Conditions: Platinum Sensitive Ovarian Cancer Ovarian Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 120
Healthy volunteers: no

Brief summary:
This is a double-blind, randomized, parallel groups Phase II trial. Patients with platinum-sensitive advanced ovarian cancer, defined as a lack of progression by RECIST v1.1 criteria following completion of standard-of-care chemotherapy, including a minimum of 4 cycles of a platinum-containing regimen. Patients will be randomized to either the vaccine regimen with GM-CSF adjuvant or GM-CSF adjuvant alone as a control group. Treatment will be administered as a consolidation therapy within one year of the last administration of platinum, targeting the first remission.

Detailed description:
This is a multicenter double-blind controlled randomized Phase II study to evaluate the activity of folate receptor alpha (FRα) peptide vaccine as a consolidation treatment following completion of no less than 4 cycles of a platinum containing regimen in patients with platinum-sensitive, non-mucinous ovarian, fallopian tube or primary peritoneal cancer.

The patients will have demonstrated a tumor response or stable disease upon their last regimen (per RECIST v1.1 and/or CA125 GCIG criteria) prior to enrolment in this study.

Following randomization, patients will be administered TPIV200 with GM-CSF adjuvant or GM-CSF control alone. Patients will have booster doses and tumor assessments done every 12 weeks ± 1 week for up to 1.5 years, until objective disease progression or the patient withdraws consent. Tumor responses will be assessed at the study sites by evaluating tumor images/scans according to RECIST v1.1.

Arms:
arm 1: FRα peptide vaccine with GM-CSF adjuvant ID administration monthly for 6 months followed by booster administrations every 3 months for up to 1.5 years arm 2: GM-CSF adjuvant alone ID administration monthly for 6 months followed by booster administrations every 3 months for up to 1.5 years

Interventions: intervention 1: FRα peptide plus Adjuvant (GM-CSF) intervention 2: Adjuvant (GM-CSF) Alone
Intervention descriptions: intervention 1: Intradermal injection FRα peptides, 500μg each - plus GM-CSF 125 μg intervention 2: Intradermal injection 125 μg GM-CSF

Protocol document:
Prot_000.pdf: 
 
 
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Folate receptor peptide vaccine in platinum- 
 
Protocol FRV-004 v04 
sensitive ovarian cancer 
 
12 Apr 2018  
 
 
 
Confidential – TapImmune Inc. 
Document Number FRV-011-004
 
 
 
 
 
CLINICAL PROTOCOL 
 
 
A randomized multicenter Phase II trial to evaluate the safety, efficacy and immunogenicity of 
vaccination with Folate Receptor Alpha peptides admixed with GM-CSF as a vaccine adjuvant 
versus GM-CSF alone in patients with Platinum Sensitive Ovarian Cancer and a response or stable 
disease to platinum therapy 
 
 
 
Protocol Number:  
 
 
FRV-004 
 
 
Document Number:  
 
 
FRV-011-004  
 
Investigational Agent: 
TPIV200 (FRα vaccine with GM-CSF adjuvant) 
 
Sponsor:  
TapImmune Inc. 
5 West Forsyth Street; Suite 200 
Jacksonville, FL 32202 
 
Trial Registration Numbers 
ClinicalTrials.gov # NCT02978222 
 
BB IND #14546 
 
Version and Date:  
 
 
04, 12 Apr 2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIALITY STATEMENT 
This document contains confidential information of TapImmune, Inc. (the Sponsor) which must not be reproduced, 
published, or otherwise disclosed to anyone other than the recipient(s), members of the ethics committee(s) or regulatory 
authorities. The document and the information contained herein cannot be used for any purpose other than the evaluation 
or conduct of the clinical investigation described in this document without prior written approval from TapImmune. The 
foregoing shall not apply to disclosure required by applicable laws or governmental regulations. Notice must be provided 
to TapImmune of any such disclosure as soon as practicable. 


 
 
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INVESTIGATOR AGREEMENT PAGE 
 
As an Investigator, I agree to the following: 
 
Keep all documentation supplied to me or developed by me concerning this study, and that has 
not been previously published, in the strictest confidence. This documentation includes, but is not 
limited to, the protocol, the Investigator’s Brochure (IB), and Case Report Forms (CRFs). 
 
That the study will not commence without prior written approval of a properly constituted 
Institutional Review Board (IRB). No changes will be made to the study protocol or consent 
forms without prior written approval of the Sponsor and the Institutional Review Board, except 
where necessary to eliminate an immediate hazard to patients. 
 
Implement and conduct the study diligently and in strict compliance with the protocol, good 
clinical practices, and all applicable laws and regulations. 
 
Accurately transfer all required data from each patient’s source documentation to the CRFs. The 
original CRFs will be submitted to the Sponsor in a timely manner at the completion of the trial, 
or as otherwise specified by the Sponsor. 
 
Keep a complete and accurate accounting during and at the completion of the trial of all 
procedures performed with the drug provided by the Sponsor. 
 
Allow authorized representatives of the Sponsor or regulatory authority representatives to 
conduct on-site visits to receive, review, audit, and copy trial documents. I will personally meet 
with these representatives at mutually convenient times to answer any trial-related questions. 
 
Provide the Sponsor with an Investigator’s summary within 90 days of completion of the final 
trial visit for the last patient enrolled, or as designated by Sponsor. 
 
Maintain all information supplied by the Sponsor in confidence and, when this information is 
submitted to an IRB or another group, it will be submitted with a designation that the material is 
confidential. 
 
This protocol was designed and will be conducted, recorded, and reported in compliance with the 
principles of Good Clinical Practice (GCP) guidelines. These guidelines are stated in U.S. Federal 
Regulations as well as “Guidance for Good Clinical Practice,” International Conference on 
Harmonisation (ICH) of the Technical Requirements for Registration of Pharmaceuticals for Human Use 
(E6). 
 
I have read this protocol in its entirety, including the preceding statements, and I agree to comply with all 
aspects of this trial. 
 
_______________________________ _______________________________ _________________ 
Investigator Printed Name 
 
Investigator Signature   
 
Date 
 
_______________________________ 
Institution Name 
 
AGREEMENT TO THE PROTOCOL BY THE SPONSOR 
 
 Richard T. Kenney, MD, FACP          
_______________________________ 12 Apr 2018 
TapImmune Medical Monitor 
 
Signature 
 
 
 
Date 
Email: rkenney@tapimmune.com 
 
 James Potts, PhD, MPH                       _______________________________ 12 Apr 2018 
Statistician 
 
 
 
Signature 
 
 
 
Date 


 
 
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sensitive ovarian cancer 
 
12Apr 2018  
 
 
Confidential – TapImmune Inc. 
Document Number FRV-011-004 
 
SPONSOR PERSONNEL 
 
Medical Monitor: 
Richard T. Kenney, MD 
TapImmune Inc. 
Phone: 206-946-8012 
Mobile: 415-741-6990 
Email: rkenney@tapimmune.com 
 
 
PROTOCOL ADVISORY COMMITTEE 
 
Dr. Robert M. Wenham (Chair) 
Department of Gynecological Oncology 
Moffitt Cancer Center  
Tampa, Florida 
 
Dr. Matthew S. Block 
Department of Medical Oncology 
Mayo Clinic 
Rochester, Minnesota 
 
Dr. Jason Konner  
Gynecological Medical Oncology 
Memorial Sloan Kettering Cancer Center 
New York, New York 
 
 
PROTOCOL REVISION HISTORY 
 
Version 
Date 
Comment 
01 
15Aug16 
Initial version 
02 
21Feb17 
Revised the disease assessment and randomization paradigms, adjusted 
histological subtypes, extended follow-up for survival, updated statistical 
justification with increased study size, added an interim analysis, clarified 
SAE reporting, and administrative edits 
03 
2May17 
1. Revised the population to target first remission and increased the total 
number of patients to 120 
2. Added booster vaccine doses at each follow-up visit 
3. Allow inclusion of patients with inactive auto-immune disease 
4. Clarified the required tests and procedures 
04 
12Apr18 
1. Removed ANA as a safety lab and entry criterion 
2. Clarified prior cancer exclusion 
3. Clarified thyroid antibody testing and administrative details 


 
 
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Document Number FRV-011-004 
TABLE OF CONTENTS 
INVESTIGATOR AGREEMENT PAGE ................................................................................................ 2 
PROTOCOL REVISION HISTORY ........................................................................................................ 3 
TABLE OF CONTENTS ........................................................................................................................... 4 
1. 
SYNOPSIS .................................................................................................................................... 9 
2. 
BACKGROUND AND RATIONALE ...................................................................................... 13 
2.1. 
OVARIAN CANCER IS A SERIOUS CONDITION ASSOCIATED WITH SIGNIFICANT MORTALITY ...... 13 
2.2. 
AN UNMET MEDICAL NEED EXISTS DESPITE AVAILABLE FDA APPROVED THERAPIES TO TREAT 
OVARIAN CANCER ...................................................................................................................... 13 
2.3. 
FOLATE RECEPTOR ALPHA AS AN IMMUNOTHERAPY TARGET ................................................... 14 
2.3.1. 
FRα as a vaccine target for ovarian cancer .......................................................................... 14 
2.3.2. 
The FRα may be an ideal target for a peptide vaccine targeting both Th cell, CTL 
and antibody immunity ......................................................................................................... 15 
2.3.3. 
Patients naturally develop immune responses to the FRα demonstrating the 
existence of a T cell repertoire. ............................................................................................ 15 
2.3.4. 
Scientific Rationale for Th peptides as Therapeutic cancer vaccines .................................. 16 
2.3.5. 
Clinical rationale for FRα vaccine strategy. ........................................................................ 17 
2.3.6. 
Booster Vaccination ............................................................................................................. 18 
2.4. 
PREVIOUS CLINICAL EXPERIENCE WITH FRΑ AS A THERAPEUTIC TARGET IN OVARIAN CANCER
 ..................................................................................................................................................... 18 
2.5. 
PRECLINICAL CANCER MODEL WITH FRΑ PEPTIDE VACCINE ...................................................... 19 
2.6. 
PREVIOUS HUMAN EXPERIENCE. ................................................................................................. 21 
3. 
OBJECTIVES ............................................................................................................................ 22 
3.1. 
PRIMARY OBJECTIVES: ................................................................................................................ 22 
3.2. 
SECONDARY OBJECTIVES: ........................................................................................................... 23 
3.3. 
EXPLORATORY OBJECTIVES ........................................................................................................ 23 
4. 
MATERIALS AND METHODS .............................................................................................. 23 
4.1. 
STUDY DESIGN ............................................................................................................................ 23 
4.2. 
STUDY SITES ............................................................................................................................... 24 
4.3. 
STUDY POPULATION .................................................................................................................... 24 
4.3.1. 
Patient Screening and Enrollment ........................................................................................ 24 
4.3.2. 
Criteria for Inclusion ............................................................................................................ 24 
4.3.3. 
Criteria for Exclusion ........................................................................................................... 25 
4.4. 
PATIENT REPLACEMENT .............................................................................................................. 26 
4.5. 
DESCRIPTION OF CLINICAL SUPPLIES .......................................................................................... 26 
4.5.1. 
FRα peptide vaccine ............................................................................................................. 26 
4.5.2. 
Sargramostim (Leukine®, GM-CSF) .................................................................................... 26 
4.6. 
VACCINATION BY ID INJECTIONS ................................................................................................ 27 
5. 
STUDY PLAN ............................................................................................................................ 28 
5.1. 
STUDY TABLE.............................................................................................................................. 28 
5.2. 
PRE-TREATMENT PERIOD ............................................................................................................ 30 
5.2.1. 
Screening Procedures ........................................................................................................... 30 
5.2.2. 
Informed Consent ................................................................................................................. 30 
5.3. 
METHOD OF ASSIGNING TREATMENT NUMBERS TO PATIENTS .................................................. 30 


 
 
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5.4. 
PATIENT ASSESSMENT AT BASELINE PRIOR TO VACCINATION .................................................. 30 
5.5. 
STUDY PERIODS .......................................................................................................................... 31 
5.5.1. 
Evaluation During the Vaccination Period ........................................................................... 31 
5.5.2. 
Booster Vaccinations and Evaluation During Study Follow-up .......................................... 31 
5.5.3. 
Methods for Unblinding of the Study ................................................................................... 31 
5.5.4. 
Dosing Schedule ................................................................................................................... 32 
5.5.5. 
Vaccine Schedule Modification and Discontinuation. ......................................................... 32 
5.5.6. 
Criteria for discontinuation of vaccination ........................................................................... 33 
5.5.7. 
Accountability of Study Drug .............................................................................................. 33 
5.6. 
DESCRIPTION OF ADVERSE EVENTS ............................................................................................ 34 
5.6.1. 
Serious Adverse Event, Pregnancy and Adverse Events of Special Interest ........................ 35 
5.6.2. 
Concomitant Medications .................................................................................................... 35 
5.7. 
CRITERIA FOR DISCONTINUATION .............................................................................................. 36 
5.8. 
WITHDRAWAL OF A SUBJECT PRIOR TO STUDY COMPLETION .................................................... 36 
6. 
BIOSPECIMENS FOR RESEARCH ...................................................................................... 38 
6.1. 
SUMMARY TABLE OF RESEARCH BLOOD SPECIMENS TO BE COLLECTED .................................. 38 
6.2. 
COLLECTION AND PROCESSING ................................................................................................... 39 
6.2.1. 
Collection will be done in the following order from a peripheral vein or port (where 
order is reversed): ................................................................................................................. 39 
6.2.2. 
Processing, Shipping, and Handling ..................................................................................... 39 
6.2.3. 
Methodology ........................................................................................................................ 39 
7. 
PATHOLOGY CONSIDERATIONS/TISSUE BIOSPECIMENS ....................................... 40 
7.1. 
RESEARCH TISSUE SPECIMENS TO BE COLLECTED FOR THIS PROTOCOL ................................... 40 
7.2. 
TISSUE COLLECTION FOR IHC .................................................................................................... 40 
8. 
SAFETY STOPPING RULES .................................................................................................. 40 
9. 
ANALYSIS OF STUDY END-POINTS AND STATISTICS ................................................. 42 
9.1. 
RANDOMIZATION AND STRATIFICATION ..................................................................................... 42 
9.2. 
JUSTIFICATION OF SAMPLE SIZE ................................................................................................. 42 
9.3. 
DATA COLLECTION ..................................................................................................................... 43 
9.4. 
EFFICACY PARAMETERS .............................................................................................................. 43 
9.4.1. 
Radiological efficacy assessment ......................................................................................... 43 
9.4.2. 
Methods of assessment ......................................................................................................... 44 
9.4.3. 
Derivation or calculation of outcome variable ..................................................................... 45 
9.4.4. 
Tumor assessments for patients with non-measurable disease only at baseline ................... 45 
9.4.5. 
Methods for Evaluation of Disease ...................................................................................... 45 
9.4.6. 
Response Criteria ................................................................................................................. 46 
9.5. 
DATA ANALYSIS.......................................................................................................................... 48 
9.5.1. 
Demographics, Baseline and Other Characteristics ............................................................. 49 
9.5.2. 
Safety and Tolerability ......................................................................................................... 49 
9.5.3. 
Evaluation for Efficacy ........................................................................................................ 49 
9.5.4. 
FRα tumor expression .......................................................................................................... 50 
9.5.5. 
Immune Monitoring ............................................................................................................. 50 
9.5.6. 
Exploratory Correlative Research ........................................................................................ 51 
10. 
MANAGEMENT AND REPORTING OF SAES AND SPECIAL SITUATIONS .............. 51 
10.1. DEFINITION OF SERIOUS ADVERSE EVENTS ................................................................................ 51 


