Conditions: Brain Cancer Brain Neoplasm, Primary Brain Neoplasms, Recurrent Brain Tumor Cancer of the Brain
Keywords: Immunotherapy Adult
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 24
Healthy volunteers: no

Brief summary:
Potential subjects with progressive Grade II primary brain tumor that have IDH1 positive testing from the primary tumor (initial diagnosis) will be offered this treatment study in order to test the safety of the PEPIDH1M vaccine in combination with standard chemotherapy (temozolomide).

Detailed description:
After informed consent has been signed, subjects will undergo standard of care vaccination with 0.5 mL of Td (tetanus and diphtheria toxoids adsorbed) intramuscularly into the deltoid muscle to ensure adequate immunity to the tetanus antigen.

Eligible subjects will undergo a 1-2 hour leukapheresis (to pull off white blood cells) for immune monitoring. Within 48 hours of leukapheresis, subjects will receive vaccine site pre-conditioning as a single dose of Td toxoid (in a total volume of 0.4 mLs salt water/saline) given in the intradermal space (just under the surface of the skin) to the right groin area. The pre-conditioning will be administered one day prior to receiving PEPIDH1M vaccine. The peptide vaccine is administered in the upper thigh area approximately 4 inches below the groin in the intradermal space as vaccine # 1. Subsequent vaccines will be given on day 15 ±3 days (vaccine #2) and day 29 ±3 days (vaccine #3). Each injection of the peptide vaccine will be given half on the right groin and half on the left groin. The first 3 peptide vaccine injections will occur without temozolomide (standard of care chemotherapy).

Seven to twelve days after the 3rd vaccine, subjects will have standard of care surgery to remove the tumor. Tumor samples will be evaluated for the IDH1 markers and analyzed for other cells that may have entered the tumor.

Based on the the tissue obtained at surgery, subjects with stable histologic grade at recurrence will then be treated with vaccine and temozolomide. During monthly cycles of temozolomide, subjects will receive the vaccine on day 22 (+ 2 days) for a maximum of 15 total vaccines (which includes the first 3 bi-weekly vaccines). Patients that have transitioned to a higher grade brain tumor at the time of surgery will receive temozolomide and radiation therapy per standard of care and monthly vaccines (vaccines #4-6). After completion of radiation therapy, subjects in this treatment group will receive vaccines monthly on day 22 (+2 days) with post-RT cycles of TMZ to a maximum of 15 vaccines.

All Adverse Events will be collected from time of consent until off study. The treatment phase of the study will end 1 month after the last vaccine. Patients will be followed only for overall survival, progression-free survival, and subsequent therapies thereafter.

Subjects will have blood collected for immune monitoring and biomarker testing during the following times: prior to initiating vaccine therapy (at the leukapheresis visit), prior to surgery to remove the tumor, at the clinic visit prior to starting first cycle of temozolomide after surgery (or radiation therapy and temozolomide for those who transition to higher grade), at vaccine #6, and at end of vaccine treatment (1 month after vaccine #15 or time the subject comes off study, whichever comes first).

Subjects will be imaged with contrast-enhanced magnetic resonance imaging (MRI) according to standard of care every 10 weeks (+/- 4 weeks) while on temozolomide and afterward, per the treating neuro-oncologist's recommendation. Revised Assessment in Neuro-Oncology (RANO) criteria will be used for assessment of pseudoprogression and tumor progression. Subjects demonstrating definitive progression will be removed from study.

As part of standard care for these subjects, upon tumor progression, participants may undergo biopsy or resection. As this is not a research procedure, consent will be obtained separately. Subjects that have this procedure done within the Duke University Health System will be asked to have a portion of the tumor sample, if possible, to assess immunologic cell infiltration, antigen expression, and biomarkers for immunologic response.

Please note, data collection will continue to occur outside of the defined primary and secondary outcomes for exploratory objectives.

The specific exploratory objective involves describing the progression free survival (PFS) and overall survival (OS). The endpoint is the proportion of patients alive without disease progression 6 months after initial vaccine treatment, and both the median PFS, and the median OS.

The objective will be reviewed at 3 years after the last subject came off study.

Arms:
arm 1: PEPIDH1M vaccine is made up of a peptide that spans the mutated region of IDH1R132H (Isocitrate Dehydrogenase 1). The peptide is administered with GM-CSF (Granulocyte Macrophage Colony Stimulating Factor) mixed with Montanide ISA 51.

Interventions: intervention 1: PEPIDH1M vaccine intervention 2: Tetanus-Diphtheria Toxoid (Td) intervention 3: Temozolomide
Intervention descriptions: intervention 1: PEPIDH1M vaccine is made up of 500 µg of 25 amino acid peptide administered with 150 µg of GM-CSF mixed 1:1 with Montanide ISA 51 administered intradermally. The peptide vaccine is administered in the groin area approximately 10 cm below the inguinal ligament. intervention 2: After consent has been signed, all subjects will undergo standard of care vaccination with 0.5 mL of Td (tetanus and diphtheria toxoids adsorbed) intramuscularly (I.M.) into the deltoid muscle to ensure adequate immunity to the tetanus antigen. Within 48 hours of leukapheresis, subjects will receive a vaccine site pre-conditioning as a single dose of Td toxoid (1 flocculation unit, Lf, in a total volume of 0.4 mLs saline) administered intradermally to the right side of the groin one day prior to receiving the first PEPIDH1M vaccine. intervention 3: Subjects are treated with temozolomide (TMZ) at a targeted dose of 50-100mg/m2/d for 21 days every 28 days for up to 12 cycles. Subjects that have transitioned to a higher grade brain tumor at time of surgery will receive TMZ and radiation therapy per standard of care before starting TMZ cycles.

Protocol document:
Prot_SAP_000.pdf: 
CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and 
regulations. Written authorization from the coordinating site and sponsor is required for disclosure otherwise. 
PT-PhI-II v05.22.12 
 
 
 
 
RESIST:  Patients with IDH1 Positive Recurrent 
Grade II Glioma Enrolled in a Safety and 
Immunogenicity Study of Tumor-Specific Peptide 
Vaccine 
 
Document Date: 2017-10-11 
 
NCT02193347 
 
 
 


PT-PhI-II v05.22.12 
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CONFIDENTIAL 
 
 
RESIST:  Patients with IDH1 Positive Recurrent 
Grade II Glioma Enrolled in a Safety and 
Immunogenicity Study of Tumor-Specific Peptide 
Vaccine 
 
 
Sponsor: 
PI – Duke Cancer Institute 
 
 
Funding 
Source: 
NIH Grant 
 
 
Protocol 
Source: 
PI - Duke Cancer Institute 
 
 
Duke IRB#: 
Pro00054746 
 
 
IND#: 
16647 
 
 
Principal Investigator 
Katherine Peters, MD, PhD 
katherine.peters@duke.edu 
 
Sub-Investigator(s) 
Gary Archer, Ph.D. 
gerald.archer@duke.edu 
 
Annick Desjardins, M.D. 
annick.desjardins@dm.duke.edu 
 
Henry Friedman, M.D. 
henry.friedman@duke.edu 
 
Darell Bigner, M.D. 
darell.bigner@duke.edu 
 
John Sampson, M.D., Ph.D. 
john.sampson@duke.edu 
 
Dina Randazzo, D.O. 
dina.randazzo@duke.edu 
 
Elizabeth Reap, Ph.D. 
elizabeth.reap@duke.edu 
 
Peter Fecci, M.D., Ph.D. 
peter.fecci@duke.edu 
 
Hai Yan, M.D., Ph.D. 
hai.yan@duke.edu 
 
Brian Soher, Ph.D. 
brian.soher@duke.edu 
 
 
Statistician 
James E. Herndon II, Ph.D. 
james.herndon@duke.edu 
 
Lead Study Coordinator 
Sarah Woodring 
sarah.woodring@duke.edu 
 
Regulatory Coordinator 
Rachel Hesler, Ph.D. 
rachel.hesler@duke.edu 
 
Therapeutic Material Manufacture 
Manager 
Gary Archer, Ph.D. 
gary.archer@duke.edu 
 
Data Manager 
Eric Lipp 
eric.lipp@duke.edu 
 
 
 
 
 
Original version: 
20140718 
 
Amended version 1: 
20150831 for IND Submission 
Updated information  in Figure 4 and in 
paragraph describing Figure 4 and 
inserted reference (Section 7.2.4); Added 


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NCT# (Section 7.2.6); Inserted references 
(Section 9.2); Updated the study drug 
manufacturing company (Section 10.3); 
Corrected and updated reconstitution 
information of the study drug (Section 
10.4.2); Updated references (Section 17); 
removed Td manufacturer name 
(Sections 9 and 10). 
Amended version2: 
20151005 for FDA modifications 
20151216 for IRB AMD002 
Removed the saline injection to the 
contralateral leg (Section 10.4.1); 
Removed reference to femoral artery for 
administering vaccines (Sections 9.1 and 
10.4.2); Added CBC and CMP blood draw 
time point in the table of scheduled 
assessments for leukapheresis screening 
with ionized calcium and pregnancy 
testing per Apheresis practice in footnote 
(Section 12); Clarified “continues to do 
well” by defining criteria for vaccine 
therapy if pseudoprogressioin is 
suspected and clarified definition of 
progression vs pseudoprogression 
(Section 12.7.3); More clearly defined the 
definition of unacceptable toxicity 
(Sections 8, 9.1.1, & 15.4.1); Updated the 
definition of SAE to match 21CFR312.23 
(Section 13.2); Added the FDA for all 
adverse event reporting (Section 13.2.1); 
Corrected mis-numbering of inclusion 
criteria (Section 11.1); Added the 
exclusion of subjects unable to undergo 
MRI (Sections 11.2 & 12.8.2); Removed 
the word “transmural” from the 4th 
exclusion criterion (Section 11.2); 
Removed ACD description of red top 
tubes (Section 12); Added an additional 
clinic visit with blood work to assess for 
delayed toxicity 1 month following last 
vaccine (Section 12). 
Amended version 3 
20151216 for IRB AMD002 
Removed exploratory objective 
comparison to historical controls (Section 
8); Better described evaluable subjects 
(Sections 9.4 and 15.4.2); Updated 
location of paper documents (Section 0); 
Changed DLT to unacceptable toxicity 
(12.6.1);  Removed statistical estimate 
(Section 15.4.2) 
Amended version 4 
20160201 for IRB AMD004 
Added investigators Dr. Fecci & Dr. Yan 
to cover page. 
Typographical error corrected in Section 
11 for inclusion criterion on KPS score 
from 60 to 70%.   
Changed wording from “recurrent” to 
“progressive” (Sections 8, 9, 11, 12, and 
15). 
Removed the prior chemotherapy 
exclusion criterion (Section 11). 
Amended version 5 
20160517 for IRB AMD010 
Updated eligibility criterion on pregnancy 
testing to within 72 hours prior to 
leukapheresis (Section 11). 
Amended version 6 
20160519 for IRB AMD011 
Clarified difference between Td booster 
and pre-conditioning by adding route of 
administration as well as changed 
booster for ALL subjects (Sections 6, 9, 
10, & 12); Allowed subjects that transition 
to a higher grade glioma to continue on 
vaccines monthly during SOC XRT/TMZ 
(Sections 6, 8, 9, 12, and 15); Updated 
immune monitoring blood work and 


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biomarker testing and removed urine 
sampling (Sections 6, 8, 9 12, & 15); 
Added genomic analyses (Sections 8, 9,  
12, and 15); Added MRS for 2HG 
measurements (Sections 6, 8, 9, 12 & 
15); Changed wording from specifically 
study coordinator to study team (Section 
9); Included standard language for 
leukapheresis preparation (Section 12); 
Increased the dexamethasone from 2 mg 
to 4 mg max (Section 12); clarified KPS 
and physical exam to occur during 
standard BTC visit with the Td pre-
conditioning (Section 12); clarified tumor 
sampling for IHC analysis (Section 12); 
added language regarding antihistamine 
usage (Section 12); Included SOC 
language for XRT/TMZ and adjuvant TMZ 
in the appendices as a reference 
(Sections 18.4 & 18.5). 
Amended version 7 
20160808 for IRB AMD015 
Adjusted timing of immune monitoring 
and genomic proteomic analysis in those 
who’ve transformed to a higher grade 
(Sections 6, 9.4, and 12); Clarified the 
description of study procedure following 
consent (Section 9); Clarified pregnancy 
testing and MRIs in table of events as 
well as pathology testing (Section 12); 
Corrected error in timing of vaccine #1 
(Section 12); allowed for every 3 month 
MRI in low grade setting (Section 9 and 
12); Updated screening examination to 
match current practice and updated 
location of paper CRFs (Section 12); and 
Corrected error that vaccine #3 is actually 
given on day 29 not day 30 (Sections 6, 
9, and 12). 
Amended version 8 
20161128 for IRB AMD023 
Formatted for FDA electronic submission; 
Changed the lead study coordinator and 
regulatory coordinator; Reformatted Table 
2: Screening and On-Study Tests and 
Procedures (Section 12); Clarified that 
vaccine will be given on day 22 (+2), not 
day 21 (+/-2) of monthly cycles of TMZ 
because vaccine cannot be given on the 
same day as TMZ (Section 6, 
throughout); Clarified that Single-Voxel 
MR will be done before Td booster 
(Section 6, Section 9.5); Removed 
requirement that leukapheresis be 
performed within 2 weeks of consent 
(Section 9.1, Section 12); Corrected 
guidelines for dose delay, reduction, and 
discontinuation to fit 21-day TMZ, not 
standard 5-day TMZ (Section 18.5.2); 
Grade 3 subjects receiving RT/TMZ can 
delay TMZ more than a week without 
coming off study (Section 18.5.1); 
Corrected CTQA to the new name OARC 
(Section 4, Section 14.2); Immunization 
mixture will be given half in right groin 
and half in left groin for each vaccine 
(Section 9.1, Section 10.4.2, Table 2); 
Changed SOC abbreviation to standard 
of care, not Safety Oversight Committee 
(Section 13.3)  
Amended version 9 
20170106 for IRB AMD027 
Added additional MRS time points 
(Sections 6, 9.1, 9.5, 12); Corrected MRS 
data acquisition time from 30 minutes to 


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1-2 hours (Section 9.5); Baseline MRS is 
before PEPIDH1M vaccine #1 (Section 9.5) 
Amended version 10 
20170127 for IRB AMD030 
Removed recommendation that the 
needle be 25 gauge for injection of study 
vaccine because it is too narrow a bore 
for the vaccine (Section 10.4.2); Added 
that EMLA ® cream, or equivalent topical 
analgesic, can be offered to subjects who 
experience local pain at the injection site 
(Section 12.8.2); Corrected the number of 
patients to 24 in the Study Schema 
(Section 6); Testing of leukapheresis 
blood for HIV, hepatitis, and syphilis was 
re-moved (Section 12.8.2) 
Amended version 11 
20170215 for IRB AMD035 
Added immune monitoring time point at 
vaccine #6 (Sections 6, 9.1, and 12) 
Amended version 12 
20170223 for IRB AMD037 
Changed Principal Investigator (title page, 
Section 13.2.1) 
Amended version 13 
20171011 for IRB AMD054 
Primary objective wording changed from 
“proportion” to “percentage” (Sections 8 
and 15.4.1); Changed wording of the 
timing of the Td from “12-24 hours” before 
vaccine #1 to “one day” before (Sections 
6, 9.1, 10.4.1, and 12); Clarified 
documentation of review of aggregate 
summary of AE information (Section 
13.1.1); Added that providers will take 
pictures of the injection site at clinic visits 
at pre-op time point and at other time 
points at discretion of physician (Sections 
9 and 12); Added collection of research 
blood at end of vaccine treatment (1 
month after vaccine #15 or time the 
subject comes off study, whichever 
comes first) (Section 12): Changed total 
enrollment from 24 to 28, keeping the 
number of evaluable subjects that will 
receive at least 6 vaccines at 20 
(Sections 6 and 15.4.2) 


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1 TABLE OF CONTENTS 
1 
TABLE OF CONTENTS ................................................................................................................ 2 
2 
LIST OF FIGURES ........................................................................................................................ 5 
3 
LIST OF TABLES .......................................................................................................................... 5 
4 
LIST OF ABBREVIATIONS ........................................................................................................... 6 
5 
PROTOCOL SYNOPSIS AND SUMMARY .................................................................................. 9 
6 
STUDY SCHEMA ........................................................................................................................ 10 
7 
BACKGROUND AND SIGNIFICANCE ....................................................................................... 11 
7.1 
Study Disease ......................................................................................................................... 11 
7.2 
Study Agents ........................................................................................................................... 12 
7.2.1 
PEPIDH1M .......................................................................................................................... 12 
7.2.2 
GM-CSF .......................................................................................................................... 12 
7.2.3 
Montanide ISA 51 (Incomplete Freund’s Adjuvant) ........................................................ 12 
7.2.4 
Tetanus-diphtheria toxoid (Td) ........................................................................................ 12 
7.2.5 
Pre-clinical experience .................................................................................................... 14 
7.2.6 
Clinical experience .......................................................................................................... 16 
7.3 
Study Purpose and Rationale ................................................................................................. 17 
7.3.1 
Temozolomide, Lymphopenia, and Homeostatic Proliferation ....................................... 17 
7.3.2 
Peptide Vaccines for Cancer ........................................................................................... 19 
7.3.3 
Summary of Study Purpose/Rationale ............................................................................ 20 
8 
OBJECTIVES AND ENDPOINTS ............................................................................................... 21 
9 
INVESTIGATIONAL PLAN .......................................................................................................... 22 
9.1 
Study Design ........................................................................................................................... 22 
9.1.1 
Definition of Unacceptable Toxicity ................................................................................. 23 
9.1.2 
Concomitant Medications ................................................................................................ 23 
9.2 
Rationale for Selection of Dose, Regimen, and Treatment Duration ...................................... 23 
9.3 
Rationale for Correlative Studies ............................................................................................ 23 
9.4 
Rationale for Genomic Proteomic Analyses ........................................................................... 24 
9.5 
Single-Voxel MR Spectroscopy ............................................................................................... 24 
9.6 
Definition of Evaluable Subjects, On Study, and End of Study ............................................... 25 
9.7 
Early Study Termination .......................................................................................................... 25 
10 
STUDY DRUG............................................................................................................................. 26 
10.1 
Names, Classification, and Mechanism of Action ............................................................... 26 
10.2 
Packaging and Labeling ...................................................................................................... 26 
10.3 
Supply, Receipt, and Storage ............................................................................................. 26 
10.4 
Dispensing, Preparation and Administration ....................................................................... 26 
10.4.1 
Td ................................................................................................................................ 26 
10.4.2 
PEPIDH1M Vaccine with GM-CSF and Montanide ISA 51 ............................................ 26 


