consequently, survivin confers growth and survival advantages to cells that express it. A large 
number of human glioma specimens have been examined using several different techniques and 
survivin expression has been found in at least 90% of human malignant gliomas.
1.3
Immunization
Patients with cancers, including malignant gliomas, have immunologic responses to survivin. 
Antibodies to survivin and T cells that are specifically reactive to survivin epitopes have been 
detected in cancer patients (12-15). Therefore, survivin is clearly immunogenic and stimulation of 
memory responses might be elicited by active specific vaccination to survivin epitopes. Since 
survivin is an intracellular protein, it is processed by the proteosome and can directly enter the 
MHC class I pathway. Peptide epitopes from intracellular proteins are presented at the cell 
surface by MHC class I molecules leading to CD8+ T-cell-mediated immune responses. There is 
substantial experimental evidence that survivin vaccination leads to anti-tumor immune 
responses in tumor-naive and tumor-bearing animals (16-20).
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1.4
Study Drugs
1.4.1
SVN53-67/M57-KLH (SurVaxM)
1.4.1.1 Peptide selection for SurVaxM
The survivin peptide in SurVaxM is a defined, 15 amino acid antigenic peptide capable of 
binding several human MHC class I molecules, as well as murine H2-Kb molecules (as a model 
of the human response). SurVaxM contains a core epitope SVN56-64/M57 modified by 
substitution of methionine for cysteine at amino acid position 57, with flanking amino acids 53-
56 and 65-67. This allows the core epitope in SurVaxM to be more immunogenic than the wild-
type survivin peptide in humans since it binds HLA-A*02 molecules to a much greater extent 
(16). While SurVaxM was designed to bind HLA-A*0201, computer algorithms predict its 
binding to numerous MHC class I molecules (including HLA-A*02, HLA-A*03, HLA-A*11 
and HLA-A*24) that collectively represent a large patient population. Thus, SurVaxM is 
predicted to be effective at generating CTL in a diverse patient population with limited HLA 
restriction.
1.4.1.2 Immunization against intracellular proteins
Epitopes of intracellular proteins, if correctly presented on the surface of tumor cells with MHC 
class I expression, and recognizable by specific effector T cells, can serve as targets for cytotoxic 
antitumor responses. Thus, cell-surface expression of an entire tumor antigen is not required for 
effective anti-tumor immunologic responses. Instead, intracellular proteins like survivin are 
processed by the proteasome and their epitopes are presented by MHC class I molecules on the 
tumor cell’s surface where they are recognizable by specific effector CTL.
The immune system of cancer patients is often primed to recognize survivin epitopes.  
Circulating anti-survivin antibodies have been detected in vaccine-naïve patients with cancer, but 
not in normal volunteers. Peptide epitopes from tumor-associated antigens (TAA), including 
survivin, can be recognized by cytotoxic T lymphocytes (CTL) in the context of MHC 
molecules. In a first-in-human phase I clinical study, vaccination with SurVaxM produced 
specific anti-survivin CD8+ T cells and anti-survivin antibodies in patients with recurrent 
malignant gliomas, primarily glioblastoma multiforme.
1.4.1.3 MHC class II ligands and CD4+ helper support for vaccines
To activate a CD4+ T-cell response, antigens must be presented to CD4+ T cells in conjunction 
with an MHC class II antigen (21). Once CD4+ cells have been activated, they proliferate and 
produce cytokines (e.g. IFN-α, IL-2, and IL-4) that enhance the immune response (22, 23). These 
cytokines are essential to provide a fully activated CD8+ antitumor CTL response (24). The 
presence of MHC class II-restricted CD4+ T cells that are specific for tumor associated antigens 
has been recognized to be an important element for providing essential helper factors to elicit 
and sustain cytotoxic CD8+ responses against tumors (25, 26) . Vaccination with SurVaxM 
produces cytokine support as well as specific CTL responses and has the potential to stimulate 
more effective antitumor immunity than peptide vaccines that contain only class I epitopes.
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1.4.1.4 Altered peptide antigens (molecular mimicry)
T cell clones with the capacity to be activated by self-proteins are frequently preserved following 
negative selection of higher affinity, self-recognizing clones in the thymus (27). These potentially 
self-reactive cells remain tolerized under normal conditions (28). Altered peptide ligands (mimics) 
can provide a way to break tolerance to the natural self-epitope. Altered peptide ligands 
generated by substituting single amino acids within a peptide epitope can markedly alter immune 
responses. This strategy may be used to increase the affinity of the peptide for MHC-I via 
alterations in the binding anchor residues (29, 30). Effects of this manipulation can range from the 
induction of TCR antagonism, to T cell anergy, to enhancement of T cell responses (31). A 
number of investigators have used altered immunogens (mimics) to enhance the immunogenicity 
of tumor-associated antigens. The cysteine-to-methionine substitution present in SurVaxM 
greatly enhances binding to HLA-A*0201 molecules leading to increased immunogenicity that is 
cross reactive to the wild type survivin molecule present in tumor cells. Thus, the design of 
SurVaxM incorporates several strategies to create an effective antitumor immunogen: 1) multiple 
epitopes, 2) peptide mimicry, and 3) antigen-specific cytokine support.
1.4.2
Montanide ISA 51
Montanide ISA 51, NSC 675756, is an oil-based adjuvant product similar to Incomplete Freund's 
Adjuvant, which when mixed with a water-based solution in 1:1 w/w ratio, forms a water-in-oil 
emulsion. It consists of highly purified oil (Drakol VR), and a surfactant, mannide oleate. 
Montanide ISA 51 is manufactured by  Seppic, Inc., and is provided in amber glass ampoules 
containing 3 mL of the solution. It is non-irritating to the skin of rabbits and slightly irritating to 
the eye. Montanide ISA 51 will be provided through the RPCI Pharmacy. It is commonly used in 
human clinical vaccine protocols in the United States and is classified as an Investigational New 
Drug. Montanide ISA 51 acts to enhance immune responses to vaccines. Peptide-based vaccines 
in Montanide ISA-51 have been safely administered to more than 200 research participants and 
have induced T-cell responses against the immunizing peptides without major toxicities. 
Toxicities mostly commonly observed include local discomfort, induration, and erythema at the 
injection site. Addition of Montanide ISA 51 to various antigens induces both humoral and 
cellular immune responses. The precise mode of Montanides’ action is unknown. Montanide ISA 
51 is stored at room temperature.
1.4.3
Sargramostim
Sargramostim (Leukine®) is recombinant human GM-CSF, a glycoprotein produced by 
recombinant DNA technology in a yeast expression system. GM-CSF has many actions, 
including stimulating proliferation and differentiation of hematopoietic progenitor cells and as a 
dendritic cell (DC) attractant.
Please refer to the Physician Desk References and package insert for complete information.
SVN53-67/M57-KLH, Montanide ISA 51 and sargramostim will be provided at no cost to the 
patient or the patient’s insurance carrier.
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1.4.4
Temozolomide
Temozolomide (Temodar®) is an alkylating drug indicated for the treatment of adult patients 
with newly diagnosed glioblastoma multiforme (GBM) concomitantly with radiotherapy and 
then as maintenance treatment.
The most common adverse reactions (≥10% incidence) reported for temozolomide include: 
alopecia, fatigue, nausea, vomiting, headache, constipation, anorexia, convulsions, rash, 
hemiparesis, diarrhea, asthenia, fever, dizziness, coordination abnormal, viral infection, amnesia, 
and insomnia.
The most common Grade 3 to 4 hematologic laboratory abnormalities (≥10% incidence) that 
have developed during treatment with temozolomide are: lymphopenia, thrombocytopenia, 
neutropenia, and leukopenia.
Allergic reactions have also been reported.
Please refer to the Physician Desk References and package insert for complete information.
Temozolomide is part of the standard of care for glioblastoma and the patient and/or patient’s 
insurance carrier will be responsible for charges related to its administration and for medications 
that may be needed to prevent or control side effects.
1.5
Pharmacodynamics of SVN53-67/M57
1.5.1
Peptide Binding Analysis
SurVaxM epitopes (Figure 1-A, blue) are capable of displacing HPV at low concentrations 
similar to that observed with other known MHC class I ligands gp100-209-217, and Flu-58-66. 
In contrast to the mimic peptides, the wild type peptides (red) could only displace the HPV 
peptide at almost 1,000-fold higher concentration. In addition, the core peptide of the mimic 
(SVN56-64/M57) had 74-fold higher binding to HLA-A*0201 than that of the wild type (Figure 
1-B). Therefore, SVN53-67/M57 would be expected to lead to improved presentation of the 
MHC I binding epitopes to the human immune system. This leads to a longer association time 
between the mimic epitopes and the MHC I molecules. In turn, this should increase binding to 
lower affinity T cell receptors, which have not been deleted during development, can induce the 
proliferation of cross-reactive T cell clones that recognize wild type survivin epitopes.
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Figure 1: (A) MHC class I (HLA-A*0201) peptide competitive displacement assays. IC50 represents 
concentration of survivin peptide required to displace HPV 18-27 (known MHC I ligand) pre-loaded on human T2 
cells. Flu and gp100 are known immunogenic MHC class I ligands. (B) REVEAL™ assays performed by 
ProImmune. Pentamer binding assay of SVN56-64 wild type and SVN56-64/M57 mimic peptides showing binding 
affinity of each for MHC class I.
1.5.2
Murine CTL studies of SurVaxM
A stronger ex vivo lytic response against murine glioma cells is observed with SurVaxM than 
with the corresponding wild type survivin peptide (Figure 2). This is associated with a 
concomitant increase in CD4+ T cell derived cytokine support (Figure 3). IFNα and IL-2 
secretion was much greater in cultures stimulated with 15mer SVN53-67/M57 over that observed 
in cultures stimulated with the 9mer SVN56-64/M57 core peptide suggestive of CD4+ T cell 
help.
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Figure 2: CTL responses against GL261 glioma cells using splenocytes of mice vaccinated with SVN53-67/M57-
KLH. Data represent mean percent specific lysis ± S.E.M. of triplicate samples.
Figure 3: Intracellular IFN-γ and IL-2 production in vitro by CD4+ cells from SVN53-67/M57-KLH immunized 
mice restimulated ex vivo with SVN53-67/M57 overnight (with BD GolgiPlug). A standardized control (Mouse 
Cytokine Intracellular Control lymphocytes; eBioscience, San Diego, CA) were used as positive controls for IFNγ 
and IL-2 expression.
1.5.3
Pre-clinical Human CTL studies of SurVaxM
•
Fresh PBMC from glioma patients were used to produce dendritic cells (DC) in vitro so 
that the ability of survivin peptides to stimulate CTL responses could be assessed against 
autologous human tumor cells ex vivo. It was demonstrated that the responses obtained 
are clearly linked to HLA status since an HLA mismatch of PBMC and tumor target cells 
led to an abrogation of cell-mediated cytotoxicity (Figure 4-A). HLA-A*0201, and 
HLA-A*0301 patients were able to be stimulated to lyse an allogeneic-matched and 
autologous glioma cells (Figure 4-B, C, D). In addition, this CTL activity was also found 
against autologous (HLA-A*2901/A*3002) primary CNS lymphoma (PCNSL) cells 
(Figure 4-E) and chronic lymphocytic leukemia (CLL) cells (Figure 4-F). As compared 
to the wild type peptide, SVN53-67/M57 elicits a 3- to 5-fold increase in CTL mediated 
killing against autologous human tumor cells (Figure 4). SVN53-67/M57 can elicit a 
cell-mediated immune response that is significantly greater than that induced by the wild 
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type peptide. Thus, SVN53-67/M57 may have broad applicability against cancers that 
express survivin.
Figure 4: (A) HLA-A*0301 patient effector cells vs. allogeneic-mismatched HLA-A*0201 human U87 target 
glioma cells; (B) HLA-A*0201 patient effector cells vs. allogeneic-matched U87 glioma cells; (C) HLA-A*0301 
patient effector cells vs. allogeneic-matched patient-derived tumor cells; (D) HLA-A*0301/HLA-A*2901 patient 
effector cells vs. autologous patient-derived glioma cells. (E) HLA-A*2901/HLA-A*3002 patient effector cells vs. 
autologous patient-derived PCNSL target cells; (F) HLA-A*01/HLA-A*24 patient effector cells vs. autologous 
patient-derived CLL target cells. Legend: Control DC = Flu/58-66; Positive control = gp100/209-217; SVN wt = 
SVN53-67; SVN Mimic = SVN53-67/M57.
•
Multimers (ProImmune “pentamers”) loaded with the core CTL epitope of SVN 53-67 
(SVN 56-64) were used to show that significant T cell reactivity could be detected in 
HLA-A*0201 patient samples. Tetramer reactivity is used to measure T cell-derived 
immune responses. Antigen presenting cells were stimulated in cell culture with 
SurVaxM peptides to produce pentamer-reactive T cells which are cross reactive to the 
wild type survivin peptide (Figure 5A). These CTL are also capable of lysing autologous 
glioma target cells and lysis can be blocked with MHC I blocking antibody (Figure 5B).
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Figure 5: Pentamer binding assay using patient derived CTL. A) HLA-A*0201 pentamer binding of CD8+ T cells 
specific for SVN55-64 wild type peptide, SVN56-64 wild type peptide, SVN55-64/M57 peptide mimic or SVN56-
64/M57 peptide mimic as a result of ex vivo SVN53-67/M57 stimulation in cell culture. Percentage shown in the 
upper right quadrant of each flow cytometry data panel represents double labeled pentamer+/CD8+ T cells. Control 
column are parallel ex vivo cell cultures that did not receive additional peptide. B) CTL Assay performed in parallel 
using patient cells shown in (A). Control cells are those not receiving additional peptide. Flu peptide represents a 
non-specific peptide stimulus. Blocked cells are target cells treated prior to T cell exposure with W6/32 anti-MHC I 
antibodies known to interfere with T cell receptor interaction. The HLA mismatched cells are shown to assess 
allogenic specificity against a second glioma cell line carrying the mismatched A*0301 MHC I allele.
1.5.4
Pre-clinical survivin reactive IgG antibodies in human serum
In a consecutive series of 6 vaccine-naïve glioma patients, 5 had moderate titers of survivin-
reactive antibodies to whole recombinant survivin protein (see Figure 6 below). Data indicate 
the possibility that previous immune exposure to survivin may naturally occur in GBM patients.
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0.15
0.2
0.25
0.3
0.35
0.4
0.45
0.5
0.55
0.6
100
1000
10000
100000
Dilution Factor
Patient 1
Patient 2
Patient 3
Patient 4
Patient 5
Patient 6
Normal
A
0.15
0.2
0.25
0.3
0.35
0.4
0.45
0.5
0.55
0.6
100
1000
10000
100000
Dilution Factor
Patient 1
Patient 2
Patient 3
Patient 4
Patient 5
Patient 6
Normal
A
Figure 6: Serum ELISA for SVN53-67 reactive IgG antibodies in glioma patients who have not been vaccinated.
1.6
Safety Pharmacology
Peptides used for vaccination studies do not follow standard pharmacokinetics and such data are 
not likely to be useful to ascertain peptide safety. Previous studies of similar peptide designs 
have not shown any pharmacological effects upon vital functions. Consequently, 
pharmacological distribution studies of SurVaxM have not been performed.
Considering the route of administration (i.e., subcutaneous injection), it is very likely that 
SurVaxM will remain locally at the injection site for a long period and not be systemically 
available in any significant amount. Much of the peptide will be taken up by antigen presenting 
cells (APC) locally and then processed for presentation to the immune system. In addition, some 
fraction will be degraded locally by peptidases to produce clinically insignificant quantities of 
free amino acids and smaller peptides. Therefore, as with many other peptide vaccines tested to 
date, SurVaxM should not reach vital organs to directly affect them. Nonetheless every effort has 
been made to address the safety of SurVaxM through pre-clinical animal toxicity studies.
According to the study entitled “Subcutaneous Repeated Dose Toxicity Study of 012410-2 in 
C57BL/6 Mice with a Two-Week Recovery (Study No. 20003268)”, subcutaneous 
administration of SurVaxM at a dose of 500 mcg in adjuvant Montanide ISA 51 VG injected 
with sargramostim every other week for 12 weeks was well tolerated by male and female mice 
throughout the dosage and recovery periods. Administration of SurVaxM did not cause mortality 
or adverse signs of toxicity as evaluated by clinical or skin reaction observations, changes in 
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body weights, ophthalmologic observations, necropsy observation, terminal body weights and 
organ weights, clinical pathology and histopathological observations.