 
 
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10.2. SPECIAL SITUATIONS FOR REPORTING ........................................................................................ 52 
10.2.1. Adverse Events of Special Interest ....................................................................................... 52 
10.2.2. Secondary Malignancy ......................................................................................................... 52 
10.2.3. Pregnancy ............................................................................................................................. 52 
10.3. REPORTING PROCEDURES ........................................................................................................... 53 
11. 
ETHICAL ASPECTS ................................................................................................................ 53 
11.1. ETHICS AND GOOD CLINICAL PRACTICE ..................................................................................... 53 
11.2. REGULATORY FILES .................................................................................................................... 54 
11.3. CONFIDENTIALITY REGARDING STUDY SUBJECTS ..................................................................... 54 
11.4. FINANCIAL DISCLOSURE ............................................................................................................. 54 
11.5. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE ....................................... 54 
11.6. INFORMED CONSENT ................................................................................................................... 54 
12. 
ADMINISTRATIVE REQUIREMENTS ................................................................................ 55 
12.1. MONITORING PROCEDURES ........................................................................................................ 55 
12.2. PROTOCOL DEVIATION ................................................................................................................ 55 
12.3. INVESTIGATIONAL SITE TRAINING .............................................................................................. 55 
12.4. RECORDING OF DATA AND RETENTION OF DOCUMENTS ............................................................ 55 
12.5. DISCLOSURE AND CONFIDENTIALITY ......................................................................................... 56 
12.6. DISCONTINUATION OF STUDY ..................................................................................................... 56 
13. 
DATA MANAGEMENT ........................................................................................................... 56 
13.1. DATA COLLECTION ..................................................................................................................... 56 
13.2. DATA CLARIFICATION ................................................................................................................. 56 
14. 
REFERENCES ........................................................................................................................... 57 
15. 
APPENDIX 1: ECOG / KARNOFSKY PERFORMANCE STATUS .................................. 62 
16. 
APPENDIX 2: IMMUNE MONITORING METHODS ........................................................ 63 
16.1. BACKGROUND ............................................................................................................................. 63 
16.2. METHODS .................................................................................................................................... 63 
16.2.1. FRα-specific antibody enzyme-linked immunosorbent assay ............................................. 63 
16.2.2. Flow cytometric analysis of circulating regulatory T cells (Tregs) and MDSC .................. 63 
17. 
APPENDIX 3 – TISSUE IMMUNOCHEMISTRY METHODS ........................................... 64 
18. 
APPENDIX 4 - DISEASES THAT MAY BE AUTOIMMUNE RELATED ........................ 65 


 
 
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ABBREVIATIONS 
 
Acronym 
Term 
ADCC 
Antibody-Dependent Cellular Cytolysis 
AE 
Adverse Event 
AJCC 
American Joint Committee of Cancer 
ALT 
Alkaline Phosphatase 
ANA 
Anti-Nuclear Antibody 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate Aminotransferase 
BC 
Breast Cancer 
BUN 
Blood urea nitrogen concentration 
CA125 
Cancer Antigen 125 
C/A/P CT 
Chest / Abdomen / Pelvis Computerized Tomography Scan 
CBC 
Complete Blood Count 
CD4 
Cluster of Differentiation 4 
CFR 
Code of Federal Regulation 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP  
Cancer Therapy Evaluation Program 
CTLA 
Cytotoxic T Lymphocyte-associated Antigen 
CR 
Complete Response 
CYP 
Cyclophosphamide 
DCIS 
Ductal Carcinoma In Situ of the Breast 
DNA 
Deoxyribonucleic Acid 
DSMB 
Data Safety Monitoring Board 
DTH 
Delayed Type Hypersensitivity 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
eDCF 
Electronic Data Clarification Form 
EGFR 
Epidermal Growth Factor 
ELIspot 
Enzyme-Linked Immunosorbent spot 
ER 
Estrogen Receptor 
ERS 
Electronic Registration System 
FR 
Folate Receptor 
FRA or FRα 
Folate Receptor Alpha 
FRα-mAb 
FRα specific monoclonal Antibody 
GITR 
Glucocorticoid-induced tumor necrosis factor receptor 
GM-CSF 
Granulocyte-Macrophage Colony-Stimulating Factor 
GMP 
Good Manufacturing Practice 
GPI 
Glycosyl-Phosphatidylinositol 
Her2-neu 
Human epidermal growth factor receptor 2 
hFR 
Human Folate Receptor 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
HLA-A2 
Human Leukocyte Antigen Class I A2 
HLA-DR 
Human Leukocyte Antigen Class II DR 
huFR 
Human Folate Receptor 


 
 
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ICH 
International Conference for Harmonization – Good Clinical Study 
ICOS 
Inducible Costimulatory Molecule 
ID 
Intradermal 
IFN-γ  
Interferon gamma 
IHC 
Immunohistochemistry 
IL-2 
Interleukin 2 
IMGN853 
Mirvetuximab Soravtansine from Immunogen 
IR/SD 
Incomplete Response / Stable Disease 
IRB/IEC 
Independent Review Board / Independent Ethic Committee  
irRC 
Immune-related Response Criteria 
MDSC 
Myeloid Derived Suppressor Cells 
NA 
No Applicable 
NE 
Not evaluable 
NED 
No Evidence of Disease 
NCCN 
National Comprehensive Cancer Network 
NTL 
Non Target Lesion 
OCP 
Worldwide Organization for Collaborations in the Pharmaceutical 
ORR 
Objective Response Rate 
PBMC 
Peripheral Blood Mononuclear Cell 
PD 
Progressive Disease 
PI 
Principal Investigator 
PR 
Progestogen Receptor 
PR 
Partial Response 
RFC 
Reduced Folate Carrier 
RFS 
Relapse–Free Survival 
ROS 
Review of System 
SAE 
Serious Adverse Events 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SOC 
Standard of Care 
SOC 
System Organ Class 
SPECT 
Single Photon Emission Computed Tomographic 
SWFI 
Sterile Water For Injection 
TEAE 
Treatment-emergent adverse event 
TERT 
Telomerase Reverse Transcriptase 
TIL 
Tumor-infiltrating lymphocytes 
TL 
Target Lesion 
TNBC 
Triple Negative Breast Cancer 
Treg 
Regulatory T-cell 
TRAIL 
TNF-related apoptosis inducing ligand 
TSH 
Thyroid Stimulating Hormone 
TT 
Tetanus Toxin 
ULN 
Upper Limit of Normal 
WOCBP 
Women of child bearing potential 
 
 


 
 
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1. 
SYNOPSIS 
Title of Study: 
A randomized multicenter Phase II trial to evaluate the immunogenicity and 
efficacy of vaccination with Folate Receptor Alpha peptides with GM-CSF 
versus GM-CSF alone in patients with Platinum Sensitive Ovarian Cancer and a 
response or stable disease to platinum therapy 
Sponsor: 
TapImmune, Inc. 
Trial Sites: 
Up to 24 sites in the United States 
Trial Phase: 
Phase 2 
Investigational 
Drug Products: 
TPIV200: Folate Receptor alpha (FRα) vaccine, composed of FR30, FR56, 
FR76, FR113, and FR238 peptides with Granulocyte-Macrophage Colony-
Stimulating Factor (GM-CSF) adjuvant 
GM-CSF: a hematopoietic growth factor that stimulates proliferation and 
differentiation of hematopoietic progenitor cells 
Purpose & Study 
Rationale: 
This exploratory study will investigate the safety and preliminary efficacy of a 
peptide vaccine in patients with platinum-sensitive ovarian cancer. Preclinical 
studies have demonstrated that dosing of TPIV200 can increase detectable FRα-
specific T cells, increase tumor-infiltrating lymphocytes, and suppress tumor 
growth. The Phase 1 study demonstrated safety and immunogenicity in humans. 
Main Objectives: 
 
Primary Objectives: 
 
To determine the efficacy of a hu-FRα peptide vaccine with GM-CSF immune adjuvant 
compared to GM-CSF alone assessed by progression-free survival (PFS) by RECIST v1.1. 
 
To evaluate the safety and tolerability of a hu-FRα peptide vaccine with GM-CSF versus GM-
CSF alone. 
 
Secondary Objectives: 
 
To determine the efficacy of a hu-FRα peptide vaccine with GM-CSF immune adjuvant 
compared to immune adjuvant alone by assessment of: 
- 
Overall survival (OS) 
- 
Best overall response rate (CR+PR), and duration of response (DOR) 
- 
Disease control rate (CR+PR+SD) 
- 
Response rate by irRECIST criteria 
- 
Cancer Antigen (CA)-125 response (Gynecologic Cancer InterGroup [GCIG] criteria) 
- 
Progression free rate (PFR) at 6 months. 
 
Exploratory Objectives 
 
Determine the ability of laboratory biomarkers to predict response: 
- 
Tumor tissue expression of FRα 
- 
Tumor tissue immune related gene signature and immune response 
- 
Circulating tumor biomarkers 
Study Design:  
This is a double-blind, randomized, parallel groups Phase II trial. Patients with platinum-sensitive 
advanced ovarian cancer, defined as a lack of progression by RECIST v1.1 criteria following 
completion of standard-of-care chemotherapy, including a minimum of 4 cycles of a platinum-
containing regimen. Patients will be randomized to either the vaccine using GM-CSF as an adjuvant or 
the GM-CSF adjuvant alone as a control group. Treatment will be administered as a consolidation 
therapy within one year of the last administration of platinum, targeting the first remission. 


 
 
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The vaccine will be administered in two phases, a vaccination period and a booster period. The 
vaccination period will include 6 administrations of the study drug at 4-week intervals. The booster 
period will include administration of the study drug every 12 weeks during the 18-month follow-up 
period or until cancer recurrence. Treatment is not administered at the final safety visit. Whether they 
progress or discontinue, patients will be monitored for tumor response to subsequent chemotherapy and 
for remission, relapse or progression, as well as survival by quarterly contact with their physician until 
study completion. 
 
The maximum duration of the patient’s participation in the study will be 2 years. Assessment for tumor 
response, disease progression, and recurrence will be conducted every 12 weeks from the beginning of 
treatment until confirmed disease progression. 
 
Vaccination will be administered via the intradermal (ID) route. 
 
Number of Patients Planned:  
Up to 60 patients will be enrolled in each group. Dropouts will not be replaced once treatment begins. 
Diagnosis and Criteria for Inclusion:  
1. Female patient > 18 years.  
2. Willing and able to give informed consent. 
3. Stage III-IV platinum-sensitive (defined as a lack of progression by RECIST v1.1 criteria 
following completion of standard of care chemotherapy, including a minimum of 4 cycles of a 
platinum-containing regimen) epithelial ovarian, fallopian tube or primary peritoneal 
carcinoma in first remission. 
4. Histologic documentation of diagnosis of carcinoma is required and the following histologic 
subtypes are eligible: high grade (grade ≥3+) serous or endometrioid carcinoma, 
carcinosarcoma, or poorly-differentiated adenocarcinoma, or mixed (including above 
subtypes). Note that synchronous serous or endometrioid uterine or fallopian cancers are 
allowed. 
5. The patient must have demonstrated an objective response (PR or CR) or stable disease (SD) 
with the last chemotherapy prior to enrollment and this response must be stable (without 
progressive disease) until randomization. 
6. Patients must receive their first dose of vaccine within 1 year of completion of their final dose 
of a chemotherapeutic agent of the platinum-containing regimen.  
7. Adequate organ and marrow function without therapeutic intervention within 14 days prior to 
first vaccine administration: 
Absolute neutrophil count > 1.5 x 109/L 
Platelet > 100 x 109/L 
Hemoglobin > 9.0 g/dL 
Serum bilirubin < 1.5 times ULN (unless Gilbert’s syndrome without concurrent 
clinically significant liver disease) 
AST/ALT < 2.5 ULN unless liver metastasis in which case it must be < 5 x ULN 
Serum creatinine CL > 40 mL/min by calculation 
8. Female subjects must either be of non-reproductive potential (i.e. post-menopause by history: 
> 60 years old and no menses for > 12 months naturally or secondary to 
radiation/chemotherapy; OR serum FSH, LH and estradiol levels in the post-menopausal 
range; OR history of hysterectomy; OR history of bilateral tubal ligation; OR history of 


 
 
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bilateral oophorectomy), or must have a negative serum or urine pregnancy test upon study 
entry. 
9. Life expectancy > 24 weeks. 
10. ECOG performance status of 0 or 1. 
11. Formalin fixed, paraffin embedded tumor sample from the primary cancer should be available 
for central testing. 
Criteria for Exclusion:  
1. Histology consistent with non-serous, non-endometrioid (i.e. mucinous or clear cell), or low-
grade or borderline serous ovarian carcinoma. 
2. Patients with a history of invasive cancers (other than non-invasive skin cancers) within the 
past 3 years. 
3. Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, targeted 
therapy, biological/cell therapy, tumor embolization, monoclonal antibodies, other 
investigational agent) < 28 days prior to the first dose of study drug. 
4. Current or prior use of immunosuppressive medication within 28 days prior to the first dose 
of study drug with the exception of topical, intranasal or inhaled corticosteroids or systemic 
corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an 
equivalent corticosteroid. 
5. Active autoimmune disease requiring therapy within the past 2 years Note: patients with 
vitiligo, Grave’s disease or psoriasis not requiring systemic treatment within the past 2 years 
are not excluded. 
6. History of hypersensitivity to GM-CSF. 
7. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, 
cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses including 
any subject known to have evidence of acute or chronic hepatitis B, hepatitis C or human 
immunodeficiency virus (HIV), or psychiatric illness/social situations that would limit 
compliance with study requirements or compromise the ability of the subject to give written 
informed consent. 
8. Symptomatic thyroid disease, unless negative for thyroid antibodies (typically including TSH 
receptor, thyroid peroxidase antibody, and/or thyroglobulin antibody). 
9. Subjects who are pregnant or are breast feeding. 
10. Subjects who or of reproductive potential, and are either: 
- 
Not abstinent;  
- 
Not in an exclusive relationship with a partner who is surgically sterile; 
- 
Not employing an effective method of birth control. 
11. Any condition that, in the opinion of the investigator, would interfere with evaluation of study 
treatment or interpretation of patient safety or study results. 
12. Symptomatic or uncontrolled brain metastasis requiring concurrent treatment, inclusive of but 
not limited to surgery, radiation and/or corticosteroids. 
13. Subject with uncontrolled seizures. 
 