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10.5 
Compliance and Accountability ........................................................................................... 27 
10.6 
Disposal and Destruction .................................................................................................... 27 
11 
SUBJECT ELIGIBILITY ............................................................................................................... 27 
11.1 
Inclusion Criteria.................................................................................................................. 27 
11.2 
Exclusion Criteria ................................................................................................................ 28 
12 
SCREENING AND ON-STUDY TESTS AND PROCEDURES .................................................. 28 
12.1 
Screening ............................................................................................................................ 33 
12.2 
Treatment Period................................................................................................................. 33 
12.3 
End of Treatment................................................................................................................. 33 
12.4 
Follow-up Period ................................................................................................................. 33 
12.5 
End of Study ........................................................................................................................ 33 
12.6 
Early Withdrawal of Subject(s) ............................................................................................ 33 
12.6.1 
Criteria for Early Withdrawal ....................................................................................... 33 
12.6.2 
Follow-up Requirements for Early Withdrawal ............................................................ 34 
12.6.3 
Replacement of Early Withdrawal(s) ........................................................................... 34 
12.7 
Study Assessments ............................................................................................................. 34 
12.7.1 
Medical History ............................................................................................................ 34 
12.7.2 
Physical Exam ............................................................................................................. 34 
12.7.3 
Use of Antihistamines.................................................................................................. 34 
12.7.4 
Radiologic Evaluations ................................................................................................ 35 
12.8 
Risk/Benefit Assessment .................................................................................................... 35 
12.8.1 
Potential Benefits ........................................................................................................ 35 
12.8.2 
Potential Risks ............................................................................................................. 35 
13 
SAFETY MONITORING AND REPORTING ............................................................................... 37 
13.1 
Adverse Events ................................................................................................................... 37 
13.1.1 
Reporting of AEs ......................................................................................................... 38 
13.2 
Serious Adverse Events ...................................................................................................... 38 
13.2.1 
Reporting of SAEs ....................................................................................................... 38 
13.3 
Safety Oversight Committee ............................................................................................... 38 
14 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................................. 39 
14.1 
Monitoring ............................................................................................................................ 39 
14.2 
Audits .................................................................................................................................. 39 
14.3 
Data Management and Processing ..................................................................................... 39 
14.3.1 
Study Documentation .................................................................................................. 39 
14.3.2 
Data Management ....................................................................................................... 40 
14.3.3 
Data Management and Data Verification .................................................................... 40 
14.3.4 
Coding of Adverse Events ........................................................................................... 40 
14.3.5 
Study Closure .............................................................................................................. 40 
15 
STATISTICAL METHODS AND DATA ANALYSIS .................................................................... 41 


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15.1 
Analysis Sets ....................................................................................................................... 41 
15.2 
Patient Demographics and Other Baseline Characteristics ................................................ 41 
15.3 
Treatments .......................................................................................................................... 41 
15.4 
Primary Objective ................................................................................................................ 41 
15.4.1 
Variable ....................................................................................................................... 41 
15.4.2 
Statistical Hypothesis, Model, and Method of Analysis ............................................... 41 
15.4.3 
Handling of missing values, censoring, and discontinuations ..................................... 43 
15.5 
Secondary Objective ........................................................................................................... 43 
15.6 
Exploratory Objectives ........................................................................................................ 43 
15.7 
Interim Analysis ................................................................................................................... 44 
15.8 
Sample Size Calculation ..................................................................................................... 44 
16 
ADMINISTRATIVE AND ETHICAL CONSIDERATIONS ........................................................... 44 
16.1 
Regulatory and Ethical Compliance .................................................................................... 44 
16.2 
DUHS Institutional Review Board and DCI Cancer Protocol Committee ............................ 44 
16.3 
Informed Consent ................................................................................................................ 44 
16.4 
Privacy, Confidentiality, and Data Storage ......................................................................... 45 
16.5 
Data and Safety Monitoring ................................................................................................. 45 
16.6 
Protocol Amendments ......................................................................................................... 46 
16.7 
Records Retention............................................................................................................... 46 
16.8 
Conflict of Interest ............................................................................................................... 47 
16.9 
Costs to the Subject ............................................................................................................ 47 
16.10 
Registration Procedure ................................................................................................... 47 
17 
REFERENCES ............................................................................................................................ 48 
18 
APPENDICES ............................................................................................................................. 55 
18.1 
Protocol Synopsis and Summary ........................................................................................ 55 
18.2 
Special or Representative SOPs and FORMs .................................................................... 77 
18.3 
DSMBplus Monitoring Plan ................................................................................................. 78 
18.4 
Standard Radiation Therapy ............................................................................................... 79 
18.5 
Temozolomide Therapy ...................................................................................................... 80 
18.5.1 
Concurrent TMZ and RT ............................................................................................. 80 
18.5.2 
Guidelines for 21-day TMZ Therapy ........................................................................... 80 
 
 
 


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2 LIST OF FIGURES 
Figure 1. Study Schema .............................................................................................................................. 10 
Figure 2. Highly reactive transferred cells traffic to brain and destroy tumor deposit in melanoma patients.
 .............................................................................................................................................................. 11 
Figure 3. Host-derived antitumor T cells treat lesions in the brain.............................................................. 11 
Figure 4. Genetically engineered antitumor T cells treat lesions in the brain ............................................. 12 
Figure 5. Tetanus pre conditioning, imiquimod and GM-CSF increases the number of IDH1 mutant specific 
T cells after vaccination. ....................................................................................................................... 14 
Figure 6. The murine homologue of the IDH1R132H mutation is functional. ............................................. 15 
Figure 7. Human IDH1R132H protein sequence and human and mouse wild type sequences. ............... 15 
Figure 8. PEPIDH1M vaccination is immunogenic and specific in several mouse strains. ........................ 15 
Figure 9. PEPIDH1M vaccination is immunogenic and specific in the context of human HLA. ................. 16 
Figure 10. Splenocytes from mice immunized with different lengths of mutant IDH1 peptides. ................. 16 
Figure 11. Lymphocyte counts of patients with newly-diagnosed GBM receiving standard dose adjuvant 
TMZ (200 mg/m2/5d) and dose-intensified TMZ (100 mg/m2/21d). ...................................................... 17 
Figure 12. Antibody titers in patients during standard-dose TMZ (200 mg/m2/5d) and dose-intensified TMZ 
(100 mg/m2/21d). .................................................................................................................................. 18 
Figure 13. DTH responses to EGFRvIII vaccination. .................................................................................. 19 
 
3 LIST OF TABLES 
Table 1. Objectives and Endpoints ............................................................................................................. 21 
Table 2. Screening and On-Study Tests and Procedures .......................................................................... 31 
Table 3. Conditions under Which Accrual will be Suspended .................................................................... 42 
Table 4. Probability of Accrual Suspension as a Function of the True Unacceptable Toxicity Rate .......... 42 
Table 5: Temozolomide Dosing Interruption or Discontinuation during Concomitant Radiotherapy .......... 80 
Table 6. Dose Modifications of Temozolomide during Radiation Therapy ................................................. 80 
Table 7. Criteria to Resume Temozolomide after Radiation ....................................................................... 81 
Table 8. Temozolomide Dose Delay, Reduction, or Discontinuation During 21-day Treatment ................ 81 
 
 


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4 LIST OF ABBREVIATIONS 
2HG 
R-2-Hydroxyglutarate 
Ab 
Antibody 
ABC 
Automated Blood Count 
ACD 
Acid Citrate Dextrose 
ACLS 
Advanced Cardiac Life Support 
ACTH 
Adrenocorticotropic Hormone 
AE 
Adverse Event 
αKG 
Alpha-ketoglutarate 
AML 
Acute Myeloid Leukemia 
APAAP 
Alkaline Phosphatase Antialkaline Phosphatase Complex 
ALT 
Autologous Lymphocyte Transfer 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate Aminotransferase 
AT 
Ambient Temperature 
BBB 
Blood Brain Barrier 
β-HCG 
Beta-Human Chorionic Gonadotropin 
BMT 
Bone Marrow Transplant 
BTC 
Brain Tumor Center 
BUN 
Blood Urea Nitrogen 
Ca++ 
Calcium 
caBIG® 
Cancer Biomedical Informatics Grid 
CAMRD 
Center for Advanced MR Development 
CAR 
Chimeric Antigen Receptor 
CBC 
Complete Blood Count 
CCL3 
C-C motif Chemokine Ligand 3 
cDNA 
Complimentary Deoxyribonucleic Acid 
CFA 
Complete Freund’s Adjuvant 
CFC 
Cytokine Flow Cytometry 
CLIA 
Clinical Laboratory Improvement Act 
CMP 
Comprehensive Metabolic Panel 
CNC 
Clinical Neurologic Change 
CNS 
Central Nervous System 
CPC 
Cancer Protocol Committee 
CIMP 
CpG-Island Methylator Phenotype 
CRF 
Case Report Form 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTL 
Cytotoxic T-Lymphocyte 
DAR 
Drug Accountability Record 
DBTIP 
Duke Brain Tumor Immunotherapy Program 
DC 
Dendritic Cell 
DCCC 
Duke Comprehensive Cancer Center 
DCI 
Duke Cancer Institute 
DOB 
Date of Birth 
DSMB 
Data and Safety Monitoring Board 
DSMP 
Data and Safety Monitoring Plan 
DTH 
Delayed-type Hypersensitivity 
DUHS 
Duke University Health System 
EAE 
Experimental Autoimmune Encephalomyelitis 
EBRT 
External Beam Radiation Therapy 
eCRFs 
Electronic Case Report Forms 
ELISA 
Enzyme-Linked ImmunoSorbent Assay 


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ELISPOT 
Enzyme-linked Immunospot 
EGFR 
Epidermal Growth Factor Receptor 
EGFRvIII 
EGFR variant III 
FACS 
Fluorescence Activated Cell Sorting 
FDA 
Federal Drug Administration 
FEV 
Forced Expiratory Volume 
GBM 
Glioblastoma 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GM-CSF 
Granulocyte Macrophage Colony Stimulating Factor 
HIV 
Human Immunodeficiency Virus 
HLA 
Human Leukocyte Antigen 
HMG 
Hemoglobin 
HMO 
Health Maintenance Organization 
HPLC 
High Pressure Liquid Chromatography 
IBA 
Ion Beam Applications 
IC 
Intracerebral(ly) 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IDH1 
Isocitrate Dehydrogenase 1 
IEC 
Independent Ethics Committee 
IFA 
Incomplete Freund’s Adjuvant 
IFN-γ 
Interferon-gamma 
IHC 
Immunohistochemistry 
IL-4 
Interleukin-4 
IL-12 
Interleukin-12 
IL-13 
Interleukin-13 
IRB 
Institutional Review Board 
KLH 
Keyhole Limpet Hemocyanin 
KPS 
Karnofsky Performance Status 
LAL 
Limulus Amoebocyte Lysate 
LGG 
Low Grade Glioma 
MAb 
Monoclonal Antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
MG 
Malignant Glioma 
MHC 
Major Histocompatibility Complex 
MRI 
Magnetic Resonance Imaging 
MRN 
Medical Record Number 
mRNA 
Messenger Ribonucleic Acid 
MRS 
Magnetic Resonance Spectroscopy 
MTD 
Maximally Tolerated Dose 
NA 
Non-adherent 
NCI CTC 
National Cancer Institute Common Toxicity Criteria 
NIH 
National Institutes of Health 
NK 
Natural Killer 
OARC 
Office of Audit, Risk, and Compliance 
OS 
Overall Survival 
PBL 
Peripheral Blood Lymphocyte 
PBMC 
Peripheral Blood Mononuclear Cells 
PBS 
Phosphate-Buffered Saline 
PET 
Positron Emission Tomography 
PD 
Progressive Disease 
PHA 
Phytohemagglutinin 


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PFS 
Progression Free Survival 
PI 
Principle Investigator 
PRTBTC 
Preston Robert Tisch Brain Tumor Center 
PT 
Prothrombin Time 
PTT 
Partial Thromboblastin Time 
PTMs 
Post-Translational Modifications 
QC/QA 
Quality Control/Quality Assurance 
R-2HG 
R-2-hydroxyglutarate  
RANO 
Revised Assessment in Neuro-Oncology 
RDSPs 
Research Data Security Plans 
RECIST 
Response Evaluation Criteria in Solid Tumors 
reGBM 
Recurrent Glioblastoma 
reLGG 
Recurrent Low Grade Glioma 
RIO 
Research Integrity Office 
RNA 
Ribonucleic Acid 
RT 
Radiation Therapy 
RT-PCR 
Reverse Transcriptase Polymerase Chain Reaction 
SAE 
Severe Adverse Event 
scFV 
Single Chain Variable Antibody Fragment 
SFC 
Spot-Forming Cells 
SOC 
Standard of care 
SOP 
Standard Operating Procedure 
SPECT 
Single Photon Emission Computed Tomography 
TCA 
Trichloroacetic Acid 
TCR 
T cell Receptor 
Td 
Tetanus-diphtheria toxoid 
TGF-β 
Transforming Growth Factor-β 
TMZ 
Temozolomide 
TNF-α 
Tumor Necrosis Factor-α 
Tregs 
Regulatory T cells 
TTP 
Time to Progression 
TTRNA 
Total Tumor mRNA 
VDLNs 
Vaccine-site Draining Lymph Nodes 
WHO 
World Health Organization 
WOCBP 
Women Of Childbearing Potential 
XRT 
Radiation Therapy 
 
 


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5 PROTOCOL SYNOPSIS AND SUMMARY 
Please see separate document (available upon request). 
 


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6 STUDY SCHEMA 
 
 
 
Figure 1. Study Schema 
 
 
 


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7 BACKGROUND AND SIGNIFICANCE 
7.1 Study Disease 
Malignant primary brain tumors are the most frequent cause of cancer death in children and young 
adults and account for more deaths than cancer of the kidney or melanoma.3  Gliomas are the most common 
primary brain tumors with GBMs, astrocytomas and oligodendrogliomas comprising the large majority of 
subtypes.4 Primary GBM, WHO grade IV, occurs de novo and is the most common and aggressive glioma 
with a median OS of <15 months.5  Patients with lower grade II or III astrocytomas, oligodendrogliomas or 
mixed gliomas have a more favorable OS. However, lower grade astrocytomas can progress to secondary 
GBM and malignant progression is assured in almost all cases with patients succumbing to disease within 
a decade. Moreover, current therapy for malignant primary brain tumors is incapacitating6 and limited by 
non-specific toxicity to systemic tissue or surrounding eloquent brain. 
In contrast, immunotherapy promises an exquisitely precise approach and substantial evidence 
suggests that immunotherapeutic intervention can eradicate well-established tumors in mice and humans, 
even when tumors reside within the “immunologically privileged” brain. (See Figure 2, Figure 3, and Figure 
4)1,2,7,8 There is a clear and urgent need for the development of targeted therapeutics that can improve 
outcomes for patients with glioma without adding significant toxicity to current treatment regimens. 
Immunotherapy targeting tumor-associated antigens holds significant promise to meet this need.  
 
Figure 2. Highly reactive transferred cells traffic to brain and destroy tumor deposit in melanoma 
patients.  Arrows represent location of melanoma metastases. (From Johnson et al., Blood 2009)1 
 
 
Figure 3. Host-derived antitumor T cells treat lesions in the brain. Arrows represent location of 
metastases. (A&C) Pretreatment (B) 14 months after cell transfer (D) 6 months after cell transfer. (From 
Hong et al., Clinical Cancer Research)2 
 


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Figure 4. Genetically engineered antitumor T cells treat lesions in the brain Arrows represent location 
of metastases. (A&C) Pretreatment (B) 6 months after cell transfer (D) 30 months after cell transfer. (From 
Hong et al., Clinical Cancer Research)2 
7.2 Study Agents 
The study agent will consist of a 25 amino acid peptide (PEPIDH1M) and the adjuvants GM-CSF and 
Montanide ISA-51. 
7.2.1 PEPIDH1M 
PEPIDH1M is a 25 amino acid peptide that spans the mutated region of IDHR132H. 
7.2.2 GM-CSF 
Recombinant GM-CSF, Leukine® (sargramostim), is a normal human cytokine that increases the 
number and function of granulocytes (neutrophils, eosinophils, and basophils) and monocytes. It has been 
FDA-approved for clinical use for more than a decade. It is usually used following induction chemotherapy 
in older adult patients with AML to shorten time to neutrophil recovery, but has also been used previously 
as a vaccine adjuvant.9 It is contra-indicated in patients with excessive leukemic myeloid blasts (which we 
would not expect in the disease under study in this protocol), patients with known hypersensitivity to GM-
CSF, yeast-derived products, or any component of Leukine. Serious allergic or anaphylactic reactions have 
been reported with Leukine. 
7.2.3 Montanide ISA 51 (Incomplete Freund’s Adjuvant) 
Montanide ISA 51 or Incomplete Freund’s Adjuvant (IFA) is a water-in-oil (w/o) emulsion with 
immunomoadjuvant activity. Montanide ISA 51 enhances the immune system’s CTL response against 
antigen(s) in vaccines. Peptide vaccinations employing GM-CSF and Montanide ISA-51 as adjuvants have 
generally been well tolerated in human patients in numerous phase I-III trials. 
7.2.4 Tetanus-diphtheria toxoid (Td) 
The current use of Td toxoid is for active immunization in children and adults against infection with the 
bacteria Clostridium tetani and Corynebacterium diphtheria. Tetanus infection is manifested primarily by 
neuromuscular dysfunction caused by a potent exotoxin released by C. tetani. Diphtheria is an acute toxin-
mediated infectious disease caused by toxigenic strains of C. diphtheriae. Protection against disease is due 
to the development of neutralizing antibodies to the diphtheria toxin. Td toxoids adsorbed are readily 
available as several approved administrations [i.e. Daptacel (DTaP), Infanrix (DTap), Tenivac (Td adult), 
Boostrix (Tdap)10. Protection against disease is due to the development of neutralizing antibodies to the 
tetanus toxin. A serum tetanus antitoxin level of at least 0.01 IU/mL, measured by neutralization assays, is 
considered the minimum protective level. A level ≥0.1 IU/mL by ELISA has been considered as protective11. 
A serum diphtheria antitoxin level of 0.01 IU/mL, measured by neutralization assays, is the lowest level 
giving some degree of protection; a level of 0.1 IU/mL by ELISA is regarded as protective. Diphtheria 
antitoxin levels ≥1.0 IU/mL by ELISA have been associated with long-term protection. 
 


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Following deep s.c./i.m. administration of the tetanus toxoid vaccine, toxoid molecules are taken up at 
the vaccination site by immature DCs, which are professional antigen-presenting cells. Within these cells, 
they are processed through the endosomal pathway (involving the phagolysosome) where they are bound 
to MHC type II molecules on the surface of DCs. The MHC II:toxoid complex then migrates to the cell 
surface. While this process is happening within the cell, the now activated mature DC at the vaccine site 
migrates along lymph channels to the draining lymph node where they encounter naive TH2 cells, each 
with their own unique TCR. Identifying and then binding of the MHC II:toxoid to the specific TH2 receptor 
then activates the naive T cell, causing it to proliferate. Simultaneously, toxoid molecules not taken up by 
DCs pass along lymph channels to the same draining lymph nodes where they come into contact with B 
cells, each with their own unique B-cell receptor (BCR). Binding to the B cell through the specific 
immunoglobulin receptor that recognizes tetanus toxoid results in the internalization of toxoid, processing 
through the endosomal pathway and presentation on the cell surface as an MHC II:toxoid complex, similarly 
to DCs undergoing the same process12.  
 
These two processes occur in the same part of the lymph node with the result that the B cell with the 
MHC II:toxoid complex on its surface now comes into contact with the activated TH2 whose receptors are 
specific for this complex. The process, termed linked recognition, results in the TH2 activating the B cell to 
become a plasma cell with the production initially of IgM, with a later switch to IgG antibodies produced. 
Additionally, a subset of these B cells becomes memory cells12. 
 
The novelty of using Td toxoid vaccination lies in the ability of this potent recall antigen to enhance 
antitumor responses as part of a cancer vaccination protocol. Td toxoid induces an inflammatory milieu 
within the intradermal vaccine site, thereby promoting the migration of injected tumor-specific DCs. 
Additionally, in the context of vaccinating the host with tumor-derived peptides, conditioning the vaccine 
site with Td toxoid has demonstrated enhanced immunogenicity with these peptides.  
 