1.7
Pharmacokinetics
The uptake of peptides used for vaccination studies is thought to be via phagocytosis by 
macrophages and dendritic cells, which do not follow established pharmacokinetic models. 
Absorption, distribution, metabolism and excretion of a 15 amino acid peptide and its composite 
naturally occurring amino acids cannot be confidently ascertained by standard methods. Upon 
administration, biological peptides essentially begin to be degraded to peptide fragments and 
amino acids masked by the systemic milieu. No formal pharmacokinetic studies have been 
conducted in either animals or humans since the drug is not systemically distributed upon 
administration.
1.8
Efficacy
1.8.1
Pre-clinical Data
1.8.1.1 SurVaxM in Syngeneic, Immunocompetent, Murine, Intracerebral Glioma Model
Beginning four days after tumor implantation, mice were immunized with either SVN53-67/M57 
peptide-loaded dendritic cells or, by direct subcutaneous injection of 100 μg SVN53-67/M57-
KLH peptide [in Incomplete Freund’s Adjuvant (IFA)] plus 100 ng sargramostim. Vaccinations 
were repeated (boosted) every 7 days up to a total of 3 immunizations, and long-term survivors 
were confirmed to be tumor-free by MRI (Figure 7). SurVaxM produced enhanced survival in 
mice with GL261 cerebral gliomas with some survivors alive 1 year after implantation without 
detectable tumor. No significant difference was observed between survivin peptide-loaded DC or 
the peptide-KLH conjugate (SurVaxM), provided that sargramostim was used as a supporting 
adjuvant.
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Figure 7: Survival of C57BL/6 mice bearing 1x10
5 GL261 intracerebral gliomas. 1) Control DC: n=10, survival 
range 18-24 days, with median survival 19.5 days; 2) OVA: n=7, survival range 19-22 days, with median survival 
21 days; 3) SVN53-67/M57 DC: n=14, survival range 40-120+ days, with median survival 55 days; 4) SVN53-
67/M57 KLH: n=8, survival range 25-120+ days, with median survival 56.5 days. SVN53-67/M57-KLH or SVN53-
67/M57 DC vs. control DC both p>0.0001.
1.8.1.2 SurVaxM with Temozolomide in Glioma-bearing C57BL/6 Mice
Mice with intracranial GL261 murine gliomas were treated with temozolomide 5 mg/kg/day for 
10 days following tumor implantation. SurVaxM was administered as 100 ug peptide in 
Montanide with 100 ng sargramostim on day 12.  
Median survival for mice receiving 
combination of temozolomide and SurVaxM was 46 days, compared to 32 days for mice 
receiving SurVaxM alone. Significant differences were observed in terms of median survival but 
not overall survival. This study demonstrated that: 1) the combination of temozolomide and 
SurVaxM while not synergistic, was not detrimental to immunization response and had minimal 
toxicity and, 2) treatment with SurVaxM at a late stage (12 days post-implantation to 
accommodate temozolomide administration) was still effective (compared to initiation of 
vaccinations 4 days post-implantation in earlier studies, with much smaller tumor mass).
1.8.2
Clinical Data
The literature provides several immunotherapy trials that incorporate wild type survivin peptides 
as target antigens and show the induction of specific T-cell activity in a limited number of 
patients with advanced solid tumors (32-35). A phase II trial (36) in 61 HLA-A1/-A2/-B35-positive, 
metastatic melanoma patients, using survivin-targeted peptide vaccination demonstrated 
prolonged OS in 13/41 patients who exhibited survivin-specific T-cell reactivity (SSTR) (median 
19.6 vs 8.6 months; p=0.0077). It also revealed that the induction of SSTR was associated with 
gender and disease stage, rather than age, HLA type, performance status or vaccination regimen.  
It was observed that the majority of treatment-related side effects were mild to moderate (CTC 
grade 1-2), including fever, chills on the day of vaccination and inflammatory reactions at the 
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injection sites. The occurrence of these post-vaccination inflammatory reactions was strongly 
associated with the presence of SSTR and a trend toward favorable survival.
SVN53-67/M57-KLH has been studied in a phase I clinical trial sponsored and conducted by 
Roswell Park Cancer Institute. In that trial, nine patients with recurrent, survivin-positive 
malignant gliomas who had failed standard therapy, received SVN53-67/M57-KLH [(500 mcg) 
in Montanide ISA 51 with sargramostim (100 mcg)] subcutaneously at two-week intervals, for 
four doses, until tumor progression. In addition, patients who survived six months or more 
without tumor progression, serious adverse events, or regimen limiting toxicity received 
maintenance phase dosing every three months. Toxicity attributable to SVN53-67/M57-KLH 
was mostly limited to mild injection site reactions. SVN53-67/M57-KLH-Montanide-
sargramostim was well tolerated and the majority of AE were grade one. Six of nine patients 
experienced injection site reactions, all grade one, including localized areas of erythema related 
to vaccination. Three patients reported fatigue (grades 1 and 2), two patients experienced 
myalgias (grade 2). Lymphopenia was seen in 3 patients (all grade 1) and leukopenia (grades 1 
and 2) occurred in three patients. The only grade 3 AE, a seizure, was not related to the vaccine. 
One SAE (renal failure) occurred in the maintenance phase in one patient but was unrelated to 
the study drug.
1.9
Risks and/or Benefits
1.9.1
SVN53-67/M57-KLH
Minor risks due to injection of SVN53-67/M57-KLH include:
•
minor pain at the injection sites (common),
•
local swelling of the subcutaneous tissues that may last several minutes to an hour 
(common)
•
itching or redness at the injection site (common)
•
infection is a possible risk of any injection (rare)
Major risks of SVN53-67/M57-KLH arise from the fact that although the survivin protein is 
rarely present in normal cells of the body, some normal cells could contain survivin making it 
possible that the vaccine could cause a reaction against normal tissues (autoimmunity). Patients 
will be observed for signs of such a reaction, using physical examinations and blood studies. A 
second major risk of treatment with SVN53-67/M57-KLH is that of a severe allergic or 
anaphylactic reaction. In the initial phase I clinical study, no allergic reactions or autoimmune 
phenomena were seen. All patients in this phase II study will be followed carefully for signs and 
symptoms of autoimmunity and allergic reactions.
1.9.2
Risks Associated with Montanide
SurVaxM (SVN53-67/M57-KLH) will be given together as an injection with Montanide ISA 51. 
Together these two agents will be injected just under the skin. Montanide helps to stimulate the 
immune system and keep the SurVaxM confined to the injection site so that it can work locally 
on the immune system. Montanide ISA 51 has been used extensively in clinical trials of vaccine 
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treatments and its risks are minor. These risks include: pain at the injection site, which can be 
treated with pain medicine; local skin irritation (swelling, local skin redness and sometimes 
itching) at the injection site; flu-like symptoms including muscle and joint aches.
Rarely, necrotizing granulomatous panniculitis with scarring and possible skin ulceration may 
occur as a result of subcutaneous injection of vaccines containing Montanide ISA 51.  In suchy 
lesions, deep nodularity can occur at injection sites.  High frequency ultrasound may be used to 
evaluate the injection sites of patients who complain of persistent tenderness or induration lasting 
over 4 weeks after injection to aid in the diagnosis.
If panniculitis is superficial it may affect the vascular supply to the epidermis leading to 
superficial skin ulceration.  The risk of this complication may be minimized by ensuring that 
vaccine injection is not given too superficially. Patients that experience skin necrosis or 
ulceration may be treated with intralesional injection of Kenalog (1 ml lof 5 mg/ml solution) at 
the vaccine injection site approximately 4 weeks after vaccination. The injection site will be re-
assessed 4 weeks after Kenalog administration and further doses be modified based on clinically 
determined response.  It is possible that intralesional Kenalog could attenuate the desired 
immunological response to vaccination.  If skin ulceration occurs, secondary cellulitis in the area 
of ulceration is possible.  In such cases, microbial culture and appropriate antibiotic therapy may 
be indicated. 
1.9.3
Risks Associated with Sargramostim
Sargramostim is indicated for use in a limited number of clinical settings, including post 
hematopoietic stem cell transplantation; where the recommended dose (250 mcg/m2 daily, for 
multiple days) far exceeds the dose used in the current trial of SurVaxM. Many of the side-
effects of sargramostim have been seen when the drug has been injected into a vein, rather than 
subcutaneously. Overall, the risks of short-term treatment in our study with low dose 
sargramostim administered subcutaneously are expected to be low.
There is the possibility that patients vaccinated with SurVaxM and sargramostim could develop 
an immune response against the pharmaceutical sargramostim, potentially neutralizing it and 
rendering the patient unresponsive to future use of this drug. The risk of this occurrence is not 
defined, but there is very little risk of these patients subsequently developing a condition where 
sargramostim therapy would be appropriate since allogeneic stem cell transplantation is not a 
current standard therapy for patients with recurrent glioblastoma.
•
Minor Risks:
o
Tiredness and Headache. Headache can be treated with pain medicine.
o
Bone, joint and muscle pain. The doses at which these occur are generally higher 
than the dose used in this study.
o
Skin rash and itching.
o
Local skin irritation (swelling, local skin redness and sometimes itching) may 
occur at the injection site.
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o
Localized and widespread skin reactions are uncommon.
o
Serious and potentially life-threatening allergic reactions with sargramostim are 
rare.
o
Fluid retention. This is usually reversible after sargramostim is stopped or drugs 
to reduce fluid retention are given.
o
High or low white blood cell or platelet counts.
•
Major Risks:
o
Pericarditis (irritation of the covering of the heart)
o
Pericardial effusion (fluid around the heart)
o
Hypotension (low blood pressure) may occur as part of a "first-dose" reaction to 
sargramostim. This is much less common when sargramostim is injected under 
the skin, rather than into a vein. This reaction is accompanied by some or all of 
the following symptoms:
o
Low blood pressure
o
Rapid heart beat
o
Fainting
o
Fever
o
Flushing
o
Nausea
o
Vomiting
o
Sweating
o
Back pain
o
Leg spasms
o
Shortness of breath
Patients who have first-dose reactions may need treatment with fluids by vein and oxygen. 
Acetaminophen (Tylenol), Ibuprofen or narcotics (Lortab, Morphine or Dilaudid) may be given 
for pain relief. This reaction usually does not happen again with further doses of sargramostim 
during the same course of treatment.
•
Abnormal heart beat (rare - less than 1%). This is reversible when the medicine is 
stopped. It occurs more commonly in patients with a history of abnormal rapid heart 
beating.
•
Poor kidney function has occurred in patients with previous kidney problems. Patients 
with kidney problems are not eligible for this study.
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•
Problems with liver function. While there have been no reports of severe liver problems, 
reversible increases in liver enzymes have occurred with sargramostim.
2
RATIONALE
Despite advances in surgery, radiation therapy and chemotherapy, including establishment of 
concurrent radiation and temozolomide followed by temozolomide as standard of care, 
glioblastoma (GBM) remains an incurable disease with a dismal median overall survival of less 
than 15 months(1).
This phase II study in patients with newly diagnosed glioblastoma follows a completed phase I 
study of patients with recurrent malignant glioma who had failed standard treatment, including 
temozolomide. In that study, all patients had received extensive treatment with temozolomide 
prior to receiving SVN53-67/M57-KLH with Montanide and GM-CSF.
There is a strong rationale for moving vaccine-based cancer therapy to the upfront setting in 
which a patient’s immune system is best able to respond to the treatment. Numerous studies have 
shown that patients with glioblastoma have severe immunosuppression that improves 
significantly following surgical tumor resection. Tumor-mediated immunosuppression returns 
when the tumor recurs following failure of standard therapy. Therefore, vaccine-based therapy 
given soon after initial surgical resection stands the best chance of improving time to tumor 
progression and overall survival for GBM patients. In addition, studies of one other KLH-
conjugated peptide vaccine (CDX-110; rindopepimut) to treat glioblastoma, Sampson et al.(37) 
showed that temozolomide-induced leukopenia is associated with an enhanced immunologic 
response to that vaccine. The mechanism for this is unclear, although it may involve differential 
susceptibility of certain immunomodulatory cells to temozolomide.
The rationale for proceeding directly to a phase II study is based on the following four points. 
First, the completed phase I trial of SVN53-67/M57-KLH showed very little toxicity with no 
grade III or IV adverse events and no serious adverse events attributable to the study drug. 
Second, there is no scientific rationale to posit additive or synergistic toxicity between the two 
drugs, given that temozolomide is an alkylating agent and SVN53-67/M57-KLH is a peptide 
vaccine. Third, in three separate GBM trials (ACTIVATE(38), ACT II(39) and ACT III(37)), 
rindopepimut vaccine given in combination with temozolomide showed no serious toxicity with 
only minor injection site reactions, similar to expectations for SVN53-67/M57-KLH. Fourth, in 
addition to evaluation of immune responses and PFS, the current phase II design includes 
rigorous evaluation of toxicity of each drug with CTCAEv4.0 (see Sections 6.2.1 and 6.2.2).
3
OBJECTIVES
3.1
Primary Objective
To evaluate 6-month progression-free survival (PFS6) in patients with survivin positive newly 
diagnosed glioblastoma multiforme (GBM) treated with at least 4 doses of SurVaxM and 
standard of care temozolomide. PFS6 is defined as the percentage of patients without tumor 
progression or death from any cause 6 months after the date of diagnosis by biopsy.
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3.2
Secondary Objectives
•
To determine the safety and tolerability of SurVaxM in patients receiving standard care 
adjuvant temozolomide.
•
To evaluate overall survival (OS) in patients with survivin positive newly diagnosed 
GBM treated with SurVaxM and adjuvant temozolomide. 
•
To describe the immune response in patients treated with SurVaxM and predictors of 
response.
•
To evaluate objective tumor response rate (applicable only for patients with evaluable 
disease at study entry, as defined per RANO criteria (40)) and predictors of response.
4
METHODOLOGY
4.1
Study Design
This is a multi-center, open label, single arm, phase II trial in adult patients with newly 
diagnosed GBM, evaluating the efficacy and safety of SurVaxM and adjuvant temozolomide 
after patients have received concurrent radiation and temozolomide.
Patients will receive a postoperative MRI, within 96 hours of surgical resection, followed by ~4 
weeks recovery time. Then they will receive 6-week duration of radiation therapy with 
temozolomide. A post-chemoradiation MRI will be performed within 1-28 days to ensure no 
tumor recurrence or progression.
             Figure 8             Pre-Study Treatment and Imaging Requirements 
     Post-op MRI
Baseline MRI
w/n 96 hours of surgery            
   w/n 1-28 days of completion of chemo-radiation
Vaccine #1
Tumor   _______________
___________________
resection 
~3-4 week healing                          ~6 weeks                            ~Up to 4 weeks
HLA tests and tumor testing for survivin status can be performed at any time prior to vaccine 
priming, while the rest of screening assessments should be performed after completion of chemo-
radiation and prior to vaccine priming.
               Chemo-radiation
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As shown in Figure 8, first priming administration of SurVaxM should occur within 7-28 days 
after completion of chemoradiation. Adjuvant temozolomide therapy (TMZ) will begin ≥ 28 
days after completion of concomitant temozolomide radiation therapy and given for 6 cycles or 
more (at the discretion of the investigator), or until intolerance or tumor progression.
Figure 8
Treatment Schema
C1D1-5
C2D1-5
C3D1-5
C4D1-5
C5D1-5
C6D1-5
V1
V2
V3
V4
Vaccine Priming
(Every 2 weeks x 4 doses)
(+ 3 days)
Vaccine Maintenance
Dose given every 12 weeks
+ 2 weeks)
Vaccine
Administration
TMZ
Administration
Adjuvant temozolomide (TMZ)
(28-day cycle + 2 weeks)
SurVaxM should be administered approximately every 2 weeks (+ 3 days) during the priming 
phase and then approximately every 12 weeks (+ 2 weeks) during the adjuvant phase.  Following 
completion or discontinuation of TMZ in the absence of progression, SurVaxM may be 
continued approximately every 12 weeks during the maintenance phase until intolerance or 
disease progression.