 


 
 
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Study Schema:  
 
 
 


 
 
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2. 
BACKGROUND AND RATIONALE 
2.1. 
Ovarian Cancer is a Serious Condition associated with significant mortality  
Ovarian cancer is the most lethal gynecologic malignancy, with a 5-year survival rate of 45% due to it being 
rarely diagnosed while the cancer is still localized [1]. Ovarian cancer patients are usually diagnosed with 
the disease in its most advanced state (i.e. stages III and IV). After initial surgical debulking, standard 
chemotherapeutic agents used include platinum/taxane combinations. Nearly 80% of patients with 
advanced stage disease respond to these drugs [1]. However, at least 70% of patients with an initial complete 
clinical response to treatment will subsequently experience recurrent disease. While second-line treatments 
are available and widely used, once ovarian cancer recurs it is not generally considered curable.  
Thus, significant effort has been dedicated to improving the outcome of primary therapy to avoid 
recurrences, including increased intensity of primary chemotherapy, addition of new agents to the standard 
regimen, or continuation of primary therapy in the form of either consolidation or maintenance therapy. In 
general, consolidation therapy is designed to be a short-term treatment boost after initial therapy to 
consolidate the initial response to therapy. Maintenance therapy is designed to maintain the disease-free 
period as long as possible, while delivering a reduced dose of chemotherapy over a longer period of time 
(eg, 6 cycles or more). It has been speculated that continued reduction of residual cancer cells by extending 
the period of chemotherapy administration will diminish the risk of tumor regrowth. The concept of 
maintenance therapy has its roots in the experience extracted from the treatment of acute lymphoblastic 
leukemias, where post-remission therapy continued to reduce the burden of residual cancer cells, eventually 
yielding eradication of the disease. 
2.2. 
An Unmet Medical Need Exists Despite Available FDA Approved Therapies to 
Treat Ovarian Cancer 
While optimal debulking and chemotherapy results in complete clinical remission in the majority of 
patients, most will relapse due to tumorigenic tissue that resists conventional treatment. Thus, continued 
intervention during the tumor-free period to eradicate resistant deposits of tumor is essential to prevent 
recurrence. 
 
The median overall survival for optimally debulked ovarian cancer patients has increased to more than 5 
years, but less than 30% will remain disease-free following surgery and platinum-based chemotherapy [2]. 
Many patients will be highly responsive to additional chemotherapy at recurrence, and some can reenter 
successively shorter complete clinical remissions with additional treatment [3, 4]. Most studies of 
consolidation have been performed in the first clinical remission setting and include a variety of cytotoxic 
and immunologic strategies. No randomized study has provided a statistically significant improvement in 
overall survival [5-7].  
 
Bevacizumab (Avastin®), a vascular endothelial growth factor-specific angiogenesis inhibitor, is now a 
well-established component of treatment programs for recurrent ovarian cancer [8]. Maintenance 
bevacizumab increases progression-free survival (PFS) when given after adjuvant chemotherapy in the 
upfront [9, 10] and recurrent platinum-sensitive [11] and platinum-resistant [12] settings. Bevacizumab is 
indicated in the subset of patients with platinum-resistant recurrent epithelial ovarian, fallopian tube or 
primary peritoneal cancer. 
 
Liposomal doxorubicin (Doxil®) is a standard anthracycline topoisomerase inhibitor encapsulated in long-
circulating Stealth® liposome with surface bound methoxypolyethylene glycol (MPEG) [a process often 
referred to as pegylation], to protect liposomes from detection by the mononuclear phagocyte system (MPS) 


 
 
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and to increase blood circulation time for IV administration. Doxil® is also indicated in the subset of 
patients with platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer. 
 
Olaparib (Lynparza®) is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated as monotherapy in 
patients with deleterious or suspected deleterious germline BRCA mutated (as detected by an FDA-
approved test) advanced ovarian cancer who have been treated with three or more prior lines of 
chemotherapy.  
 
Niraparib (Zejula®) is another PARP inhibitor that was recently approved for the maintenance treatment 
of patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, whose tumors 
have achieved complete or partial response to platinum-based chemotherapy, irrespective of BRCA status. 
The median PFS for patients taking niraparib who had a germline BRCA mutation during their second 
remission was 21 months, compared to 5.5 months for the same patient population taking a placebo. The 
median PFS for patients taking niraparib who did not have a germline BRCA mutation was 9.3 months 
compared to 3.9 months for the same patient population taking a placebo. 
 
These approved treatments are limited to patients with advanced disease. Efficacy of treatment has only 
been shown for time to progression and a minority of patients have a clinically significant tumor response 
(rate of CR <20%) and a short duration of response (median duration < 9-12 months) [12-14]. 
 
The notion of extended treatment is an active area of research extending far beyond the realm of traditional 
cytotoxic regimens. PARP inhibitors, immuno-vaccinations, endothelial and epithelial growth factor 
inhibitors, novel VEGF receptor inhibitors continue to be evaluated in ongoing clinical trials [5]. 
 
The proposed approach is to vaccinate patients with ovarian cancer at high risk of recurrence with the multi-
epitope Folate Receptor Alpha peptide vaccine during their first remission following platinum-based 
chemotherapy. Vaccination may reduce the tumor burden (tumor shrinkage) and may prevent recurrence of 
the cancer (extension of the relapse free survival), reduce the requirement of toxic salvage cytotoxic 
therapies and extend overall survival.  
2.3. 
Folate Receptor Alpha as an Immunotherapy Target 
2.3.1. FRα as a vaccine target for ovarian cancer  
The FRα receptor (also referred to as folate binding protein) is a glycophosphatidyl-anchored membrane 
glycoprotein that mediates cellular uptake of folate [15]. FRα attachment at the apical surface of cells 
situates it away from, and out of direct contact with folate in the circulation. In normal kidney cells, it 
functions in the absorption/re-absorption of folate from the luminal cavities. FRα has restricted expression 
in normal cells, but is highly expressed in various epithelial non-mucinous tumors [16]. This protein is 
overexpressed on greater than 90% of ovarian cancers at levels of up to 80-90-fold relative to the levels 
observed on normal tissues [17]. Furthermore, this expression is maintained in the majority of patients 
relapsing following conventional therapies (unpublished observations). It is overexpressed on ~ 50% of 
breast tumors [18]. It confers a growth advantage to the tumor by modulating folate uptake [19]. Increased 
growth and folate accumulation by cancer cells is associated with elevated FRα, suggesting that 
overexpression allows tumor cells to meet their folate needs [20]. It has recently been shown that 
FRα expression is common in metastatic foci present at the time of diagnosis of ovarian cancer as well as 
on recurrent tumors, indicating that FRα is a good tumor target regardless of whether the patient is newly 
diagnosed or experiencing disease recurrence [17].  


 
 
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2.3.2. The FRα may be an ideal target for a peptide vaccine targeting both Th cell, CTL and antibody 
immunity 
The FRα may be an ideal target for immunotherapy for a number of reasons. First, the fact that it is 
expressed in nearly all ovarian cancers strongly suggests that its expression confers a significant advantage 
to the tumor. In fact, in a study by Figini and colleagues, it was found that blockade of FRα function with 
intra-cellularly expressed FRα-specific antibodies prevented tumor cell growth in soft agar colony assays 
and reverted the transformed phenotype of ovarian cancer cell lines [21]. Studies have examined human 
tumor levels of FRα and patient survival. In non-mucinous epithelial ovarian carcinoma FRα-positive 
expression is associated with tumor progression [22] and platinum-therapy resistance, and poor prognosis 
in high-grade tumors [23]. Toffoli et al. investigated whether FRα in epithelial ovarian cancer specimens is 
a predictor of response to chemotherapy and survival. Among 58 patients with residual epithelial ovarian 
cancer after primary surgery, failure to respond to chemotherapy (complete or partial remission) was about 
15-fold higher (95% confidence interval, 2.96–77.43) when tumors had elevated (>median) FRα levels 
following multivariable adjustment, although this estimate was based on 8 cases. Further, patient survival 
at 3 years was 30% among patients with high FRα (n = 30) compared to 62% among patients with tumors 
with low FRα levels (n = 28; p = 0.06). Among possible hypotheses to explain their findings included that 
FRα may increase folate uptake which could stimulate cells to repair DNA damage caused by platinum, or 
high level overexpression is significantly advantageous because both MHC class II and MHC class I 
epitopes (i.e. subdominant epitopes) within the FRα are expressed that would not ordinarily be processed 
and expressed in normal tissues.  
 
Furthermore, the basal level of expression of the FRα in non-tumor tissues is very low, and therefore the 
potential for autoimmune toxicity is also low. Although it is found in the kidney, its expression on the 
luminal side of the proximal tubule would prevent it from being recognized by antibodies, which could 
potentially lead to autoimmunity. In contrast, FRα in cancer is highly overexpressed and accessible to folate 
in the circulation. The expression of FRα therefore appears to be restricted to immune privileged sites and 
immunity to the FRα appears not to be detrimental to normal host tissue because it can be detected in 
otherwise healthy women [24, 25].  
2.3.3. Patients naturally develop immune responses to the FRα demonstrating the existence of a T cell 
repertoire.  
From an historical perspective, the FRα was one of the first tumor antigens to be described for ovarian 
cancer [26]. Both Peoples and Knutson et al. found that patients with ovarian cancer develop endogenous 
immune responses to multiple targets within the FRα [26, 27]. FRα-specific lymphocytes that recognized 
several epitopes from FRα could be readily detected in the ascitic fluid of advanced ovarian cancer patients 
and CD8 T cells are among those localized to the tumor microenvironment [26]. This indicates that the 
FRα antigen is naturally recognized in patients with ovarian cancer. 
 
This demonstrates that the ability to mount an immune response against FRα is intact and therefore should 
be able to be boosted. 
 
To identify the vaccine constituents, we used the RANKpep algorithm and predicted fourteen potential 
MHC class II (HLA-DR) epitopes from the FRα. We chose peptides based on their potential to bind 
to at least three distinct HLA-DR alleles (i.e. degenerate epitopes). The peripheral bloods from 30 breast 
and ovarian cancer patients and 18 normal healthy volunteers were assessed for immune responses to each 
of the fourteen peptide epitope and the whole protein using T cell ELIspot assays and antibody ELISAs. 
Highly sensitive IFN-γELIspot analysis identified four peptides (FR30, FR56, FR 113, and FR238) that 
generated responses in more patients than in healthy donor counterparts. Overall, 70% of these patients 
showed FR-specific immunity to at least one epitope of FRα.  


 
 
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We also found that epitopes could potentially contain embedded MHC class I epitopes. Among patients 
who had helper T cell immunity to FR56, a majority also had CD8 T cell reactivity to the same peptide. 
FR56 contains predicted high affinity binders for HLA-A2 and –A3, and patients were genotyped with 
one of these class I molecules.  
 
We also tested for the presence of increased levels of antibodies as compared to the normal healthy 
individuals. We chose to evaluate IgG immunity to FR76 since this 18-mer peptide contains a B cell 
epitope that is predicted as a top candidate using B cell epitope prediction algorithms, ABCpred and 
Antigenic (Data not shown). Patients demonstrated higher antibody immunity to this peptide compared 
to control (p<0.0001). Although patients did not demonstrate elevated preexisting T cell immune responses 
to this epitope, the fact that the peptide was a potential B cell target and demonstrated a high level of 
degeneracy with respect to predicted HLA-DR binding led to its inclusion in the vaccine as well. The 
tetanus toxin antibody response was similar amongst the 2 populations. There was no response by either 
group to control peptides (data not shown). In conclusion, these results indicate that some patients with 
FRα-expressing tumors have developed a c oordinated multi-epitope immune response to the FRα, 
suggesting that the T cell and B cell repertoire are preserved and have not been subjected to tolerance. 
Furthermore, this body of information provided the basis for our final vaccine pool, which consisted 
of FR30, FR56, FR76, FR113 and FR238. 
2.3.4. Scientific Rationale for Th peptides as Therapeutic cancer vaccines 
The objective of administration of a therapeutic cancer vaccine to a patient is to induce or enhance an 
adaptive antitumor immunity, B cells or T cells against a tumor antigen present on tumor cells. In this trial 
the vaccine targets the FRα antigen [27]. Peptide based vaccines have been widely used in clinical trials to 
increase tumor specific immune response. Although therapeutic cancer vaccines have very good safety and 
tolerability, their observed clinical efficacy appeared weakened, probably on account of the immune-
suppressive tumor microenvironment [28, 29].  
 