Our data from the ATTAC clinical trial (Duke IRB Protocol # Pro00003877) demonstrating the capacity 
to enhance DC migration to VDLNs via Td pre-conditioning of the vaccine site offer potential therapeutic 
interventions whereby we can enhance the immunologic responses to ultimately overcome the inherent 
challenges in faithfully eradicating established tumors. In a completed randomized clinical trial, we found 
that migration of injected DCs to VDLNs following vaccine site pre-conditioning with Td toxoid was 
significantly increased compared to controls and that the efficiency of DC migration was strongly associated 
with clinical outcomes of patients with newly-diagnosed GBM, the most fatal type of malignant brain 
tumors13. To address this observation, we took our Td pre-conditioning platform back into the preclinical 
setting using transgenic mouse models and were able to corroborate the effects of Td pre-conditioning on 
increasing the lymph node homing of intradermally administered DCs. Moreover, Td administration at a 
single vaccine site increases the migration of a bilateral DC vaccine to both inguinal lymph nodes. 
Regardless of the side of the Td intradermal skin prep, DC migration to bilateral inguinal VDLNs was equally 
increased, supporting a systemic response to recruit peripherally administered DCs.  
 
Our Td pre-conditioning platform in the context of DC vaccination also elicited superior anti-tumor 
responses compared to controls receiving DC vaccines without Td pre-conditioning. In our clinical trial, 
patients with newly-diagnosed GBM who were administered the Td skin prep before DC vaccination 
revealed significantly longer progression-free and overall survival rates compared to the control cohort. In 
evaluating the relationship between DC migration and clinical responses, we observed a modest positive 
correlation between levels of DC migration and survival. In our preclinical model, Td pre-conditioning prior 
to vaccination with tumor antigen-specific DCs dramatically suppressed the growth of established and 
highly aggressive B16-F10/OVA tumors. The use of Td with a DC vaccine increased antitumor responses 
in an antigen-specific manner, as non-specific DC vaccines were not potentiated with Td pre-conditioning. 
Furthermore, in a challenge setting, where mice are administered the treatment platform prior to challenge 
with tumor inoculation, Td pre-conditioning at the vaccine site induced a significant survival benefit 
compared to controls. 
 
For this clinical trial evaluating PEPIDH1M, we are also proposing to use Td as an adjuvant based on 
the pre- clinical data described below. Here, mice were immunized with 25mer mutant and wildtype peptides 
with two clinically relevant adjuvants: granulocyte-macrophage colony stimulating factor (GM-CSF), a 


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cytokine known to have a principle role in the activity of antigen presenting cells, and imiquimod, a topical 
TLR7 agonist administered at the vaccine site and tetanus-preconditioning.  Immunogenicity of each 
adjuvant/vaccine combination was measured via IFNγ ELISpot; administration of imiquimod at the site of 
vaccination results in a more robust mutant-specific immune response compared to GM-CSF, Notably, 
immunogenicity of the mutant peptide in mice that received imiquimod emulsified in IFA/IFA/IFA is 
comparable to the immune response seen in mice that received CFA/IFA/IFA, a treatment course with 
widely known strong adjuvant activity (Figure 5). 
 
 
Figure 5. Tetanus pre conditioning, imiquimod and GM-CSF increases the number of IDH1 mutant 
specific T cells after vaccination. Mice were immunized with (three weekly 100 ug of peptide emulsified 
in IFA/IFA/IFA), and immunogenicity was measured via IFNγ ELISPOT against both the wild-type and 
mutant 25mer peptides. 
7.2.5 Pre-clinical experience 
We have developed a functional murine homologue (Figure 6) of the human IDH1R132H mutant enzyme, 
cloned syngeneic murine gliomas that express this mutation, mapped peptide sequences specific to this 
mutation in either species (Figure 7), and demonstrated mutation-specific immunogenicity of these peptides 
(Figure 8 and Figure 9). Preliminary ELISpot data from our laboratory demonstrates that splenic 
lymphocytes isolated from mice immunized with peptides of various lengths containing the IDH1R132H 
mutation (PEPIDH1M) are activated by mutant but not wild type peptide, demonstrating both specificity and 
immunogenicity (Figure 10). Vaccination with PEPIDH1M in 3 different strains of mice has produced no 
toxicity. 


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Figure 6. The murine homologue of the IDH1R132H mutation is functional. Murine cells were 
transduced with the IDH1R132H mutation or left untransduced as controls. Whole cell extracts were 
submitted for quantification of R-2-hydroxyglutarate by LC-negative electrospray ionization-MS/MS. Values 
were normalized to total protein levels in each sample. 
 
 
Figure 7. Human IDH1R132H protein sequence and human and mouse wild type sequences. The 
mutation is highlighted in yellow. Purple highlights nearest sequence difference between human (S) and 
mouse (T) protein which is not included in the 25mer IDH1R132H (PEPIDH1M) peptide. PEPIDH1M  (red 
text) is identical between human and mouse. 
 
 
Figure 8. PEPIDH1M vaccination is immunogenic and specific in several mouse strains. Different 
mouse strains were immunized weekly for 3 weeks with PEPIDHM1 in CFA. After 7 days splenic 
lymphocytes were derived and stimulated with mutant or wildtype IDH1 peptide and IFNy secretion was 
assessed by ELISpot. *p<0.05 by t-test 
 


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Figure 9. PEPIDH1M vaccination is immunogenic and specific in the context of human HLA. HLA-
A2 Transgenic mice were immunized weekly for 3 weeks with 25mer or 9mer length peptides in CFA 
containing PEPIDHM1. 9mer peptides consisted of a peptide mix of 9 different peptides all spanning the 
IDH1R132H mutation. After 7 days, splenic lymphocytes were derived and stimulated with mutant or wild 
type IDH1 25mer peptide and IFNy secretion was assessed by ELISpot. 
 
 
Figure 10. Splenocytes from mice immunized with different lengths of mutant IDH1 peptides. Mice 
were immunized weekly for 3 weeks with different length peptides in CFA containing the IDH1R132H 
mutation. After 7 days, splenic lymphocytes were derived and stimulated with the 25mer mutant peptide 
(PEPIDH1M) or wildtype IDH1 peptide and IFNy secretion was assessed by ELISpot.  
7.2.6 Clinical experience 
This is a Phase I safety study. PEPIDH1M has not been used in humans previously. Recombinant GM-
CSF is FDA-approved for human use. 
Our previous experience with a peptide vaccine corresponding to a similar tumor specific mutation, 
EGFRvIII, in clinical trials has shown that a dose of 500 µg of peptide with 150 µg of GM-CSF yields effective 
immunity against tumors in the brain without any toxicity. EGFRvIII is a tumor-specific mutation of the 
epidermal growth factor receptor that is expressed in primary GBMs and other common neoplasms.14 
Because the wild type sequences of human and mouse overlap adjacent to the EGFRvIII mutation, we 


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were previously able to create a murine homologue of this mutation to test its immunogenicity without 
concerns that the results would be influenced by xenogeneic responses.15 Using this approach, we 
demonstrated that a peptide vaccine (PEPvIII) specific for the tumor-specific mutation EGFRvIII is capable 
of eliciting EGFRvIII-specific immune responses in mice with orthotopic gliomas.16 This was possible 
despite these mice exhibiting profound, tumor-induced immunosuppressive deficits that mirror those seen 
in humans with malignant brain tumors.9,16-18 Moreover, these immune responses were capable of 
eliminating EGFRvIII-expressing tumor cells in these tumors and extending survival of tumor-bearing 
mice.16 When translated into humans with EGFRvIII-expressing GBM, similar results were seen.9,16-18 
Despite no evidence of EGFRvIII-specific immune responses prior to vaccination, EGFRvIII-specific 
immune responses were generated in almost all patients and EGFRvIII-expressing tumor cells were nearly 
universally eliminated without attendant toxicity.16-18 Based on these data, this EGFRvIII-targeted vaccine 
is now being tested in an international Phase III trial (NCT01480479). Unfortunately, EGFRvIII is 
heterogeneously expressed and tumors recur as a result of outgrowth of the EGFRvIII negative tumor cells.9  
Montanide ISA 51 has proved to be a very efficient adjuvant, activating the cellular and the humoral immune 
response. It has been administered to more than 10,000 patients throughout the world. 
Our overall goal is to utilize our vast experience in peptide-based immunotherapy to provide a PEPIDH1M 
vaccine that is both safe and immunogenic in patients with IDH1 mutant-expressing WHO Grade II gliomas. 
7.3 Study Purpose and Rationale 
7.3.1 Temozolomide, Lymphopenia, and Homeostatic Proliferation 
TMZ is an alkylating chemotherapeutic that has recently been shown to prolong survival in patients with 
GBM.5 As a result, it has become part of the standard regimen used to treat these patients. TMZ induces a 
transient lymphopenia, and although counterintuitive, we and others have shown that following periods of 
lymphopenia, immune responses can be markedly enhanced.19-23 Probably as a result of a surge in 
cytokines (IL-7, IL-15) in response to lymphopenia, lymphocytes undergoing homeostatic proliferation enjoy 
a reduced activation threshold,24,25 differentiate directly into effector memory T-cells capable of rapid and 
intense response to antigen,26 display increased expression of anti-apoptotic molecules, and are less 
sensitive to immunosuppressive NK cell-mediated lysis.26 Still, lymphocytes must encounter their cognate 
antigen and compete for limiting amounts of these homeostatic cytokines to proliferate under these 
conditions.25 Thus, B- or T-cells specific for antigens that predominate during this recovery period, like those 
provided in the form of a vaccine, have a competitive advantage and become disproportionately over-
represented in the recovering lymphocyte population both in murine models19,27 and in humans.23 These 
skewed homeostatic responses have been shown to enhance antitumor immunity19,27,28 but can also 
increase the risk of autoimmunity.  
 
Figure 11. Lymphocyte counts of patients with newly-diagnosed GBM receiving standard dose 
adjuvant TMZ (200 mg/m2/5d) and dose-intensified TMZ (100 mg/m2/21d). Standard dose TMZ induces 
Grade 2 lymphopenia in 100% of patients (<800 cells/uL; blue line) and transient Grade 3 lymphopenia in 
40% of patients. Sustained Grade 3 lymphopenia (<500 cells/uL; red line) was induced by dose-intensified 
TMZ cycle #3 in all patients. 
 
Vaccine 1
Vaccine 2
Vaccine 3
Pre-TMZ
TMZ Cycle-1
TMZ Cycle-2
TMZ Cycle-3
TMZ Cycle-4
TMZ Cycle-5
TMZ Cycle-6
0
100
200
300
400
500
600
700
800
900
1000
1100
1200
1300
1400
1500
1600
1700
Standard Dose TMZ (200mg/m2/5d) (N=5)
Dose-Intesified TMZ (100mg/m2/21d) (N=8)
Grade 3 (<500 cells/µL)
Grade 2 (<800 cells/µL)
Absolute Lymphocyte Count (Day 21)
(cells/µL blood)


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Leveraging this principle, Rosenberg and colleagues have produced dramatic clinical responses21,29-32, 
along with some autoimmune toxicity, in patients with advanced malignant melanoma.20,22 After 
lymphodepletion, T-cells can expand dramatically and tumor-specific T-cells can constitute up to 90% of 
the host’s T-cell repertoire and can be maintained for months,20,33 and in these studies clinical regressions 
correlate with the frequency of tumor-specific T-cells achieved in the peripheral blood and persistence of 
these cells in vivo.21,29-32,34-36 
TMZ produces a survival benefit in patients with GBM and has become a routine part of the therapy for 
these patients. Due to the known myelosuppressive and immunosuppressive effects of TMZ37-40 and its 
potential negative implications for immunotherapy targeting GBMs, we evaluated the impact of TMZ 
treatment, in the context of our EGFRvIII peptide vaccine trial (now CDX-110, Pfizer, Inc.), on the 
lymphocyte compartment and immunologic responses of patients with newly-diagnosed GBM undergoing 
two different dose regimens of adjuvant TMZ. These regimens were evaluated in a randomized, Phase III 
trial (RTOG 052541). After concurrent TMZ with EBRT, patients received TMZ for either 5 days (200 mg/m2) 
or 21 days (100 mg/m2) of each 28 day cycle. 100% of patients receiving the standard 5 day schedule 
exhibited Grade 2 lymphopenia (<800 cells/uL) (Figure 11) with nadirs occurring 14-21 days after the first 
dose (n=5). Grade 3 lymphopenia was observed in only 1 patient with this regimen. Sustained Grade 3 
lymphopenia (<500 cells/uL) was induced in all patients receiving the 21 day regimen, however, by the fifth 
cycle of TMZ. Despite the profound lymphopenia, we have been able to induce and maintain potent 
EGFRvIII-specific immune responses (Figure 12 and Figure 13) in patients with GBM receiving serial cycles 
of TMZ.42 
 
 
Figure 12. Antibody titers in patients during standard-dose TMZ (200 mg/m2/5d) and dose-intensified 
TMZ (100 mg/m2/21d). All patients receiving the 21 day dose regimen developed EGFRvIII-specific 
antibodies with titers detectable at greater than 1:100,000 dilution. Humoral and cellular immune responses 
have been dramatically better in patients receiving the higher TMZ dose. 
 
Vaccine 3
Vaccine 4
Vaccine 5
Vaccine 6
Vaccine 7
Vaccine 8
10,000
100,000
1,000,000
200 mg/m2/5d
100 mg/m2/21d
1 / Titer
P=0.0093, Two-way 
ANOVA, repeated 
measures, For 
Interaction
ACTIVATE: 7/15
ACT II: 15/15
(P = 0.0022, 
Fisher’s exact)


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Vaccine DTH Response
Pre Vaccine
Dose 1 TMZ
Dose 3 TMZ
Dose 5 TMZ
0
20,000
40,000
60,000
80,000
100,000
Standard  200mg/m2/5d
Undectable
Undectable
Dose-Intensified 100mg/m 2/21d
mm squared
Candida DTH Response
Pre Vaccine
Dose 1 TMZ
Dose 3 TMZ
Dose 5 TMZ
0
2,000
4,000
6,000
8,000
Standard  200mg/m2/5d
Undetectable
Dose-Intensified 100mg/m 2/21d
mm squared
 
Figure 13. DTH responses to EGFRvIII vaccination. DTH responses to EGFRvIII vaccination (Left) in 
patients receiving lymphodepletive TMZ (100 mg/m2/d x 21 days) cycles (black) were increased when 
compared with standard dosing (200 mg/m2/d x 5 days) with continued vaccination. DTH responses to the 
recall antigen Candida (Right) in patients receiving lymphodepletive TMZ (100 mg/m2/d x 21 days) cycles 
(black) were decreased when compared with standard dosing (200 mg/m2/d x 5 days) with continued cycles 
of TMZ. 
7.3.2 Peptide Vaccines for Cancer 
Peptide vaccines encoding minimal CD8+ CTL epitopes have been demonstrated in many contexts to 
induce protective immunologic responses in experimental animals and mediate regressions of established 
tumors.43,44 However, with few several notable exceptions,36,45-48 vaccine-based cancer immunotherapy in 
humans is in need of significant improvement in immunogenicity and clinical outcomes.21  
The addition of CD4+ T cell helper epitopes to peptide vaccine formulations is widely believed to be an 
advantageous strategy for enhancing anti-tumor immunity.49 This presumption is supported by the 
observation that CD4+ T cell directed therapy can mediate effective anti-tumor immunity in humans and 
experimental animals.50-52 CD4+ T helper cells deliver assistance for CD8+ effector cells by fully activating 
dendritic cells through the CD40-CD40L signaling pathway.53 However, vaccination with T helper epitope 
encoding peptides has yielded mixed results in human clinical trials as a method to enhance anti-tumor 
cytotoxic T-cell responses in vivo50,54-56 and thus warrants systematic evaluation.  
Recent studies have highlighted the use of longer peptides (15-30 amino acids in length) instead of 
minimal CTL epitopes (typically 8-10 amino acids) for induction of a more robust, long lived CD8+ cytotoxic 
T-cell responses in experimental animals.36,57 The expanded length of the peptide requires it be processed 
by antigen-presenting cells. Minimal CTL epitopes do not require processing by antigen-presenting cells 
and thus are free to bind directly to T-cell receptors. This can induce tolerance due to a lack of co-stimulatory 
molecules that are presented to T-cells during antigen presentation by dendritic cells, however this area of 
peptide formulation requires further evaluation.58  
Peptide vaccination in humans has exhibited an excellent safety profile with virtually no dose limiting 
toxicities.36,56 Most toxicities occur when peptide vaccines are used in conjunction with immunostimulatory 
cytokines such as IL-2, which are expected results of IL-2 therapy.59 This feature of peptide vaccinations 
allows it to be used in combinatorial immunotherapeutic strategies and/or as salvage therapies in resistant 
disease.60,61 


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7.3.3 Summary of Study Purpose/Rationale 
Primary brain tumors are the most frequent cause of cancer death in children and young adults. GBM, 
the most malignant primary brain tumor, has a median OS of <15 months,5 and patients with lower grade 
gliomas progress to this universally lethal tumor type within ten years. Moreover, current therapy for these 
tumors is incapacitating6 and limited by non-specific toxicity. In contrast, immunotherapy promises an 
exquisitely precise therapeutic approach, and substantial evidence suggests that activated T-cells can 
eradicate large tumors, even within the “immunologically privileged” brain.1  
EGFRvIII is a tumor-specific mutation that is expressed in primary GBMs.14 We have previously 
demonstrated that EGFRvIII-specific immune responses could be generated in mice, and this predicted the 
ability to generate similar immune responses in humans.9,16-18,62 These were sufficient to eliminate 
orthotopic gliomas expressing a murine homologue of EGFRvIII in mice and were sufficient to consistently 
eliminate all EGFRvIII-expressing tumors cells in mice and humans without toxicity.9,17,63,64 Based on these 
observations, our EGFRvIII-targeted vaccine is now being tested in an international Phase III trial. 
Unfortunately, EGFRvIII is heterogeneously expressed and tumors recur as a result of outgrowth of the 
EGFRvIII negative tumor cells.9 
Recently, unbiased, genome wide sequencing has been shown to be a powerful approach for 
identifying other recurring mutations like EGFRvIII. Using next-generation sequencing, we discovered 
tumor-specific mutations exclusively in codon 132 of the active site of IDH165,66 – an evolutionarily-
conserved enzyme essential to cell function.67 Further study revealed that IDH1 mutations occur in >70% 
of almost all glioma subtypes, except primary GBM. Greater than 90% of all IDH1 mutations occur from a 
substitution of histidine for arginine resulting in the highly conserved and tumor-specific mutation, 
IDH1R132H.68 Immunohistochemical analysis shows that IDH1R132H is homogeneously expressed in all tumor 
cells, including single infiltrating tumor cells69 but is absent in normal cells.66,70 The high frequency, 
specificity, and homogeneous expression of the IDH mutation make it an ideal target for therapeutic 
intervention. 
Although IDH mutations can be seen in tumors with longer overall survival,71 IDH status has been 
occasionally misunderstood to function as an inhibitor of tumor growth. Rather it denotes a genetically 
distinct subset of tumors. Within those tumors, however, IDH mutations are oncogenic and cause grossly 
aberrant methylation as well as impaired differentiation that promotes tumorigenesis.72-78 While wildtype 
IDH1 converts isocitrate to αKG as part of cellular respiration, IDH1R132H mutations impair normal function 
resulting in the conversion of αKG into the onco-metabolite R-2HG.76,79 R-2HG impairs αKG-dependent 
histone and DNA demethylases resulting in a global epigenetic CIMP, obstructed differentiation, and 
tumorigenesis.72-78  
Mutant enzyme inhibition in gliomas using recently discovered small molecule inhibitors, while inhibiting 
tumor growth slightly, does not induce apoptosis, and tumor cells maintain logarithmic growth.76 Thus 
enzyme inhibition may only be partially effective as a therapeutic approach.72,76,80 In contrast, T cells 
targeted to these tumor-specific mutations are agnostic to the biologic function of the mutation and kill cells 
expressing the mutation indiscriminately. Our ability to eliminate EGFRvIII positive cells in GBM using a 
vaccine strategy similar to this proposal, also argues strongly for the potential of IDH-targeted 
immunotherapy. Moreover, the homogeneous expression of IDH1R132H and the apparent dependence on 
IDH1R132H for tumorigenicity may protect against the antigen escape seen with EGFRvIII-targeted vaccines. 
Here we propose to leverage our experience targeting tumor-specific antigens to assess the potential 
of an IDH1 mutation-specific vaccine as a treatment for patients with tumors containing IDH1R132H 
mutations.  
 