All participants will sign an informed consent prior to study related tests. All participants will 
meet the inclusion and exclusion criteria summarized in Section 5.1 and Section 5.2 Participants 
will be treated on an outpatient basis.
4.2
Target Accrual and Study Duration
The target accrual for this phase II trial is 50 evaluable patients with survivin positive newly 
diagnosed GBM. Approximately 2 patients per month will be enrolled, with follow-up of at least 
12 months after the last enrolled patient. Patients will be followed until death to determine 
overall survival. The participants will initially receive treatment with radiation and chemotherapy 
with temozolomide as per standard of care. Thereafter, patients will receive SurVaxM and 6 
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cycles of adjuvant temozolomide (or more at the discretion of the investigator), until intolerance 
or tumor progression. Patients are eligible for treatment with SurVaxM until disease progression 
or unacceptable toxicity.
5
PARTICIPANT SELECTION
5.1
Inclusion Criteria
To be included in this study, participants must meet the following criteria:
1. Age ≥ 18 years of age.
2. Have a Karnofsky performance status ≥ 70 (i.e. the patient must be able to care for 
himself/ herself with occasional help from others; refer to Appendix B).
3. Documented survivin-positive tumor status.
4. Pathologically confirmed diagnosis of glioblastoma multiforme (GBM). Or WHO grade 
IV [gliosarcoma]
5. Have the following clinical laboratory values obtained within 14 days prior to 
registration:
•
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
•
Platelets ≥ 100 x 109/L
•
Hemoglobin (Hgb) > 9.0 g/dL
•
Serum total bilirubin: ≤ 1.5 x ULN
•
ALT and AST ≤ 4.0 x ULN 
6. Patients on full-dose anticoagulants (e.g., warfarin or LMW heparin) must meet   the 
following criteria:
o
No active bleeding or pathological condition that carries a high risk of bleeding 
(e.g., tumor involving major vessels or known varices)
7. Adequate renal function, as defined below:
o
Creatinine ≤ 1.8 mg/dl
8. HLA-A*02, HLA-A*03, HLA-A*11  or HLA-A*24 positive patients.
9. MRI (completed within 96 hours after surgery) documenting gross total resection 
consisting of no gadolinium enhancement; or subtotal resection consisting of linear 
enhancement with (or without) nodular gadolinium enhancement measuring no greater 
than 1 cm x 1 cm x 1 cm total volume or 100 mm2 in cross sectional area.
10. No evidence of true progressive disease from the postoperative period to the post-
chemoradiation period, based on changes in the neurologic exam, steroid use, or evident 
radiographic progression, according to RANO criteria (see Appendix C). Patients with 
increased or new gadolinium enhancement may continue on protocol if in the 
investigator’s judgment that enhancement is likely due to pseuodoprogression. The use of 
correlative imaging studies (including PWI) or diffusion weighted imaging (DWI), and 
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repeat  imaging after an interval of 2-4 weeks is strongly encouraged to help distinguish 
between pseudoprogression and true progression.  
11. Participants of child-bearing potential must agree to use adequate contraceptive methods 
(e.g., hormonal or barrier method of birth control; abstinence) prior to study entry and, 
have a negative pregnancy test prior to starting study treatment. Should a woman become 
pregnant or suspect she is pregnant while she or her partner is participating in this study, 
she should inform her treating physician immediately.
12. Dexamethasone dose less than or equal to 4 mg daily at time of study enrollment.
13. Patients must have completed initial radiation therapy (RT) and temozolomide (TMZ) for 
the treatment of their glioblastoma (i.e., completed 6-week course of RT and, completed 
≥ 75% of 6-week course of induction TMZ chemotherapy).
14. Participant or legal representative must understand the investigational nature of this study 
and sign an Independent Ethics Committee/Institutional Review Board approved written 
informed consent form prior to receiving any study related procedure.
5.2
Exclusion Criteria
Participants will be excluded from this study for the following:
1. The patient must not have received any immunotherapy for their brain tumor.
2. Patients with serious concurrent infection or medical illness, which in the treating 
physicians opinion would jeopardize the ability of the patient to receive the treatment 
outlined in this protocol with reasonable safety.
3. Patients who are pregnant or breast-feeding.
4. Patients receiving concurrent therapy for their tumor (i.e. chemotherapeutics or 
investigational agents) other than temozolomide.
5. Patients with a concurrent or prior malignancy are ineligible unless they are patients with 
curatively treated carcinoma-in-situ or basal cell carcinoma of the skin. Patients who 
have been free of disease (any prior malignancy) for at least 3 years are eligible for this 
study.
6. Patients who have had repeat craniotomy for tumor therapy after receiving RT and TMZ 
treatment.
7. Patients who received other chemotherapeutics or investigational agents in addition to 
their radiation therapy and concomitant temozolomide treatment.
8. Patients who have received Gliadel wafers or alternating electrical field therapy are not 
eligible for this study.
9. Known history of an autoimmune disorder.
10. Known human immunodeficiency virus (HIV) positivity or acquired immunodeficiency 
syndrome (AIDS) related illness or other serious medical illness.
11. Patients who have contraindication to MRI.
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12. Unwilling or unable to follow protocol requirements.
13. Any condition which in the Investigator’s opinion deems the participant an unsuitable 
candidate to receive study drug.
14. Received an investigational agent within 30 days prior to registration.
5.3
Inclusion of Women and Minorities
Both men and women and members of all races and ethnic groups are eligible for this study.
6
TREATMENT PLAN
6.1
Dosing and Administration
Treatment will be administered on an outpatient basis. Reported adverse events (AEs) and 
potential risks are described in Section 1.9. Appropriate dose modifications are described in 
Section 6.2.
Vaccine Priming Phase
Beginning 7-28 days after completion of standard chemoradiation therapy, patients will receive 
the first of four priming doses of SurVaxM in emulsion with Montanide with Sargramostim. 
Subsequent priming doses are given every other week (on priming Days 15, 29 and 43 ± 3 days) 
via subcutaneous injection. Patients will receive approximately 500 mcg SurVaxM in 50/50 
volume emulsion with Montanide ISA 51 (1 cc total) and a second separate injection of 100 mcg 
sargramostim in close proximity (1-3 cm) to the first injection.
Adjuvant Temozolomide (TMZ) / Vaccine Phase
TMZ will begin no sooner than 28 days after completion of concomitant temozolomide radiation 
therapy and only when the absolute neutrophil count (ANC) is ≥ 1500/μL and the platelet count 
is ≥ 100,000/μL.
TMZ will be dosed on days 1-5 of repeated 28-day cycles. A dose of 150 mg/m2 body surface 
area per day will be given for the first cycle of TMZ. This dose will increase to 200 mg/m2 body 
surface area per day in subsequent TMZ cycles, in the absence of Grade 3 and Grade 4 
hematological toxicity and with adequate count recovery after the first cycle. Any change in 
weight of more than 10% will require re-calculation of the administered TMZ dose; otherwise, 
dosing may be based on the baseline weight. The total dose of TMZ shall be rounded to the 
nearest 10 mg increment. TMZ should continue for six cycles, or until intolerance or progression 
in accordance with RANO criteria. 
Vaccine Maintenance Phase
Following completion or discontinuation of TMZ for reasons other than tumor progression, 
SurVaxM should be administered every 12 weeks (± 2 weeks) after the priming phase until 
intolerance or tumor progression. 
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6.1.1
Administration of SurVaxM
SurVaxM must be administered at the clinical trial site by appropriately trained staff.
SurVaxM injections must be performed using an appropriate needle for subcutaneous 
administration. A 23-gauge needle is recommended. Each dose of SurVaxM vaccine in emulsion 
with Montanide ISA 51 will be given in a total volume of 1.0 mL. Each dose will contain 
500 mcg SurVaxM and will be administered subcutaneously. The location of each injection will 
be recorded. In addition, 100 mcg sargramostim will be administered subcutaneously as a second 
injection given in close proximity (1-3 cm) to the SurVaxM injection. The injection site should 
be administered on the opposite side of the body from the previous injection.
Injections over the deltoid muscle are preferred, and the site of administration should alternate 
between left and right arms for each successive treatment. Alternative sites, including the 
anterior thigh, may be used if necessary. SurVaxM injections should not be given to areas of skin 
with dermatologic conditions (such as persistent injection site reactions, infection, edema, or 
scarring) that will not allow easy access for study drug administration or evaluation of localized 
adverse events. If such conditions or other circumstances contraindicate injections as outlined 
above for an individual patient, alternate sites can be used, but this should be discussed with the 
Study Principal Investigator.
Following administration of SurVaxM, patients must remain in clinic for observation a minimum 
of one hour following each vaccination to evaluate and treat any potential immediate 
hypersensitivity reactions.
Measurement of Local Reaction: Measurement of any local reaction that may occur once the 
patient leaves the clinic will be performed by the patient or caregiver. At the time of injection, 
study staff should mark the outline of the injection site on the skin. Patients/caregiver will then 
be instructed by the study staff to measure the area of local reaction at its perceived maximum 
(using the diameter of a U.S. quarter – approximately 1 inch – as a reference standard), between 
24-48 hours of administration of SurVaxM. Patients (or caregivers) will be asked to record the 
approximate dimensions of the reaction (if any) and the date it was measured. The study 
coordinator will contact the patient (or caregiver) within 3 to 5 days hr after the injection to 
obtain and record the patient’s local reaction measurement.
6.1.2
Administration of Temozolomide
Temozolomide (TMZ) will be orally self-administered, or administered IV in the clinic, around 
the same time each day (in the evening) on days 1 through 5 of each cycle during the adjuvant 
phase. A dose of 150 mg/m2 body surface area per day will be given for Cycle 1 of TMZ. This 
dose will increase to 200 mg/m2 body surface area per day in subsequent TMZ cycles pending 
hematologic count recovery. Any change in weight of more than 10% will require re-calculation 
of the administered temozolomide dose; otherwise, dosing may be based on the baseline weight. 
The total dose of TMZ shall be rounded to the nearest 10 mg increment. Dosing should occur 
according to instructions in the product label and per standard practice, with consideration to the 
guidance outlined below (see Section 6.2.2). Patients who want to get their Temozolomide 
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locally and closer to home may do so by their oncologists.  However, patients would still get 
their vaccine doses and disease assessments done at their enrollment site.
6.2
Dose Modifications
Every effort should be made to administer trial treatment on the planned schedule. In the event 
that individual patients experience treatment related toxicity, subsequent trial treatment may be 
delayed, omitted and/or discontinued as described below
6.2.1
SurVaxM Dose Omission or Discontinuation
Since all toxicities related to SurVaxM are expected to be immunologically mediated, no 
adjustment to the administered dose will be allowed.
If any unexpected significant toxicity (e.g., CTCAEv4 Grade 3) is observed, and there is a 
reasonable likelihood that the event may be associated with administration of SurVaxM and/or 
sargramostim, the next immunization for that patient should be withheld until the toxicity 
improves to mild severity or less. The immunization may be held for up to 2 weeks following the 
withheld dose. If significant toxicity is observed again or is not reversible, all further 
immunizations should be discontinued. 
If vaccinations are discontinued for any reason, temozolomide administration may continue at 
the Investigator’s discretion
6.2.2
Temozolomide Dose Adjustments
Temozolomide dose adjustments should be prescribed as clinically appropriate, as per the 
Investigator’s discretion with consideration to the product label recommendations (which may be 
more conservative than the guidance below).
Initiation of TMZ should not begin until the patient’s peripheral blood counts have recovered 
from chemoradiation such that absolute neutrophil count (ANC) is ≥ 1500/μL and platelet count 
is ≥ 100,000/μL. Delays in the initiation of temozolomide will be recorded in the CRF.
During temozolomide cycles, up to a three-week dose delay in temozolomide administration may 
be considered until the patient’s blood count returns to an acceptable level (ANC ≥ 1500/μL and 
platelet count ≥ 100,000/μL).
Deviations from the above-outlined treatment schedule are allowed and will not represent 
protocol violations, when appropriate as per standard of care. However, such deviations must be 
discussed with the Study Principal Investigator in advance to ensure appropriate visit scheduling.
Table 1
Temozolomide Dose Levels for Maintenance Treatment
Dose
Level Dose (mg/m2/day)
Remarks
-1
100
Reduction for prior toxicity
0
150
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1
200
Dose during Cycles ≥ 2 in absence of Grade 3 
or higher toxicity
Table 2
Temozolomide Dose Levels for Maintenance Treatment
Toxicity * Discontinue TMZ
Reduce TMZ by 1 Dose Level
Discontinue TMZ
Absolute Neutrophil Count
less than 1.0 x 109/L
See footnote†
Platelet Count
less than 50 x 109/L
See footnote†
CTC Non-Hematological Toxicity
(except for alopecia, nausea, vomiting)
CTC Grade 3
CTC Grade 4†
*TMZ dose levels are listed in Table 1.
†TMZ is to be discontinued if dose reduction to less than 100 mg/m2 is required or if the same 
Grade 3 non-hematological toxicity (except for alopecia, nausea, vomiting) recurs after dose 
reduction. TMZ=temozolomide; CTC=Common Toxicity Criteria.
If temozolomide is discontinued for any reason other than tumor progression, SVN53-67/M57-
KLH vaccinations may continue at the Investigator’s discretion
6.3
General Concomitant Medication and Supportive Care
The use of all standard supportive medication is permitted, although concurrent treatment with 
immunosuppressive or immunomodulatory agents is strongly discouraged. Concomitant 
systemic corticosteroids are to be avoided if at all possible. If used, doses of steroids should be 
the minimum necessary for appropriate clinical management. If any new or increased dose of 
steroids is necessary due to signs or symptoms, a rigorous evaluation for recurrent glioblastoma 
should be conducted and, in the absence of progressive disease, every effort should be taken to 
taper the patient off steroids as quickly as clinically feasible. If clinically necessary, topical or 
systemic non-steroidal anti-inflammatory or antihistamines may be used as alternatives.
When clinically appropriate, patients should strictly follow the study-prescribed treatment 
regimen. Therefore, patients should not receive additional investigational agents or anti-cancer 
therapies, unless progression of disease warrants discontinuation of study treatment and 
commencement of alternate therapies. Patients who begin new anti-cancer therapy, including 
investigational therapy, chemotherapy, cytokine therapy, immunotherapy (including other 
vaccines), or alternating electrical field therapy must discontinue SurVaxM, and will be followed 
for survival. Patients who undergo surgical resection or biopsy in the absence of progression 
may, upon consultation and agreement with Roswell Park Cancer Institute, be eligible to 
continue to receive study treatment with follow up to document persistent disease growth.
All concomitant medication will be documented in the CRF if taken within 30 days prior to 
Priming Phase through (whichever occurs first) either, a) 30 calendar days after the last 
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administration of study treatment or, b) initiation of alternate anticancer therapy. All concomitant 
medications required to treat study-drug related toxicity should be reported regardless of the 
timeframe relative to study drug dosing. All anti-cancer medications taken throughout the 
duration of study follow-up should also be recorded.
Participants may be pretreated for nausea and vomiting with appropriate anti-emetics.
6.3.1
Guidance for Management of Expected Toxicity
6.3.1.1 Local Injection Site Reaction
Based on the experience with SurVaxM and other peptide vaccines, local injection site reactions 
are likely to be the most common event associated with the administration of SurVaxM. 
However, not all patients may experience an injection site reaction with the first few 
administrations of vaccines, and not all patients who experience injection site reactions may 
experience a reaction with every injection of vaccine. Erythema and pruritus occurred most 
frequently, but localized swelling, pain, rash, induration, bruising and urticaria are also possible, 
and may be relatively common. Some injection site reactions may extend for multiple 
centimeters into the surrounding dermis and take up to several days to resolve.
The clinical experience to date suggests that nearly all injection site reactions are tolerable and 
resolve without the need for intervention. Topical corticosteroids are permitted to treat injection 
site reactions at the discretion of the investigator. Nevertheless, systemic corticosteroids should 
be reserved for severe injection site reactions only since they may also compromise the immune 
response to the vaccine and could negate its effect. Topical or systemic non-steroidal anti-
inflammatory agents (e.g. ibuprofen, naproxen, aspirin) or antihistamines (e.g. Claritin®, 
Allegra®, Benadryl) may be used as alternatives; however, routine use to prevent injection site 
reactions should be avoided, and doses should be the minimum necessary for appropriate clinical 
management.