Until recently, cytotoxic CD8 T cells have been considered to be the major component of anti-tumor 
immune response from cancer vaccines. More recently, it has been shown that CD4 T-cells may also be 
effective in mediating anti-tumor response [30-34]. This has been reviewed in detailed by Galaine et al. 
[35]. Several approaches have been developed to stimulate antitumor CD4 T cell immunity. In this trial we 
use the FRα peptide vaccine as a mix of 5 peptide sequences containing subdominant promiscuous Class II 
(Th) epitopes. 
 
CD4 T cells orchestrate a broad range of immune responses and are equipped to differentiate into multiple 
sub-lineages, which can induce and maintain immune responses against tumor antigens. Although 
originally defined as Th1 and Th2 subsets, new Th CD4 T cells subsets have been characterized including 
suppressive regulatory T cells (Tregs) and pro-inflammatory Th17, and others [36, 37]. Among these 
various Th subpopulations, the Th1 subset that produces interferon-gamma (IFN-γ), tumor necrosis factor-
alpha (TNF-γ) and interleukine-2 (IL-2) plays a clear antitumor role by orchestrating cell-mediated 
immunity against cancer cells [38, 39]: 
 
 
Successful generation of antitumor CD8+ T cell responses depend on the presence of CD4+ T 
cells;  
 
The induction of DC activation represents one major helper mechanism used by Th1 cells to 
sustain antigen presentation and to provide costimulatory signals such as CD40-CD40L to 
effector CD8 T cells; 
 
Th1 cells enhance the CD8+ T cells infiltration into the tumor. 


 
 
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CD4+ Th1 cells also exhibit direct (i.e. CD8+ T cell independent) antitumor activity. The IFN-γ secreted 
by Th1 cells exerts anti-proliferative, pro-apoptotic actions and inhibit angiogenesis in tumor cells and 
upregulate major histocompatibility complex (MHC) molecules on tumor cells leading to enhanced effector 
T cells recognition [40]. This mechanism enables MHC Class II restricted killing independently of B, NK 
or other T cells [41, 42]. Th1 cells also recruit and activate inflammatory cells (macrophages, granulocytes, 
eosinophils and NK cells) in around the tumor [37, 40]. Some CD4+ Th1 cells have also direct tumor-
recognizing ability [43]. They are able to kill MHC-II+ tumors through perforine and granzyme, TNF-
related apoptosis inducing ligand (TRAIL) receptor and Fas/Fas ligand (FasL) pathways.  
 
In cancer patients, spontaneous CD4+ T cell responses against tumor antigens have been detected in several 
studies and a high density of tumor-infiltrating Th1 cells has been identified as a good prognostic marker 
in several human cancers [44, 45].  
 
In recent randomized vaccine trials, melanoma patients were vaccinated with multi melanoma-derived 
cytotoxic T lymphocytes (CTL) peptides vaccine either in the presence of a tetanus-derived helper peptide 
or with melanoma-derived helper peptides [32, 46]. In contrast to the group that received CTL peptides and 
tetanus helper peptide, a high clinical objective response rate (ORR) was observed in patients treated with 
Melanoma-derived helper peptides [31, 47]. Interestingly, significant ORR was also observed when 
melanoma-helper peptides were used alone as compared to CTL-peptides vaccination. One possible 
explanation for these observations is that helper peptides unrelated to tumor antigens may be ineffective in 
guiding effector CD8 T cells within the tumor [48]. Results consistent with these observations are in line 
with previous reports by using tumor-derived helper peptides such as HER2-neu and hTERT [49, 50]. 
Hence, called GV1001 has been evaluated in many cancers [51]. In lung cancer patients an hTERT-derived 
helper peptide vaccine induced a durable T-cell memory response and increased survival in immune 
responders [50]. However, this hTERT vaccination failed to reach the main end point overall survival in 
pancreatic adenocarcinoma [52]. 
 
Finally, there is clear support for the epitope spreading, following immunization of cancer patients with 
tumor-reactive helper peptides [53, 54].  
 
Based on the critical role of CD4+ Th1 cells in antitumor immunity, we believe that the induction of a FRα 
specific Th response will yield a favorable tumor microenvironment for the immune effector cells action 
(CD8+ T cells, NK cells and MAC macrophages) and a reduce the effect of the immune suppressive cells 
(Tregs, MDSC, etc.). The FRα Class II vaccine approach has several favorable features: i/ the Class II 
epitope selected are derived from overexpressed FRα tumor antigen [55]; ii/ the selected epitopes are 
promiscuous and immunize a large proportion of the US patient population [17, 27]; iii/ the FRα appears 
to have a crucial role in tumor cells as it affect TNBC patient’s prognosis [56, 57] and is retained in tumor 
progression and metastasis indicating that it may avoid immune escape [17, 58]; iv/ vaccination with FRα 
Class II peptides induced a robust Th1 clonal response detected by IFNγ producing ELISPOT. 
2.3.5. Clinical rationale for FRα vaccine strategy. 
Ovarian cancer patients are usually diagnosed with the disease in its most advanced state (i.e. stages III and 
IV). While optimal debulking and chemotherapy results in complete clinical remission in the majority of 
patients, most will relapse due to tumorigenic tissue that resists conventional treatment. Thus, continued 
intervention during the tumor-free period to eradicate resistant deposits of tumor is essential to prevent 
recurrence. Efficacy of currently approved treatment is mediocre and few patients have a clinically 
significant tumor response (rate of CR <20%) and a short duration of response (median duration < 9-12 
months) [12-14].  


 
 
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Our proposed strategy to eradicate residual tumor is to augment tumor antigen-specific immunity with the 
huFRα vaccine. Indeed, ovarian cancer is an immunologically active tumor and may be amenable to 
vaccination strategies. Over the past several years, many studies have demonstrated the importance of the 
immune system in affecting patient outcome. Notably, Zhang and colleagues published a study that 
demonstrated that the majority of patients had infiltrating CD3 T cells and that infiltration was positively 
associated with survival [59]. Patients with T cell infiltration had a 5-year overall survival rate of 38% 
compared with a 4.5% rate for those who lacked T cells [59]. Importantly, the presence of T cells was 
particularly beneficial for those individuals who demonstrated a complete clinical response to surgery and 
chemotherapy. The five-year survival for this group was 74% for patients with T cells compared to 12% 
for those without. Subsequent studies have refined our understanding of intra-tumoral T cells, notably CD8 
cytotoxic T cells (CTL). Sato and colleagues showed that patients that had high levels of infiltrating CTL 
had a median survival of 55 months versus those with little or no CTL who had a survival of 26 months 
[60].  
 
Furthermore, the basal level of expression of the FRα in other tissues is very low and therefore the potential 
for autoimmune toxicity is also low. Although it is found in the kidney its expression on the luminal side 
of the proximal tubule would prevent it from being recognized by antibodies, which could potentially lead 
to autoimmunity. The expression of FRα therefore appears to be restricted to immune privileged sites and 
immunity to the FRα appears not to be detrimental to normal host tissue because it can be detected in 
otherwise healthy women. This indicates that administration the FRα vaccine may have no unrelated organ 
toxicity and be well tolerated in patients who develop an immune response to the FRα vaccine.  
 
The development of an ovarian cancer vaccine to prevent relapse after conventional treatment of primary 
tumor would be of enormous clinical value, may benefit most patients with ovarian cancer as an adjuvant 
to cytotoxic chemotherapy and may be better tolerated than standard chemotherapeutic interventions.  
2.3.6. Booster Vaccination 
An activated immune response maintained through booster vaccines can patrol for residual disease over an 
extended period. The selected booster regimen of an injection repeated every 3 months until recurrence or 
progression is similar to one developed for AE37, the li-Key hybrid peptide of HER2 776-790 (AE36), 
based on the result of a phase II trial of high-risk node negative breast cancer. In this study, peptide vaccine 
booster given every 6 months enhanced the immune response against HER-2 elicited during the primary 
vaccination series as evaluated by IFNγ ELISPOT and in vivo by intradermal reactions [61]. Safety and 
tolerability of booster dosing of TPIV200 is being evaluated in ongoing Phase 2 studies (NCT02593227 in 
TNBC and NCT02111941 in ovarian cancer). The 12-week schedule being used here is based on the more 
aggressive nature of ovarian cancer. 
2.4. 
Previous clinical experience with FRα as a therapeutic target in ovarian 
cancer 
There have been several therapeutic trials using an immune agent to target the FRα. The group of G. Peoples 
is currently evaluating E39 and J65, HLA-A2 restricted peptide vaccines in patients with ovarian and 
endometrial cancer (NCT02019524). Preliminary results of six monthly intradermal of E39 with GM-CSF 
indicate that the vaccine is well tolerated and elicit a strong in vivo immune response as assessed by DTH 
[62].  
 
Several monoclonal antibodies targeting the FRα have also been tested in cancer patients. Farletuzumab, 
an anti-FRα MAb, shown to induce ADCC in preclinical models is currently in Phase III trial in subjects 
with low CA125 platinum-sensitive ovarian cancer (NCT02289950). In Phase II evaluation platinum-


 
 
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sensitive ovarian cancer farletuzumab was well-tolerated as single agent, without additive toxicity when 
administered with chemotherapy. Of 47 subjects who received farletuzumab with chemotherapy, 38 
(80.9%) normalized CA125 [63]. IMGN853 is a FRα-specific antibody-mytansoid conjugate. In a Phase I 
trial of IMNG853 in patients with recurrent ovarian cancer showed preliminary evidence of clinical benefit 
and levels of FRα measured by immunohistochemistry correlated with response. Although FRα can be 
detected in small amounts in healthy adult lung and kidney, pulmonary toxicities were rare and renal 
toxicity was not observed [64].  
 
Furthermore, no significant pulmonary or renal toxicity was encountered in studies using farletuzumab, an 
anti-FRα MAb, shown to induce ADCC in preclinical models, despite radiolabeling studies confirming 
tumor-targeting; nor was such toxicity seen in clinical trials with vintafolide, a folate-vinca conjugate, also 
demonstrated to home to tumors by radio-imaging SPECT studies. 
2.5. 
Preclinical cancer model with FRα peptide vaccine 
The FRα vaccine was evaluated in an murine immunocompetent model for examining immune-based 
approaches to treating ovarian cancer [65]. Transplanted tumor cells generate tumors after intraperitoneal 
injection. 61 days following tumor challenge, tumors develop on the greater omentum (GO), the peritoneal 
lining, and organs. Ascites also develops in these mice.  
 
As is the case in human ovarian cancer, murine ovarian tumors are immunogenic, overexpressing self-
antigens such as FRα. Rather than using the human vaccine peptides animal testing requires a species-
specific vaccine. Thus, the FRα vaccine for mouse was composed of native murine sequences containing 
Class I and II murine epitopes. Finally, the vaccination was done with the classical complete Freund’s 
adjuvant (CFA) and incomplete Freund’s adjuvant (IFA) rather than a murine GM-CSF as an immune 
adjuvant.  
 
Naïve, non-tumor-bearing, healthy mice immunized with the pool of peptides in the presence of the 
adjuvant CFA had detectable FRα-specific T cells in the spleen toward each of the peptides by IFN-
γ ELISpot analysis. Sera from the same immunized mice had elevated levels of tumor-specific IgG that 
bind to FRα+ tumor cells. ELISAs confirmed that IgG immunity targeted the FR9, FR74 and FR173 
peptides.  
 
In order to determine whether induction of immunity with FRα vaccine results in tumor reduction, tumor-
bearing mice were vaccinated three times with the peptide pool along with CFA/IFA as adjuvant. After 40 
days, the tumors were assessed for infiltration and weighed. As shown in Figure 1A, immunization resulted 
in influx of lymphocytes into the tumor, constituting about 50% of the total tumor mass as compared with 
control mice in which lymphocytes constituted about 10% of total tumor. Importantly, immunization with 
FRα peptide vaccine significantly prevented tumor growth (Figure 1B). 


 
 
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Figure 1: Immunization with FRα peptide vaccine augments lymphocyte infiltration into tumors and 
suppresses tumor growth. Mice (n=5) were challenged with tumor cells and 10 days later were immunized 
with the FRα multi-peptide three times with CFA/IFA as an adjuvant. On Day 40 following tumor challenge, 
the tumor were removed, weighted and assessed for lymphocytes as a fraction of total tumor cells as assess 
by flow cytometry. Each bar is the mean of 2 measurements from 2 different tumors. Panel B show the 
mean tumor burden in control and immunized mice. Each bar is the mean (+/- s.e.m.) of 5 mice. 
 
 
 


 
 
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2.6. 
Previous human experience.  
The first in human evaluation of the FRα multi-epitope vaccine was conducted at the Mayo Clinic, 
Rochester MN. Patients were 18 years or older women, diagnosed with Stage II-III breast cancer or Stage 
II-IV ovarian, primary peritoneal or fallopian tube cancer. All patients had completed standard of care neo-
adjuvant or adjuvant therapy at least 90 days prior to enrollment and were clinically without evidence of 
disease recurrence.  
 
The primary clinical endpoint of the study was the proportion of patients who experience severe toxicities 
(Grades 3-5 of the National Cancer Institute’s Cancer Therapy Evaluation Program (CTEP) Common 
Terminology Criteria for Adverse Events, version 4.0) attributable to therapy during the course of treatment. 
The primary translational endpoint was the evaluation of the vaccine-induced FRα-specific T cells immune 
response. 
  
The study schema is outlined above. Following registration and consent, patients received a priming cycle 
with oral cyclophosphamide, followed by 6 monthly ID injections with the FRα vaccine mixed with GM-
CSF as an immune adjuvant.  
 