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8 OBJECTIVES AND ENDPOINTS 
 
Table 1. Objectives and Endpoints 
 
Objective 
Endpoint 
Analysis 
Primary 
To assess the safety of the 
PEPIDH1M vaccine alone and in 
combination with adjuvant TMZ 
and/or XRT/TMZ in adult patients 
with progressive, resectable 
WHO grade II gliomas that are 
confirmed Grade II or transition to 
a higher grade glioma at the time 
of surgery. 
The percentage of patients who 
experience an unacceptable toxicity 
defined as any Grade 3 toxicity at least 
possibly attributed to the vaccine (or 
vaccine + TMZ and/or RT) that does not 
resolve to baseline within 3 weeks, any 
Grade 3 hypersensitivity reactions 
requiring steroids, any Grade 4 toxicity, 
including neurologic events not due to 
progressive disease, or any life 
threatening-event not attributable to 
concomitant medication, co-morbid event, 
or disease progression.  
See Section 15.4 
Secondary 
To assess the immunogenicity of 
the PEPIDH1M vaccine with 
adjuvant TMZ using ELISpot. 
 
Mean difference in the number of SFC 
per 106 lymphocytes for cells cultured 
with and without IDH1 peptide 
See Section 15.5 
Exploratory 
To describe PFS and OS. 
 
Proportion of patients alive without 
disease progression 6 months after initial 
vaccine treatment; median progression-
free survival and median overall survival. 
See Section 15.6 
Exploratory 
To determine if ELISpot results 
after vaccination predict PFS or 
OS. 
 
Number of SFC per 106 lymphocytes 
above pre-vaccine baseline is a predictor 
of PFS or OS 
See Section 15.6 
Exploratory 
To estimate radiographic 
response rate prior to surgical 
resection and PFS after resection 
using RANO criteria. 
Proportion of patients with radiographic 
response (complete + partial response) 
observed prior to surgical resection. 
Proportion of patients alive without 
disease progression 6 months after 
resection. 
See Section 15.6 
Exploratory 
To determine if tumors are IDH1 
negative by immunohistochemical 
analysis and microarray analysis 
at the time of post-vaccine 
surgery. 
 
Proportion of tumors that are IDH1 
negative at the time of surgery 
See Section 15.6 
Exploratory 
To characterize immunologic cell 
infiltrate in tumors at the time of 
post-vaccine surgery.  
 
Median number of immunologic cell 
infiltrates at the time of surgery 
See Section 15.6 
Exploratory 
To determine if tumor-specific 
circulating DNA containing the 
c.395G>A (R132H) mutation can 
be detected in plasma before, 
during, and after study drug 
treatment. 
Detection of tumor-specific circulating 
DNA containing R132H mutation.  
Mean changes in R132H mutation from 
baseline. 
See Section 15.6 
Exploratory 
To determine if 2-HG, a 
metabolite specifically produced 
by tumors with IDH R132H, can 
be detected in plasma by mass 
spectrometry before, during, and 
after study drug treatment. 
Detection of 2-HG in plasma. 
Mean changes in 2-HG in plasma from 
baseline. 
See Section 15.6 
Exploratory 
To explore the impact of PEPIDH1M 
vaccination on genetic 
alternations, differential protein 
expressions or post-translational 
modifications (PTMs) using 
quantitative proteomic strategies 
in patient-derived samples. 
Changes between baseline and surgery 
in genetic alternations, differential protein 
expressions and post-translational 
modifications (PTMs) 
See Section 15.6 


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Exploratory 
To demonstrate quantitative 
repeatable measures of 
metabolism change in IDH1+ 
gliomas via a standardized MRS 
protocol, patients will be scanned 
on the research MR scanner to 
establish same-day and 
longitudinal metabolite coefficient 
of variance and possible 
longitudinal metabolite changes. 
Difference in levels of metabolism 
measured at same assessment. 
Changes from baseline in metabolism 
levels at each follow-up assessment. 
See Section 15.6 
9 INVESTIGATIONAL PLAN 
9.1 Study Design 
Subjects with radiographic and/or clinical progressive and resectable Grade II glioma with expression of 
IDH1R132H from the primary tumor (initial diagnosis) will be enrolled after signing informed consent. After 
consent has been signed, all subjects will undergo standard of care vaccination with 0.5 mL of Td (tetanus 
and diphtheria toxoids adsorbed) intramuscularly (I.M.) into the deltoid muscle to ensure adequate immunity 
to the tetanus antigen. The tetanus vaccine will be obtained through Duke ICS Pharmacy.  
 Eligible subjects will undergo a 1-2 hour leukapheresis for immune monitoring.  Within 48 hours of 
leukapheresis, subjects will receive a vaccine site pre-conditioning as a single dose of Td toxoid (1 
flocculation unit, Lf, in a total volume of 0.4 mLs saline). This will be administered one day prior to receiving 
PEPIDH1M vaccine intradermally (i.d.) to the RIGHT groin area (as described below).  The peptide vaccine 
is administered in the groin area approximately 10 cm below the inguinal ligament as vaccine # 1. 
Subsequent vaccines will be given on day 15 ±3 days (vaccine #2) and day 29 ±3 days (vaccine #3). These 
injections will occur without TMZ. Each injection of the peptide vaccine will be given half on the right groin 
and half on the left groin.    
Seven to 12 days after the 3rd vaccine, subjects will undergo surgical resection of tumor, which is part of 
the SOC for these subjects. If possible, the provider will take a photo of the injection site at the pre-op 
appointment seven to twelve days after the 3rd vaccine to document the subject’s reaction to the vaccine.  
Tumor samples from the surgical resection will be evaluated as outlined in the Exploratory Objectives. 
Based on tissue obtained at surgical resection, subjects with stable histologic grade at recurrence will 
then be treated with vaccine and adjuvant TMZ at a targeted dose of 50-100mg/m2/d for 21 days every 28 
days for up to 12 cycles (please see Section 18.5 in the Appendices for TMZ). During monthly cycles of 
TMZ, subjects will receive the vaccine on day 22 (+ 2 days) for a maximum of 15 total vaccines (which 
includes the first 3 bi-weekly vaccines). Patients that have transitioned to a higher Grade brain tumor will 
receive TMZ and radiation therapy per standard of care and monthly vaccines. 
All Adverse Events will be collected from time of consent until the end of the treatment phase of the 
study. The treatment phase of the study will end 1 month after the last vaccine (Section 12.3). Patients will 
be followed only for overall survival, progression-free survival, and subsequent therapies thereafter. For 
higher grade gliomas undergoing RT (please see Section 18.4 in the Appendices for SOC RT), vaccine #4 
will be given during the SOC clinic visit prior to initiating RT, and vaccine # 5 will be given 4 weeks later (± 
1 week) during RT.  Vaccine #6 will be given at the end of RT during the SOC clinic visit to review MRI and 
begin post-RT TMZ, if MRI stable.  Then, subjects in this treatment group will receive vaccines monthly on 
day 22 (+2 days) with post-RT cycles of TMZ to a maximum of 15 vaccines. 
For immune monitoring and biomarker testing, subjects will have blood collected, as described in Section 
12, during the following times:  prior to vaccine therapy (at leukapheresis visit), prior to surgical resection 
(at the pre-op screening visit), prior to either RT/TMZ or first cycle of adjuvant TMZ (at SOC clinic visit) 
depending on tumor pathology, at vaccine # 6, and at End of Treatment (follow-up visit 1 month after vaccine 
#15; If a subject decides to stop participating in the study prior to vaccine #15, blood will be obtained at that 
time, if possible; If a subject progresses prior to vaccine #15, blood will be obtained at that time, if possible) 
.For genomic proteomic analyses, blood and tumor samples will be obtained as described below in Section 
9.4. 
Subjects will be imaged with contrast-enhanced MRI according to the SOC every 10 weeks (+/- 4 weeks) 
while on TMZ and afterward, per the treating neuro-oncologist’s recommendation. RANO criteria will be 
used for assessment of pseudoprogression and tumor progression (please see Section 12.7.3 for further 
detail).  Subjects demonstrating definitive progression will be removed from study.  


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In addition, to demonstrate quantitative repeatable measures of 2HG in IDH1+ gliomas, subjects will be 
imaged using magnetic resonance spectroscopy (MRS) at baseline (prior to vaccine #1 following consent), 
and up to 4 times prior to surgery (please see Section 9.5 below for further information). 
As part of standard care for these subjects, upon tumor progression, participants may undergo 
stereotactic biopsy or resection. As this is not a research procedure, consent will be obtained separately. 
Subjects that have this procedure done within the Duke University Health System may be approached to 
participate in the Duke Brain Tumor Center Biorepository study (Pro00007434). Tissue obtained from 
subjects who consented to the Duke Brain Tumor Center Biorepository will be used to assess immunologic 
cell infiltration, antigen expression, and biomarkers for immunologic response.  
9.1.1 Definition of Unacceptable Toxicity 
Toxicities will be graded according to the NCI CTCAE version 4 criteria. An unacceptable toxicity is 
defined as any Grade 3 toxicity at least possibly attributed to the vaccine (or vaccine + TMZ +/- RT) that 
does not resolve to baseline within 3 weeks, any Grade 3 hypersensitivity reactions requiring steroids, any 
Grade 4 toxicity, including neurologic events not due to progressive disease, or any life–threatening event 
not attributable to concomitant medication, co-morbid event, or disease progression. 
Please refer to the Potential Risks Section 12.8.2 of this protocol. 
9.1.2 Concomitant Medications 
Concomitant medications will be managed by the treating neuro-oncologist and recorded at each study 
visit by the study team. 
9.2 Rationale for Selection of Dose, Regimen, and Treatment Duration 
The PEPIDH1M vaccine dose that will be evaluated in this trial will be 500 µg with 150 µg of GM-CSF 
mixed 1:1 with Montanide ISA 51 administered intradermally as vaccine # 1. Subsequent vaccines will be 
given on day 15 ±3 days (vaccine #2) and on day 29 ±3 days (vaccine #3). The same dose will be 
administered on day 22 (+ 2 days) of each monthly cycle of adjuvant TMZ following surgical resection for 
those with confirmed Grade II. For those who transition to a higher grade glioma, they will be undergoing 
RT (please see Section 18.4 in the Appendices for SOC RT), thus, vaccine #4 will be given during SOC 
clinic visit prior to initiating RT, and vaccine # 5 will be given 4 weeks later (± 1 week) during RT.  Vaccine 
#6 will be given at the end of RT during the SOC clinic visit to review MRI and begin post-RT TMZ, if MRI 
stable.  Then, subjects in this treatment group will receive vaccines monthly on day 22 (+ 2 days) with post-
RT cycles of TMZ to a maximum of 15 vaccines, as the confirmed Grade IIs.  
The nearly universal expression of IDH1 in secondary GBMs and low-grade gliomas may make 
excellent anti-tumor immunotherapeutic targets. Vaccination and adoptive T-cell strategies in humans in 
other contexts have been safe and effective. Therapeutic TMZ induces a profound lymphopenia that may 
enhance anti-tumor vaccination responses when given during the homeostatic T-cell proliferation that 
occurs in response to lymphodepletion. Other peptide vaccines given to patients with high-grade gliomas 
during recovery from TMZ-induced lymphopenia have produced potent tumor-specific immune responses 
and have been well tolerated9,17,81. 
9.3 Rationale for Correlative Studies 
While the primary goal of this study is to assess safety of the PEPIDH1M vaccine, a secondary endpoint 
will be to determine whether this vaccine is capable of eliciting an immune response in patients with IDH1 
mutation-expressing tumor. The primary measure of immunogenicity will be by ELISpot to the immunizing 
peptide. For the immune system to recognize the tumor specific IDH1 mutant, this mutant peptide must be 
presented by human leukocyte antigens (HLA) on the surface of a tumor cell for recognition by a T cell. 
There are a tremendous number of HLA alleles with variable expression from person to person. As certain 
peptides are able to bind with much greater affinity to certain HLA alleles, the ability of one individual to 
present the IDH1 mutant peptide will be dependent upon their unique set of HLA alleles and may differ 
greatly from another individual with differing HLA. Therefore, it is critical to know the HLA type of a patient 
receiving the peptide vaccine as this may reveal if certain HLA types are associated with enhanced vaccine 
induced immune responses. Such information may suggest certain HLA types present the mutant peptide 
in a superior fashion and may be valuable in stratifying patients for clinical trials using this vaccine. We 


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intend to identify HLA types from PBMCs taken at the leukapheresis time point. The purpose of collecting 
these data will be to determine whether there may be immune correlates that associate with clinical 
outcomes such as PFS and OS following vaccination with the PEPIDH1M vaccine. Although this Phase I 
study is not designed to be definitive towards this end, these analyses will provide the initial data necessary 
to adequately power future studies. Any evidence of tumor response will be determined according to the 
Duke PRTBTC SOP (available upon request). RANO criteria82 will be used for assessment of 
pseudoprogression. Tumor progression will need to be documented histologically, unless there are clinical 
contraindications, to exclude inflammatory responses presenting as radiographic or clinical changes, which 
could indicate potentially toxic or therapeutic responses and not tumor progression. Patients will be followed 
until death.  
 
9.4 Rationale for Genomic Proteomic Analyses 
IDH1 mutation is a critical factor in glioma classification and a key determinant of clinical outcome. First, 
though the effect of mutant IDH1 in tumor cells have been well-established at the genetic and epigenetic 
levels (e.g., closely associated with several other genes, and has a profound impact in DNA methylome), 
the effect of the IDH1 mutant on the proteomic level is unclear, thus presenting a great opportunity for 
understanding glioma pathogenesis and developing new therapeutics. Second, in addition to IDH1 
mutations, other genetic alterations and their associated mutant peptides may serve as multi variant factors 
underlying patient treatment outcome. It is critical to have a bird’s eye view of and dissect all the genetic 
and peptide components that help stratify patients for clinical trials. 
 
We intend to identify genetic alterations, differential protein expressions or post-translational 
modifications (PTMs) via our comprehensive ‘inside-out’ quantitative proteomic strategies in patient-derived 
tumor samples.  Genetic alterations, differential protein expressions or PTMs that have been identified will 
be further tested in all patients enrolled in this clinical trial. We propose to obtain the following specimens, 
from patients both before and after treatment, for both genomic and proteomic analyses.  
(1) Tumor tissues – 500 mg fresh frozen tumor tissue will be requested, as well as tissues from 
previous surgery. If frozen tissues from previous surgery are not available, fifteen 5 μm sections of 
FFPE samples are requested. If available, these samples will be used for genomic and proteomic 
analysis. 
(2) PBCs – to determine proteomic profiling with a focus on immune system, and also for immune 
monitoring and tumor circulating DNA detection. Twenty mLs of peripheral blood (3 yellow top 
tubes) is requested (1) before vaccine with the leukapheresis visit, (2) at the pre-op screening visit 
before surgery, (3) At the SOC clinic visit prior to starting the 1st cycle of TMZ for those who are 
confirmed Grade II, or at the SOC clinic visit prior to starting RT/TMZ for those who have 
transitioned to a higher grade glioma, (4) Vaccine #6, and (5) End of Treatment (follow-up visit 1 
month after vaccine #15). If a subject decides to stop participating in the study prior to vaccine #15, 
blood will be obtained at that time (if possible).  If a subject progresses prior to vaccine #15, blood 
will be obtained at that time (if possible).  PBMCs and plasma will be separated. Plasma will used 
for the detection of IDH1 mutation before surgery.   
These experiments will:  
- 
Identify genetic alterations and changes in protein before and after treatment with peptide vaccine 
in tumor cells. 
- 
Identify proteins showing differential expressions or PTMs in immune cells, with and without IDH1 
mutant, and before and after IDH1 vaccination, with a potential of revealing how immune cells 
response to IDH1 mutant, before and following vaccination. 
We will perform proteomics, exome sequencing and RNA-sequencing on the resected tumors (after 
three IDH1 vaccines). We will use patient samples before IDH1 vaccination as controls.  Radiographic and 
clinical tumor progress, as well as IDH1 mutation status in patient’s plasma will be recorded. 
9.5 Single-Voxel MR Spectroscopy 
To demonstrate quantitative repeatable measures of metabolism change in IDH1+ gliomas, patients 
will be scanned on the research MR scanner using standardized MRS protocol to assess same-day 
repeatability and to assess longitudinal metabolite changes. 


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The IDH1 mutation causes extreme overexpression of the onco-metabolite R-2-hydroxyglutarate (2HG) 
in all tumor cells. This can be non-invasively measured using clinical MRS methods. 2HG is a specific 
marker for IDH1 mutated gliomas because its concentration in ‘wild’ IDH1 gliomas is below the level of 
measurement of MRS.  
Duke Radiology has a standard protocol for 2HG measures using a proven 2HG MEGA-LASER pulse 
sequence for Siemens MR scanners and Dr. Soher’s open source “Vespa” software for spectral simulation 
and fitting of the MEGA-LASER data. The protocol is available for immediate use on our research scanner 
as a part of the Duke Radiology’s Center for Advanced MR Development (CAMRD).  
We will assess subjects at up to 5 time points: baseline (after consent and before PEPIDH1M vaccine 
#1), and up to 4 times prior to surgery. This will provide between 6-8 weeks of tumor/vaccine interaction. A 
typical 2HG protocol consists of 12-15 minutes of anatomical MRI and ~15-30 minutes of MRS data 
acquisition. An IDH1+ patient can usually be processed in a 1-2 hour time slot.  
In order to establish same-day coefficients of variance and/or optimized acquisition parameters, 
patients may be scanned twice within a time point. Patients will be positioned and scanned in the MR 
scanner, then completely removed and put back into the scanner, and then positioned and scanned a 
second time. If necessary for patient comfort, this evolution can be done immediately or with a short rest 
period so long as scanning is finished within the booked period of time. Longitudinal acquisitions will also 
be analyzed for longitudinal metabolite coefficients of variance and possible longitudinal metabolite 
changes. 
 
9.6 Definition of Evaluable Subjects, On Study, and End of Study 
For the initial monitoring of adverse events (see Section 15.4.2), evaluable patients will include the first 
6 accrued patients who received 3 vaccinations or experienced an unacceptable toxicity due to one of the 
first 3 vaccinations. 
For the final analysis of the primary objective (See section 15.4.2), evaluable patients will include all 
patients who received at least 6 vaccinations or experienced an unacceptable adverse event that was 
related to vaccine (or vaccine + TMZ).  
Once the patient signs ICF, that subject will be considered “on study.”  Rationale for taking patient off 
protocol treatment will be documented. End of study is defined as 2 months following last vaccine for 
purposes of toxicity monitoring. 
9.7 Early Study Termination 
This study can be terminated at any time for any reason by the PI-sponsor. If this occurs, all subjects 
on study should be notified as soon as possible. Additional procedures and/or follow up should occur in 
accordance with Section 12.5. Section 12.6 describes procedures and process for prematurely withdrawn 
patients. 
 