SurVaxM injection sites should be rotated in accordance with the applicable study protocol; 
injections should not be given to areas with evidence of persistent local reaction.
Injection site reactions are considered adverse events and should be reported as such, using an 
appropriate descriptive term. (For example, “injection site erythema” should be used rather than 
the less descriptive term “injection site reaction”.) Section 10.1.2.1 provides guidance for the 
severity ratings of possible injection site reactions.
6.3.1.2 Hypersensitivity Reactions
Hypersensitivity-like reactions could occur. Precautions should be taken to prepare for the 
possibility of anaphylactic/hypersensitivity reactions after SurVaxM/Montanide/sargramostim 
administration. Patients should be observed as per institutional standards, but for a minimum of 
1 hour following each vaccination to evaluate and treat any potential immediate hypersensitivity 
reactions. The use of all routine supportive medication is permitted for hypersensitivity reactions, 
although routine use of prophylactic antihistamines, nonsteroidal anti-inflammatory agents and 
concomitant systemic corticosteroids are to be avoided if at all possible. If used, doses of steroids 
should be the minimum necessary for appropriate clinical management. If any new 
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administration of or increased dose of systemic steroids is necessary, every effort should be 
taken to taper, and preferably discontinue treatment with them, as quickly as clinically feasible.
For pain or fever, acetaminophen (325 mg tabs, 1 or 2 p.o. every 4 hours p.r.n.) will be utilized 
preferentially. Pretreatment of participants with acetaminophen may be instituted as warranted 
for a temperature of 38°C. Fevers lasting more than 8 hours after treatment will be evaluated in 
terms of potential infection. Aspirin, naproxen and ibuprofen are acceptable alternatives to 
acetaminophen for pain or fever, but are not preferred.
For mild to moderate local injection site pain that is unresponsive to acetaminophen, oral opiates 
will be used (oxycodone, 5–10 mg p.o. every 4 hours, p.r.n.). Pain that is of more than mild to 
moderate grade will be investigated for sources other than the therapy, and managed accordingly.
Anticonvulsant, antihypertensive and antidiabetic medications should be used as indicated. 
Antiemetics may be administered at the discretion of the treating physician.
For delayed hypersensitivity reactions, investigators should treat for symptomatic relief but avoid 
corticosteroid use whenever possible.
6.3.1.3 Non-Injection Site Rashes
Investigators should treat for symptomatic relief but should avoid systemic corticosteroid use if 
at all possible.
6.4
Duration of Treatment
Participants may remain on study and continue to receive treatment in the absence of: disease 
progression, unacceptable toxicity, intercurrent illness that prevents further administration of 
treatment, participant demonstrates an inability/refusal to comply with oral medication regime, 
or participant withdraws from study.
6.5
Duration of Follow-Up
All patients treated on study will be followed until death or loss of follow-up.
6.6
Treatment Discontinuation
Upon treatment discontinuation, all end of treatment evaluations and tests will be conducted. All 
participants who discontinue due to an AE must be followed until the event resolves or stabilizes. 
Appropriate medical care should be provided until signs and symptoms have abated, stabilized, 
or until abnormal laboratory findings have returned to acceptable or pre-study limits. The final 
status of the AE will be reported in the participant’s medical records and the appropriate eCRF.
A patient should be withdrawn from study treatment if, in the opinion of the Investigator, it is 
medically necessary. In addition, patients will be withdrawn from treatment in the case of:
1. RANO criteria defined disease progression. In cases where RANO criteria cannot be 
applied, progression should be based on unequivocal evidence of progressive disease 
sufficient to require a change in therapy.
2. A need for surgery, radiation, or for other anticancer therapy not specified in the protocol.
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3. Lost to follow-up or noncompliant.
4. Pregnancy. Pregnant patients should be followed for the duration of the pregnancy and 
the outcome of the pregnancy should be documented.
5. Death
6. Participant voluntary withdrawal
a.
A participant may withdraw from the study at any time, for any reason. If a 
participant discontinues treatment, an attempt should be made to obtain 
information regarding the reason for withdrawal.
7. Investigator decision.
7
INVESTIGATIONAL PRODUCTS
7.1
SVN53-67/M57-KLH (SurVaxM)
The synthetic peptide in SurVaxM (SVN53-67/M57) spans amino acids 53 through 67 of the 
mature human (and mouse) survivin protein sequence and contains a substitution of methionine 
(M) for cysteine (C) at position 57 which leads to enhanced MHC class I binding. The peptide is 
conjugated to Keyhole Limpet Hemocyanin (KLH). SVN53-67/M57-KLH contains a peptide 
mimic that is immunogenic in humans and in C57BL/6 mice. The planned investigational study 
is based on extensive experimental observation concerning the ability of SurVaxM to elicit 
potent and specific immune responses that are capable of inhibiting the growth of cerebral 
gliomas in mice and killing human glioma cells ex vivo via cytotoxic T lymphocyte (CTL) 
activity.
7.1.1
Pharmacological Class
This peptide is to be used as a vaccine and is a biological drug by class.
7.1.2
Structural Formula
SVN53-67/M57-KLH is 15-amino acids in length with the amino acid sequence: 
DLAQMFFCFKELEGW. It is conjugated to Keyhole Limpet Hemocyanin (KLH), which serves 
as a carrier protein and immune adjuvant.
7.1.3
All Active Ingredients
SVN53-67/M57-KLH is conjugated to Keyhole Limpet Hemocyanin (KLH). SVN53-67/M57-
KLH is administered emulsified in Montanide ISA 51 VG, (Cross-Referenced Drug Master File 
10870,  Seppic, Inc. France) and is co-administered with a separate local injection of 
sargramostim; Leukine®).
7.1.4
Drug Shipment
SVN53-67/M57-KLH will be shipped to all participating sites from The University of Iowa 
Pharmaceuticals as individual vials containing 1 mg sterile lyophilized powder in 2 mL clear 
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borosilicate glass crimped rubber stopper vials. Labeled boxes of peptide holding 80 vials each 
are supplied and shipped at -20oC in a Styrofoam insulated cardboard carton.
The date of receipt, condition of the shipment, and the amount of drug received will be 
documented. Drug shipment records will be retained by the investigational pharmacist or 
designee.
7.1.5
Preparation
Each vial of SVN53-67/M57-KLH peptide-conjugate, as delivered by The University of Iowa 
Pharmaceuticals, contains 1 milligram of lyophilized drug per vial. The peptide conjugate is 
reconstituted in the Investigational Drug Service Pharmacy with 1 mL sterile bacteriostatic saline 
injected into the primary 2 mL stock vial to yield a 1 mg/mL solution. The reconstituted solution 
will either be used for vaccine preparation or discarded.
7.1.6
Storage and Stability
Upon arrival, SVN53-67/M57-KLH is stored at  -20°C in a locked, temperature alarmed and 
remotely monitored freezer under the control of the Investigational Drug Service Pharmacy. 
Stability testing will be performed on a regular schedule in accordance with applicable FDA 
regulations and the IND for SVN53-67/M57-KLH.
7.1.7
Handling and Disposal
The Investigator or designee will be responsible for prescribing all investigational drug provided 
by RPCI exercising accepted medical and pharmaceutical practices. Study drugs must be handled 
as cytotoxic agents and appropriate precautions taken per the institution’s environmentally safe 
handling procedures. All investigational drugs will be dispensed in accordance with the 
Investigator’s prescription or written order.
All products dispensed will be recorded on a product accountability record. Records of product 
lot numbers and dates received will be entered on a product accountability form. It is the 
Investigator’s responsibility to ensure that an accurate record of investigational drug issued and 
returned is maintained.
Used vials (excess drug) will be destroyed according to standard practices after properly 
accounting for the dispensing. Partially used vials of study drug will not be re-used for other 
participants.
Under no circumstances will the Investigator supply investigational drug to a third party or allow 
the investigational drug to be used in a manner other than as directed by this protocol.
7.2
Vaccine Preparation: SVN53-67/M57-KLH, Montanide® ISA 51 and Sargramostim
For each vaccination, SVN53-67/M57-KLH will be mixed with Montanide® ISA-51 VG to 
create an emulsion using the standard operating procedures established in Appendix D. 
Sargramostim (Leukine) will be delivered locally as a separate injection.
Leukine (Sargramostim), NDC Product Code 50419, is an approved drug.
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7.2.1
Interaction with Other Medicinal Products and Other Forms of Interaction
There have been no unexpected interactions observed between SurVaxM and other drugs as of 
the data cut-off date.
7.2.2
Overdose
No specific antidotes exist for the treatment of SurVaxM overdose.
7.2.3
Pregnancy, Lactation, and Pediatric Use
Fertility and teratology studies with SurVaxM have not been conducted. Safety for women of 
childbearing capacity cannot be implied from the existing data. Patients who are pregnant or are 
breast feeding are excluded from all SurVaxM clinical trials. Female patients must be surgically 
sterile or be postmenopausal, or must agree to use effective contraception during the period of 
treatment. All female patients with reproductive potential must have a negative pregnancy test 
prior to treatment with SurVaxM. Male patients must be surgically sterile or must agree to use 
effective contraception during the period of treatment. The safety of SurVaxM in pediatric 
patients has not been evaluated and, therefore, SurVaxM should not be administered to 
patients <18 years of age.
7.3
Adjuvant Temozolomide
Temozolomide will not be provided for this study and will be paid for by the patient’s insurance 
carrier as part of the standard-of-care treatment of newly diagnosed glioblastoma.
8
STUDY PROCEDURES
Informed consent MUST be completed prior to receiving any study related procedures.
Unless otherwise defined in the written protocol text, all procedures/assessments will be 
conducted in accordance with RPCI Clinical Research Services Standard Operating Procedures.
8.1
Schedule of Investigations and Data Collection
The study is divided into phases with associated evaluations and procedures that must be 
performed at specific time points, as described in the following sections. The study Schedule of 
Procedures and Observations (Table 3) summarizes the frequency and timing of various 
activities, safety, and other measurements.
Every effort should be made to ensure that the protocol required tests and procedures are 
completed as described. However it is anticipated that from time to time there may be 
circumstances outside of the control of the investigator that may make it unfeasible to perform 
the test. In these cases the investigator will take all steps necessary to ensure the safety and well-
being of the patient. When a protocol required test cannot be performed, the study investigator 
will document the reason for this and any corrective and preventive actions that have been taken 
to ensure that normal processes are adhered to as soon as possible. The study team will be 
informed of these incidents in a timely fashion.
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8.1.1
Screening Period
Prior to the performance of any study-specific procedures, the patient will have the nature of the 
study explained to them, and will be asked to give written informed consent. Informed consent 
must be obtained prior to any study-specific procedures that do not form a part of the patient’s 
normal care. However, assessments performed according to standard of care prior to receipt of 
informed consent may be utilized to fulfill the screening requirement, if completed within the 
required window for screening.
The assessments outlined for the Screening Visit in the study Schedule of Procedures and 
Observations (Table 3) will be completed for each patient prior to inclusion in the study, and 
results will be evaluated to verify entry criteria prior to study entry.
8.1.2
Treatment Phase
The patient should begin protocol treatment with Priming Vaccine Day 1 within 7-28 days after 
completion of standard chemoradiation. The study Principal Investigator is to be contacted for 
any extenuating circumstances that could prevent timely initiation of protocol treatment.
The on-study period will be divided into three components, to include the vaccine priming phase 
(four doses of SurVaxM), adjuvant temozolomide with SurVaxM (the adjuvant phase) and the 
SurVaxM maintenance period (the maintenance or boosting phase). Specific procedures to be 
performed throughout the treatment phases are illustrated in the Schedule of Procedures and 
Observations (Table 3).
8.1.3
Treatment Completion/Discontinuation
The End of Treatment Visit should be performed within 30 days (± 3 days) after last study drug 
dosing, or prior to initiation of alternate therapies (whichever occurs sooner). Follow-up and 
documentation of adverse events and concomitant medications should continue through day 30. 
Specific procedures to be performed at this visit are illustrated in the Schedule of Procedures and 
Observations (Table 3).
8.1.4
Post-Treatment Follow-up Phase
Patients who discontinue study treatment should be followed for survival with visits or phone 
contact every 12 weeks (± 4 weeks) until death or lost to follow-up.
.
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Table 3
Schedule of Procedures and Observations
Protocol Activity
Screen
Vaccine Priming Phase1
Adjuvant 
Temozolomide2 
Vaccine 
Maintenance 
Phase3
Disease 
Assessment 
End of 
Treatment4
Survival 
Follow-up5
V1 
V2 
V3 
V4 
Day 1 of each 
28 day cycle
Every 12-weeks 
(± 2 weeks)
Every 
8 weeks 
(± 4 weeks)
Every 12 
weeks (± 
4 weeks)
Tumor tissue
X
Medical history
X
Physical 
examination
X
X
X
X
X
X
X
X
Neurological 
examination/ 
MMSE14
Vital Signs(to 
include weight)
X
X
X
X
X
X
X
X
Karnofsky 
Performance 
Status
X
X
X
X
X
X
X
X
Hematology6
X
X
X
X
X
X
X
Chemistry7
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
Pregnancy Test 
(serum)8
X
X
X
X
X
X
HLA typing13
X
Humoral and 
Cellular Immune 
Reponses9
X
X
X
Brain MRI10
X
X
X
Study Vaccine
X
X
X
X
X

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Protocol Activity
Screen
Vaccine Priming Phase1
Adjuvant 
Temozolomide2 
Vaccine 
Maintenance 
Phase3
Disease 
Assessment 
End of 
Treatment4
Survival 
Follow-up5
V1 
V2 
V3 
V4 
Day 1 of each 
28 day cycle
Every 12-weeks 
(± 2 weeks)
Every 
8 weeks 
(± 4 weeks)
Every 12 
weeks (± 
4 weeks)
Measurement of 
local reaction15
X
X
X
X
X
Adjuvant 
Temozolomide
X
Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X11
Adverse Events 
Assessment12
X
X
X
X
X
X
X
X
Contact 
Information for 
survival follow-up
X
Footnotes for Schedule of Procedures and Observations:
Note: Unless otherwise noted, study assessments should be completed prior to dosing at each treatment visit.
1.
V1 within 7-28 days after completion of chemoradiation and then every two weeks (14 days ± 3 days) for a total of 4 doses.
2.
Adjuvant temozolomide therapy (TMZ) will begin ≥42 days after completion of concomitant temozolomide radiation therapy and given for 6 cycles 
or more (at the discretion of the investigator), or until intolerance or tumor progression. Temozolomide to be taken on Day 1 through Day 5 of each 
28-day cycle ± one week window for tests and visit.
3.
Maintenance Vaccine Phase: SurVaxM should be administered every 12 weeks (± 2 weeks) after the priming phase until intolerance or tumor 
progression (12-week cycle ± one week window for tests and visit).
4.
The End of Treatment visit should be performed within 30 days (± 3 days) after last study drug dosing, or prior to initiation of alternate therapies 
(whichever occurs sooner). Follow-up and documentation of adverse events and concomitant medications should continue through day 30 
(± 3 days), or until lost to death or follow-up.
5.
Patients who discontinue study treatment should be followed on study for survival, with visits or phone contact every 12 weeks (±4 weeks) until 
death or lost to follow-up. 

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6.
Hematology: CBC with differentials, platelets.
7.
Chemistry: (CMP) defined as: chloride, CO2, potassium, sodium, BUN, glucose, calcium, creatinine, total protein, albumin, total bilirubin, alkaline 
phosphatase, AST, ALT, A/G ratio, BUN/creatinine ratio, osmol (Calc), anion gap.
8.
Pregnancy test is required for women of child bearing potential only. A serum pregnancy test must be performed during screening. If the serum 
pregnancy test is not performed within 7 days of dosing on Priming Phase V1-Day 1, a urine pregnancy test must be performed on Priming Phase 
V1-Day 1 with results reviewed prior to dosing. Testing may be repeated throughout the study as indicated.
9.
Blood: six 10 mL green top tubes and one 3.5 mL gold top tube to be collected for in vitro immunological assays (see Section 8.2).