Vaccination of the first patient began in September 2012. The trial is fully accrued and as August 26, 2014, 
all patients have completed their vaccinations.  
 
Eight women with HER2-negative breast cancer, thirteen with ovarian cancer and one with fallopian tube 
cancer were enrolled on study. Out of the 22 women enrolled, 3 with ovarian cancer relapsed early in the 
course of study. Although the phase I was not designed to evaluate patient benefit, at this time all of the 
other women remain free of disease relapse. Immune responses were measured, using IFN-γ ELIspot assays 
in the 21 patients who had given adequate numbers of specimens. Increased specific T cell immune 
responses were detected in all evaluable patients. All 5 of the constituent peptides were found to be 
immunogenic and all patients appeared to have developed immune responses to at least 2 and, in the 
majority, more than 3 of the vaccine peptides (Figure 2). Importantly, vaccination with peptide led to the 
generation of T cell that recognize naturally processed antigen. Lastly, 76% of patients achieved levels of 
FRα-specific T cells that were within 2 standard deviations of the mean levels of protective TT-specific 
immunity (not shown). Antibody responses have yet to be examined.  


 
 
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Figure 2: FRα vaccine generates immunity to the FRα in patients with breast and 
ovarian cancer. Shown are the frequencies of T cell specific for the vaccine 
peptides, whole FR protein and a pan DR binder from cyclin D1 as a control. 
Plotted are the pre-immunization levels and the maximum post-vaccine levels. 
Each dot represents a unique patient (calculated in replicate). P values are 
calculated from a student t test. Insert bars represent the mean. 
The majority of the adverse events were grade 1 injection site reactions and other grade 1 toxicities. 
Two severe adverse events (grade 3-4) have been reported. One patient demonstrated grade 4 sepsis 
during priming with cyclophosphamide and another patient demonstrated a  grade 3 injection site 
reaction. 
Refer to the TPIV200 Investigator’s Brochure for additional information on the FRα peptide vaccine 
including efficacy in the ID8 ovarian cancer mice model and toxicology evaluation during acute and sub-
acute administration. 
 
3. 
OBJECTIVES 
3.1. 
Primary Objectives: 
 
 
To determine the efficacy of a hu-FRα peptide vaccine with GM-CSF immune adjuvant 
compared to GM-CSF alone assessed by PFS by RECIST v1.1. 
  
 
To evaluate the safety and tolerability of a hu-FRα peptide vaccine with GM-CSF versus GM-
CSF alone. 
 


 
 
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3.2. 
Secondary Objectives: 
 
 
To determine the efficacy of a hu-FRα peptide vaccine with GM-CSF immune adjuvant 
compared to immune adjuvant alone by assessment of: 
- 
Overall survival (OS) 
- 
Best overall response rate (CR+PR), and duration of response 
- 
Disease control rate (CR+PR+SD) 
- 
Response Rate by immune-related RECIST (irRECIST) criteria 
- 
Cancer Antigen (CA)-125 response (Gynecologic Cancer InterGroup [GCIG] criteria) 
- 
Progression free rate (PFR) at 6 months 
 
3.3. 
Exploratory Objectives 
 
 
Determine the ability of laboratory biomarkers to predict response: 
- 
Tumor tissue expression of FRα 
- 
Tumor tissue immune related gene signature and immune response 
- 
Circulating tumor biomarkers 
 
4. 
MATERIALS AND METHODS 
4.1. 
Study Design 
This is a multicenter double-blind controlled randomized Phase II study to evaluate the activity of folate 
receptor alpha (FRα) peptide vaccine as a consolidation treatment following completion of no less than 4 
cycles of a platinum containing regimen in patients with platinum-sensitive, non-mucinous ovarian, 
fallopian tube or primary peritoneal cancer.  
 
The patients will have demonstrated a tumor response or stable disease upon their last regimen (per 
RECIST v1.1 and/or CA125 GCIG criteria) prior to enrolment in this study.  
 
Following consent the patient eligibility will be confirmed. Patients will need to start treatment with study 
drug within one year of their last dose of a chemotherapeutic agent of a platinum-containing regimen. 
Patient randomization will be stratified based on: 
 
1. The stage of disease at diagnosis and debulking status (stage III cancer and maximal residual lesion 
diameter ≤1 cm vs. stage III cancer and maximal residual lesion diameter >1 cm vs. stage IV 
cancer), and 
 
2. Objective response to the last chemotherapy regimen prior to enrollment on the study: i/ CR 
(defined as normal radiological findings and CA125 within the normal range); ii/ PR (defined as a 
RECIST PR and/or GCIG CA125 response); iii/ SD (defined as RECIST SD [<30% decrease and 
<20% increase per RECIST v1.1] and/or lack of GCIG CA125 response/progression). Please 
refer to eligibility criteria and relevant literature [66, 67]. 
 
Following randomization, patients will be administered TPIV200 with GM-CSF as an adjuvant or GM-
CSF control alone and will be followed up per the schedule of events (table 5.1). Patients will have 
booster doses and tumor assessments done every 12 weeks ± 1 week for up to 1.5 years, until objective 
disease progression or the patient withdraws consent. Tumor responses will be assessed at the study sites 


 
 
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by evaluating tumor images/scans according to RECIST v1.1. It is important to follow the assessment 
schedule as closely as possible. Staging scans will be collected for QC at the central facility and 
adjudication may be performed by blinded independent central review (BICR) following the same rules at 
a later date.  
 
An interim analysis will be done and reviewed by the DSMB once 50 events or 50% total PD events are 
observed. Once a patient is off study and study drugs have been discontinued for more than 30 days, 
survival and cancer status will be followed by quarterly contact until study completion. 
 
Safety will be evaluated with the monitoring of all serious and non-serious AEs, as well as AEs of Special 
Interest (AESIs), graded according to the current CTCAE v4.03. A safety-stopping rule will be used to 
terminate the study prematurely if excess toxicity is encountered. 
Study Schema 
 
4.2. 
Study Sites 
Up to 24 clinical sites in the USA will participate in the trial and recruit patients. 
4.3. 
Study Population 
4.3.1. Patient Screening and Enrollment  
Informed consent will be obtained from each potential patient during the prescreening period. Upon 
completion of the platinum-containing regimen, eligibility of the patient will be assessed by the site and 
the results will be reviewed and approved by the TapImmune Medical Monitor before randomization of 
up to 120 patients.  
4.3.2. Criteria for Inclusion 
1. Female patient ≥ 18 years.  
2. Willing and able to give informed consent. 
3. Stage III-IV platinum-sensitive (defined as a lack of progression by RECIST v1.1 criteria 
following completion of standard-of-care chemotherapy, including a minimum of 4 cycles of a 
platinum-containing regimen) epithelial ovarian, fallopian tube or primary peritoneal carcinoma 
in first remission. 
4. Histologic documentation of diagnosis of carcinoma is required and the following histologic 
subtypes are eligible: high grade (grade ≥3+) serous or endometrioid carcinoma, carcinosarcoma, 
or poorly-differentiated adenocarcinoma, or mixed (including above subtypes). Note that 
synchronous serous or endometrioid uterine or fallopian cancers are allowed. 


 
 
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5. The patient must have demonstrated an objective response (PR or CR) or stable disease (SD) with 
the last chemotherapy prior to enrollment and this response must be stable (without progressive 
disease) before randomization. 
6. Patients must receive their first dose of vaccine within 1 year of completion of their final dose of 
a chemotherapeutic agent of the platinum-containing regimen 
7. Adequate organ and marrow function without therapeutic intervention within 14 days prior to 
first vaccine administration: 
- 
Absolute neutrophil count > 1.5 x 109/L 
- 
Platelet > 100 x 109/L 
- 
Hemoglobin > 9.0 g/dL 
- 
Serum bilirubin < 1.5 times ULN (unless Gilbert’s syndrome without concurrent 
clinically significant liver disease 
- 
AST/ALT < 2.5 ULN unless liver metastasis in which case it must be < 5 x ULN 
- 
Serum creatinine CL > 40 mL/min by calculation. 
8. Female subjects must either be of non-reproductive potential (i.e. post-menopause by history: > 
60 years old and no menses for > 12 months naturally or secondary to radiation/chemotherapy; 
OR serum FSH, LH and estradiol levels in the post-menopausal range; OR history of 
hysterectomy; OR history of bilateral tubal ligation; OR history of bilateral oophorectomy), or 
must have a negative serum or urine pregnancy test upon study entry. 
9. Life expectancy > 24 weeks. 
10. ECOG performance status of 0 or 1. 
11. Formalin fixed, paraffin embedded tumor sample from the primary cancer should be available 
and sent for central testing. 
4.3.3. Criteria for Exclusion 
1. Histology consistent with non-serous, non-endometrioid (i.e. mucinous or clear cell), or low-
grade or borderline serous ovarian carcinoma. 
2. Patients with a history of invasive cancers (other than non-invasive skin cancers) within the past 3 
years. 
3. Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, targeted therapy, 
biological/cell therapy, tumor embolization, monoclonal antibodies, other investigational agent) < 
28 days prior to the first dose of study drug. 
4. Current or prior use of immunosuppressive medication within 28 days prior to the fist dose of 
study drug with the exception of topical, intranasal or inhaled corticosteroids or systemic 
corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an 
equivalent corticosteroid. 
5. Active autoimmune disease requiring therapy within the past 2 years. Note: patients with vitiligo, 
Grave’s disease or psoriasis not requiring systemic treatment within the past 2 years are not 
excluded. 
6. History of hypersensitivity to GM-CSF. 
7. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac 
arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses including any subject 
known to have evidence of acute or chronic hepatitis B, hepatitis C or human immunodeficiency 
virus (HIV), or psychiatric illness/social situations that would limit compliance with study 
requirements or compromise the ability of the subject to give written informed consent 
8. Symptomatic thyroid disease, unless negative for thyroid antibodies (typically including TSH 
receptor, thyroid peroxidase antibody, and/or thyroglobulin). 
9. Subjects who are pregnant or are breast feeding. 
10. Subjects who or of reproductive potential, and are either: 


 
 
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- 
Not abstinent;  
- 
Not in an exclusive relationship with a partner who is surgically sterile; 
- 
Not employing an effective method of birth control. 
11. Any condition that, in the opinion of the investigator, would interfere with evaluation of study 
treatment or interpretation of patient safety or study results. 
12. Symptomatic or uncontrolled brain metastasis requiring concurrent treatment, inclusive of but not 
limited to surgery, radiation and/or corticosteroids. 
13. Subject with uncontrolled seizures. 
4.4. 
Patient Replacement 
Once treatment is initiated, patients will not be replaced, even if they discontinue for reasons unrelated to 
progression or safety. 
4.5. 
Description of clinical supplies 
The TPIV200 peptides will be provided by TapImmune to the site research pharmacy. The site research 
pharmacy will be responsible for preparation of the vaccine for injection per the randomization schedule. 
 
GM-CSF will be either sourced locally or provided by TapImmune.  
4.5.1. FRα peptide vaccine  
Formulation: TPIV200 peptides (composed of the five peptides formulated together) will be lyophilized 
and provided in a single glass vial. Each vial will contain 0.55 mg of each of the 5 peptides for a total of 
2.75 mg. The peptides and formulation are GMP quality. The vial contains a 10% overage to account for 
volume loss during syringing. The nominal dose of 0.50 mg of each of the 5 peptides for a total of 2.50 mg 
is indicated on the label.  
 
 
Storage: TPIV200 vials should be stored at -20ºC ±5 or 2 to 8 ºC using a controlled temperature freezer or 
refrigerator, respectively. 
 
Refer to the TPIV200 investigator brochure for detailed information about the vaccine. 
 
Dosage Preparation: Details on the preparation of TPIV200 are included in the Investigational Product 
Handling Manual. 
4.5.2. Sargramostim (Leukine®, GM-CSF) 
Background: Sargramostim stimulates proliferation, differentiation and functional activity of neutrophils, 
eosinophils, monocytes, and macrophages. 
 
Formulation: Commercially available 
Injection, powder for reconstitution: 250 mcg [contains mannitol 40 mg/mL and sucrose 10 mg/mL]. 
 
Storage: Store intact vials under refrigeration at 2 to 8 ºC (36 to 46 ºF); do not freeze.  
 
Refer to the labelling information for Leukine®. 
 
Dosage Preparation: Details on the preparation of GM-CSF are included in the Investigational Product 
Handling Manual. 
 


 
 
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4.6. 
Vaccination by ID injections 
The ID syringes for injection of the TPIV200 with adjuvant (GM-CSF) or GM-CSF control will be prepared 
prior to each injection by unblinded personnel at the site pharmacy according to the instruction in the 
Investigational Product Handling Manual. The blinded syringes will then be delivered to the clinic for use 
as soon as practical but the drug must be administered no more than 6 hours after preparation. 
 
If the prepared syringes cannot be administered rapidly after preparation (i.e. within approximately 1-2 
hours) or need to be transported to an outside facility, then keep the vaccine/syringes refrigerated or on ice.  
 
The vaccine mixture will be injected intradermally (ID) at three sites, spaced approximately 1 inch apart 
(shown as red dots below) on the upper leg or arm at about 3 inches below the inguinal crease or shoulder 
apex. Vaccination sites should be rotated to an alternate limb for subsequent doses. 
 