 


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10 STUDY DRUG 
10.1 
Names, Classification, and Mechanism of Action 
The name of the drug will be PEPIDH1M vaccine. The class of action is a biological.  
10.2 
Packaging and Labeling 
Name 
MRN 
DOB  
Drug: PEPIDH1M 
Lot #: Lot 001 
Caution New Drug Limited By Federal Law To Investigational Use 
10.3 
Supply, Receipt, and Storage 
The PEPIDH1M will be manufactured under GMP conditions by Bachem Americas, Inc., and stored in the 
investigational pharmacy.  Montanide is supplied by Seppic and stored at 4OC in the investigational 
pharmacy.   
GM-CSF (LEUKINE®; sargramostim) will be obtained from commercial supply, as a sterile, white, 
preservative-free powder lyophilized powder in a vial containing 250 mcg to be reconstituted in 0.5 mL of 
sterile water for injection.  
Store GM-CSF under refrigeration at 2-8°C (36-46°F). Vials must not be frozen.  
Lyophilized GM-CSF vials contain no antibacterial preservative, and therefore solutions prepared with 
Sterile Water for Injection, USP should be administered as soon as possible, and within 6 hours following 
reconstitution. The vial should not be re-entered or reused. Do not save any unused portion for 
administration more than 6 hours following reconstitution. Bacteriostatic Water for Injection, USP (0.9% 
benzyl alcohol) should NOT be used.  
Aseptic technique should be employed in the preparation of all GM-CSF solutions. To assure correct 
concentration following reconstitution, care should be exercised to eliminate any air bubbles from the needle 
hub of the syringe used to prepare the diluent. During reconstitution of lyophilized GM-CSF, the diluent 
should be directed at the side of the vial and the contents gently swirled to avoid foaming during dissolution.  
PEPIDH1M will be stored at -80OC, thawed, and inspected visually for particulate matter and discoloration 
prior to administration. If particulate matter is present or the solution is discolored, the vial should not be 
used. Before use, the vial should be gently swirled to ensure uniform mixing of the contents. Avoid 
excessive or vigorous agitation; do not shake. 
Td is indicated for active booster immunization against tetanus, diphtheria, and pertussis as a single 
dose; substitute 1-time dose of Tdap for Td booster, then standardly boost with Td every 10 years. Please 
refer to section 7.2 on the use of Td in this protocol. This study agent Td (Tetanus diphtheria toxoid 
adsorbed) is supplied by Duke Pharmacy and stored at 4oC. 
10.4 
Dispensing, Preparation and Administration 
10.4.1 
Td 
The Td booster vaccine will be administered at the initial consent visit only after the subject has signed 
consent.  Administration will be done as per standard of care and according to package insert instructions 
(please see appendices in Section 18) with 0.5 mL of Td (tetanus and diphtheria toxoids adsorbed) I.M. 
into the deltoid muscle. In addition, vaccine site pre-conditioning will be performed as a single dose of Td 
toxoid (1 flocculation unit, Lf, in a total volume of 0.4 mLs saline) administered i.d. to the RIGHT side of the 
groin one day prior to the first vaccine. 
10.4.2 
PEPIDH1M Vaccine with GM-CSF and Montanide ISA 51 
The PEPIDH1M vaccine and GM-CSF will be mixed with Montanide ISA 51 (shortened to PEPIDH1M 
vaccine for the other sections of this protocol) in the investigational pharmacy and will be delivered directly 
to the bedside under the supervision of the research nurse. Vaccines will be administered according to 


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protocol. The patient’s name, Study ID, DOB, and MRN will be double verified prior to vaccine 
administration.  
PEPIDH1M will be co-administered with GM-CSF and mixed 1:1 with Montanide ISA 51.  
Lyophilized GM-CSF should be reconstituted with Sterile Water for Injection, USP. Bacteriostatic Water 
for Injection, USP (0.9% benzyl alcohol) should NOT be used. During reconstitution, the diluent should be 
directed at the side of the vial and the contents mixed by gently swirling to avoid foaming during dissolution. 
Avoid excessive or vigorous agitation; do not shake. 
Each vial of lyophilized GM-CSF (250 mcg/vial) should be reconstituted with 0.43 ml of Sterile Water 
for Injection, USP 0.35 ml of reconstituted GM-CSF will be withdrawn, under aseptic conditions, using a 
hypodermic needle and syringe.  
Each vial of PEPIDH1M will be thawed at room temperature PEPIDH1M should fully thawed within 0.5 
to 3 minutes, with no remaining visible frozen drug or particulate. The resultant solution of PEPIDH1M (0. 
4 ml of 2.0 mg/ml PEPIDH1M) is a clear and colorless solution.  
The syringe with the previously withdrawn GM-CSF (0.35 ml volume containing 203 mcg GM-CSF), will 
be used to withdraw 0.35 mL of peptide. The aqueous peptide/GM-CSF is mixed 1:1 with 0.7 mL of 
Montanide ISA 51 according to the manufacturer’s instructions. One mL of the mixture will be administered 
by intradermal injection (in divided doses) in the patient’s groin. 
After mixing, the PEPIDH1M/GM-CSF/Montanide mixture will contain approximately 500 mcg 
PEPIDH1M and 150 mcg GM-CSF in 1 mL of mixture.  
PEPIDH1M, GM-CSF and Montanide ISA 51 contain no antibacterial preservative, and therefore 
solutions prepared with Sterile Water for Injection, USP should be administered as soon as possible. The 
peptide mixture can be stored for not more than 6 hours at 2-8°C and for not more than 3 hours at room 
temperature. 
Each PEPIDH1M/GM-CSF/Montanide immunization should be administered i.d. near the groin, divided 
into 2-8 separate injections, as tolerated. It is recommended that the injections be given approximately 10 
cm below the inguinal ligament.  At each administration session, half of the immunization mixture will be 
given on the right groin and half on the left groin. Vaccine injections must be performed using an appropriate 
needle for intradermal administration.  
Following administration of the PEPIDH1M vaccine, the patient should be retained for observation for a 
minimum of 30 minutes. 
10.5 
Compliance and Accountability 
Upon receipt from the manufacture the PEPIDH1M and the GM-CSF/Montanide will be stored in the 
investigational pharmacy in a temperature controlled, locked access controlled storage unit. All drug 
transfers, receipts, and disposals are recorded in the Web-based drug accountability system. The vaccine 
will be signed out and distributed by the investigational pharmacist. The Duke investigational pharmacy 
personnel use safe medication practices to reduce the risk of medication errors and adverse events when 
setting up study drug procedures. They are clearly labeled with the identity of the study drug and other 
control numbers.  
10.6 
Disposal and Destruction 
Unused drug will be autoclaved. 
 
11 SUBJECT ELIGIBILITY 
11.1 
Inclusion Criteria 
1. Age ≥ 18 years. 
2. IDH1R132H expression in primary tumor 
3. Clinical and/or radiographic, progressive and resectable Grade II glioma. 
4. Signed informed consent.  
5. For females of child-bearing potential, negative serum pregnancy test at screening (within 48 
hours prior to leukapheresis). 


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6. Women of childbearing potential and male participants must agree to practice adequate 
contraception. 
7. KPS of ≥ 70. 
8. CBC/differential with adequate bone marrow function as defined below within 2 weeks of 
enrollment:   
a) Absolute neutrophil count, ≥ 1500 cells/mm3. 
b) Platelet count, ≥ 100,000 cells/mm3. 
c) Hemoglobin ≥ 10 g/dl. (Note: the use of transfusion or other intervention to achieve Hgb ≥ 
10 g/dl is acceptable.) 
9.  Adequate renal function as defined below within 2 weeks of enrollment: 
a) BUN ≤ 25 mg/dl. 
b) Creatinine ≤ 1.7 mg/dl. 
10.  Adequate hepatic function as defined below within 2 weeks of enrollment: 
a) Bilirubin ≤ 2.0 mg/dl. 
b) ALT ≤ 3 x normal range. 
c) AST ≤ 3 x normal range. 
11.2 
Exclusion Criteria 
1. Prior invasive malignancy (except for non-melanomatous skin cancer) unless disease free for ≥ 3 
years. (For example, carcinoma in situ of the breast, oral cavity, and cervix are all permissible.) 
2. Metastases detected below the tentorium or beyond the cranial vault. 
3. Severe, active co-morbidity, defined as follows: 
a. Unstable angina and/or congestive heart failure requiring hospitalization. 
b. Myocardial infarction within the last 6 months. 
c. Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC definition; note, 
however, that HIV testing is not required for entry into this protocol. The need to exclude 
patients with AIDS from this protocol is necessary because treatments involved in this 
protocol may be significantly immunosuppressive. 
d. Major medical illnesses or psychiatric impairments that in the investigator's opinion will 
prevent administration or completion of protocol therapy. 
4. Pregnant or lactating women, due to possible adverse effects on the developing fetus or infant due 
to study drug. 
5. Prior allergic reaction to temozolomide. 
6. Patients treated on any other therapeutic clinical protocols within 30 days prior to study entry or 
during participation in the study. 
7. Patients with known hypersensitivity to GM-CSF, yeast-derived products, or any component of 
Leukine®. 
8. Allergy or hypersensitivity to tetanus vaccine or any component of the tetanus vaccine. 
9. Unable to undergo MRI imaging. 
12 SCREENING AND ON-STUDY TESTS AND PROCEDURES 
Progressive patients will be offered treatment options during this PRTBTC clinic visit. CMP and CBC 
with differential, and physical and neurologic examination with KPS score will be performed within 6 weeks 
prior to consent and may be taken from the previous standard of care Duke PRTBTC clinic visit. All subject 
data is standard of care evaluations that occur for all patients being seen in the PRTBTC, regardless of 
study entry. Screening examination must include pathology report from initial diagnosis to confirm IDH1+ 
WHO Grade II glioma diagnosis with MRI showing progressive lesion located in resectable areas. Once 
consent is obtained, subjects will receive Td booster immunization I.M. Study-mandated leukapheresis is 
scheduled to occur followed by Td i.d. pre-conditioning scheduled 48 hours or less. Vaccine #1 is then 
given one day after Td pre-conditioning. Within 72 hours prior to undergoing the leukapheresis procedure, 
patients will have blood samples taken for the following tests as required by the Duke Apheresis Center: 
CBC w/diff, CMP, ionized Calcium, and β-HCG (for females of child-bearing potential). Total estimated 
blood volume required for these evaluations is 12-15 mLs. For patients without sufficient venous access for 
leukapheresis, a temporary central intravenous catheter may be inserted. To prevent the development of 
hypocalcemia from the citrate used for leukapheresis, all patients will be instructed to take oral Tums, 2 


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tablets three times a day and at bedtime the day before and the day of the leukapheresis procedure. 
Patients who have lower levels of calcium will be treated per Apheresis lab standard protocols under the 
direction of apheresis attending physician. An aliquot of 107 PBMCs will be collected from this leukapheresis 
and sent to UNC Center for AIDS Research Virology, Immunology, & Microbiology Core Laboratory at 250 
Bell Tower Drive, Genome Sciences Building, Room 2158, Chapel Hill, NC 27599-7291. This blood sample 
will be sent to UNC for HLA assessment and analysis (please see Section 9.3 for rationale). 
Subsequent vaccines will be given on day 15 ±3 days (vaccine #2) and day 29 ±3 days (vaccine #3). 
Seven to 12 days after the 3rd vaccine, subjects will undergo surgical resection which is part of the SOC for 
these subjects. Patients with re-confirmed Grade II will be treated with adjuvant TMZ and vaccine. Patients 
that have transitioned to a higher Grade brain tumor will receive TMZ and radiation therapy per standard of 
care and monthly vaccines.  For higher grade gliomas undergoing RT, vaccine #4 will be given during SOC 
clinic visit prior to initiating RT, and vaccine # 5 will be given 4 weeks later (± 1 week) during RT.  Vaccine 
#6 will be given at the end of RT during the SOC clinic visit to review MRI and begin post-RT TMZ, if MRI 
stable.  Then, subjects in this treatment group will receive vaccines monthly on day 22 (+2 days) with post-
RT cycles of TMZ to a maximum of 15 vaccines.     
If possible, the provider will take a photo of the injection site at the pre-op appointment seven to twelve 
days after vaccine #3 to document the subject’s reaction to the vaccine. The provider may take additional 
pictures of the injection site at other clinic visits at the discretion of the treating physician or Principal 
Investigator. There will be no identifiers on the photographs. The photographs will be taken by the subject’s 
provider and may be uploaded to their electronic medical record or kept in a separate electronic or paper 
research file. The photographs will be uploaded to the electronic medical record by using electronic 
applications called Haiku for iPhones or Cantu for iPads. These applications allow for the photograph to be 
uploaded directly to the electronic medical record without the photographs being stored on the device taking 
the picture.  A ruler will be included in the photo to allow measurement of the size of the injection site 
reaction.  
To demonstrate quantitative repeatable measures of 2HG change in IDH1+ gliomas, patients will be 
scanned on the CAMRD MR scanner using a an MRS protocol. We will acquire MRS data at up to 5 time 
points: baseline (after consent and before PEPIDH1M vaccine #1) and up to 4 times prior to surgery (please 
refer to Section 9.5 for more detail). 
 
IDH1 R132H biomarker component of the protocol and immune monitoring: 
a) Study of tumor-specific circulating nucleic acid from plasma of patients with gliomas with 
IDH1 R132H: 
We plan to isolate circulating nucleic acids from the plasma of patients affected by glioma and attempt 
to detect tumor-specific circulating DNA containing the c.395G>A (R132H) mutation. We will follow the 
protocol as described by Boisselier, et al., Neurology 201283 for plasma collection. Twenty mLs of blood will 
be the appropriate amount for our analyses (should yield ~10mL of plasma).  At the same time, we will 
collect peripheral blood for immune monitoring. Ideally, we would like to have these blood samples 
collected: 
- 
(1) Prior to initiating vaccine therapy at the leukapheresis visit, 
- 
(2) Prior to surgical resection at the pre-op screening visit, 
- 
(3) Prior to first cycle of TMZ at the SOC clinic visit (confirmed Grade IIs), or prior to RT/TMZ at 
SOC clinic visit (higher Grade Gliomas), 
- 
(4) Vaccine #6 
- 
(5) End of Treatment (follow-up visit 1 month after vaccine #15). If a subject decides to stop 
participating in the study prior to vaccine #15, blood will be obtained at that time (if possible).  If a 
subject progresses prior to vaccine #15, blood will be obtained at that time (if possible).  
b) Study of 2-Hydroxyglutarate levels in patients with gliomas with IDH1 R132H: 
The second approach to be used will be a mass spectrometry-based approach for detection of 2-
hydroxyglutarate (2-HG), a metabolite specifically produced by tumors with the IDH1 c.395G>A (R132H) 
mutation. This metabolite can be sensitively detected by mass spectrometry and has been found to be 
elevated in the tissue of IDH1 R132H-containing gliomas as well as in the plasma of other solid tumors 
containing the same mutation (cholangiocarcinoma, subsets of breast carcinoma). A small portion of the 


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previously mentioned isolated plasma will be used for a LC-MS/MS based approach for sensitive detection 
of circulating 2-HG levels.  
Tumor tissue – we are planning to obtain a snap-frozen tumor tissue sample after the surgical resection 
for possible presence of IDH1 mutation and gene up-regulation.   
 
Tumor Sampling Analyses: 
At the time of surgical resection, excess tumor tissue will be obtained through the Duke Biorepository, 
and IHC analyses will be performed to assess immunologic infiltrate which will be identified by cell type and 
reactivity state. 
 


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Table 2. Screening and On-Study Tests and Procedures 
 
 
 
 
 


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Screening  
Leukapheresis2 
 
One day 
prior to 
vaccine 
#1 
Vaccine 
#1 
Vaccine  
#2 
Vaccine 
#3 
Pre-
Surgery 
Surgery7 
Post-
Surgery 
Pre TMZ 
visit9 
Radiation 
Therapy 
and TMZ8 
TMZ 
Cycles  
1-12 9,10 
End of 
Treatment 
(1 month 
after 
Vaccine 
#15) 
 Progression 
*followed for 
survival 
ICF 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
History/ 
Baseline 
symptoms 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
Tumor 
pathology  
X 
 
 
 
 
 
 
X 
 
 
 
 
X  
If possible 
Blood for 
Immune 
monitoring/
Biomarker 
testing5  
 
X 
3 red  
 
 
 
 
X 
17 
yellow, 
1 red 
 
X 
17 
yellow,  
1 red 
X 
17 yellow,  
1 red 
 
At vaccine 
#6 
X 
17 
yellow, 1 
red 
 
At 
vaccine 
#6 
X 
17 yellow,  
1 red 
 
CBC/diff and 
CMP3  
X 
X 
 
 
 
 
X 
 
X 
X8 
X 
X 
 
Beta HCG 
(for WOCBP) 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
Ionized Ca 
 
X 
 
 
 
 
 
 
 
 
 
 
 
TD Booster4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
MRI1 
X 
 
 
 
 
 
 
X 
 
X 
 
 
X 
every 2-3 
months 
 
 
MRS 2HG6 
 
X 
 
X 
X 
X 
X 
 
 
 
 
 
 
Pre-
conditioning 
TD11  
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
TMZ 50-100 
mg/m2 21 of 
28 days x 12 
cycles  
 
 
 
 
 
 
 
 
 
 
X 
 
 
Radiation 
Therapy8 
 
 
 
 
 
 
 
 
 
X8 
 
 
 
TMZ 
75mg/m2/day 
for 42 days8 
 
 
 
 
 
 
 
 
 
X8 
 
 
 
Vaccine10 
Total of 15 
vaccines  
 
 
 
X 
 
X 
 
X 
 
 
 
 
X10 
 
X10 
 
 
 
Physical 
Exam,  
Neuro exam, 
KPS 
X 
 
X 
 
X 
X 
 
 
X 
X8 
X 
X 
 
Con Meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X8 
X 
X 
 
AE/SAE 
collection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X8 
X 
X 
 
Photo of 
injection site 
(Optional to 
subject)12 
 
 
 
 
 
 
X 
 
If 
possible 
 
 
 
 
 
 
1 Initial standard of care MRI report to confirm eligibility must be performed within 10 weeks (+/- 4 weeks) of signing consent. MRI or contrasted CT, every 
10 weeks (+/- 4 weeks) per PRTBTC standard of care (may be adjusted by the treating neuro-oncologist).  MRI will be done pre- and post-surgery per 
surgeon discretion and standard of care.  
2 1-2 hour leukapheresis within 2 weeks of enrollment. Within 72 hours of leukapheresis, patients will have blood samples taken for the following tests 
as required by the Duke Apheresis Center: CBC, CMP, ionized Calcium, and β-HCG (for females of child-bearing potential). Total estimated blood volume 
required for these evaluations is 12-15 mLs. An aliquot of PBMCs from this pheresis will be sent to UNC for HLA analysis. 
3 CMP and CBC (with differential) to confirm eligibility, and as per standard of care prior to and following surgery, and during monthly cycles of TMZ. CBC 
and CMP will be repeated along with a physical examination 1 month following last vaccine to assess for delayed toxicity to vaccine therapy. 
4 Td booster will be given I.M. into the deltoid muscle after consent on all subjects.  
5 Immune monitoring and Biomarker testing will be drawn before initiation of vaccine therapy (at leukapheresis visit), prior to surgical resection, prior to 
RT/TMZ and vaccine #4 or cycles of TMZ (depending on tumor pathology), at vaccine # 6, and at end of treatment (at the follow-up visit 1 month after 
vaccine #15, at the time come off study treatment, or at progression, whichever comes first).  Blood for immune monitoring and Biomarker testing will be 
placed in 14 yellow containing ACD and 1 red vacutainer tube for a total of 90 mLs delivered to the BTIP lab for processing (3  red tops will be drawn 
with leukapheresis instead). Genomic proteomic analyses will include tumor sample at surgery and 20 mLs of blood (3 yellow ACD tubes) drawn at 
leukapheresis visit, at the pre-op screening visit prior to surgery, and depending on tumor pathology at the SOC clinic visit prior to starting either RT/TMZ 
(and receiving the 4th vaccine) or the 1st cycle of TMZ, at vaccine #6, and at end of treatment (at the follow-up visit 1 month after vaccine #15, at the time 
come off study treatment, or at progression, whichever comes first). 
6 To demonstrate quantitative repeatable measures of metabolism change in IDH1+ gliomas via a standardized MRS protocol, patients will be scanned 
on the research MR scanner at up to 5 time points per subject: baseline (after consent and before PEPIDH1M vaccine #1), and up to 4 times prior to 
surgery.  Up to 5 MRS scans can be scheduled between consent and surgery, but they are not required to be scheduled on the same day as PEPIDH1M 
vaccines #1-3. 