10. Brain MRIs must be obtained from the postoperative period (ideally with 72 hours) and post-chemoradiation period (within 1-14 days of completion 
of chemoradiation). 
11. Subsequent to progression, medication review is limited to new anti-cancer regimens. 
12. Documentation of adverse events occurring from the date the participant signs the study consent until 30 days after the last intervention or a new 
treatment is started, whichever occurs first. Any serious adverse event occurring any time after the reporting period must be promptly reported if a 
causal relationship to study treatment is suspected.
13. HLA –A low resolution panel
14. MMSE: Mini Mental State Exam will be done at the discretion of the PI. (41)
15. Patient to be instructed to check injection site for 24 to 48 hr post injection: staff to call within 3 to 5 days to document any reaction (see Section 
6.1.1).

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8.2
Blood Draws for Humoral and Cellular Immune Response
Whole blood samples for humoral and cellular immune response analysis will be collected via 
venipuncture using six 10 mL green top tubes and one 3.5 mL gold top tube.
Sample collection: Immunological analyses will be conducted on blood samples obtained prior to 
the patient’s scheduled vaccination dosing (i.e., predosing), and at all study follow-up visits as 
indicated on Table 3. (to be drawn on day of priming vaccine one (V 1), with disease assessment 
every 8 weeks (± 4 weeks), and at progression or end of treatment). On each occasion, 
approximately 50 mL of blood will be obtained from a peripheral venipuncture and collected in 
six green top (heparinized) tubes and one 3.5 mL gold top tube. Blood tubes will be kept at room 
temperature until pickup for processing.
Additional End of Treatment blood draw (optional):
All collected blood samples from within RPCI will be sent from Phlebotomy directly to the 
RPCI Immunomonitoring Facility for PBMC separations and freezing.
Center for Immunotherapy
Immune Analysis Facility Shared Resource
Cancer Cell Center (CCC), C-416
Tel: 716-845-8459 (office)
Tel: 716-845-8952 (lab)
Junko.Matsuzaki@RoswellPark.org 
Serum will be separated from whole blood gold top tube and frozen at -70°C. Whole blood will 
be processed to obtain PBMC and aliquoted into 2-10 cryovials per time-point containing 
1 million cells per vial (number of vials is dependent upon cell number recovered: see Appendix 
E). Screw cap polypropylene cryogenic tubes will be labeled with the participant’s MR number, 
participant’s initials, participant’s study number, clinical study number, protocol time point, 
dose, and protocol day. The samples will immediately be frozen at -70ºC or below until 
analyzed. Samples collected after hours will be maintained at room temperature and processed 
within 24 hours in the Immune Analysis Facility (IAF). 
A blood intake and inventory log will be maintained in the Immune Analysis Facility (IAF).
In vitro immunological assays will be performed at RPCI as a central immunomonitoring site. 
Pre-immune serum for baseline anti-survivin and anti-KLH antibody titers and T cell multimer 
assays will be performed in the Neuro-Oncology lab; cytokine analysis and ELISPOT assays will 
be performed in the RPCI Immune Analysis Facility (IAF). As noted above six 10 mL green top 
tubes and one 3.5 mL gold top tube will be processed for these assays. Serum from one 3.5 ml 
gold top tube will be directed to antibody assessments; PBMC collected from green top tubes 
(approximately equal to that collected from three tubes) will be designated for multimer studies. 
Remaining PBMC from green top tubes will be used for cytokine analysis and ELISPOT as well 
as repeat assays or multimer assay if there is a shortfall of PBMC.
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Results will be collected at multiple time points throughout the study as groups of patient 
samples become available for complete analysis. Data will be reported in spreadsheet (Excel) 
format to be provided to CRS data management for entry.
NETWORK SITES: Follow directions above for blood sample collection and processing 
(PBMC isolation procedure: see Appendix E). PBMC tubes will be labeled with the 
Subject ID # (unique to Network patients), initials, the participant’s study number, clinical study 
number, protocol time point, dose, and protocol day. PBMC samples from outside RPCI will be 
shipped frozen on dry ice via Federal Express Overnight in styrofoam-insulated containers, with 
delivery on Mon-Fri. NO SATURDAY OR SUNDAY DELIVERY. All samples should be 
shipped, along with the sponsor-provided shipping log, to the address below with e-mail 
notification to the Basic Science Co-investigator (Michael.Ciesielski@RoswellPark.org):
Roswell Park Cancer Institute
Cancer Cell Center (CCC), C-416
Attn: Immune Analysis Facility – I 259614
Elm & Carlton Streets
Buffalo, New York 14263
Tel: 716-845-8459 (office)
Fax: 716-845-1595
For additional information regarding the handling of samples please contact RPCI’s Immune 
Analysis Facility Shared Resource at 716-845-1574 or 716-845-6555.
NOTE: In the event that a network site cannot process PBMC samples, whole blood may be 
shipped at ambient temperature overnight to the RPCI Immune Analysis Facility (IAF). Samples 
will be maintained at room temperature and processed within 24 hours.
 8.3.1  Pathology
Survivin Expression Status
Over 85% of glioblastomas have survivin protein expression that is detectable by 
immunohistochemistry. A determination of survivin positivity by central pathology review is 
required for eligibility. All patients will have unstained slides or tissue blocks submitted to the 
central pathology core (Roswell Park Cancer Institute) for survivin testing.
A. Patients from Roswell Park Cancer Institute:
1. Unstained Slides:
•
Send all slides within 6 weeks of cutting
•
At least  24 unstained slides or one tissue block
•
Precut slides from paraffin blocks in 5 micron sections
•
Mount on Poly-L-Lysine-coated or plus (+) slides
•
Air dry. Do not oven dry
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•
Store specimen at room temperature
B. Patients from Network Sites:
1. Unstained Slides:
•
Send all slides within 6 weeks of cutting
•
At least  24 unstained slides or one tissue block
•
Precut slides from paraffin blocks in 5 micron sections
•
Mount on Poly-L-Lysine-coated or plus (+) slides
•
Air dry. Do not oven dry
•
Store specimen at room temperature
While unstained slides are preferred, tissue blocks are acceptable. If tissue blocks are being sent 
instead of unstained slides, please follow the procedure below for processing and shipping.
Fixed Paraffin Block with Corresponding H&E:
•
Tissue should be well-fixed in formalin. If alternative fixative is used, it should be 
noted on the requisition.
•
0.2 cm x 0.2 cm x 0.2 cm tissue
•
Store specimen at room temperature.
•
Use cold pack for transport. Be sure cold pack is not in direct contact with 
specimen during transport.
For Network Sites: Send samples, along with the sponsor-provided shipping log, using study-
specific subject ID number and tissue accession number to RPCI Pathology Network Shared 
Resource (Attn: Protocol Lab Team). The shipping label should read as follows:
Roswell Park Cancer Institute 
Correlative Sciences Pathology Office, S-636
Attn:  Protocol Lab Team – I 259614 Samples
Elm & Carlton Streets
Buffalo, NY  14263
(716) 845-8917
Email:  CRSLabPathTeam@RoswellPark.org
Samples will be analyzed in RPCI’s Pathology Network Shared Resource by Dr. Jingxin Qiu 
(Tel: 716-845-3457, Fax: 716-845-3427).
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Tissue will also be tested for Survivan, MGMT methylation status, IDH-1, and PDL-1 
expression.  MGMT and IDH-1 tests require 6 unstained slides for each test. Survivan and PD-
L1 immunohistochemistry stains on tumor tissue each require 3 unstained slides.  For evaluable 
patients only, OmniSeq Comprehensive and OmniSeq Immune Advance will also be tested.  3 
unstained slides are required for each of these. 
Unstained slides will be sent for the following tests:
Test
Slides required
Survivin
3 unstained slides
PDL-1
3 unstained slides
Omniseq Comprehensive
3 unstained slides
Omniseq Immune Advance
3 unstained slides
IDH-1
6 unstained slides
MGMT methylation
6 unstained slides
9
EFFICACY EVALUATIONS
9.1
Objective Tumor Response
All protocol-defined imaging studies must be performed at the investigative site or sponsor-
approved facility using protocol-defined parameters. The same method of assessment and the 
same technique should be used to characterize each identified and reported lesion at baseline and 
during follow-up. The Modified Response Assessment in Neuro-Oncology (RANO) Response 
Criteria (Appendix C) will be used to define tumor response and progression (40). 
It is important to use the same method of assessment from one scan to the subsequent scans.
Rarely, patients undergoing vaccine therapy for tumor can develop an inflammatory response in 
the tumor bed that mimics either true tumor recurrence or pseudoprogression.  If a patient who 
has completed the 4-dose vaccine priming phase of treatment undergoes either biopsy or re-
resection of new contrast-enhancing tissue and no tumor is determined by the local 
neuropathologist to be present on histologic exam, the patient may continue on treatment under 
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protocol with approval of the lead principal investigator.  If any amount of tumor is found to be 
present at re-biopsy, the patient must be declared to have progressed as of the date of the MRI 
scan that first showed the new enhancement.  Patients with new enhancement during the priming 
phase that is not suspected to be pseudoprogression are not eligible to continue treatment on 
protocol. 
9.2
Evaluation of Response
The largest cross-sectional area on the T1-weighted contrast-enhanced images will be selected 
and measured in 2 dimensions with linear measures on the baseline MRI axial sequence.  In 
addition, the largest cross-sectional area of a contiguous hyperintense lesion on FLAIR 
sequences will be measured on the baseline MRI axial sequence. If there is no enhancement on 
the baseline MRI done with 72 hours post-op, this should be noted as no evidence of disease 
(NED). All subsequent scans will be compared against these baseline measures (for both CE and 
FLAIR). New foci of FLAIR signal abnormality will be recorded on each subsequent evaluation.  
Response will be scored based on a combination of imaging and clinical features as defined by 
the modified RANO criteria (40). Objective response rate is defined as the sum of partial 
responses plus complete responses.
For the purpose of treatment decisions, progression will be assessed by the treating investigator. 
20% to 30% of patients who receive chemoradiotherapy for newly diagnosed glioblastoma can 
exhibit transient increase in tumor enhancement that eventually subsides without change in 
therapy (pseudoprogression) (40). The protocol allows for investigators to confirm progression 
before removal of patients from study treatment, thus ensuring radiographic follow-up to a valid 
disease progression time point. In every case when there is doubt about progression versus 
“pseudoprogression”, use of perfusion and diffusion weighted imaging is encouraged. Patients 
may continue on treatment and remain under close observation and evaluation at four-week 
intervals if there is uncertainty regarding whether apparent radiographic progression may 
represent “pseudoprogression” and the patient is doing well clinically or is clinically stable. If 
subsequent evaluations indicate that the patient is in fact experiencing progression, then the date 
of progression should be the time point at which this issue was first raised.
9.2.1
Survival
Duration of survival will be defined as the time from date of diagnosis to death due to any cause.
In all cases, progression-free survival will be assessed using the RANO response criteria for 
GBM which considers radiologic imaging, neurological status, and steroid dosing. According to 
these criteria, progression of disease will be assumed if any of the following criteria are met:
•
≥ 25% increase in the sum of the products of perpendicular diameters of enhancing 
lesions compared with baseline (post-chemoradiation) or best response after initiation of 
therapy.
NOTE: Due to the fact that little to no residual disease will be present at baseline in these 
patients, a 25% increase in area could easily reflect only imaging variance. Therefore, in order to 
be considered progressive disease, a > 5 mm increase in maximal diameter, as well as ≥ 25% 
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increase in the sum of the products of the progressing lesions will be required to assign a status 
of progressive disease.
•
Significant increase in T2/FLAIR non-enhancing lesion compared with baseline (post-
chemoradiation) or best response after initiation of therapy, not caused by comorbid 
events (e.g., radiation therapy, demyelination, ischemic injury, infection, seizures, 
postoperative changes, or other treatment effects).
•
Clear progression of non-measurable disease.
•
Any new lesion.
NOTE: Patients may continue on treatment and remain under close observation and evaluation at 
four-week intervals if there is uncertainty regarding whether apparent radiographic progression 
may represent “pseudoprogression”. If subsequent evaluations suggest that the patient is in fact 
experiencing progression, then the date of progression should be the time point at which this 
issue was first raised. Similarly, stable disease may be assigned in cases of presumed 
“pseudoprogression” associated with decreased steroid use.
•
Clear clinical deterioration not attributable to other causes apart from the tumor (e.g., 
seizures, medication adverse effects, complications of therapy, cerebrovascular events, 
infection, and so on) or changes in corticosteroid dose 
•
Failure to return for evaluation as a result of death or deteriorating condition 
NOTE: Any cystic or surgical cavity should not be measured in determining response. At 
baseline, tumor around the surgical cavity should generally be considered nonmeasurable unless 
there is a nodular component measuring 10 mm in diameter.
10
SAFETY EVALUATION
10.1 Adverse Events
10.1.1 Definition
An adverse event or adverse experience (AE) is any untoward medical occurrence associated 
with the use of a drug in humans, whether or not considered drug related. Therefore, an AE can 
be ANY unfavorable and unintended sign (including an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of a medicinal (investigational) product, whether or 
not considered related to the medicinal (investigational) product (attribution of ‘unrelated’, 
‘unlikely’, ‘possible’, ‘probable’, or ‘definite’).
An AE is considered “unexpected” if it is not listed in the investigator brochure or is not listed at 
the specificity or severity that has been observed; or if an investigator brochure is not required or 
available, is not consistent with the risk information described in the general investigational plan 
in other study-related documents.
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10.1.1.1 Diagnosis Versus Signs and Symptoms
If known, a diagnosis should be recorded on the CRF rather than individual signs and symptoms 
(e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases). However, if a constellation of signs and/or symptoms cannot be clinically 
characterized as a single diagnosis or syndrome at the time of reporting, each individual event 
should be recorded as an AE or SAE on the CRF. If a diagnosis is subsequently established, it 
should be reported as follow-up information.
10.1.1.2 Adverse Events Occurring Secondary to Other Events
In general, AEs occurring secondary to other events (e.g., cascade events or clinical sequelae) 
should be identified by their primary cause. For example, if severe diarrhea is known to have 
resulted in dehydration, it is sufficient to record only diarrhea as an AE or SAE on the CRF.
However, clinically significant AEs occurring secondary to an initiating event that are separated 
in time should be recorded as independent events on the CRF. For example, if a severe 
gastrointestinal hemorrhage leads to renal failure, both events should be recorded separately on 
the CRF.
10.1.1.3 Abnormal Laboratory Values
Only clinically significant laboratory abnormalities that require active management will be 
recorded as AEs or SAEs on the CRF (e.g., abnormalities that require study drug dose 
modification, discontinuation of study treatment, more frequent follow-up assessments, further 
diagnostic investigation, etc.).
If the clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 x the upper limit of normal associated with 
cholecystitis), only the diagnosis (e.g., cholecystitis) needs to be recorded on the Adverse Event 
CRF.
If the clinically significant laboratory abnormality is not a sign of a disease or syndrome, the 
abnormality itself should be recorded as an AE or SAE on the CRF. If the laboratory abnormality 
can be characterized by a precise clinical term, the clinical term should be recorded as the AE or 
SAE. For example, an elevated serum potassium level of 7 mEq/L should be recorded as 
“hyperkalemia”
Observations of the same clinically significant laboratory abnormality from visit to visit should 
not be repeatedly recorded as AEs or SAEs on the CRF, unless their severity, seriousness, or 
etiology changes.
The following clinical laboratory tests will be performed during this study to assess safety (see 
Schedule of Procedures and Observations: Table 3, for specific tests):
•
Hematology 
•
Serum Chemistries 
•
Urinalysis
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The following evaluations will also be performed during the study to measure the safety and 
tolerability of study treatment:
•
Vital sign measurements 
•
Physical examination 
•
Neurological examination 
•
Karnofsky Performance Status
10.1.1.4 Preexisting Medical Conditions (Baseline Signs and Symptoms)
A preexisting medical condition should be recorded as an AE or SAE only if the frequency, 
severity, or character of the condition worsens during the study. When recording such events on 
an Adverse Event CRF, it is important to convey the concept that the preexisting condition has 
changed by including applicable descriptors (e.g., “more frequent headaches”).