Intradermal Injection Sites: 
 


 
 
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5. 
STUDY PLAN 
5.1. 
Study Table 
 
 
 
 
 
 
 
 
 
Vaccination Period 
 
 
 
            Booster Period 
Tests and Procedures 
Screening/ 
Baseline 1 
Cycle 
1  
Cycle 
2 
Cycle 
3 
Cycle 
4 
Cycle 
5 
Cycle 
6 
28 Days post 
vaccination 
Booster and 
Follow-up 2  
Informed Consent, I/E Criteria, 
Registration 3 
X 
 
 
 
 
 
 
 
 
Submission of most recent staging scans 
before the baseline set 
X 
 
 
 
 
 
 
 
 
Submission of tumor specimen 4 
X 
 
 
 
 
 
 
 
X 
Weight 
X 
 
 
 
 
 
 
X 
X 
Demographics, Medical history, PE, 
Vitals, Disease staging, and Cancer 
treatment history 
X 
 
  
 
 
 
 
 
 
Pregnancy test 5 
X 
X 
X 
X 
X 
X 
X 
 
X 
ECOG 
X 
 
 
 
X 
 
 
X 
X 
Symptom directed physical examination, 
vitals  
 
X 
X  
X 
X 
X 
X 
X 
X 
Adverse events 6 
 
X 
X 
X 
Concomitant medications 
 
X 
X 
X 
CBC with diff and platelet count 7 
X 
 
X 
 
X 
 
X 
X 
 
Chemistry profile 7 
X 
 
X 
 
X 
 
X 
X  
 
TSH 8  
X 
 
 
 
X 
 
 
X 
 
CA125  
X 
 
 
 
X 
 
 
X 
X 
Research Blood Samples for biomarker 
analysis 9 
X 
 
X 
 
  
 
 
X 
X 
Urinalysis for proteinuria 10 
X 
 
X 
 
X 
 
X 
 
 
Radiographic disease assessment 11 
X  
 
 
 
X  
 
 
X 
X 
Randomization 12 
X 
 
 
 
 
 
 
 
 
Vaccination  
 
X 
X 
X 
X 
X 
X 
 
X 
Approximate blood volume (mL) 
91 
 
50 
 
20 
 
10 
76 
40 
Cumulative blood volume (mL) 
91 
 
141 
 
161 
 
171 
247 
287 
 


 
 
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1.  Screening studies must be done within 28 days of the first dose. Each cycle will be 28 days ± 4 days in length. 
2. 
In the second phase of the study, patients will be followed in the clinic every 12 weeks (±1 week) for up to 1.5 years for booster injection and disease evaluation, unless 
they come off study due to progression or withdraw consent. No booster injection should be given at the last visit. Once a patient is off study, their survival and cancer 
status will be followed by quarterly contact with the referring provider until TapImmune notifies the study sites that all patients have completed the trial and the 
database is locked. 
3. 
Once the enrollment tests are available, the completed Registration Form and supporting documents required will be sent to the TapImmune Medical Monitor for approval 
prior to randomization.  
4. 
Biopsy testing for FRα antigen and tumor biomarkers does not need to be done prior to enrollment, although submission is mandatory. Biopsy should be obtained at 
recurrence, if feasible, and submitted as well. 
5. 
Serum or urine pregnancy testing is required for women of child-bearing potential only. A negative result must be obtained <7 days prior to each treatment. 
6. 
All AEs should be collected until 28 days after each dose and followed until resolution if related. SAEs are collected from the time the patient signs consent until they 
come off study, whether or not considered to be related to study drug, as booster doses will continue during follow-up. (see Section 10.1 for details). 
7. 
Testing for CBC (with differential and platelet counts) and serum chemistries (BUN, creatinine [or clearance], sodium, potassium, chloride, CO2, calcium, total bilirubin 
[if >2xULN and no evidence of Gilbert’s syndrome then fractionate into direct and indirect bilirubin], total protein, albumin, alkaline phosphatase, AST, ALT) must be 
done within 14 days of the first dose. 
8. 
Thyroid antibody testing (typically including TSH receptor, thyroid peroxidase antibody, and thyroglobulin antibody) is only required for patients with systemically 
treated thyroid disease at baseline. Prior testing results should be recorded if available. If tested at baseline, follow-up testing performed during the study will be 
collected on the eCRF. 
9. 
Samples will be collected at baseline, prior to dosing Cycle 2, 28 days after Cycle 6, and 12 months after enrollment. See Sections 5.5.2 and 6.1 
10. All patients must have a urinalysis. If ≥ 2+ proteinuria, a 24-hour urine should be collected for protein quantification. Hold vaccine until 24-hour urine protein < 2.0 
gm/24hrs. See Paragraph 5.5.6. 
11. The imaging modalities used for RECIST assessment will be CT (preferably) or MRI scans of chest, abdomen, and pelvis (C/A/P) with other regions as clinically 
indicated for the assessment of disease. The tumor assessment must be performed no more than 28 days before the first dose of study medication. Follow-up 
assessments will be performed every 12 weeks +/-1 week relative to the date of the first dose during the study and interpreted according to the discussion in Section 9.4. 
Patients should be followed for survival regardless of whether study treatment is discontinued or delayed and/or protocol deviation – see Section 5.5.2.  
12. Patients should be randomized no more than 4 days before the first dose of study drug. 
 
 


 
 
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5.2. 
Pre-treatment Period 
5.2.1. Screening Procedures  
To determine whether a patient meets the eligibility criteria, patient care providers will examine the patient 
and review medical records, including the ovarian cancer medical history and may contact patients who are 
currently treated with, or have recently completed, a platinum-containing regimen course. The Investigator 
will discuss the study with suitable participants. The specific items of this review may include: 
a. Underlying disease 
b. Ovarian cancer treatment history and staging (including chemotherapy, endocrine therapy, surgery, 
radiation, and immunotherapy) 
c. Known chronic conditions that would exclude the patient 
d. The patient mental status; ability to read and understand the consent 
e. Medication record for drugs that would exclude the patient 
f. Recent pregnancy test for female patients of childbearing potential 
 
If the subject does not meet eligibility criteria, only the demographic data and reason for screen failure will be 
collected in the eCRF. 
5.2.2. Informed Consent 
Obtain written informed consent from the patient using the IRB-approved forms. If a screening consent is 
used, the main consent will need to be signed prior to performing any trial-mandated activities and tests. 
 
Collect appropriate contact information to conduct follow-up assessment (i.e. name, mailing address, Email 
and phone number of patient, and as appropriate contact for caregiver and treating physicians). This 
confidential information should NOT be transmitted to TapImmune personnel and should be stored 
accordingly.  
5.3. 
Method of Assigning Treatment Numbers to Patients 
Before signing the consent, the patients can be identified by first, middle and last initials. If the patient has no 
middle initial, a dash is to be used.  
 
After written informed consent has been obtained, the study site will add the subject to the IBM Clinical 
Development database. The system will automatically assign the patient a unique four-digit number. The first 
two digits will identify the site and the last two digits will be assigned sequentially to each new patient at the 
site. The same number will be used to randomize the patients in the EDC. The Investigator is responsible for 
assuring that results from all screening tests have been performed and that all eligibility criteria have been met 
before randomization.  
 
Once the last cycle of chemotherapy is completed and enrollment tests are available, the information will be 
reviewed and approved by the TapImmune Medical Monitor. The study site can then randomize the patient 
within the EDC. The randomization information will be made available only to the unblinded pharmacy 
personnel at the corresponding site and appropriate measures will be in place to avoid unblinding the site 
personnel. TapImmune personnel will remain blinded to the patient’s assigned randomization. 
5.4. 
Patient Assessment at Baseline Prior to Vaccination 
- 
Medical History, including all treatment received for ovarian cancer prior to enrollment 
- 
Current medications 


 
 
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- 
Vitals including temperature, heart rate, and blood pressure 
- 
Weight and height 
- 
Physical examination and medical symptoms 
- 
Radiographic tumor measurement (C/A/P CT [preferably] or MRI) with RESIST v1.1 scoring within 
28 days of dosing 
- 
Request archival tumor tissue (8-15 PPFE slides) 
- 
Complete blood count (CBC) with differential and platelets (within 14 days of first dose) 
- 
Chemistry profile (BUN, creatinine [or clearance], sodium, potassium, chloride, CO2, calcium, total 
bilirubin [if >2xULN and no evidence of Gilbert’s syndrome then fractionate into direct and indirect 
bilirubin], total protein, albumin, alkaline phosphatase, AST, ALT) (within 14 days of first dose) 
- 
TSH test (with negative anti-thyroid antibodies if thyroid disease is being treated systemically) 
- 
Collect baseline research blood samples 
- 
CA125 
- 
Urinalysis 
- 
Urine or serum pregnancy test (for women of child bearing potential) 
5.5. 
Study Periods 
5.5.1. Evaluation During the Vaccination Period 
All assessments are described in the Study Table in Section 5.1. All assessments are to be performed pre-
injection unless stated otherwise. Patients who complete the six cycles, as well as those who discontinue during 
the vaccination period, should return for a follow-up safety evaluation about 28 days after their last vaccination 
in the first portion of the study.  
5.5.2. Booster Vaccinations and Evaluation During Study Follow-up 
Patients will have a staging visit at 24 weeks, which is about 28 days after Cycle 6, then will be followed every 
12±1 weeks for the next 18 months until study completion or progression. Patients who have not discontinued 
vaccination by the end of the initial vaccination period will receive a booster vaccination during these visits. 
Patients whose tumors progress will go off study, once the 28-day safety follow-up has been completed (note: 
a CA125-only progression is not a reason to discontinue vaccination – see Section 9.4.6 for a detailed 
discussion of the potential to keep a patient on study).  
 
If any patient comes off study at any time during vaccination cycles 1-6, they should complete a safety visit at 
least 28 days after the last vaccination or prior to the start of a new treatment regimen, which ever comes first 
(the post 28 day cycle 6 visit procedures should be performed). If they come off study during the booster 
period, they should complete the last visit procedures and no booster injection should be given at the last visit. 
Once the patient is off study, their survival and cancer status will be followed by quarterly contact with the 
referring provider until TapImmune notifies the study sites that all subjects have completed the trial and the 
database is locked. Preparation of blinded study drug 
 
The study drug will be prepared by unblinded research pharmacy personnel according to the procedures 
outlined in the Investigational Product Handling Manual. The procedure and instructions may be edited from 
time to time by way of an administrative change.  
5.5.3. Methods for Unblinding of the Study 
Individual treatment codes will be available to the investigator(s) from the EDC system for emergency 
unblinding. Routines for this will be described in the EDC user manual that will be provided to each center. 
 


 
 
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The treatment code must not be broken except in exceptional medical emergencies and only when the clinical 
management of the patient necessitates knowledge of the treatment randomization. If the treatment code is 
broken, then the investigator(s) must document and report to TapImmune. If time allows, discussion should 
be had with the TapImmune Medical Monitor before breaking the code. 
 
The TapImmune Medical Monitor may break the code for SAEs that are unexpected and are suspected to be 
causally related to the study drug.  
5.5.4. Dosing Schedule 
Study Treatment will be administered as outlined in the tables below:  
 
 
Vaccination  
 
 
The vaccine mixture should be injected about 3 inches below the inguinal crease or shoulder apex. Vaccination 
sites should be rotated to an alternate limb for subsequent doses. 
5.5.5. Vaccine Schedule Modification and Discontinuation. 
Allowable schedule modification: If a patient presents with an acute illness (cold, influenza, etc.), vaccination 
will be withheld until the illness has resolved. Subsequent cycles will be adjusted in consultation with the 
Medical Monitor to bring the dosing back in line with the original schedule. However, tumor reassessments 
will continue on the original schedule. 
 
There will not be any modifications to the dose of vaccine used. There may be only allowances for the timing 
of the administration of vaccine to accommodate patient schedules or special circumstances. Such variations 
in the timing of vaccinations will be decided in advance after allowance by the study Medical Monitor on a 
case-by-case basis. Patient will be followed if study treatment is discontinued for toxicity.  
 
Agent 
Doses 
(Blinded) 
Presentation 
Route 
Start 
Re-
Treatment 
 
TPIV200 
FRα peptide 
vaccine 
With adjuvant  
 
TPIV200 + adjuvant:  
-5 huFRα peptides, 
~500µg each  
-GM-CSF (Leukine®) 
~125 µg 
 
3 ID syringes  
each with approx. 
0.4mL 
Intradermal 
injection at no 
less than 3 
sites ~ 1” apart 
– on the upper 
leg or arm. 
Day 1 of 
Cycle 1 
every 28 days 
(±4 days) for 
6 doses, then 
quarterly 
boosts until 
progression 
 
Adjuvant alone:  
-GM-CSF (Leukine®) 
~125 µg  
 


 
 
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Vaccine treatment will be discontinued for unacceptable toxicity that is possibly related to the study drug, as 
outlined in the following table. 
 
CTCAE 
System/Organ/ 
Class (SOC) 
ADVERSE EVENT 
ACTION 
Immune system 
disorders 
Allergic reaction 
≥Grade 2 
Autoimmune disorder 
≥Grade 2 
Discontinue vaccination and go to observation phase 
 
Discontinue vaccination and go to observation phase 
General disorders 
and administration 
site conditions 
Injection site reaction 
manifesting as an 
ulceration- ≥Grade 3 
Discontinue vaccination and go to observation phase 
Renal and urinary 
disorders 
Proteinuria 
≥Grade 2 
If 24-hour urine protein ≥ 
2.0 gm/24hrs 
Hold vaccine until 24- hour urine protein < 2.0 
gm/24hrs 
 
Discontinue vaccination if urine protein does not 
recover to < 2.0 gm/24hrs after 4 weeks of vaccine 
interruption and go to observation phase 
All other adverse 
events 
Hematologic ≥Grade 3  
 
Non-hematologic 
(excluding alopecia) 
≥Grade 3  
 
Neurologic ≥Grade 2 
Hold vaccine. Repeat in 2-4 weeks. 
 If toxicity level normalizes vaccination may 
proceed. 
 If level remains positive or increase in severity, 
discontinue vaccination and patient goes to 
observation. 
 
5.5.6. Criteria for discontinuation of vaccination 
1. Request by the patient to discontinue study treatment 
2. Unacceptable toxicity (see Section 5.5.6) 
3. Treatment delay of > 6 weeks  
4. Intercurrent illness or requirement for medication that, in the opinion of the clinical investigator, 
requires discontinuation of treatment 
5. Symptomatic tumor progression or tumor recurrence per RECIST v1.1 criteria (Note: A CA125-
only progression is not a reason to discontinue vaccination. Progression should be shown in the EDC 
as study completion, not discontinuation.) 
 