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7 Tissue obtained will be used to reconfirm the Grade and assess immunologic cell infiltration, antigen expression, and biomarkers for immunologic 
response, specifically IDH1 T cell response. 
8 Only for those whose pathology reveals transition from Grade II to Grade III at time of surgery. 
9 Monthly cycles of TMZ will be initiated and adjusted at the discretion of the treating neuro-oncologist. 
10 For higher grade gliomas undergoing RT, vaccine #4 will be given during SOC clinic visit prior to initiating RT, and vaccine # 5 will be given 4 weeks 
later (± 1 week) during RT.  Vaccine #6 will be given at the end of RT during the SOC clinic visit to review MRI and begin post-RT TMZ, if MRI stable.  
Then, subjects in this treatment group will receive vaccines monthly on day 22 (+2 days) with post-RT cycles of TMZ to a maximum of 15 vaccines.  
Subjects with a stable grade glioma at time of surgery will receive vaccines #4-15 monthly on day 22 (+2 days) of TMZ cycles.  
11Tetanus pre-conditioning will be done i.d. into the right groin one day before vaccine #1, as described in protocol. 
12 Photo may be repeated at additional clinic visits at discretion of the treating physician or Principal Investigator 
12.1 
Screening  
Screening will take place at the Duke PRTBTC clinic visit. An informed consent must be signed by the 
patient before any study-specific procedure takes place. CMP and CBC with differential, and physical and 
neurologic examination with KPS score will be performed within 6 weeks prior to consent and may be taken 
from the previous standard of care Duke PRTBTC clinic visit. All subject data is standard of care evaluations 
that occur for all patients being seen in the PRTBTC. If the subject is considered a screen failure prior to 
initial protocol treatment, the source documents for electronic data entry will be stored in EPIC Electronic 
Medical Record or, if in paper form, a locked cabinet in a locked room in the PRTBTC.  
12.2 
Treatment Period 
Patients that have consented onto this study will receive 3 vaccines as indicated above and then 
undergo surgical resection. Unless a patient is determined at the time of surgery to have transitioned to a 
higher grade brain tumor, vaccines will then continue monthly along with adjuvant cycles of TMZ on day 22  
(+ 2 days) for a maximum of 15 vaccines, unless the patient has tumor progression prior to completing 12 
cycles of TMZ. Subjects that have transitioned to a higher grade glioma at the time of surgery will continue 
on study treatment, however, they will need to undergo standard of care chemoradiation therapy.  
Therefore, the vaccines will be given before, during and following RT as described above. Subjects will 
return one month following the last vaccine for blood work (CBC and CMP) and clinical assessment to 
monitor for delayed toxicity. 
12.3 
End of Treatment 
One month after final vaccination or once all the blood for immune monitoring has been collected 
following progression (whichever comes first), the treatment phase of the study will be completed. 
12.4 
Follow-up Period 
Once the treatment phase has been completed, patients will be followed for OS, PFS, and subsequent 
therapies and data recorded by the study team. For recording of subsequent therapies, the type, agent, 
and duration of therapy(ies) that the subject receives will be recorded.  
12.5 
End of Study 
End of study will be declared after the death of the last subject on the study. However, one month after 
the last enrolled subject receives the final vaccine, the investigational vaccine treatment will be considered 
as complete and collected data will be analyzed for safety and toxicity.   
Subjects will be followed for OS, PFS, and subsequent therapies and data will be updated. Furthermore, 
in case of disease progression, every attempt will be made to obtain tissue for immune monitoring (if biopsy 
or resection performed).  
12.6 
Early Withdrawal of Subject(s) 
12.6.1 
Criteria for Early Withdrawal 
Subjects may voluntarily withdraw from the study at any time. The PI may also withdraw a subject from 
the study at any time based on his/her discretion. Reasons for PI-initiated withdrawal may include, but are 
not limited to the following: 
• 
Progressive disease as documented by MRI or physical examination at any time after the 
initiation of post-op immunotherapy or post-RT immunotherapy (for those who’ve transitioned 
to a higher grade at time of surgery) 


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• 
Development of unacceptable toxicity, as defined in section 9.1.1 
• 
Pregnancy 
• 
Need for corticosteroids > 4mg/day at time of 1st vaccine 
• 
Upon request of the subject 
• 
If, in the investigator’s medical judgment, further participation would be injurious to the 
subject’s health or wellbeing 
• 
Development of intolerable symptoms 
• 
Protocol deviation 
• 
Administrative reasons, such as a major violation of the clinical trial protocol 
• 
Non-compliance of the subject 
• 
Clinical decline or inability to be weaned off steroids following surgery 
• 
Failure to undergo surgery following the 3rd vaccine 
• 
Failure to tolerate TMZ therapy. 
12.6.2 Follow-up Requirements for Early Withdrawal 
Subjects treated on this study that are withdrawn by the PI for any of the aforementioned reasons will 
continue to be followed for survival by the study coordinator until death or are lost to follow up. Subjects 
that voluntarily withdraw will be asked permission to follow for survival. Subjects that are withdrawn prior to 
vaccine treatment for any of the aforementioned reasons will be considered eligibility failures and thus will 
not be followed for survival.  
12.6.3 Replacement of Early Withdrawal(s) 
Subjects who voluntarily withdraw prematurely (i.e. before receiving the first 3 vaccinations) or who are 
withdrawn by the PI prior to treatment will be replaced unless the subject experienced an unacceptable 
toxicity as defined in section 9.1.1. 
12.7 
Study Assessments 
12.7.1 Medical History 
Medical history will be obtained from the Duke electronic medical records system and from the subject 
and/or family at the screening visit and reviewed at each study visit. This data may include the following: 
• 
All past medical and surgical history 
• 
Current medications  
• 
Changes in physical or neurologic symptoms 
• 
Any adverse events  
12.7.2 Physical Exam 
Vital signs and physical and neurologic examinations will be assessed and recorded along with a KPS 
score prior to enrollment, at the Td pre-conditioning i.d. visit, and at each vaccine visit (with the exception 
of vaccine #1 where only vital signs will be assessed). 
 
12.7.3 
Use of Antihistamines 
Subjects will be advised to avoid antihistamine use 48 hours prior to each vaccine administration, the 
day of vaccine administration, and for 48 hours following each vaccine administration.  If the subject has a 
pre-existing condition that requires antihistamine usage, the PI and the treating oncologist will decide if it is 
safe and appropriate for the subject’s antihistamines to be held before and following vaccine 
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12.7.4 
Radiologic Evaluations 
Patients with progressive Grade II LGGs will be imaged by MRI as per standard of care for eligibility 
and baseline measurements, and to assess progression prior to vaccine therapy. Although the purpose of 
this study is not to detect tumor responses, any evidence of tumor response will be determined according 
to the Duke PRTBTC SOP (available upon request). RANO criteria82 will be used for overall assessment of 
tumor response and pseudoprogression versus progression. Progression by RANO response criteria is 
defined as follows:  1) New contrast-enhancing lesion outside of radiation field on decreasing, stable, or 
increasing doses of corticosteroids; 2) ≥ 25% increase in the sum of the products of perpendicular diameters 
between the first post radiotherapy scan, or a subsequent scan with smaller tumor size, and the scan at 12 
weeks or later on stable or increasing doses of corticosteroids; 3) Clinical deterioration not attributable to 
concurrent medication or comorbid conditions is sufficient to declare progression on current treatment but 
not for entry onto a clinical trial for recurrence; 4) For patients receiving antiangiogenic therapy, significant 
increase in T2/FLAIR non-enhancing lesion may also be considered progressive disease. The increased 
T2/FLAIR must have occurred with the patient on stable or increasing doses of corticosteroids compared 
with baseline scan or best response after initiation of therapy and not be a result of comorbid events (e.g., 
effects of radiation therapy, demyelination, ischemic injury, infection, seizures, postoperative changes, or 
other treatment effects). Since some of these subjects will not be undergoing radiation therapy, and the 
possibility to exhibit pseudoprogression is likely due to inflammation from immune response at the site of 
the tumor, RANO criteria will be used to monitor for pseudoprogression versus progression. If 
pseudoprogression is suspected, the subject will continue with vaccine therapy for a minimum of 2-3 
subsequent months so long as subject remains clinically and radiographically stable compared to the MRI 
showing suspected pseudoprogression as long as the following criteria are met: 1) the subject experiences 
investigator-assessed clinical benefit (i.e., no new clinical symptoms contributed to disease progression) 
and 2) the subject is tolerating the study treatment (i.e., no expected toxicities higher than grade 3 or 
unexpected toxicities).  If the subject continues to do well beyond the 3 months, they will continue on study 
as planned. 
12.8 
Risk/Benefit Assessment 
12.8.1 
Potential Benefits 
The potential benefits may include reduction or remission of the subject’s brain cancer. Because 
this procedure is experimental, it cannot be guaranteed that subjects will receive any benefit as a result 
of participating in this research study. The information collected in this research may help scientists 
better understand the mechanisms involved in the immune system’s ability to fight cancer. If such an 
understanding comes from this research, then it may benefit society by furthering the development of 
improved treatment methods for human malignant brain tumors in the future. 
12.8.2 
Potential Risks 
Td 
Injection of Td toxoid may produce inflammation, edema, induration, erythema, or pruritus at the 
injection site. Administration may cause occasional pain and discomfort up to three days after the 
vaccine is given. 
Allergic Reactions to PEPIDH1M 
Injection of antigen presenting cells may result in an allergic reaction, which could include redness 
and swelling at the injection site, itching, hives, low blood pressure, difficulty breathing, or in the most 
extreme circumstances, death. In addition, if the immune system becomes overly activated, potential 
discomforts may include pain, redness and swelling at the injection site. 
Injection Site 
EMLA ® cream, or equivalent topical analgesic, can be offered to subjects who experience local 
pain at the injection site.  
Cerebral Edema 
Cerebral edema may be secondary to the disease process itself, the surgical procedure, radiation 
therapy, necrosis from previous radiation, or inflammation due to immune infiltration of the brain or 
destruction of tumor cells. Symptoms may include, but are not limited to, severe headache, confusion, 


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lethargy, unresponsiveness, coma, or focal neurological deficits. Patients will be monitored throughout 
the course of the study and those patients with any signs or symptoms of cerebral edema may need 
their steroid doses increased, treatment with an osmotic diuretic, or surgical decompression. Edema 
that fails to respond to aggressive therapy may lead to permanent neurological impairment. The 
probability of this risk can be predicted to some degree based upon tumor size, location, pre-operative 
neurological impairment, and post-operative course prior and after PEPIDH1M injections. Patients will be 
monitored throughout the course of the study. 
Infection 
The PEPIDH1M vaccine injections may include the risk of infection due to potential contamination of 
the peptides in the laboratory. This may result in localized redness, swelling, or induration at the 
injection site. In the most extreme situation, this may lead to systemic bacterial/fungal sepsis and 
possibly death. The probability of this risk is relatively low, given the small injection volume (1 mL 
divided between >2 intradermal locations) and the fact that the peptides will be strictly tested for sterility 
prior to each injection. The risk of infection due to potential contamination of the peptides in the 
laboratory will be minimized by biosafety quality assurance and testing. All cell cultures will be handled 
under sterile conditions in a core tissue culture facility dedicated to the processing of human cells. Prior 
to injection into patients, peptides must pass sterility tests in thiglycolate broth, tryptic soy blood agar, 
and inhibitory Sabouraud agar. Following injections, patients will be monitored throughout the course 
of the study for any signs and symptoms of infection. There have been no infections to date in the 
recent VICTORI (IRB #3108-05-9R4) or ACTIVATE (IRB #5421-05-1R1) clinical trials testing similar 
approaches in a similar patient population. If an active infection is suspected, patients will be cultured 
and treated with appropriate antibiotics. 
Delayed Autoimmune Diseases 
It is possible that delayed autoimmune disease(s) may develop as a result of injection with PEPIDH1M 
vaccine. This means that the immune system may be stimulated to attack natural tissue in the body. 
Animal studies have reported the development of autoimmunity in the context of vaccination and 
recovery from lymphopenia. However, our current experience with peptide vaccination in glioma 
patients has not demonstrated evidence of autoimmunity in treated patients. Furthermore, the doses of 
TMZ used in this study for induction of lymphopenia are standard doses administered to patients with 
gliomas. It therefore, is unknown what the risk of delayed autoimmune disease is for this study. 
Phlebotomy 
Drawing blood or inserting an intravenous catheter into an arm vein may result in bruising or 
swelling in the area of the insertion, bleeding at the site of the needle puncture, light headedness, 
fainting and very rarely, local infection, which may be severe. These risks are reduced by the fact that 
the blood will be drawn by a qualified physician, nurse or phlebotomist (a professional trained to draw 
blood). 
Leukapheresis 
As with any donation of blood, a variety of minor reactions may occur with leukapharesis, which 
include fainting, dizziness, or nausea. Uncommon but serious complications may also result, which 
include bleeding, infection, an adverse reaction to the anticoagulant or replacement fluids, 
hypocalcemia, hypotension, shock, convulsions, air emboli, heart failure, or the inability to transfuse 
blood back into the patient. These risks are reduced by the fact that the procedure will be performed 
by qualified staff at a specialized clinical hemapheresis unit. Patients will be carefully monitored 
throughout the procedure by trained nursing and medical staff. Calcium gluconate (2 gm) will be given 
to minimize the risks of hypocalcemia, fluid supplementation will be given to minimize hypotension. 
MRI 
The risks and/or discomforts associated with the performance of MRI include the anxiety produced 
from being in a tight, enclosed space (claustrophobia). In addition, the machine operates using a large 
and powerful magnet. The magnetism of the machine attracts certain metals: therefore, people with 
these metals in their bodies (specifically pacemakers, infusion pumps, metal aneurysm clips, metal 
prostheses, joints, rods or plates) will be excluded from the study if they are unable to undergo MRI 
imaging. Patients will also be checked to make sure that they do not bring any metal objects into the 
MRI facility. Dental fillings are less affected by the magnetic fields generated and are therefore 
permitted. It will be asked that patients let the physicians conducting this study know of any metal in 
their bodies other than dental fillings.  
Allergic Reactions to Contrast Agents 


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During the MRI, patients will be given a contrast agent. The agent is given routinely to obtain 
enhanced MRI scans of the brain. The agent is administered through the vein and requires the 
placement of an IV catheter. The catheter placement is similar to drawing blood except that the catheter 
remains in the vein during the time the agent is actively delivered. The risks of a blood draw and 
insertion of a catheter are similar. There have been a few, rare cases of allergies to the agent used in 
MRI contrast enhanced scans. Patients with any known severe allergies to contrast agents will be 
excluded from the study. Patients with mild allergies (i.e., rash only) will be pretreated with Tylenol and 
Benadryl prior to injection of the contrast agent. 
Radiation Therapy 
Early side effects of radiation include hair loss, scalp redness, inflammation of the ear canals, and 
fatigue. In a few patients, radiation contributes to headaches or nausea. Rarely, tumors may swell 
during radiation causing neurological symptoms such as weakness on one side, visual loss, or changes 
in mental function. There is a small chance of long-term effects from radiation, occurring months or 
years after completion. These may include worsening of mental function, hearing, vision, strength and 
coordination. Rarely, radiation may cause the development of benign or malignant tumors around the 
brain or skull. It is unknown whether temozolomide increases the risk of any of the early or late side 
effects of radiation. 
Temozolomide 
TMZ has been well tolerated by both adults and children with the most common toxicity being mild 
myelosuppression. Other, less likely, potential toxicities include nausea and vomiting, constipation, 
headache, alopecia, rash, burning sensation of skin, esophagitis, pain, diarrhea, lethargy, 
hepatotoxicity, anorexia, fatigue and hyperglycemia. Hypersensitivity reactions have not yet been noted 
with TMZ. As in the case with many anti-cancer drugs, TMZ may be carcinogenic. Rats given TMZ 
have developed breast cancer. The significance of this finding for human is not presently known. TMZ 
therapy will be followed but given as standard of care. If toxicities occur, the Principle investigator and 
primary physician will titrate therapy based on standard clinical guidelines as outlined above. 
GM-CSF 
Injection of GM-CSF may increase the risk of infection, lower platelets, or cause fluid retention. 
GM-CSF also may result in an allergic reaction, which could include redness and swelling at the 
injection site, itching, hives, flushing, syncope, low blood pressure, difficulty breathing, or in the most 
extreme circumstances, death. In addition, if the immune system becomes overly activated, potential 
discomforts may include pain, redness and swelling at the injection site. 
Montanide ISA 51 
Montanide ISA 51 adjuvant is well tolerated. Local reactions may include granuloma, local pain, 
tenderness and erythema. Montanide ISA 51 may also cause flu like symptoms, nausea and vomiting. 
Unknown Risks 
The overall risk classification of this research is unknown. Clinical trials using peptide-based 
immunizations on brain tumor patients have only recently been published. From our experience with 
40 patients in ongoing and previous trials we have not seen any toxicities or serious unexpected 
adverse events. 
 