10.1.2 Grading and Relationship to Drug
The descriptions and grading scales found in the CTEP Version 4 of the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) will be utilized for AE reporting. CTEP
Version 4 of the CTCAE is identified and located at:
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
AEs not covered by specific terminology listed should be reported with common medical 
terminology, and documented according to the grading scales provided in the CTCAE Version 4.
The relationship of event to study drug will be documented by the Investigator as follows:
•
Unrelated: The event is clearly related to other factors such as the participant’s clinical 
state, other therapeutic interventions or concomitant drugs administered to the participant.
•
Unlikely: The event is doubtfully related to investigational agent(s). The event was most 
likely related to other factors such as the participant’s clinical state, other therapeutic 
interventions, or concomitant drugs.
•
Possible: The event follows a reasonable temporal sequence from the time of drug 
administration, but could have been produced by other factors such as the participant’s 
clinical state, other therapeutic interventions or concomitant drugs.
•
Probable: The event follows a reasonable temporal sequence from the time of drug 
administration, and follows a known response pattern to the study drug. The event cannot 
be reasonably explained by other factors such as the participant’s clinical state, 
therapeutic interventions or concomitant drugs.
•
Definite: The event follows a reasonable temporal sequence from the time of drug 
administration, follows a known response pattern to the study drug, cannot be reasonably 
explained by other factors such as the participant’s condition, therapeutic interventions or 
concomitant drugs; AND occurs immediately following study drug administration, 
improves upon stopping the drug, or reappears on re-exposure.
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10.1.2.1 Severity assessment of Injection Site Reaction
10.1.3 Reporting Adverse Events
Table 4
Guidelines for Routine Adverse Event Reporting for Phase 2 Studies 
(Regardless of Expectedness)
Attribution
Grade 1
Grade 2
Grade 3
Grade 4
Unrelated
X
X
Unlikely
X
X
Possible
X
X
X
X
Probable
X
X
X
X
Definite
X
X
X
X
Routine AEs occurring between the start date of intervention until 30 days after the last 
intervention or until the event has resolved, the study participant is lost to follow-up, the start of 
a new treatment, or until the study investigator assesses the event(s) as stable or irreversible, will 
be reported. New information will be reported after it is received.
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10.2 Serious Adverse Events
10.2.1 Definition
A serious adverse event (SAE) is any adverse event (experience) that in the opinion of either the 
investigator or sponsor results in ANY of the following:
•
Death.
•
A life-threatening adverse event (experience). Any AE that places a participant or 
participant, in the view of the Investigator or sponsor, at immediate risk of death from the 
reaction as it occurred. It does NOT include an AE that, had it occurred in a more severe 
form, might have caused death.
•
Inpatient hospitalization or prolongation of existing hospitalization (for > 24 hours).
•
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions.
•
A congenital anomaly or birth defect.
•
Important Medical Event (IME) that, based upon medical judgment, may jeopardize the 
participant and may require medical or surgical intervention to prevent one of the 
outcomes listed above.
10.2.2 Reporting Serious Adverse Events
All new SAEs occurring from the date the participant signs the study consent until 30 days after 
the last intervention or a new treatment is started, whichever comes first, will be reported. The 
RPCI SAE Source Form is to be completed with all available information, including a brief 
narrative describing the SAE and any other relevant information. 
SAEs occurring after the 30 day follow-up period that the investigator determines to be possibly, 
probably or definitely related to the study intervention should be reported.
SAEs identified as an Unanticipated Problem by the Investigator must be reported. Please refer 
to Section 10.4 for details on reporting Unanticipated Problems.
10.3 Follow-Up for Serious Adverse Events
All related SAEs should be followed to their resolution, until the study participant is lost to 
follow-up, the start of a new treatment, or until the study investigator assesses the event(s) as 
stable or irreversible. New information will be reported when it is received.
10.4 Unanticipated Problems
10.4.1 Definition
An Unanticipated Problem (UP) is any incident, experience, or outcome that meets all of the 
following criteria:
•
Unexpected (in terms of nature, severity, or frequency) given:
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a) The research procedures that are described in the study-related documents, including 
study deviations, as well as issues related to compromise of participant privacy or 
confidentiality of data.
b) The characteristics of the participant population being studied.
•
Related or possibly related to participation in the research (possibly related means there is 
a reasonable possibility that the incident, experience, or outcome may have been caused 
by the procedures involved in the research).
•
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized and if in relation to an AE is also deemed Serious per Section 10.2.
10.4.2 Reporting Unanticipated Problems
Unanticipated problem reporting will begin at the time of participant consent. The Unanticipated 
Problem Form will be submitted to the CRS Compliance Office within 1 business day of 
becoming aware of the Unanticipated Problem.
When becoming aware of new information about an Unanticipated Problem, submit the updated 
information to CRS Compliance with an updated Unanticipated Problem Form. The site 
Investigator or designated research personnel will report all unanticipated problems, whether 
related or unrelated to the investigational agent(s) to the IRB in accordance with their local 
institutional guidelines.
10.5 FDA Reporting
When RPCI is the IND holder the following describes the FDA reporting requirements by 
timeline for AEs and new safety findings that meet the criteria outlined below:
Within 7 Calendar Days
Any adverse event that meets ALL the following criteria:
•
Related or possibly related to the use of the study drug;
•
Unexpected; and
•
Fatal or life-threatening.
Within 15 Calendar Days
Any adverse event that meets ALL the following criteria:
•
Related or possibly related to the use of the study drug;
•
Unexpected; and
•
Serious but not fatal or life-threatening;
Or, meets ANY of the following criteria:
•
A previous adverse event that is not initially deemed reportable but is later found to fit 
the criteria for reporting (report within 15 days from when event was deemed reportable).
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•
Any findings from other studies, including epidemiological studies, pooled analysis of 
multiple studies, or other clinical studies conducted with the study drug that suggest a 
significant risk in humans exposed to the drug.
•
Any findings from animal or in vitro testing that suggest a significant risk for human 
participants including reports of mutagenicity, teratogenicity, or carcinogenicity or 
reports of significant organ toxicity at or near the expected human exposure.
•
Any clinically important increase in the rate of occurrence of a serious, related or 
possibly related adverse event over that listed in the protocol or investigator brochure.
Sponsors are also required to identify in IND safety reports, all previous reports concerning 
similar adverse events and to analyze the significance of the current event in the light of the 
previous reports.
Reporting Process
The principal investigator or designee will complete and submit a FDA Form 3500A MedWatch 
for any event that meets the above criteria. Forms will be submitted to the CRS Compliance 
Office via email to CRSCompliance@RoswellPark.org. Network sites: refer to Appendix A.
11 DATA AND SAFETY MONITORING
The RPCI Data and Safety Monitoring Board will assess the progress of the study, the safety 
data, and critical efficacy endpoints. The DSMB will review the study annually and will make 
recommendations that include but not limited to; (a) continuation of the study, (b) modifications 
to the design (c) or termination of the study.
12 STATISTICAL METHODOLOGY
12.1 Study Design
This is a multi-center, open-label; prospective one-arm phase II clinical trial evaluating the safety 
and efficacy of SurVaxM and adjuvant temozolomide in adult patients with newly diagnosed 
GBM. The statistical design is based on an assessment of the efficacy of the study treatment for 
patients as compared to an external standard, i.e., historical control. All enrolled patients will 
receive the study treatment and initiation of the treatment should take place as soon as possible 
following study enrollment. A total of up to 65 patients will be enrolled to meet our target of at 
least 50 evaluable patients. An evaluable subject is defined as a subject who meets eligibility 
requirements and who completes the initial four priming doses of the vaccine. If a patient signs 
an Informed Consent and does not receive all four priming injections or, the patient withdraws 
their consent before receiving the priming injections, the patient will be classified as unevaluable 
and will be replaced. Analyses will be performed with a focus on estimation of specific clinically 
important parameters for use in the planning of larger subsequent comparative trials designed to 
fully assess efficacy and safety.
All analyses will be performed using the SAS® statistical software system.
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12.1.1 Missing Data
The amount and nature of missing data will be characterized and no method of imputation will 
be used for missing data. A summary of missing data will be provided according to the number 
of subjects, the time points where the data are missing, and clinical center. For each clinical 
center, the number and percent of subjects with no missing data will be presented in tabular 
form.
All analyses will be performed using the SAS® statistical software system.  
12.2 Study Objectives
The primary objective of this study is:
•
To evaluate 6 month progression-free survival (PFS) rates in patients with survivin 
positive newly diagnosed GBM treated with SurVaxM and adjuvant temozolomide.
The secondary objectives of this study are:
•
To determine the safety and tolerability of SurVaxM in patients receiving standard of 
care temozolomide.
•
To evaluate overall survival (OS) in patients with survivin positive newly diagnosed 
GBM treated with SurVaxM and adjuvant temozolomide. 
•
To describe the immune response in patients treated with SurVaxM and predictors of 
response.
•
To evaluate objective tumor response rate (applicable only for patients with evaluable 
disease at study entry, as defined per RANO criteria) and predictors of response.
12.3 Study Endpoints
Primary Endpoint:
•
PFS is defined as the time from date of diagnosis to the date of first observed disease 
progression or death due to any cause. All patients will be followed for a minimum of 6 
months relative to evaluating the primary endpoint.
Secondary Endpoints:
•
OS is defined as the time from date of diagnosis until date of death or the last date patient 
known alive (if death is not observed).
•
Number of Grade 3 or 4 toxicities, according to National Cancer Institute Common 
Toxicity Criteria for Adverse Events (NCI CTCAEs) Version 4 
•
Immune responses to SurVaxM and predictors of response 
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12.4 Sample Size Determination
The primary endpoint will be the 6 month PFS survival fraction. Let π represent the 6 month PFS 
survival fraction.  A true rate of the 6 month PFS survival fraction greater than π0=0.55 is 
considered acceptable and evidence such that we will the treatment worthy of further study.  The 
null and alternative hypotheses to be tested are Ho:π= π0 versus Ha:π>π0. We hypothesize that 
patients treated with SurVaxM and adjuvant temozolomide will have a 6 month PFS survival 
fraction of 0.70 or larger. The sample size calculation is based on testing the hypotheses 
concerning the proportion of the population with a response to the treatment: Ho:π= π0 versus 
Ha:π>π0. For our calculations π0=0.55,α =0.10, 1-β=0.80. Based on an exact one-sided test the 
sample size calculation yields n=50 patients.
Subjects will be accrued to the study on a first-come basis. The projected accrual is 
approximately 2 subjects per month, and therefore recruitment is expected to be complete at 25 
months following the study starting point. Subjects will be followed to determine time to tumor 
progression (PFS) and until death to determine overall survival (OS).
12.5 Demographics and Baseline Characteristics: Descriptive Analyses
Measured outcome variables will be summarized overall and by relevant demographic and 
baseline variables. Descriptive statistics such as frequencies and relative frequencies will be 
computed for all categorical variables. Numeric variables will be summarized using simple 
descriptive statistics such as the mean, standard deviation and range. A variety of graphical 
techniques will also be used to display data, ex. histograms, boxplots, scatterplots, etc.
12.6 Safety Analysis
Safety and tolerability will be assessed by incidence, severity, and changes from baseline of all 
relevant parameters including adverse events (AEs) (see Section 12.8), laboratory values and 
vital signs.
Vital sign results (systolic and diastolic blood pressure, pulse, respiration, and temperature) will 
be summarized descriptively for each scheduled and unscheduled protocol time point. Changes 
will be calculated relative to the assessments at baseline.
The changes in hematology, chemistry, and other laboratory values will be summarized 
descriptively for each scheduled and unscheduled protocol assessment time point. Changes will 
be calculated relative to the values collected at baseline. Data listings of all laboratory data 
collected during the study will be presented. Laboratory values outside normal limits will be 
identified in data listings and will include flags for high and low values.
12.7 Efficacy Analysis
12.7.1 Primary Analysis
The primary objective is to evaluate the 6 month PFS survival fraction in patients with newly 
diagnosed GBM treated with at least 4 priming doses of SurVaxM and standard-of-care adjuvant 
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temozolomide as compared to historical control. PFS is defined as the time from date of 
diagnosis to the date of first observed disease progression or death due to any cause. Patients 
who are alive and disease free at the last study assessment will be treated as censored.
Historical Control: Patients in this population defined by the eligibility criteria receive standard-
of-care which consists of concurrent temozolomide and radiation followed by adjuvant 
temozolomide. Based on provided historical information, the 6 month PFS survival fraction is 
assumed to be 0.55. We hypothesize that treatment with SurVaxM and adjuvant temozolomide 
will increase the 6 month PFS survival fraction to 0.70. Therefore the PFS survival fraction will 
be measured after all patients have been followed for 6 months.
The 6 month PFS survival fraction is estimated as standard binomial proportion. An exact one-
sided binomial test will be used to test our primary hypothisis. The nominal significance level to 
be used for this test is 0.10. In addition, a Kaplan-Meier curve for PFS will be used calculated to 
generate summary descriptive statistics, e.g. median PFS. 
Secondary Analyses
The estimated distributions of overall survival (OS), defined as the time from date of diagnosis to 
death due to any cause, will be obtained using the Kaplan-Meier method. Estimates of quantities 
such as median survival will be obtained. Corresponding confidence intervals will be computed.  
It is assumed a priori that any drop out times will be non-informative in terms of the censoring 
mechanism. 
Groups 
defined 
by 
levels 
of 
categorical 
or 
dichotomized 
numeric 
demographic/baseline variables will be compared in regards to time-to-event distributions using 
the log-rank test. Cox proportional hazards model regression will be utilized for multivariate 
analyses.
A summary of anticancer therapies received following the discontinuation of protocol therapy 
will be provided. Such therapies will be classified as chemotherapy, biological therapy, radiation, 
surgery, or other.
Both objective tumor response rate (applicable only for patients with evaluable disease at study 
entry, as defined per RANO criteria) and toxicity rate (Grade 3 or Grade 4 toxicities, according 
to National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAEs) 
Version 4) will be estimated using simple relative frequencies. The corresponding 95% 
confidence intervals for the estimated probabilities will be computed using the method proposed 
in Clopper and Pearson, 1934 (43). The relationship between binary outcomes and collected 
demographic and baseline variables will be statistically assessed using logistic regression in an 
exploratory fashion. Maximum likelihood estimation will be utilized in the model fitting 
procedures as implemented by SAS PROC LOGISTIC. Wald tests of the model effects will be 
performed to assess statistical significance; see SAS documentation for details. See Hosmer and 
Lemeshow, 2000 (44) for a discussion of such techniques. Alternative parametric models will be 
considered if model fit is found to be inadequate.
Objectives based on continuous outcomes such as immune response measured over time will be 
address in a similar fashion. A series of exploratory analyses will initially take place including 
individual subject-level profile plots and overall mean plots used to examining the mean 
structure. Formal statistical examination of longitudinal patterns will be done through the use of 
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a mixed model. Restricted maximum likelihood estimation will be utilized in the model fitting 
procedures as implemented by SAS PROC MIXED (version 9.2). Once the model is fit, specific 
linear contrasts based on the estimated model parameters will be constructed and used to test 
hypotheses concerning between time point comparisons. We acknowledge the possibility of 
informative missingness, that is, the probability of a particular observation being missing may be 
related to the health of the subject, and therefore analyses will be interpreted with caution.
All tests will be two-sided and tested at a 0.05 nominal significance level. Standard diagnostic 
plots will be used to assess model fit and transformations of variables may be considered in order 
to meet statistical assumptions.
12.8 Adverse Event
AEs will be coded using the latest available version of the Medical Dictionary for Regulatory 
Activities (MedDRA). AEs will be summarized for each treatment arm by the number and 
percentage of patients who experienced the event, according to system organ class and preferred 
term. Additional summaries will also be provided by severity grade and relationship to study 
drug, and for SAEs and events resulting in the permanent discontinuation of therapy. A patient 
reporting multiple cases of the same AE will be counted once within each system organ class and 
similarly counted once within each preferred term, and adverse events will be graded by worst 
severity grade. Unless specified otherwise, the denominator for these calculations will be based 
on the number of patients in each treatment arm who receive at least one dose of study drug, 
irrespective of the total number of doses administered. All participants who receive any study 
treatment will be considered evaluable for toxicity.