Patients who discontinue vaccination after receiving at least one dose of vaccine will return for safety follow-
up at least 28 days later unless they are discontinued from the study as detailed in Section 5.7. See also Section 
5.5.2. 
5.5.7. Accountability of Study Drug 
The site personnel will maintain an accounting of TPIV200 deliveries and track preparation and dispensing of 
vaccine. Certificates of delivery must be retained in the pharmacy or investigator site files. At the end of the 
study it must be possible to reconcile delivery records with records of vaccine preparation. 


 
 
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There is no need to retain empty TPIV200 vials, these may be discarded per usual pharmacy practice. 
5.6. 
Description of Adverse Events 
The term “adverse event” could include any of the following events that develop or increase in severity during 
the course of the study: 
 
1. Any signs or symptoms, regardless of severity, and whether or not ascribed to the test article; 
2. Any clinically significant laboratory abnormality, and; 
3. Any abnormality detected during physical examination. 
 
The Principal Investigator will follow all subjects withdrawn from the study due to any adverse event, until 
the outcome is determined and where appropriate, additional written reports will be provided. 
 
All treatment-emergent adverse events (TEAEs) are collected from the day of first vaccine administration until 
28 days after each dose and recorded in the eCRFs. TEAEs considered to be possibly related will be followed 
until resolution, stabilization, or the Investigator determines that no further information can be obtained. 
 
Adverse events are graded using the NCI CTCAE version 4.03 severity grading scheme. If CTCAE grading 
does not exist for an adverse event, the severity of mild (1), moderate (2), severe (3), life-threatening (4), and 
death related to an adverse event (5) will be used. Adverse event monitoring should be continued until adverse 
event resolution/stabilization (whichever is later).  
 
Medical conditions/diseases present before consenting the patient are only considered adverse events if they 
worsen after receiving any study drug. All laboratory values are to be reviewed by the Investigator and 
medically relevant abnormal values will be graded according to the CTCAE Version 4.03 as well. 
  
A laboratory abnormality is considered an adverse event if it results in 
1. Discontinuation from study drug, 
2. Necessitates therapeutic medical intervention, 
3. If the Investigator assesses the abnormality as an adverse event, or 
4. Any laboratory test that is clinically significant or meets the definition of an SAE 
 
Relationship of AEs to Study Drug 
 
When assessing whether an adverse event is related to a medical treatment or procedure, the following 
attribution categories are utilized: 
 
 
Definite - The adverse event is clearly related to the agent(s). 
 
Probable - The adverse event is likely related to the agent(s). 
 
Possible - The adverse event may be related to the agent(s). 
 
Unlikely - The adverse event is doubtfully related to the agent(s). 
 
Unrelated - The adverse event is clearly NOT related to the agent(s). 
 
Events determined to be possibly, probably, or definitely attributed to a medical treatment suggest 
there is evidence to indicate a causal relationship between the drug and the adverse event. 
 


 
 
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AEs and Disease Progression 
 
Disease progression can be considered as a worsening of a patient’s condition attributable to the type of cancer 
for which the study drugs are being studied. It may be an increase in the severity of the cancer or an increase 
in the symptoms of the cancer. Expected progression of the patient’s cancer and/or expected progression of 
signs and symptoms of the cancer, unless more severe in intensity or more frequent than expected for the 
patient’s condition, should not be reported as an AE. Any events that are unequivocally due to progression of 
disease must not be reported as an AE. 
 
The development of new metastases, or progression of existing metastases to the primary cancer under study, 
should be considered as disease progression and not an AE. Signs and symptoms clearly associated with 
metastases present at study entry should not be reported as AEs unless they are newly emergent (i.e. not 
previously observed in the patient), judged by the Investigator to be unusually severe or accelerated, or if the 
Investigator considers deterioration of disease related signs and symptoms to be caused directly by the study 
medication. 
 
Procedures for Recording AEs 
 
1) TEAEs are to be assessed in all subjects and documented as events occur. Each treatment-emergent AE 
should be reported spontaneously or in response to general, non-directed discussion with the attending 
nurse or physician (e.g., has there been any change in subject status since the last assessment period?). For 
each TEAE, the investigator should obtain all the information required to complete the AE page of the 
eCRF, in accordance with the guidelines that accompany it. 
 
2) All TEAEs, regardless of seriousness, severity, or presumed relationship to study therapy, must be 
recorded using medical terminology in the source document and graded according to the NCI CTCAE 
(version 4.03). Whenever possible, diagnoses should be given when signs and symptoms are due to a 
common etiology. Investigators must record their opinion concerning the relationship of the AE to study 
therapy on the AE page. 
 
3) All TEAEs considered to be possibly, probably, or definitely related will be followed until resolution, 
stabilization, or the Investigator determines that no further information can be obtained. Measures required 
for AE management and the ultimate outcome of the AE must be recorded in the source document and 
reported on the AE page. 
 
5.6.1. Serious Adverse Event, Pregnancy and Adverse Events of Special Interest   
Detailed procedures for reporting are in Section 10.  
 
  
5.6.2. Concomitant Medications 
Patients should receive full supportive care while on this study. This includes blood product support, antibiotic 
treatment, and treatment of other newly diagnosed or concurrent medical conditions. All blood products and 
concomitant medications received from the day of first vaccine administration until 30 days after the Cycle 6 
administration will be recorded in the eCRFs. 
 
The following medication are considered exclusionary during the study: 
 
Any investigational anticancer therapy other than specified in this protocol 


 
 
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 
Any concurrent chemotherapy, radiotherapy (except palliative radiotherapy), or therapy for cancer 
treatment, other than specified in this protocol. Concurrent use of hormones for non-cancer related 
conditions is acceptable. Local treatment of isolated lesions for palliative intent is acceptable (i.e. by 
local surgery or radiotherapy). Patients should not be enrolled, however, if there are plans for possible 
palliative localized treatment. Localized treatment should not be for progression of disease or the 
patient is deemed to have progressed and begins end of treatment assessments. Loss of lesion by 
localized treatment should not be the sole target lesion used for assessment of response and should be 
excluded in response assessments. Contact TapImmune medical monitor for further guidance. 
 
Immunosuppressive medications including, but not limited to systemic corticosteroids at doses 
exceeding 10 mg/day of prednisone or equivalent, methotrexate, azathioprine, and TNF-α blockers. 
Use of immunosuppressive medications for the management of investigational product-related AEs or 
in subjects with contrast allergies is however acceptable. In addition, use of inhaled and intranasal 
corticosteroids is permitted. A temporary period of steroids will be allowed for different indications, 
at the discretion of the principal investigator (e.g., chronic obstructive pulmonary disease, radiation, 
nausea, etc.) or for premedication prior to radiology. 
 
Live attenuated vaccines within 30 days of vaccination with study drug. Inactivated vaccines such as 
injectable influenza vaccine are permitted. 
 
Rescue/supportive medication/class of drug 
 
Usage: 
Concomitant medications or treatments (eg, acetaminophen or 
diphenhydramine) deemed necessary by the Investigator to provide 
adequate prophylactic or supportive care, except for those medications 
identified as “prohibited”, as listed above 
To be administered as 
prescribed by the 
Investigator 
Best supportive care (including antibiotics, nutritional support, growth 
factor support, correction of metabolic disorders, optimal symptom control, 
and pain management [including palliative radiotherapy, etc.]) 
Should be used when 
necessary for all 
patients 
 
 
5.7. 
Criteria for Discontinuation 
Subjects will discontinue vaccination for any of the following reasons: 
 
1. The patient withdraws his/her consent. 
2. The patient becomes pregnant. 
3. The site PI determines it to be in the patient’s best interest. 
4. The patient is noncompliant. 
5. The patient was ineligible for the study. 
6. The Sponsor discontinues the study. 
7. The patient dies. 
5.8. 
Withdrawal of a Subject Prior to Study Completion 
If for any reason, a subject is withdrawn before completing the study, the reason for withdrawal must be entered 
on the End of Study Form and other appropriate eCRFs must be completed. If the patient is not deceased, final 


 
 
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physical examinations and clinical laboratory assays will be performed. All data on the subject prior to 
discontinuation will be made available to TapImmune. Whether they progress or discontinue, patients will be 
monitored if possible for tumor response to subsequent chemotherapy and for remission, relapse or 
progression, as well as survival by quarterly contact with their physician until study completion. 
 
 


 
 
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6. 
BIOSPECIMENS FOR RESEARCH  
6.1. 
Summary Table of Research Blood Specimens to be Collected  
 
 
Assessment 
Type of Blood 
Collection Tube  
 
(color of tube top) 
Baseline  
(i.e. Day -28 to 
Day 1) 1 
Prior to 
vaccination of 
cycle 2 2 
28 Days post 
vaccination 
cycle 6 
12 months after 
1st Dose 
Temperature 
Conditions for 
Storage/ Shipping 
Serum biomarkers 
No additive 
(Red Top) 
5 mL (one 5 mL 
red top tube) 
 
5 mL (one 5 mL 
red top tube) 
 
Room temperature 
shipment in 
containers provided 
by TapImmune. 
Cytometry: circulating Treg and 
MDSC  
Cyto-Chex BCT 
Tube (purple/black 
top) and an EDTA 
tube 
11 mL (one 5 mL 
purple/black top 
tube and one 6 mL 
purple top tube) 
 
11 mL (one 5 mL 
purple/black top 
tube and one 6 
mL purple top 
tube) 
- 
Cellular biomarkers (analyzed at 
baseline only) 3 
 
And  
 
HuFR specific T cell immunity 
and additional exploratory 
correlative research 
Sodium Heparin 
(green top) 
(Lithium heparin 
NOT accepted) 
60 mL (Six 10 ml 
green top tubes) 
40 mL (Four 10 ml 
green top tubes) 
40 mL (Four 10 
ml green top 
tubes) 
40 mL (Four 10 
ml green top 
tubes) 
1 Must be drawn after patient signs the main consent  
2 Must be drawn prior to receiving vaccination to establish a baseline – but is not required to be on the day of vaccination 
3 For exploratory correlative research (Section 9.5.6) 


 
 
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6.2. 
Collection and Processing  
6.2.1. Collection will be done in the following order from a peripheral vein or port (where order is reversed): 
• Red top tube for serum: 5mL tube, No Additive whole blood - No mixing required, but keep in upright 
position during transport.  
• EDTA tubes for cytometry: 5 mL tubes - Immediately mix at least 10 times by gentle inversion. 
• Green top tubes for PBMC and plasma: 10 mL tubes, heparin Na+ additive - Immediately mix at least 
10 times (during sampling as necessary) by gentle inversion. 
 
NOTE: Immediately mixing the tube at least 10 times by inversion or on a rocker for at least 10 minutes is 
critical to insure that PBMC may be purified properly by ficoll gradient after transport. 
 
6.2.2. Processing, Shipping, and Handling 
A detailed set of procedures will be provided by the respective central laboratories to each clinical site for 
processing, storage and shipment of blood and tissue samples. 
 
6.2.3. Methodology 
Refer to background and methods in Section 16. 
 
 
 


 
 
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7. 
PATHOLOGY CONSIDERATIONS/TISSUE BIOSPECIMENS  
7.1. 
Research Tissue Specimens to be Collected for this Protocol 
These samples will be collected from the site pathologist from the primary tumor and when feasible from the 
site of recurrence and/or metastasis. Note that shipment of the primary tumor is a requirement for enrollment in 
this trial. An adequately sized (minimum of 2 mm x 2 mm) tumor tissue paraffin block from resection (or a core 
biopsy for recurrence of metastasis) from the primary tumor or metastases should be provided. Sections mounted 
on glass slides prepared from the block can be provided as outlined below. This material may be used for, but 
not restricted to, the elucidation of mechanism of immune response to the vaccination and improving the 
understanding of markers of disease progression.  
 
Correlative Study 
(Section for more 
information) 
Type of Tissue 
to Collect 
Block, Slides, Core, etc. 
(# of each to submit) 
Prior to 
randomization 
Analyze at 
site? (Yes 
or No) 
Temperature 
Conditions for Storage 
/Shipping 
Determination of 
FRα-specific 
expression in 
primary tumor 
 
Additional 
exploratory 
correlative research 
Formalin Fixed 
Paraffin 
Embedded  
 
From resection 
of primary 
tumor 
 
8-15 slides, each with 2 
or more 4-5 microns 
thick sections and 2 
with a 10 micron 
section and 
One H&E stained slide 
 
Tumor content >30% 
X 
No 
Ambient – using box 
provided by 
TapImmune. 
 
Ship within one week 
of sectioning 
Determination of 
FRα-specific 
expression in 
recurrent tumor 
after vaccination (if 
available and if 
feasible – not 
mandatory) 
Formalin Fixed 
Paraffin 
Embedded  
 
From resection 
or punch biopsy 
8-15 slides, each with 2 
or more 4-5 microns 
thick sections and 2 
with a 10 micron 
section and 
One H&E stained slide 
- 
7.2. 
Tissue Collection for IHC 
The availability of tissue from the primary tumor for testing for the presence of huFRα is one of the criteria for 
inclusion of a patient into the study. Submit 8-15 slides according to the instruction in Section 17. 
 
If available, at the time of recurrence submit 8-15 slides (4-5 microns on charged slides) from the recurrence or 
distant metastasis according to the instruction in Section 17  
 
8. 
SAFETY STOPPING RULES 
The Medical Monitor and the study statistician will review the study periodically to identify accrual, toxicity, 
and endpoint problems that might be developing. The study statistician will prepare a report containing accrual, 
adverse event, and any available unblinded efficacy data that will be submitted to an independent DSMB every 
3 months until all patients have completed the initial vaccination period and every 6 months thereafter. The 
DSMB will include no less than 3 members (2 physicians and a statistician). 
  
The DSMB will review unblinded data. At any point in the vaccination period after 10 or more patients have 
been enrolled in each group, if more than 20% of the enrolled patients develop a related grade 2 allergic reaction, 
grade 2 autoimmune reaction, grade 3 injection site reaction, or other grade 3+ toxicity, then enrollment to the 
trial may be suspended. All safety data will be reviewed; a trial recommendation will be formulated by the study 
team and presented to the independent DSMB. 
 