13 SAFETY MONITORING AND REPORTING 
The PI is responsible for the identification and documentation of adverse events and serious adverse 
events, as defined below. At each study visit, the PI or designee must assess, through non-suggestive 
inquiries of the subject or evaluation of study assessments, whether an AE or SAE has occurred. 
13.1 
Adverse Events 
An AE is any untoward medical occurrence in a subject receiving study drug and which does not 
necessarily have a causal relationship with this treatment. For this protocol, the definition of AE also 
includes worsening of any pre-existing medical condition. An AE can therefore be any unfavorable and 
unintended or worsening sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of the PEPIDH1M and GM-CSF, whether or not related to use of the vaccine. 
Abnormal laboratory findings without clinical significance (based on the PI’s judgment) should not be 


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recorded as AEs. But laboratory value changes that require therapy or adjustment in therapy are considered 
adverse events. All lab values that are not deemed AEs by the PI will be noted to be Non-Clinically 
Significant in the subject record and source documents. 
From the time the subject signs the informed consent form through the End of Treatment visit (as 
defined in Sections 12.3, 12.5 and 12.6), all AEs must be recorded in the subject medical record and 
electronic adverse events case report form. 
AEs will be assessed according to the CTCAE version 4.0. If CTCAE grading does not exist for an AE, 
the severity of the AE will be graded as mild (1), moderate (2), severe (3), life-threatening (4), or fatal (5). 
Attribution of AEs will be indicated as follows: 
• 
Definite: The AE is clearly related to the study drug 
• 
Probably: The AE is likely related to the study drug 
• 
Possible: The AE may be related to the study drug 
• 
Unlikely: The AE is doubtfully related to the study drug 
• 
Unrelated: The AE is clearly NOT related to the study drug 
13.1.1 Reporting of AEs 
A summary of all adverse events (not just those considered related to the study drug) will be kept which 
will categorize the event by organ system, relationship to treatment, its grade of severity, and resolution. 
The PI will periodically review the collective adverse events with the intention of identifying any trends or 
patterns in toxicity on a monthly basis. If any such trends are identified, depending on their severity and 
frequency, a protocol amendment will be considered. 
13.2 
Serious Adverse Events 
An AE is considered “serious” if in the opinion of the investigator it is one of the following outcomes: 
• 
Death, 
• 
A life-threatening adverse event, 
• 
A congenital anomaly or birth defect, 
• 
Inpatient hospitalization or prolongation of existing hospitalization, 
• 
A persistent or significant incapacity or substantial disruption in the ability to conduct normal life 
functions. 
Important medical events that may not result in death, be life-threatening, or require hospitalization may 
be considered serious when, based upon appropriate medical judgement, the event may jeopardize the 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. Furthermore, an important medical event that is not otherwise an SAE may be considered serious 
if the event may jeopardize the subject and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. 
13.2.1 Reporting of SAEs 
All SAEs should be reported immediately to Dr. Katherine Peters (Pager: 919-970-7591) or her 
designee (919-684-8111) and to the FDA. Fatal or life-threatening, unexpected adverse events will be 
reported to the FDA by telephone, facsimile, or in writing as soon as possible, but no later than 7 calendar 
days after first knowledge by the PI-sponsor followed by as complete a report as possible within 8 additional 
calendar days. Serious, unexpected adverse events that are not fatal or life-threatening will be reported to 
the FDA by telephone, facsimile, or in writing as soon as possible, but no later than 15 calendar days after 
first knowledge by the sponsor. 
All adverse events that are considered serious, unanticipated, and related or possibly related to the 
research (as defined by 21CRF312.32[a]) will be reported to the FDA and the Duke University Medical 
Center IRB using the appropriate SAE report form. At the time of the annual progress report to the FDA 
and the Duke University Medical Center IRB, a summary of the overall toxicity experience will be provided. 
13.3 
Safety Oversight Committee  
The Duke Cancer Institute Safety Oversight Committee is responsible for annual data and safety 
monitoring of DUHS sponsor-investigator phase I and II, therapeutic interventional studies that do not have 
an independent DSMB. The primary focus of the Safety Oversight Committee is review of safety data, 


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toxicities and new information that may affect subject safety or efficacy. Annual safety reviews includes but 
may not be limited to review of safety data, enrollment status, stopping rules if applicable, accrual, toxicities, 
reference literature, and interim analyses as provided by the sponsor-investigator. The Safety Oversight 
Committee in concert with the DCI Monitoring Team (see Section 14.1 for Monitoring Team description) 
oversees the conduct of DUHS cancer-related, sponsor-investigator therapeutic intervention and 
prevention intervention studies that do not have an external monitoring plan, ensuring subject safety and 
that the protocol is conducted, recorded and reported in accordance with the protocol, SOPs, GCP, and 
applicable regulatory requirements. 
14 QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 
Monitoring 
The DCI Monitoring Team will conduct monitoring visits to ensure subject safety and to ensure that the 
protocol is conducted, recorded, and reported in accordance with the protocol, standard operating 
procedures, good clinical practice, and applicable regulatory requirements. As specified in the DCI Data 
and Safety Monitoring Plan, the DCI Monitoring Team will conduct routine monitoring after the third subject 
is enrolled, followed by annual monitoring of 1–3 subjects until the study is closed to enrollment and subjects 
are no longer receiving study interventions that are more than minimal risk.  
Additional monitoring may be prompted by findings from monitoring visits, unexpected frequency of 
serious and/or unexpected toxicities, or other concerns and may be initiated upon request of DUHS and 
DCI leadership, the DCI Cancer Protocol Committee, the Safety Oversight Committee, the sponsor, the 
Principal Investigator, or the IRB. All study documents must be made available upon request to the DCI 
Monitoring Team and other authorized regulatory authorities, including but not limited to the National 
Institute of Health, National Cancer Institute, and the FDA. Every reasonable effort will be made to maintain 
confidentiality during study monitoring. 
14.2 
Audits 
The Duke School of Medicine Office of Audits, Risk, and Compliance (OARC) office may conduct audits 
to evaluate compliance with the protocol and the principles of GCP. The PI agrees to allow the OARC 
auditor(s) direct access to all relevant documents and to allocate his/her time and the time of the study 
team to the OARC auditor(s) in order to discuss findings and any relevant issues. 
OARC audits are designed to protect the rights and well-being of human research subjects. OARC 
audits may be routine or directed (for cause). Routine audits are selected based upon risk metrics generally 
geared towards high subject enrollment, studies with limited oversight or monitoring, Investigator initiated 
Investigational Drugs or Devices, federally-funded studies, high degree of risk (based upon adverse events, 
type of study, or vulnerable populations), Phase I studies, or studies that involve Medicare populations. 
Directed audits occur at the directive of the IRB or an authorized Institutional Official. 
OARC audits examine research studies/clinical trials methodology, processes and systems to assess 
whether the research is conducted according to the protocol approved by the DUHS IRB. The primary 
purpose of the audit/review is to verify that the standards for safety of human subjects in clinical trials and 
the quality of data produced by the clinical trial research are met. The audit/review will serve as a quality 
assurance measure, internal to the institution. Additional goals of such audits are to detect both random 
and systemic errors occurring during the conduct of clinical research and to emphasize “best practices” in 
the research/clinical trials environment. 
14.3 
Data Management and Processing 
14.3.1 
Study Documentation 
Study documentation includes but is not limited to source documents, case report forms, monitoring 
logs, appointment schedules, study team correspondence with sponsors or regulatory bodies/committees, 
and regulatory documents that can be found in the DCI-mandated “Regulatory Binder,” which includes but 
is not limited to signed protocol and amendments, approved and signed informed consent forms, FDA Form 
1572, CAP and CLIA laboratory certifications, and clinical supplies receipts and distribution records. 


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Source documents are original records that contain source data, which is all information in original 
records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction 
and evaluation of the trial. Source documents include but are not limited to hospital records, clinical and 
office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing 
records, recorded data from automated instruments, copies or transcriptions certified after verification as 
being accurate copies, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject 
files, and records kept at the pharmacy, at the laboratories and at medico-technical departments involved 
in the clinical trial. When possible, the original record should be retained as the source document. However, 
a photocopy is acceptable provided that it is a clear, legible, and an exact duplication of the original 
document. 
14.3.2 Data Management 
The subject’s medical records will be the primary source document for the study. Source documents 
include all information in original records and certified copies of original records of clinical findings, 
observations, or other activities in a clinical investigation used for reconstructing and evaluating the 
investigation1. Source documentations may also include paper eligibility checklists, data flowsheets, patient 
reported outcomes and other paper documents. The PI, study coordinator, study research nurse, data 
management team and all associated study key personnel, are permitted to make entries, changes, or 
corrections in the source documents or database per the study delegation of authority log. 
Errors on the source documents will be crossed out with a single line, and this line will not obscure the 
original entry. Changes or corrections will be dated, signed, initialed, and explained (if necessary). 
Database changes will be tracked via electronic trail automatically. 
14.3.3 
Data Management and Data Verification 
The DCI IT Shared Resource has developed Title 21 CFR Part 11 compliant databases for cancer 
clinical trials. DCI IT has extensive expertise in database quality assurance, data standards, and use of 
caBIG tools to support cancer researchers.  
Data queries will be generated automatically by the eCRF system. These data queries signify the 
presence of data inconsistencies. The study and data management team will cross-reference the data to 
verify accuracy. Missing or implausible data will be highlighted for the PI requiring appropriate responses 
(i.e. confirmation of data, correction of data, completion or confirmation that data is not available, etc.). 
The database will be reviewed and discussed prior to database closure, and will be closed only after 
resolution of all remaining queries. 
14.3.4 
Coding of Adverse Events 
All adverse events will be coded using CTCAE (version 4.0).  
14.3.5 Study Closure 
Following completion of the studies, the PI will be responsible for ensuring the following activities: 
• 
Data clarification and/or resolution 
• 
Accounting, reconciliation, and destruction/return of used and unused study drugs 
• 
Review of site study records for completeness 
• 
Shipment of all remaining laboratory samples to the designated laboratories 
                                                     
1 In 21 CFR 312.62(b), reference is made to records that are part of case histories as “supporting data”; 
the ICH guidance for industry E6 Good Clinical Practice: Consolidated Guidance (the ICH E6 guidance) 
(available at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
or http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm)  uses 
the term “source data/documents.” For the purpose of this guidance, these terms describe the same 
information and have been used interchangeably. 


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15 STATISTICAL METHODS AND DATA ANALYSIS 
All statistical analyses will be performed under the direction of the statistician designated in key 
personnel. Any data analysis carried out independently by the investigator must be approved by the 
statistician before publication or presentation. 
15.1 
Analysis Sets 
Subject to the availability of data, all patients who receive any protocol treatment will be included in 
analyses addressing secondary objectives.  Statistical analyses for the primary objective will exclude 
patients who terminate protocol treatment prematurely (i.e. less than 6 vaccinations) without an 
unacceptable toxicity. 
15.2 
Patient Demographics and Other Baseline Characteristics 
Summaries of clinical and socio-demographic characteristics will be generated for all patients who 
receive vaccine treatment. Categorical descriptors will be summarized using frequency distributions; 
whereas, interval variables will be summarized using percentiles, as well as means and standard 
deviations.  
15.3 
Treatments 
A frequency distribution will be generated for the number of vaccines received by patients. 
15.4 
Primary Objective 
To assess the safety of the PEPIDH1M vaccine alone and in combination with adjuvant TMZ and/or RT 
in adult patients with progressive, resectable WHO Grade II gliomas that are confirmed Grade II or transition 
to a higher grade glioma at the time of surgery. 
15.4.1 
Variable 
The percentage of patients with an unacceptable toxicity will be estimated, where unacceptable toxicity 
is defined as any Grade 3 toxicity at least possibly attributed to the vaccine (or vaccine + TMZ and/or RT) 
that does not resolve to baseline within 3 weeks, any Grade 3 hypersensitivity reactions requiring steroids, 
any Grade 4 toxicity, including neurologic events not due to progressive disease, or any life threatening-
event not attributable to concomitant medication, co-morbid event, or disease progression.  
15.4.2 Statistical Hypothesis, Model, and Method of Analysis 
Up to 28 patients will be enrolled and treated with the goal of accruing 20 patients that will receive at 
least 6 vaccines (3 pre-surgery and 3 post-surgery). Less than 20% of patients are expected to drop out 
between enrollment and the 6th vaccination.  
Initial Study Monitoring For Adverse Events: Initially 6 subjects will be accrued to the study after which 
accrual will be suspended until the last patient enrolled undergoes surgical resection to review the toxicity 
experienced by these subjects during the first 3 vaccinations. During this period of time, some of the 6 
patients may have initiated post-surgery treatment with TMZ and IDH1 vaccine. If 2 or less of these subjects 
experience an unacceptable toxicity, accrual will continue. Otherwise, modifications of the protocol will be 
considered before accruing additional subjects.  If a patient who has not experienced an unacceptable 
toxicity does not complete 3 vaccinations, that patient will be replaced for initial study monitoring. 
Overall Adverse Event Monitoring: Rigorous monitoring of long- and short-term toxicities in a manner 
similar to that found in many phase I dose-escalation studies would require accrual suspension between 
stages of patient accrual while relevant data matures. After the initial 6 patients are accrued and safely 
receive vaccine treatment, accrual will not be suspended to formally assess the toxicity profile unless the 
following guidelines are satisfied. Rather, the study will be monitored continuously for the occurrence of 
unacceptable adverse events.  
Once accrual is resumed after the initial monitoring of the first 6 subjects, aggregate summaries of 
adverse experiences will be generated and reviewed by the clinical team every 6-12 months.  The following 
are considered adequate documentation of review:  


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• 
PI review of the aggregate summary of adverse events that is generated every 6 months for the 
DSMBplus meeting.  
• 
PI signature of the collective AE listing after review with the clinical research team.  As described 
in Section 13.1.1, the PI will periodically review the collective adverse event listing with the 
clinical research team with the intention of identifying any trends or patterns in toxicity on a 
monthly basis.   
Tabulated below are the conditions under which accrual will be temporarily suspended and data 
carefully reviewed to determine the appropriate action, including permanent study termination, continuation 
with patient accrual after appropriate amendment, or continuation with patient accrual with no modification 
of the protocol (Table 3). Accrual will also be suspended whenever a death occurs that is possibly, probably, 
or definitely related to treatment with vaccine alone or vaccine and TMZ. 
Table 3. Conditions under Which Accrual will be Suspended 
Number of 
patients accrued 
Number of patients 
with unacceptable 
toxicity requiring 
accrual suspension 
6-7 
≥3 
8-10 
≥4 
11-14 
≥5 
>14 
≥5 
 
These guidelines have not been adjusted for differential length of follow-up of accrued patients. The 
probability of accrual suspension as a function of the true unacceptable toxicity rate is tabulated below 
based upon simulation studies (Table 4). These statistics were generated assuming toxicity outcome was 
known at the time of accrual, and ignored issues such as time to toxicity, accrual rate, and length of follow-
up. 
Table 4. Probability of Accrual Suspension as a Function of the True Unacceptable Toxicity Rate 
Underlying 
unacceptable 
toxicity rate 
Probability 
of 
accrual 
suspension 
Expected # 
of Patients 
0.01 
0.0002 
20 
0.05 
0.005 
19.9 
0.1 
0.034 
19.6 
0.15 
0.12 
18.8 
0.2 
0.27 
17.5 
0.25 
0.46 
15.6 
0.3 
0.65 
13.6 
0.35 
0.80 
11.7 
0.4 
0.90 
10.0 
0.45 
0.96 
8.6 
0.5 
0.98 
7.8 
 
Though few or no unacceptable toxicities are expected during pre-surgery vaccine treatment, 
unacceptable toxicities possibly attributable to either TMZ or vaccine post-surgery are expected. Yung84 
reports that 18% of patients treated with TMZ alone experienced a grade 3 or 4 adverse event. Assuming 
vaccine does not increase the chances of unacceptable toxicity and an unacceptable toxicity rate of 18% 
with TMZ, the probability of study suspension due to excessive unacceptable toxicity is 0.21. If the chances 
of unacceptable toxicity increase the overall true unacceptable toxicity rate, then the chances of study 
suspension due to excessive unacceptable toxicity increases to 0.80 with an underlying unacceptable 
toxicity rate of 35%. 
Any patient who discontinues vaccination prior to the receipt of 6 vaccines will not be evaluable for the 
primary endpoint, unless the patient experienced an unacceptable toxicity.  Per Section 12.6.3, these 
patients will be replaced. Patients who are determined at the time of surgery to have transformed from 


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Grade II to a higher grade will receive TMZ and radiation therapy per standard of care and monthly vaccines 
and will be included in the final analysis of the primary objective.   
15.4.3 
Handling of missing values, censoring, and discontinuations 
If a patient does not receive any vaccine treatment, they will be excluded from all analyses.  
15.5 
Secondary Objective 
An important secondary goal of this study is to assess the immunogenicity of the PEPIDH1M vaccine alone 
and in combination with adjuvant TMZ using ELISpot. Levels of immune response will be examined after 3 
vaccinations (i.e., pre-surgery) as well as after 3 additional post-surgery vaccinations. In previous research, 
the mean (± SD) number of SFC per 106 lymphocytes for cells cultured with no peptide in previous qualified 
assays has been 4.5 ± 3.6. The mean (± SD) response for cells cultured with an irrelevant peptide (i.e., 
actin) has been determined to be 4.2 ± 6.3. Values for cells cultured with IDH1 peptide, after subtraction of 
counts from cells cultured with no peptide, will be determined. A response will be considered positive if this 
value is greater than 20 SFC per 106 lymphocytes after determining the level of detection in the IDH 
ELISpot. With 20 patients, there is 80% power to detect a difference of 4.17 SFC per 106 lymphocytes 
between response for cells cultured in IDH1 peptide and those cultured without any peptide. This power 
calculation conservatively assumes the response to IDH1 peptide and no peptide to be independent, and 
did not adjust for multiplicity. 
15.6 
Exploratory Objectives 
Exploratory objectives include: (1) estimation of overall survival and progression-free survival, (2) 
examination of the effect of ELISpot results on subsequent OS or PFS, (3) estimation of the radiographic 
response rate, (4) determination of whether tumors are IDH1 negative at surgery, (5) characterization of 
immunologic cell infiltrate, (6) determination of whether IDH R132H can be detected in plasma and whether 
the study treatment will affect the levels detected, (7) determination of whether IDH 2HG can be detected 
in plasma and whether the study treatment will affect levels detected, (8) genomic and proteomic analyses, 
and (9) an assessment of metabolic imaging. 
 
1. The Kaplan-Meier estimator will describe the survival, PFS from vaccine #1, and PFS post-resection of 
patients treated with PEPIDH1M vaccine. Survival is defined as the time between first vaccine and death, 
or last follow-up if the patient remains alive. PFS from vaccine #1 is defined as the time between vaccine 
#1 and initial progression or death, or date of last follow-up if the patient remains alive without disease 
progression. PFS post-resection is similarly defined but starting at resection. 
The proportion of patients alive without progression 6 months after resection will be estimated from the 
Kaplan-Meier estimator. 
2. Cox proportional hazards model will be used to explore the association between ELISpot outcome and 
subsequent OS or PFS. The radiographic response rate (complete response + partial response) will be 
estimated with a 95% confidence interval.  
3. The proportion of tumors that are IDH1 negative at the time of surgery will be estimated, with a 95% 
confidence interval.  
4. Means and standard deviations, as well as quantiles, will be used to describe the distribution of 
immunologic cell infiltrates found in tumors at the time of surgery. 
5. Descriptive statistics will be used to describe the changes over time in the level of IDH R132H as 
measured from tumor-specific circulating DNA.   
6. In a similar manner, changes over time in levels of the 2-HG metabolite as measured by mass 
spectrometry will be described.   
7. Genomic and proteomic analyses of the pre-treatment pathologic specimen and the post-vaccination 
surgical sample will be conducted.  Changes in genetic alterations, differential protein expressions and 
PTMs will be described.  If statistical tests are conducted, appropriate adjustment for multiplicity will be 
considered. 
8. Measures of metabolism in IDH1+ gliomas will be assessed at several time points.  Paired comparison 
(e.g. paired t-tests) will be used to assess whether same-day measures on a patient are the same.  
Assuming repeatability, changes over time in levels of metabolism will be described. 
 