12.9 Replacement
Patients who meet either of the following conditions will be considered unevaluable for the 
primary end-point and will be replaced:
•
Failure to receive all 4 priming doses of SurVaxM (making a patient unevaluable for the 
purposes of the primary end-point), or,
•
Withdrawal of consent by patient.
Up to an additional 15 patients may be enrolled to replace unevaluable patients or patients who 
withdraw consent prior to receiving study treatment.
12.10Interim Analysis and Criteria for Early Termination of the Study
There are no planned interim analyses (unless for safety reasons) or early termination criteria 
based on the following:
1. The completed phase I trial of SVN53-67/M57-KLH showed very little toxicity with no 
grade III or IV adverse events and no serious adverse events attributable to the study 
drug.
2. There is no scientific rationale to posit additive or synergistic toxicity between the two 
drugs, given that one is an alkylating agent and the other is a vaccine.
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3. In three separate trials (ACTIVATE(38), ACT II(39) and ACT III(37)), rindopepimut (an 
immunotherapy for the treatment of EGFRvIII-expressing GBM) given in combination 
with temozolomide showed no serious toxicity with only minor injection site reactions, 
similar to SVN53-67/M57-KLH.
4. In addition to evaluation of immune responses and PFS, the current phase II design 
includes rigorous evaluation of toxicity of each drug with CTCAEv4.0 (see Sections 
6.2.1 and 6.2.2).
13
CORRELATIVE DATA ANALYSIS
13.1 Immunological Assessments and HLA Typing
Immunologic response to vaccine will be used as a secondary measure of vaccine activity. 
Survivin-specific CD8+ responses, CD4+ helper support, and anti-survivin antibody (humoral) 
responses will be measured individually by the Immunotherapy Core Facility and Neuro-
oncology Laboratory at Roswell Park Cancer Institute. PBMC and serum will be collected 
according to the schedule in Table 3. Samples from Network sites will be sent to the 
Immunotherapy Core Facility at Roswell Park Cancer Institute for processing and analysis. To 
assess immunologic responses to SVN53-67/M57-KLH (SurVaxM), PBMC will be analyzed 
using multimer, IFNγ ELISPOT and qPCR assays of cytokine expression in CD4+ and CD8+ 
cells. Antibodies to survivin peptides and KLH in serum will also be measured by ELISA to 
assess humoral immune responses. Each of these assay methods has unique advantages and 
currently, there is no uniform consensus as to which of them is the most critical indicator of an 
immunologic response to peptide vaccines. Flow cytometric analysis with multimers provides a 
relatively accurate estimation of the frequency of specific antigen-binding T cells, without 
requiring major in vitro manipulation of the patient’s leukocytes. Multimer analysis can also be 
accomplished using a small blood sample. Therefore, multimer analysis will be used as the 
primary determinant of immunological response/endpoint. Positive reactivity is defined as 
survivin-specific CD8+ T cell levels 1% greater than registration baseline. 
ELISPOT assays and qPCR analysis of cytokine expression indicate the functional status of the 
antigen-specific T cells and are important for assessing Type-1 T cell responses, but they require 
isolation of CD4+ and CD8+ populations by flow cytometry, and hence a larger blood sample 
than multimer assays. Therefore, IFNγ ELISPOT, qPCR and antibody assays will be used as 
secondary determinants of the immunological response/endpoint.
Immunological analyses will be conducted on blood samples obtained prior to vaccination and at 
all study follow-up visits. On each occasion, approximately 50 mL of blood will be obtained 
from a peripheral venipuncture and collected in six green top (heparinized) tubes and one 3.5 mL 
gold top tube. Blood tubes will be stored at room temperature until pickup for processing.
Simple HLA-A class I typing on blood samples will be performed at each study site as a part of 
screening to determine eligibility. Following entry, detailed HLA typing (MHC class I and MHC 
class II) will be performed in an exploratory fashion as part of the analysis of immunologic 
response to vaccination.
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13.2 Survivin Expression Status
Over 85% of glioblastomas have survivin protein expression that is detectable by 
immunohistochemistry. All patients will have unstained slides or tissue blocks submitted to the 
central pathology core (Roswell Park Cancer Institute) for survivin testing to determine 
eligibility.
14 ETHICAL AND REGULATORY STANDARDS
14.1 Ethical Principles
This study will not be initiated until the protocol and informed consent document(s) have been 
reviewed and approved by a properly constituted Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC). Each participant (or legal guardian) shall read, understand, 
and sign an instrument of informed consent prior to performance of any study-specific 
procedure. It is the responsibility of the investigator to ensure that the participant is made aware 
of the investigational nature of the treatment and that informed consent is given.
The Investigator is responsible for the retention of the participant log and participant records; 
although personal information may be reviewed by authorized persons, that information will be 
treated as strictly confidential and will not be made publicly available. The investigator is also 
responsible for obtaining participant authorization to access medical records and other applicable 
study specific information according to Health Insurance Portability and Accountability Act 
regulations (where applicable).
This study will be conducted in compliance with all applicable laws and regulations of the state 
and/or country and institution where the participant is treated, in accordance with the Declaration 
of Helsinki, Good Clinical Practice, and according to the guidelines in this protocol, including 
attached appendices.
14.2 Informed Consent
The Investigator (or IRB specified designee) is responsible for obtaining written consent from 
each participant or the participant's legally authorized representative in accordance with ICH-
GCP guidelines using the approved informed consent form, before any study specific procedures 
(including screening procedures) are performed. The informed consent form acknowledges all 
information that must be given to the participant according to ICH-GCP, including the purpose 
and nature of the study, the expected efficacy and possible side effects of the treatment(s), and 
specifying that refusal to participate will not influence further options for therapy. Any additional 
information that is applicable to the study must also be included. Additional national or 
institutionally mandated requirements for informed consent must also be adhered to. The 
participant should also be made aware that by signing the consent form, processing of sensitive 
clinical trial data and transfer to other countries for further processing is allowed.
The Investigator (or designee) shall provide a copy of the signed consent form to the participant 
and the signed original shall be maintained in the Investigator File. A copy of the signed consent 
form must be filed in the participant file. At any stage, the participant may withdraw from the 
study and such a decision will not affect any further treatment options.
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15 STUDY RESPONSIBILITIES
15.1 Data Collection
Data entry into the database is to be completed in a timely fashion (within 30 days) after the 
participant’s clinic visit. If an AE is considered serious it is captured on both the Adverse Event 
page and the Serious Adverse Event Source Form, which is handled in an expedited fashion.
Data management activities will be performed using eClinical. eClinical is a suite of software 
tools that enables the collection, cleaning and viewing of clinical trial data. CRS data 
management will design the study-specific database and facilitate its development by the 
eClinical Information Technology team. Once the database design is approved by the 
Investigator, Statistician, and Clinical Research Coordinator, the database will be put into 
production and data entry can begin. Data can be entered and changed only by those with the 
rights to do so into the eCRFs (via the EXPeRT Module). eClinical is compliant with all relevant 
technical aspects of relevant GCP guidelines.
•
The system can generate accurate copies of stored data and audit trail information in 
human readable form.
•
System access is limited to authorized individuals through the controlled assignment of 
unique ID and password combinations.
•
The system is designed to periodically force users to change their passwords and verifies 
that user ID and password combinations remain unique.
•
The system automatically generates a permanent time-stamped audit trail of all user 
interactions.
When data entry is complete, data management will review the data and will query any missing, 
incomplete, or invalid data points for resolution by the Clinical Research Coordinator and 
Investigator. Once all queries have been resolved, the data can be released to the statistician for 
analysis.
15.2 Maintenance of Study Documents
Essential documents will be retained per RPCI’s policy for 6 years from the study termination 
date. These documents could be retained for a longer period, however, if required by the 
applicable local regulatory requirements or by an agreement with RPCI.
16 ADMINISTRATIVE RULES
16.1 Revisions to the Protocol
RPCI may make such changes to the protocol as it deems necessary for safety reasons or as may 
be required by the U.S. FDA or other regulatory agencies. Revisions will be submitted to the 
IRB/ERC for written approval before implementation.
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16.2 Termination of the Study
It is agreed that, for reasonable cause, either the RPCI Investigators or the Sponsor, may 
terminate this study, provided a written notice is submitted within the time period provided for in 
the Clinical Trial Agreement. In addition, RPCI may terminate the study at any time upon 
immediate notice if it believes termination is necessary for the safety of participants enrolled in 
the study.
16.3 Confidentiality
Any data, specimens, forms, reports, video recordings, and other records that leave the site will 
be identified only by a participant identification number (Participant ID, PID) to maintain 
confidentiality. All records will be kept in a limited access environment. All computer entry and 
networking programs will be done using PIDs only. Information will not be released without 
written authorization of the participant.
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17 APPENDICES
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Appendix A
Instructions for Network Sites
1.
CONTACT INFORMATION
All questions related to the protocol or study implementation should be directed to:
Roswell Park Cancer Institute
CRS Network Office
ASB K 104
Buffalo, New York 14263
Telephone:
Monday - Friday; 7: 00 AM to 4: 00 PM EST
716-845-3870
After hours, weekends, and holidays request the RPCI Investigator
716-845-2300
Fax: 716-845-8743
2.
INFORMED CONSENT
•
Informed consent must be obtained by the site Investigator/designee from any 
participants wishing to participate, prior to any procedures or treatment.
•
An informed consent template is provided by RPCI and can be amended to reflect 
institutional requirements.
•
All consent changes must be reviewed by RPCI Network Office prior to submission to 
the site IRB.
•
The informed consent must be IRB approved.
•
Always check that the most up to date version of the IRB approved consent is being used.
•
Within 5 business days, notify the RPCI Network Office of all participant withdrawals or 
consent to limited study participation and appropriately document the discontinuation and 
the reason(s) why.
3.
PARTICIPANT REGISTRATION
The participant completes the Gender, Race, and Ethnicity Form and this is placed in the study 
binder.
RPCI does not grant exceptions to eligibility criteria.
Phase 2 Protocol Registration Instructions
The Subject Screening and Enrollment Log must be faxed or emailed to the RPCI Network 
Office within 1 business day of the date the participant is consented. Once the Investigator has 
determined that eligibility has been met, complete the eligibility check list and fax or email it to 
the RPCI Network Monitor at 716-845-8743.
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4.
STUDY DEVIATIONS
•
If a deviation has occurred to eliminate hazard, this must be reported to the RPCI 
Network, site IRB and any other regulatory authority involved in the study.
•
All study deviation will be recorded on the Study Deviation Log.
•
Participants inadvertently enrolled with significant deviation(s) from the study-specified 
criteria will be removed from the study, at the discretion of the Principle Investigator.
•
Notify the RPCI Network Office of any early participant withdrawal and appropriately 
document the discontinuation and the reason why, within 5 business days.
5.
STUDY DOCUMENTATION
•
Study documents must be filled out completely and correctly. Ditto marks are not 
allowed.
•
If an entry has been documented in error put a single line through the entry and initial and 
date the change. The RPCI Network Monitor must be able to read what has been deleted.
•
Do NOT use white-out, magic marker, scratch-outs.
•
Do NOT erase entries.
•
Use only black ink for documentation on the accountability form and any other study 
forms.
•
It is the responsibility of RPCI to inform the Investigator/ institution as to when these 
documents no longer need to be retained. If, for any reason, the Investigator desires to no 
longer maintain the study records, they may be transferred to another institution, another 
investigator, or to RPCI upon written agreement between the Investigator and RPCI.
6.
DRUG ACCOUNTABILITY
Drug accountability must be strictly maintained.
•
Responsibility rests solely with the Investigator but can be delegated as appropriate 
(e.g., to pharmacy personnel).
•
A drug accountability record form (DARF) will record quantities of study drug received, 
dispensed to participants and wasted, lot number, date dispensed, participant ID number 
and initials, quantity returned, balance remaining, manufacturer, expiration date, and the 
initials of the person dispensing the medication.
•
Study drug supply will only be used in accordance with the IRB approved study.
•
Drug accountability forms are protocol and agent specific, they are study source 
documents and will be used to verify compliance with the study.
•
An inventory count must be performed with each transaction. Any discrepancies shall be 
documented and explained.
•
Drug accountability forms must be stored with study related documents.
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•
Each medication provided for this study and each dosage form and strength must have its 
own DARF.
•
Dispensing the wrong study supply is considered a medication error.
•
NEVER replace investigational agents with commercial product.
•
Do NOT “transfer”, “borrow” or “replace” supplies between studies.
7.
SERIOUS ADVERSE EVENT REPORTING
The site Investigator or designated research personnel will report all SAEs, whether related or 
unrelated to the investigational agent(s) to the IRB in accordance with their local institutional 
guidelines. The site will notify the RPCI Network Monitor within 1 business day of being made 
aware of the SAE. A preliminary written report must follow within 1 business day of the first 
notification using the following forms:
•
RPCI SAE Source form
•
MedWatch 3500A
A complete follow-up report must be sent to the RPCI Network Monitor when new information 
becomes available.
8.
UNANTICIPATED PROBLEM REPORTING
An unanticipated problem (UP) is any incident, experience, or outcome that meets all of the 
criteria in Section 10.4.
For all adverse events occurring that are unanticipated and related or possibly related to the 
research drug, biologic or intervention, the participating physician or delegated research staff 
from each site will notify their local IRB in accordance with their local institutional 
guidelines. The site must also notify the RPCI Network Monitor within 1 business day of being 
made aware of the Unanticipated Problem by completing the RPCI Unanticipated Problem 
Report Form and faxing or emailing it to the RPCI Network Monitor.
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Appendix B
Karnofsky and ECOG Performance Status Scales
Status
Karnofsky
Grade
ECOG
Normal, no complaints
100
0
Fully active, able to carry 
on all pre-disease 
performance without 
restriction.
Able to carry on normal 
activities. Minor signs or 
symptoms of disease
90
Normal activity with effort
80
1
Restricted in physically 
strenuous activity but 
ambulatory and able to 
carry out work of a light or 
sedentary nature, e.g., light 
housework, office work.
Care for self. Unable to 
carry on normal activity or 
to do active work
70
Requires occasional 
assistance, but able to care 
for most of his needs
60
2
Ambulatory and capable 
of all self-care but unable 
to carry out any work 
activities. Up and about 
more than 50% of waking 
hours.
Requires considerable 
assistance and frequent 
medical care
50
Disabled. Requires special 
care and assistance
40
3
Ambulatory and capable 
of all self-care but unable 
to carry out any work 
activities.
Up and about more than 
50% of waking hours
Severely disabled. 
Hospitalization indicated 
though death non-
imminent
30
Very sick. Hospitalization 
necessary. Active 
supportive treatment 
necessary
20
Moribund
10
4
Completely disabled. 
Cannot carry on any self-
care. Totally confined to 
bed or chair.
Dead
0
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Appendix C
Response Assessment in Neuro-Oncology (RANO)
Response
T1 Contrast Enhancement (CE)
FLAIR Images
Steroids
Neurologic 
Exam
Complete 
Response
(CR)
No residual CE (complete 
disappearance of all enhancing 
measurable disease for at least 4 
weeks; confirmatory MRI at 4 
weeks is required to score as CR) 
and no new lesions.
Stable or reduced area of 
FLAIR signal 
abnormality 
No steroids 
Stable or 
improved 
from prior 
evaluation 
Partial 
Response
(PR)
>50% reduction in sum of 
products of the perpendicular 
diameters of all measureable 
enhancing lesions sustained for at 
least 4 weeks and no new lesions 
or progression of non-measurable 
lesions.
Stable or reduced area of 
FLAIR signal 
abnormality 
Stable or 
reduced 
glucocorticoids 
from baseline 
MRI 
Stable or 
improved 
from prior 
evaluation
Minor response 
(MR)
>25% reduction in sum of 
products of the perpendicular 
diameters of all measureable 
enhancing lesions and no new 
lesions (confirmatory MRI at 4 
weeks is required to score as PR).
Stable or reduced area of 
FLAIR signal 
abnormality 
Stable or 
reduced 
glucocorticoids 
from baseline 
MRI 
Stable or 
improved 
from prior 
evaluation 
Stable Disease 
(SD)
<25% reduction in area of CE 
maintained for at least 4 weeks 
duration.  Does not qualify for CR, 
PR or progression.