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Additional exploratory analyses may be conducted.  Among these additional exploratory analyses will be 
an examination of the relationship among changes in metabolism, genomic expression, 2-HG metabolite, 
and pathologic expression of IDH. 
15.7 
Interim Analysis 
Efficacy: No interim efficacy analysis is planned.  
Safety: See section 15.4.2. 
15.8 
Sample Size Calculation 
See section 15.4.2.  
16 ADMINISTRATIVE AND ETHICAL CONSIDERATIONS 
16.1 
Regulatory and Ethical Compliance 
This protocol was designed and will be conducted and reported in accordance with the ICH Harmonized 
Tripartite Guidelines for Good Clinical Practice, the Declaration of Helsinki, and applicable federal, state, 
and local regulations. 
16.2 
DUHS Institutional Review Board and DCI Cancer Protocol 
Committee 
The protocol, informed consent form, advertising material, and additional protocol-related documents 
must be submitted to the DUHS IRB and DCI CPC for review. The study may be initiated only after the 
Principal Investigator has received written and dated approval from the CPC and IRB. 
The Principal Investigator must submit and obtain approval from the IRB for all subsequent protocol 
amendments and changes to the informed consent form. The CPC should be informed about any protocol 
amendments that potentially affect research design or data analysis (i.e., amendments affecting subject 
population, inclusion/exclusion criteria, agent administration, statistical analysis, etc.). 
The Principal Investigator must obtain protocol re-approval from the IRB within 1 year of the most recent 
IRB approval. The Principal Investigator must also obtain protocol re-approval from the CPC within 1 year 
of the most recent IRB approval, for as long as the protocol remains open to subject enrollment. 
16.3 
Informed Consent 
The informed consent form must be written in a manner that is understandable to the subject population. 
Prior to its use, the informed consent form must be approved by the IRB. 
The Principal Investigator or authorized key personnel will discuss with the potential subject the purpose 
of the research, methods, potential risks and benefits, subject concerns, and other study-related matters. 
This discussion will occur in a location that ensures subject privacy and in a manner that minimizes the 
possibility of coercion. Appropriate accommodations will be made available for potential subjects who 
cannot read or understand English or are visually impaired. Potential subjects will have the opportunity to 
contact the Principal investigator or authorized key personnel with questions, and will be given as much 
time as needed to make an informed decision about participation in the study. 
Before conducting any study-specific procedures, the Principal Investigator must obtain written 
informed consent from the subject. The original informed consent form will be stored with the subject’s 
study records, and a copy of the informed consent form will be provided to the subject. The Principal 
Investigator is responsible for asking the subject whether the subject wishes to notify his/her primary care 
physician about participation in the study. If the subject agrees to such notification, the Principal Investigator 
will inform the subject’s primary care physician about the subject’s participation in the clinical study. 
The prospective participant will have as much time as he/she may need to make an informed decision 
about the study and all treatment related questions will be answered. Prospective participants will be 
consented in an exam room where it is just the research staff, the patient and his/her family, if so desired 
by the patient. Before, during, and after the consent is signed, the research team and investigators will be 
available in person and by phone to answer any questions the participants may have. Any and all other 
available treatment options are offered to the patient in order to avoid undue influence. Participants are not 
offered compensation for this study in order to avoid any monetary coercion/influence. 


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For those who cannot read or are blind, the consenter will read the consent form verbatim to those who 
are illiterate or to those who are blind in the presence of a witness. If the subject decides to participate, they 
will sign the consent form, or if they are unable to sign, make another kind of mark (like an X) to indicate 
consent. The person obtaining consent will document at the bottom of the consent form that the consent 
form was read out loud to the patient by (name of person obtaining consent). If an X or mark is used instead 
of a signature, the person obtaining consent will note on the consent form that the subject wrote a mark or 
X instead of a signature. The witness will sign the consent form. Subjects who do not read/understand 
English may be potentially enrolled following DUHS HRPP policy, including obtaining IRB approval of either 
a short form or long form consent translation. 
All of the potential subjects are patients of the PI and the PRTBTC. Patients will be recruited for this 
study as follows: Upon determination that a patient’s tumor histology and radiographic findings are 
compatible with the eligibility criteria of this protocol, the clinical study will be briefly explained to the patient 
by the principal investigator (PI) or colleague. If the patient indicates interest in study participation, patient 
education sheets and possibly the protocol consent form will be provided to the patient as these provide 
the most comprehensive explanation of the study in lay terms. If the patient shows continued interest, the 
PI or designee will thoroughly explain the required elements of informed consent and all aspects of the 
study to the subject including inclusion/exclusion criteria, risks, benefits and alternatives to study 
participation. 
16.4 
Privacy, Confidentiality, and Data Storage 
The Principal Investigator will ensure that subject privacy and confidentiality of the subject’s data will 
be maintained. RDSPs will be approved by the appropriate institutional Site Based Research group. 
To protect privacy, every reasonable effort will be made to prevent undue access to subjects during the 
course of the study. Prospective participants will be consented in an exam room where it is just the research 
staff, the patient and his family, if desired. For all future visits, interactions with research staff (study doctor 
and study coordinators) regarding research activities will take place in a private exam room. All research 
related interactions with the participant will be conducted by qualified research staff who are directly 
involved in the conduct of the research study. 
To protect confidentiality, subject files in paper format will be stored in secure cabinets under lock and 
key accessible only by the research staff. Subjects will be identified only by a unique study number and 
subject initials. Electronic records of subject data will be maintained using an electronic database housed 
by the DCI. Access to electronic databases will be limited to protocol personnel. Data stored on portable 
memory devices will be de-identified. The security and viability of the IT infrastructure will be managed by 
the DCI and/or Duke Medicine.  
Upon completion of the study, research records will be archived and handled per DUHS HRPP policy.  
Subject names or identifiers will not be used in reports, presentations at scientific meetings, or 
publications in scientific journals. 
16.5 
Data and Safety Monitoring 
Data and Safety Monitoring will be performed in accordance with the DCI Data and Safety Monitoring 
Plan.  
The Principal Investigator, CPC and DUHS IRB assess the adequacy of proposed Data and Safety 
Monitoring Plans during initial and ongoing review and ensure inclusion of adverse event reporting 
guidelines in each protocol. The sponsor-investigator is responsible for reporting all applicable events to 
the appropriate regulatory agencies as described in the protocol. 
Protocols sponsored by the NCI Cooperative Group Program (e.g., ECOG, GOG, NSABP, ADOSOG, 
SWOG, RTOG, and CTSU) are monitored by established centralized data and safety monitoring programs 
within each cooperative group. 
Phase III and IV protocols (e.g., NIH-supported, large-scale, multi-site phase III therapeutic intervention 
protocols which involve significant risk) are outside the scope of this monitoring and safety review system. 
Independent DSMBs for such studies should be established by the sponsor-investigator. NIH-supported 
phase III clinical protocols which involve only low risk (e.g. behavioral and nutritional interventions) will be 
reviewed by CPC on a case-by- case basis, as their sample size may be too large to be practically 
monitored by this system. 


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It is recognized that protocols with corporate sponsors and protocols sponsored by NCI cooperative 
groups are continually audited for compliance and assessed for scientific progress. DUHS sponsor-
investigator protocols without outside sponsorship however, are not, and are the focus of this monitoring 
plan.  
 
Safety Oversight Committee Protocol Review 
The Safety Oversight Committee conducts annual data and safety monitoring for DUHS sponsor-
investigator phase I and II, therapeutic interventional studies that do not have an independent DSMB. 
Annual safety reviews include review of safety data, enrollment status, stopping rules if applicable, accrual, 
toxicities, reference literature, and interim analyses as provided by the sponsor-investigator. Studies are 
rated satisfactory when adequate accrual with lack of excessive toxicity is present. 
The sponsor-investigator submits a Safety Oversight Committee Safety Report to the Safety Oversight 
Committee annually, upon request, or the data may be submitted simultaneously with required reporting, 
e.g., FDA annual report. Attachments (e.g., accrual tables, toxicities and reference literature) are also 
acceptable for Safety Oversight Committee review. The sponsor-investigator is notified in writing if 
additional information is needed and if protocol or operational changes are required. The Safety Oversight 
Committee will notify the sponsor-investigator and DUHS IRB when significant safety concerns are 
identified. The Safety Oversight Committee Chair has the authority to temporarily suspend accrual to the 
study pending acceptable changes. Any recommendation for temporary or permanent suspension of an 
NIH-funded clinical protocol will be reported by the sponsor-investigator via written communication to the 
responsible NCI grant program director. 
 
DCI Monitoring Team 
The DCI Monitoring Team is comprised of individuals who do not have a direct working relationship 
with the sponsor-investigator or research team. This independence of DCI Monitoring Team composition is 
intended to prevent conflicts of interest and breaches of confidentiality during monitoring visits. 
The DCI Monitoring Team conducts monitoring visits as defined by CPC, on DUHS sponsor-
investigator therapeutic intervention and prevention intervention studies that do not have an external 
monitoring plan, ensuring subject safety and that the protocol is conducted, recorded and reported in 
accordance with the protocol, SOPs, GCP, and applicable regulatory requirements. The Monitoring Team 
also provides ongoing education and resources to investigators and study teams to enhance the quality. 
Standard monitoring for therapeutic intervention and prevention intervention studies is routine 
monitoring after the third subject is enrolled, followed by annual monitoring of 1-3 subjects until the study is 
closed to enrollment and subjects are no longer receiving study interventions that are more than minimal 
risk. At the time of CPC review, the CPC may assign monitoring requirements in addition to the standard 
monitoring plan, as summarized in Table 1 on the next page. Also, additional monitoring may be prompted 
by findings from monitoring visits, unexpected frequency of serious and/or unexpected toxicities, or other 
concerns and may be initiated upon request of DUHS and DCI Leadership, CPC, Safety Oversight 
Committee, a sponsor, an investigator or the IRB. 
SOC members serve as an expert resource and back-up for the DCI Monitoring Team. The DCI 
Monitoring Team reviews the adequacy of informed consent, enrollment of appropriate patients, 
implementation of protocol-specified procedures and treatment, adequacy of data collection, and 
appropriateness of adverse event monitoring and reporting. 
16.6 
Protocol Amendments 
All protocol amendments must be initiated by the Principal Investigator and approved by the IRB prior 
to implementation. IRB approval is not required for protocol changes that occur to protect the safety of a 
subject from an immediate hazard. However, the Principal Investigator must inform the IRB and all other 
applicable regulatory agencies of such action immediately. 
Though not yet required, the CPC should be informed about any protocol amendments that potentially 
affect research design or data analysis (i.e., amendments affecting subject population, inclusion/exclusion 
criteria, agent administration, etc.). 
16.7 
Records Retention 
The Principal Investigator will maintain study-related records for the longer of a period of: 


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• 
at least two years after the date on which a New Drug Application is approved by the FDA  
• 
at least two years after formal withdrawal of the IND associated with this protocol 
• 
at least six years after study completion (Duke policy) 
16.8 
Conflict of Interest 
The Principal Investigator and Sub-Investigators must comply with applicable federal, state, and local 
regulations regarding reporting and disclosure of conflict of interest. Conflicts of interest may arise from 
situations in which financial or other personal considerations have the potential to compromise or bias 
professional judgment and objectivity. Conflicts of interest include but are not limited to royalty or consulting 
fees, speaking honoraria, advisory board appointments, publicly-traded or privately-held equities, stock 
options, intellectual property, and gifts. 
The Duke University School of Medicine’s RIO reviews and manages research-related conflicts of 
interest. The Principal Investigator and Sub-Investigators must report conflicts of interest annually and 
within 10 days of a change in status, and when applicable, must have a documented management plan 
that is developed in conjunction with the Duke RIO and approved by the IRB/IEC. 
16.9 
Costs to the Subject 
The costs of the study drug, Td, blood for immune monitoring, and the leukapheresis associated with 
this study are provided free of charge. The patient or third party payer (HMO or insurance company) will be 
responsible for all other medical costs including the standard of care chemotherapy, radiation therapy (if 
applicable), blood work, and MRI scans. Some insurance companies and HMOs may not reimburse patients 
for costs arising from investigational studies. No compensation for participation in this study will be given. 
16.10 
Registration Procedure 
After patients have been enrolled, protocol-specific information and subject registration will be entered 
into the Velos e-Research software system. This system is managed by the School of Medicine. Patients 
will also be entered under this protocol study in the Duke Epic Maestro Care system.  
 
 
 


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83. 
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18 APPENDICES 
18.1 
Protocol Synopsis and Summary 
Please see separate documents (available upon request). 
 
 
 


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18.2 
Special or Representative SOPs and FORMs 
Please see separate documents (available upon request). 
 
 


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18.3 
DSMBplus Monitoring Plan 
Please see separate document (available upon request). 
 
 
 
 


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18.4 
Standard Radiation Therapy 
Radiotherapy typically begins within ≤ 5 weeks of surgery. One treatment of 1.8-2.0 Gy/fraction should 
be given daily 5 days per week for a total of 59.4-60.0 Gy over <7 weeks. 3D conformal and intensity-
modulated RT is permitted. All portals should be treated during each treatment session. Doses are specified 
as the target dose that shall be to the center of the target volume.  
 
The gross target volume (GTV) for both the initial volume (GTV1) and the conedown volume (GTV2) 
should be based on the postoperative CT/MRI (and preferably the MRI; the preoperative scans may be 
used if postoperative scans are not available). This initial target volume (GTV1) should include the contrast-
enhancing lesion (and should include the surgical resection cavity) and surrounding edema (if it exists) 
demonstrated on CT/MRI plus a 2.0-cm margin (this 2.0-cm margin-extended volume will be considered 
the initial planning target volume, or PTV1). The initial target volume should be treated to 46 Gy at 
2Gy/fraction or 45-50.4 Gy at 1.8Gy/fraction. If no surrounding edema is present, the initial planning target 
volume (PTV1) should include the contrast-enhancing lesion (and should include the surgical resection 
cavity) plus a 2.5-cm margin. Please note that clinical judgment may be used to modify PTV1 to exclude 
sensitive structures such as the optic chiasm, non-cranial contents, or anatomic regions in the brain where 
natural barriers would likely preclude microscopic tumor extension, such as the cerebellum, the 
contralateral hemisphere, directly across from the tentorium cerebri, the ventricles, etc. After 46 Gy, the 
tumor volume (GTV2) for the conedown treatment should include the contrast-enhancing lesion (without 
edema) on the pre-surgery CT/MRI scan plus a 1.5-2-cm margin (PTV2). Treat to 14 Gy at 2Gy/fraction or 
14.4-9.0 Gy at 1.8Gy/fraction to a total of 60.0 or 59.4Gy, respectively. 
 
Dose is prescribed to the isodose line such that at least 95% of the target volume receives he prescribed 
dose. 
 
The optic apparatus should be limited to a maximum of 54Gy and no more than 5% of the volume of 
the brainstem should receive >54Gy. 
 
Radiation should be delayed or interrupted if the platelet count is < 20,000. Radiation should not begin 
or resume until the platelet count is ≥ 20,000. Hematologic toxicities should be rated on a scale of 0-5 as 
defined in the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.  If radiotherapy 
has to be temporarily interrupted for technical or medical reasons unrelated to the temozolomide 
administration, then treatment with daily temozolomide should continue. If radiotherapy has to be 
permanently interrupted then treatment with daily temozolomide should stop.  The following should be 
recorded at entry into this study: daily treatment record, all isodose distributions (in color), dose volume 
histograms including the cumulative dose to the target volumes, optic chiasm, optic nerves and brain stem, 
and the radiotherapy summary. 
 
 


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18.5 
Temozolomide Therapy 
18.5.1 
Concurrent TMZ and RT 
For subjects who progress to Grade 3 at the time of surgery, TMZ should be administered concomitant 
with standard external beam RT under the direction of the study Neuro-Oncologists (listed on title page), or 
their designees, respectively, at Duke University or another institution at the standard dose per discretion 
of the treating neuro-oncologist.  During standard RT, subjects will receive 75mg/m2/day TMZ for 42 days 
(6 weeks).  
 
Per the new NCI Temozolomide (NSC 362856) Action Letter: 
o 
Liver function tests (or CMP) should be performed: 
 
prior to treatment initiation. If abnormal, the decision to initiate temozolomide 
treatment should carefully consider the benefits and risks for the individual patient; 
 
after each treatment cycle. 
o 
For patients on a 42 day treatment cycle, liver function tests should be repeated midway 
during this cycle; 
o 
For patients with significant liver function abnormalities the benefits and risks of continuing 
treatment should be carefully considered. 
 
If any interruption occurs or dose reduction is required, TMZ may be resumed when re-treatment criteria 
are met as outlined in Table 5 and Table 6.   
 
Dose reduction or alteration during this period due to toxicity is standardly performed as outlined in 
Table 5. 
 
Table 5: Temozolomide Dosing Interruption or Discontinuation during Concomitant Radiotherapy 
Toxicity  
TMZ Interruptiona  
TMZ Discontinuation  
Absolute Neutrophil Count  
>0.5 and <1.0 x 109/L  
<0.5 x 109/L  
Platelet Count  
>10 and <100 x 109/L  
<10 x 109/L  
Common 
toxicity 
criteria 
(CTC2) 
Non-
hematological Toxicity (except for alopecia, 
nausea, vomiting)  
CTC Grade 2  
CTC Grade 3 or 4  
a: Treatment with concomitant TMZ can be continued when all of the following conditions are met: 
absolute neutrophil count >1.0 x 109/L; platelet count >100 x 109/L; CTC non- hematological toxicity 
<Grade 1 (except for alopecia, nausea, vomiting).  
 
The dose may be modified as outlined in Table 6 at the discretion of the treating oncologist. 
 
Table 6. Dose Modifications of Temozolomide during Radiation Therapy 
Dose at Toxicity 
Modified Dose 
75 mg/m2 (during XRT) 
60 mg/m2 
60 mg/m2 (during XRT) 
50 mg/m2 
 
18.5.2 
Guidelines for 21-day TMZ Therapy 
Subjects with stable histologic grade at time of surgery (Grade 2) will be treated with adjuvant TMZ at 
a targeted dose of 50-100mg/m2/day for 21 days every 28 days for up to 12 cycles.  Subjects that progress 
to Grade 3 at the time of surgery will receive SOC RT with TMZ x 6 weeks following surgery. Once RT is 
complete, subjects that progressed to Grade 3 at the time of surgery will have a 3 ± 1 week break before  
                                                     
2 CTC, common toxicity criteria (NCI) 


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resuming TMZ (Table 7). Then, subjects should receive TMZ at a targeted dose of 50-100 mg/m2/day for 
21 days every 28 days for up to 12 cycles.  A CBC with auto differential (Lab Code 2010300) should be 
obtained at the end of each cycle for all subjects receiving 21-day TMZ. 
 
Table 7. Criteria to Resume Temozolomide after Radiation 
Absolute Neutrophil Count ≥ 1.0 x 109/L 
Platelet Count ≥ 100 x 109/L 
Resolution of CTC Non-hematologic toxicities to Grade 2 or less. 
 
Because of the risk of opportunistic infections in patients receiving TMZ, patients may receive antibiotic 
prophylaxis at the discretion of the primary Neuro-Oncologist, consisting of inhaled pentamidine or oral 
levofloxacin.  Antiemetic prophylaxis with metoclopramide or a 5-hydroxytryptamine3 antagonist will also 
be recommended before the initial doses of concomitant TMZ and may be used during the adjuvant 21-day 
course of TMZ. 
 
All subjects will start 21-day TMZ cycle 1 at a dose of 50mg/m2/day, and the dose may be increased 
up to 100mg/m2/day in subsequent cycles at the discretion of the treating physician.  During 21-day TMZ 
treatment (28 day cycles), dose adjustments to TMZ, if needed, may be conducted as outlined below: 
 
Table 8. Temozolomide Dose Delay, Reduction, or Discontinuation During 21-day Treatment 
Toxicity  
Delay TMZ Dose a 
Reduce TMZ by 25%  
(down to minimum of 50 
mg/m2) b 
Discontinue TMZ  
Absolute Neutrophil Count  >0.5 and <1.0 x 109/L 
>0.5 and <1.0 x 109/L 
<0.5 x 109/L  
Platelet Count  
>10 and <100 x 109/L 
>10 and <100 x 109/L 
<10 x 109/L  
CTC 
Non-hematological 
Toxicity 
(except 
for 
alopecia, nausea, vomiting) 
CTC Grade 3 
CTC Grade 3  
CTC Grade 4 c  
 
a: If dose is delayed, treatment with TMZ can resume when the following 
conditions are met: absolute neutrophil count >1.0 x 109/L; platelet count 
>100 x 109/L; CTC non-hematological toxicity resolved to baseline (except 
for alopecia, nausea, vomiting). 
b: For subjects whose dose was escalated above 50 mg/m2 at the discretion 
of treating physician 
c: TMZ is to be discontinued if dose reduction to <50 mg/m2 is required or if 
the same Grade 3 non-hematological toxicity (except for alopecia, nausea, 
vomiting) recurs after dose reduction or delay.