Stable or reduced area of 
FLAIR signal 
abnormality 
Stable or 
reduced 
glucocorticoids 
from baseline 
MRI 
Stable or 
improved 
from prior 
evaluation
Progressive
Disease
>25% in the sum of products of 
the perpendicular diameters of CE 
lesions; evidence of new lesion(s).
Measurable increase in 
the sum of products of 
the perpendicular 
diameters of FLAIR 
signal abnormality from 
the baseline scan or the 
scan representing the best 
response (if there was a 
response) following 
therapy and not 
attributable to other co-
morbid events (seizure, 
radiation, injury, 
infection, ischemia, etc.) 
OR presence of a new 
focus of FLAIR signal 
abnormality that cannot 
be explained by any other 
pathologic process. 
Stable or 
increased dose 
of 
glucocorticoids
Stable or 
worsening 
neurologic 
symptoms 
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Appendix D
Preparation of Peptide Vaccine Emulsion
1. Required Materials
-
1 vial containing MONTANIDE ISA 51 VG sterile
-
1 vial containing SVN53-67/M57-KLH sterile
-
3 x 2ml NORM-JECT (latex/silicone-free) Luer lock syringes (Air-Tite Products 
4020.00V0)
-
1 double sided female I-connector (Smiths Medical MX494 or equivalent)
2. Peptide Reconstitution (Aqueous phase)
Each vial of SVN53-67/M57-KLH contains 1.0 milligrams of the lyophilized peptide conjugate 
test agent. Immediately prior to use for vaccine production, lyophilized SVN53-67/M57-KLH is 
reconstituted by injecting 1.0 ml sterile bacteriostatic saline into the vial. Next, the vial is 
allowed to stand at room temperature for 5 minutes (step 1), followed by vortexing for 20 
seconds (step 2). Steps 1 and 2 may be repeated up to twice if necessary. The reconstituted 
peptide solution is to be used within 2 hours for emulsion preparation.  
3. Vaccine Preparation
Steps required to prepare 1.6 mL of vaccine emulsion in a 50/50 ratio (volume/volume) with 
Montanide ISA 51 VG:
Step 1: Loading Products
1.1. 
Using a sterile 2 ml NORM-JECT® Luer lock syringe equipped with a 20g sterile needle, 
withdraw 0.8 ml of saline-reconstituted SVN53-67/M57-KLH from the vial.
1.2. 
Discard the needle and remove the stopper from a female two-sided I-connector and 
connect the syringe to one end of the I-connector. 
1.3.
Remove all air from the system using light pressure on the syringe. 
1.4.
Place connected syringe and I-connector in sterile area. 
1.5.
Using another sterile 2 ml NORM-JECT® Luer lock syringe equipped with a 20g needle, 
withdraw 0.8 ml of Montanide ISA 51 VG from a single dose vial.
1.6.
Discard the needle and remove air with light pressure on the syringe
1.7. 
Remove the stopper from the other end of the two-sided female I-connector and connect 
the syringe containing the Montanide to that end. Make sure that both connections are secure and 
leak-free.
1.8.
An emulsion is created using a double-syringe technique via the interposed I-connector. 
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Step 2: Emulsification
2.1. The emulsification process is accomplished in 2 stages, including: A pre-emulsification 
stage, performed at low speed; and an emulsification stage, performed at high speed.
2.2. Hold the syringe-connector-syringe system firmly to maintain a secure connection. Each 
thumb will be used alternately to push the opposing plungers apart. To avoid leakage, never push 
with both thumbs simultaneously. Push on the plunger of one of the syringes in order to begin 
the mixing of both phases within a single syringe. 
2.3. Begin emulsification by transferring the entire volume from one syringe to the other slowly 
and repetitively. One cycle corresponds to passage of the entire contents of one syringe to the 
other syringe and back again. Perform the first 20 cycles at a slow rate (i.e. about 2 seconds to 
transfer the pre-mix from one side to the other or about 4 seconds for each complete cycle). This 
"pre-emulsion" stage will take about 80-90 seconds
2.4. At the end of the first stage (20 cycles), the speed of mixing is increased. The following 40 
cycles are made at high speed, or as fast as possible. When the emulsion starts to form, resistance 
can be felt when applying pressure to the syringe plunger. At this point, the mixture will take on 
a creamy appearance and will become viscous. A timer set to 40 seconds can be used to avoid 
losing count. The total process (pre-emulsion and emulsion) will take 60 cycles. The total 
process should take about 2.5 minutes.
Step 3: Testing of Emulsion
3.1  Place one droplet of the peptide emulsion into a beaker of distilled water. The droplet  
should retain its shape on the surface of the water. If it does not, vaccine preparation should be 
repeated from the beginning.
Step 4: Packaging
4.1. Transfer 1.0 ml of the emulsion into one of the two NORM-JECT syringes. 
4.2. Disconnect this syringe from the mixing assembly and connect it to a sterile 23g needle.
4.3. Follow the procedure for patient vaccination using this syringe and needle. 
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*The Seppic emulsification insert is provided below for cross-reference.
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Appendix E
Isolation of Peripheral Blood Mononuclear Cells for Immuno-Monitoring
1. PURPOSE:
1.1. To describe the general procedure for isolating and freezing PBMC/BM-MNC and 
serum from whole blood.
2. PRINCIPLE:
N/A
3. RESPONSIBILITY:
3.1. Persons who process whole blood for the purpose of isolating PBMC/BM-MNC and or 
serum.
3.2. The laboratory supervisor will oversee the process and ensure that this procedure is 
followed and properly documented.
4. SCOPE:
4.1. This protocol is currently used when processing whole blood.
5. DEFINITIONS: 
5.1. DMSO: Dymethyl Sulphoxide
5.2. FBS: Fetal Bovine Serum
5.3. HBSS: Hank’s Balanced Salt Solution
5.4. LSM: Lymphocyte Separation Medium
5.5. PBMC: Peripheral Blood Mononuclear Cells
5.6. PBS: Phosphate Buffered Saline
5.7. RBC: Red Blood Cells
5.8. RPM: Revolutions Per Minute
5.9. RT: Room Temperature
6. ATTACHMENTS:
6.1. PBMC/serum Worksheet
6.2. Freeze down medium Worksheet
7. REFERENCED DOCUMENTS:
N/A
8. MATERIALS/EQUIPMENT:
8.1. Materials
8.1.1. 5mL, 10mL, 25mL serological pipettes (Corning or equivalent)
8.1.2. Pipet-Aid (Drummond, Cat#:4-000-220 or equivalent)
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8.1.3. 125mL sterile bottle (Corning, Cat#:8388)
8.1.4. 50mL centrifuge tubes (Crystalgen, Cat#:23-2262 or equivalent) 
8.1.5. 15mL centrifuge tubes (Crystalgen, Cat#:23-2265 or equivalent)
8.1.6. 1.7mL microcentrifuge tubes (Crystalgen, 23-2052 or equivalent) 
8.1.7. 2.0mL cryovials (Simport, Cat#:T311-2 or equivalent)
8.1.8. 1000μL, 200μL, 20μL pipetman (Rainin or equivalent)
8.1.9. 1000μL, 200μL, 20μL tips for pipetman (Rainin or equivalent)
8.1.10. Cell counting slide (Bio-Rad, Cat#:145-0011)
8.1.11. Biohazard waste bags and boxes
8.1.12. Sharps container for glass tube waste
8.1.13. Nalgen cryo freezing container (Cat#:7-5100-0001)
8.2. Reagents & Solutions
8.2.1. LSM (Mediatech, Cat#:25-072-CV or equivalent)
8.2.2. HBSS (Mediatech, Cat#:21-023-CV or equivalent)
8.2.3. RedZ (Safetec, Cat#:41103)
8.2.4. CTL wash solution (Cat#: CTLW010 )
8.2.5. 50mL of CTL Wash is diluted with 500mL of RPMI-1640 medium. Store diluted 
CTL Wash at 4 °C.
8.2.6. CTL freeze down medium (Cat#: CTLC-ABC)
8.2.7. RPMI-1640 cell culture medium (Mediatech, Cat#:10-040-CV or equivalent)
8.2.8. Trypan blue (Mediatech, Cat#:25-900-CI or equivalent)
8.2.9. PBS (Mediatech, Cat#:21-031-CV or equivalent)
8.2.10. Isopropanol (Avantor, Cat#:9084-05 or equivalent)
8.3. Instrumentation
8.3.1. Centrifuge (Beckman Allegra 25R centrifuge with TS5.1 rotor or equivalent)
8.3.2. Mini Centrifuge (Eppendorf Centrifuge 5147C or equivalent)
8.3.3. Biosafety cabinet 
8.3.4. Bio-Rad TC20 cell counter (Bio-Rad, Cat#:145-0102)
8.3.5. -80°C freezer (Sanyo, Model:MDF-U76VC or equivalent)
8.3.6. Liquid nitrogen freezer (Custom BioGenic Systems, Model:V1500-AB or 
equivalent)
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9. SPECIMEN REQUIREMENTS:
9.1. After receiving the specimen processing should begin as soon as possible. 
10. SAFETY PRECAUTIONS:
10.1.
Consider all specimens for handling potentially positive for infectious agents 
including HIV, HBV and the hepatitis C virus (HCV). Observe universal precautions; 
wear protective gloves and lab coat [PPE] during all steps of this method because of both 
infectious and chemical contamination hazards. Place all plastic and glassware 
contaminated with tissue in a plastic autoclave bag for disposal. Biosafety Level 2 
containment procedures as described in CDC/NIH publication #88-8395 are to be used 
by those handling human specimens. 
10.2.
See MSDS on each particular chemical in the lab MSDS Appendix. 
10.3.
Appropriate safety precautions should be utilized for volatile solvents like 
isopropanol, including fume hood, gloves, gown and laminar flow hood.
11. PROCEDURE:
11.1.
Receiving Blood Product
11.1.1. Record sample date and time received information on PBMC worksheet, attach 
label from sample to lower right corner of worksheet. Record protocol number and 
sample id number on worksheet.
11.1.2. If personnel have received a blood sample outside of recommended tolerances 
(e.g. low volume, blood contained in different tubes, unusual surface temperature of 
tubes), personnel will notify the IAF director.
All steps from this point must be performed in a biosafety cabinet and sterile techniques should 
be used when handling samples.
11.2.
Serum Isolation
11.2.1. Place serum tube (gold or red top) in allegra centrifuge with a balance and spin at 
600 x G for 10 minutes. 
11.2.2. After centrifugation use a p1000 pipettor to collect as many aliquots as possible of 
serum (the upper phase) into sterile 1.7 mL microfuge tubes.
11.2.3. Centrifuge the microfuge tubes using the Eppendorf tabletop centrifuge at 3000 
RPM for 3 minutes.
11.2.4. Transfer the supernatant into new 1.7 mL tubes to distribute aliquots 0.5 mL per 
tube.
11.2.5. Create a label and apply to worksheet. Place serum tubes in appropriate storage 
boxes in  -20 °C freezer. Record the time when the tubes were placed in the freezer 
on the worksheet.
11.2.6. Update the electronic serum log.
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11.3.
PBMC/BM-MNCs Isolation with Green Top Tubes
11.3.1. Add 18mL of LSM to each of (4) 50mL conical tubes.
11.3.2. Pool blood from all green top tubes into one 125mL bottle using 10mL size 
pipettes (note volume from each tube and record the total volume on the worksheet).
11.3.3. Make up the volume to 96mL with HBSS, swirl gently to mix, i.e.: the volume of 
blood obtained was 46mL; 96-46= 50mL, therefore 50 mL of HBSS should be 
added to the bottle.
11.3.4. Using a 25mL pipette, layer 24mL of the blood/HBSS diluent to each of the (4) 
50mL tubes with LSM. This is done by tilting the tube and placing the tip of the 
pipette on the top of the LSM. Then slowly layer the sample on top to avoid mixing 
of the sample with the LSM (Figure 1 left).
11.3.5. Place tubes in Beckman Allegra centrifuge and spin at 400 x G for 30 minutes, 
BE SURE TO TURN OFF THE BRAKE on the centrifuge.
11.3.6. While the samples are spinning prepare new 50mL tubes for wash steps. 
11.3.6.1.
Place (4) 50mL centrifuge tubes in a rack and add 5mL of HBSS to each, 
set aside until ready to use after spin.
11.3.7. Obtain CTL/RPMI wash solution and the appropriate freeze down medium from 
the refrigerator.
11.3.7.1.
If necessary, prepare freeze down medium that will be used. 
11.3.7.1.1.
Prepare CTL-ABC freeze down medium by thawing tube B and 
combine 1000μL of tube B into tube A, this is done by pipetting 100μL at 
a time into tube A and swirling to mix. Note following protocols require 
CTL-ABC freeze down media:
11.3.8. Record all reagent lot numbers, expiration dates and the date when the reagent 
was opened on the worksheet.  
11.3.9. After centrifugation the sample is fractioned as shown in Figure1 below. (PBMC 
can be seen as cloudy and white) 
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Before centrifugation
After centrifugation
Blood/HBSS diluent
LSM
Figure 1. Before and after centrifugation
1.1.1. Using a 10mL pipette, harvest the lymphocyte layer (PBMC/BM-MNC) to ensure 
maximum recovery draw up as much of the lymphocyte layer as possible (Up to half 
of the LSM can be collected to ensure maximum recovery). Transfer layer to 
previously set up centrifuge tubes containing 5 mL of HBSS. 
1.1.2. Bring up the volume of the lymphocyte/HBSS mixture to 30mL with HBSS. 
Gently invert the tubes 5-10 times to mix then centrifuge at 600 x G for 10 minutes 
to pellet the cells. 
1.1.3. Discard supernatant in waste container and resuspend the pellet in 25mL of 
HBSS. Centrifuge the tubes at 500 x G for 5 minutes. 
1.1.4. Discard supernatant and resuspend cells in 5mL of CTL/RPMI wash solution. 
Then pool the volumes from all 4 tubes into 1 tube for a final volume of 20mL.
1.2.  Preparing PBMCs for counting and cryopreservation 
1.2.1. Combine 20μL of the cell suspension with 20μL of 0.4% Trypan Blue, and 
perform a cell count using the Bio-Rad TC20 cell counter. 
1.2.2. Centrifuge the pooled sample at 500 x G for 5 minutes.
1.2.3. Once the yield has been calculated, determine the number of tubes to freeze down 
based on the following criteria:
1.2.3.1.
Freeze down around 10 million cells/vial, regardless of how low the yield. 
1.2.3.2.
Vial number ≤ 5: < 10 million cells/vial
1.2.3.3.
Vial number > 5: > 10 million cells/vial
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1.2.4. Prepare cryovials with labels using LIMS that include the sample id, the protocol 
number, the sample type, the date, and the cell number, attach one label on the 
worksheet as a record. 
1.2.5. After the final spin, discard the supernatant and resuspend the cells in the 
appropriate freeze down medium. 
1.2.5.1.
If using CTL freeze down medium, resuspend PBMC/BM-MNC in “C” 
media at a concentration of 20 million cells/mL. Slowly over a 2 minute time 
period add an equal volume of CTL “AB” media to the cells. 
1.2.5.2.
If using 10%DMSO/90%FBS then pipette the appropriate volume of 
medium to the cells.
1.2.6. Aliquot 1.0 mL of the suspension into pre-labeled cryovials.  
1.2.7. Place cells in Mr. Frosty cross off the number of uses on the container and place 
in  -20 °C freezer. Record the time the cells were placed in the -60 to -80 °C on the 
worksheet.  Discard 5th use of isopropanol down the sink followed by water. 
Replace isopropanol in Mr. Frosty for next use.
The next working day transfer PBMC to the liquid nitrogen storage tank and update electronic 
files and LIMS for serum and PBMC inventory as well as record the locations of the tubes in the 
tank on the worksheet.
2. Endpoints
2.1. When only 1-2 vials were obtained from 5-6 green top tubes, personnel will notify the 
IAF director. 
2.2. The director or personnel will contact the PI and the CRS to determine if a redraw is 
required. 
3. Endpoints Corrective Actions:
N/A
4. Data Management:
4.1. The Director will review the worksheet to ensure that the processing is appropriate. Any 
deviations should be noted on the worksheet.
After review of the worksheet, the PBMC and serum electronic log of each protocol will be 
updated.
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Appendix F. MMSE – Mini-Mental State Examination
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