 
 
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The frequency of toxicities will be tabulated. If toxicities are observed, the DSMB may estimate an upper bound 
on the underlying toxicity rate using standard statistical methods. For example, assuming 22 patients have been 
enrolled, the upper bound of the 90% confidence interval based on an exact binomial test is as follows: 
 
Number of patients observed 
with toxicity  
0 (0%) 
1 (4.5%) 
2 (9.1%) 
3 (13.6%) 
4 (18.2%) 
Upper bound of 90% 
confidence interval for the 
underlying toxicity rate  
12.7% 
19.8% 
26.0% 
31.6% 
36.9% 
 
 
 


 
 
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9. 
ANALYSIS OF STUDY END-POINTS AND STATISTICS  
9.1. 
Randomization and Stratification 
This study will use an automated central randomization procedure to allocate patients in a 1/1 ratio to each of 
the two treatment groups. The randomization will be stratified based on:  
 
Stage of disease at diagnosis and debulking status 
o Stage III and maximal residual lesion diameter ≤1 cm 
o Stage III and maximal residual lesion diameter >1 cm 
o Stage IV 
 
Objective response to the last chemotherapy regimen prior to enrollment 
o Complete response (CR): defined as normal radiological findings  
o Partial Response (PR): deifned as RECIST PR  
o Stable Disease (SD): defined as RECIST SD [<30% decrease and <20% increase 
per RECIST v1.1], non-CR/non-PR for non-target only disease 
 
The randomization will assign patients using a permuted block design with above stratification factors (9 stratum 
levels) and is detailed in a separate randomization plan. 
9.2. 
Justification of Sample Size 
The emphasis of this Phase 2 study is an exploratory estimation of effect size and incidence of adverse events; 
it is not considered as a pivotal trial for efficacy at this time.  Therefore, a larger significance level (one-sided 
alpha=0.1) is used. The study is powered to detect a statistically significant hazard ratio (HR) of PFS of up to 
0.64, assuming an estimated median time to progression of 9 months for the control group (based on estimates 
from the ICON7 trial [9]) and 14 months for treatment. The Lan-Demets alpha spending function was used to 
approximate the O’Brien-Fleming group sequential boundaries using an overall one-sided alpha = 0.10 to 
produce efficacy stopping rules of alpha < 0.02 for the interim analysis and <0.094 for the final analysis with a 
simulated power of approximately 80%. This assumes approximately an overall 100 PD events (120 patients) at 
the final analysis and the interim analysis will be performed when 50 PD events are observed.  
 
 
The study is anticipated to enroll 120 patients over 12 months and patients will be followed for 24 months. The 
accrual rate is assumed to be approximately 0.5 to 1.0 patients per month per site, with sites being opened up 
over a 6-month period. The interim analysis would yield approximately a standard error (SE) of 0.2828 and 
upper one-sided 90% confidence intervals of potential HRs given on the left in the table below. By the end of 
the trial and assuming all enrolled and randomized patients had disease progression, are censored, died, or 
completed the trial, a SE of 0.2 is used to provide upper one-sided 90% confidence intervals of potential HRs 
given on the right in the table below. 
 
Interim Estimated 
Hazard Ratio 
One-sided Upper 90% 
Confidence Limit 
Final Estimated  
Hazard Ratio 
One-sided Upper 90% 
Confidence Limit 
0.80 
1.15 
0.80 
1.03 
0.70 
1.01 
0.70 
0.90 
0.60 
0.86 
0.60 
0.78 
0.50 
0.72 
0.50 
0.65 
0.40 
0.57 
0.40 
0.52 
0.30 
0.43 
0.30 
0.39 
0.20 
0.29 
0.20 
0.26 
 


 
 
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9.3. 
Data Collection 
Patient records will be collected on the eCRFs from the baseline evaluation until completion of study follow-up 
or disease progression or withdrawal from the trial. Only authorized staff at the study site will conduct study 
assessments and procedures and they are responsible for the data entry. TapImmune or a delegated CRO will be 
responsible for the data management, including data quality insurance. eCRFs and query documentation will be 
maintained in the EDC system’s audit trail. System backup for data stored in the EDC system will be conducted 
by the EDC vendor per the vendor standard procedures. 
 
9.4. 
Efficacy Parameters 
9.4.1. Radiological efficacy assessment  
The RECIST v1.1 guidelines [66] for measurable, non-measurable, target and non-target lesions, and the 
objective tumor response criteria (CR, PR, SD, or PD) will be used to programmatically determine best overall 
response, PFS and duration of response. Patients with a CR and non-measurable disease at baseline are not 
excluded from this study. These patients should be followed up with the same assessment schedule as those with 
measurable disease at baseline, preferably using contrast enhanced CT or MRI where CT is not feasible. Patients 
with no measurable disease only will be assessed according to RECIST criteria for non-target and new lesions. 
 
Baseline and follow-up contrast-enhanced CT of the chest, abdomen, and pelvis should be performed with other 
regions where clinically indicated for the adequate assessment of tumor burden. 
 
All baseline radiological tumor assessments must be performed between completion of last platinum containing 
regimen and the start of study treatment. Scans that were performed as part of standard of care prior to signature 
of the informed consent form can be analyzed for the purposes of the study if they were performed within the 
correct time frame and of sufficient quality. Subsequent tumor assessments according to RECIST should be 
performed at the end of every 3 cycles (12 weeks +/-1 week) for up to 2 years according to the planned study 
schedule up to objective progression by RECIST. Any other sites at which new disease is suspected should also 
be appropriately imaged. Patients must be followed until RECIST disease progression. 
 
Radiological examinations performed in the conduct of this study should be interpreted for a RECIST 
determination at the site, then forwarded to the central radiology vendor for QC and storage. 
 
For patients with measurable lesions, all measurable lesions confirmed and assessed by radiological methods 
(CT or MRI scans) up to a maximum of 2 lesions per organ and 5 lesions in total, representative of all involved 
organs, should be identified as target lesions, recorded and measured at baseline, and at the time points specified 
in the protocol. 
 
Non-target lesions will also be monitored throughout the study, and an overall assessment of response will be 
made regarding CR, incomplete response/SD or progression. Details of any new lesions will also be recorded. 
 
Tumor assessment will be performed in accordance with the protocol schedule until evidence of one of the 
following: 
 
 
Progression of disease by RECIST v1.1 
 
Death without evidence of progression 
 
Withdrawal of consent 
 
If a patient has any palliative radiotherapy to a lesion, that lesion should not be included in assessment of 
response, but should be assessed for progression. 


 
 
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A patient will be determined to have progressed if they have progression of target lesions, clear progression of 
existing non-target lesions, or the appearance of one or more new lesions. 
 
Disease progression will be determined as the appearance of one or more new soft tissue and visceral lesions, 
including lymph nodes with SD> 1.5cm. Patients with appearance of new or worsening of any effusion including 
ascites will not be determined to have disease progression, unless this it is considered to be clinically significant 
by the investigator and confirmed on radiology. 
 
Unequivocal malignant disease not identified prior to starting study treatment on additional anatomical imaging 
(eg, computed tomography (CT), magnetic resonance imaging (MRI) or bone scan confirmed by X-ray), 
prompted by symptoms is considered disease progression and should be recorded as new lesions. 
 
If a patient demonstrates CA125 progression determined by a 2-fold increase from the baseline CA125 (if above 
the ULN at baseline) or 2-fold greater than the ULN (if below the ULN at baseline) on two occasions 7 or more 
days apart, the patient may have an unscheduled RECIST assessment (CT/MRI) to assess for objective disease 
progression by RECIST. If progression is not confirmed by RECIST the patient should continue on treatment 
until the next study assessment unless they fulfill another reason for withdrawal. 
 
If a patient presents with disease related bowel obstruction they should be assessed by CT or MRI according to 
the RECIST criteria for tumor progression. If the CT or MRI findings are consistent with tumor progression in 
the view of the investigator, taking into account changes in CA125 levels indicative of progression according to 
the GCIG criteria, then this should be recorded as a new lesion, or captured appropriately for target or non- target 
lesions if present at baseline at this location. 
 
If an unscheduled radiological and clinical tumor assessment is performed, and the patient has not progressed 
according to RECIST criteria, the next scheduled tumor assessment should still be performed at the planned time 
(as detailed in the study plan) relative to the date of the first randomized treatment dose and treatment should 
continue. 
 
If at any time progression is uncertain and lesions are not symptomatic, patients may continue on treatment until 
the next scheduled assessment (ie, 12 weeks later +/- 1 week) or may have an unscheduled assessment earlier 
than this, if considered appropriate by the investigator. 
 
Death will be regarded as a progression event in those patients who die before disease progression. 
 
Lesions must be assessed using the same method and technique on each occasion. Lesions will be recorded on 
the CRF page in the same order as they were recorded at screening. 
 
Details of any new lesions will also be collected. Response will be calculated in comparison to the baseline tumor 
measurements obtained before starting treatment. Progression will be calculated in comparison to when the tumor 
burden was at a minimum. Overall visit response will be recorded on the CRF.  
9.4.2. Methods of assessment 
Response will be assessed using RECIST v1.1 criteria in patients who have measurable disease. Categorization 
of overall visit response will be based on RECIST using the following response categories: CR, PR, SD, and PD. 
In the case of stable disease, measurements must have met the stable disease criteria at least once after study start 
for a minimum interval of 6 weeks. 
 
Patients must have a CR/PR or SD prior to entry in the study. Therefore, the following criteria apply when 
assigning overall visit responses: 


 
 
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 
Only patients with PR or SD and measurable disease at entry can achieve an overall visit response of 
CR or PR. 
 
Patients with a CR at entry or non-measurable disease only at entry cannot achieve an overall visit 
response of CR or PR. 
 
Patients with a CR at baseline will progress based on new lesions only. 
 
To be assigned a status of PR or CR, changes in tumor assessments must be confirmed at the next scheduled 
tumor assessment no less than 4 weeks after the criteria for response were met. 
 
Although CA125 is measured in this study it will not be directly used for assessing the primary objective response 
or progression and patients should be continued on treatment until confirmed RECIST progression. 
9.4.3. Derivation or calculation of outcome variable 
Best overall response will be calculated as the best response recorded from date of enrollment (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started) for each patient, and will 
be used for the summaries of objective response. Best overall response will be determined programmatically 
based on the RECIST v1.1 criteria. 
9.4.4. Tumor assessments for patients with non-measurable disease only at baseline 
Patients with non-measurable disease only are not excluded from this study. These patients should be followed 
up with the same assessment schedule as those with measurable disease at baseline, preferably using contrast 
enhanced CT or MRI where CT is not feasible (see Appendix D for methods). Patients with non-measurable 
disease only will be assessed according to RECIST criteria for non-target and new lesions, as well as by the best 
overall response evaluated by CA125 as a secondary endpoint [66]. 
9.4.5. Methods for Evaluation of Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers. All baseline 
evaluations should be performed as closely as possible to the beginning of treatment and never more than 4 
weeks before the beginning of the treatment. The same method of assessment and the same technique should be 
used to characterize each identified and reported lesion at baseline and during follow up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be imaged 
but are assessable by clinical exam. 
 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules 
and palpable lymph nodes) and ≥10 mm diameter as assessed using calipers (e.g., skin nodules). In the case of 
skin lesions, documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended. 
 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined and 
surrounded by aerated lung. However, CT is preferable. 
 
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan based on the 
assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness greater than 5 mm, the 
minimum size for a measurable lesion should be twice the slice thickness. MRI is also acceptable in certain 
situations (e.g. for body scans), but NOT lung. 
 
CA125: CA125 alone cannot be used to assess response or progression, although CA125 response and 
progression information may be collected and separately analyzed and reported. If CA125 is initially above the 
upper normal limit, it must normalize for a patient to be considered in complete clinical response. 


 
 
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9.4.6. Response Criteria 
Evaluation of Target Lesions: 
 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target 
or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as 
reference the baseline sum diameters. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as 
reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition 
to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: 
the appearance of one or more new lesions is also considered progressions). 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, 
taking as reference the smallest sum diameters while on study. 
 
Evaluation of Non-Target Lesions: 
 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor marker level. 
All lymph nodes must be non-pathological in size (<10 mm short axis). Note: If CA125 is initially above the 
upper normal limit, it must normalize for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of CA125 level above 
the normal limits. 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression of 
existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must 
be representative of overall disease status change, not a single lesion increase. 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the treating physician 
should prevail in such circumstances, and the progression status should be confirmed at a later time by the review 
panel (or Principal Investigator). 
 
CA125 Progression: 
 
CA125 progression will be determined by a 2-fold increase from the baseline CA125 (if above the ULN at 
baseline) or 2-fold greater than the ULN (if below the ULN at baseline) on two occasions 7 or more days apart. 
CA125 progression is a secondary analysis endpoint and should not be used to stop treatment or follow-up of 
patients until evidence of RECIST progression. If CA125 progression occurs, a follow-up RECIST scan should 
be performed. 
 
Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment taking as reference for 
progressive disease the smallest measurements recorded since the treatment started. The patient's best response 
assignment will depend on the achievement of both measurement and confirmation criteria. 
 


 
 
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Table for Patients with Measurable Disease 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non- 
PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non- 
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non- 
PD/not 
evaluated 
No 
SD 
Documented at least once 
>4 wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
∗ 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
Note: Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as “symptomatic deterioration.” 
Every effort should be made to document the objective progression even after discontinuation of 
treatment. 
 
 
Table for Patients with Non-Measurable Disease (i.e. Non-Target Disease) 
Non-Target Lesions 
 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this category 
when no lesions can be measured is not advised 
 
Duration of Response 
 
Duration of response: The duration of response is measured from the time measurement criteria are met for CR 
or PR (whichever is first recorded) until the first date that RECIST recurrent or progressive disease is objectively 
documented (taking as reference for progressive disease the smallest measurements recorded since the treatment 
started). The duration of overall CR or PR is measured from the time measurement criteria are first met for CR 
or PR until the first date that progressive disease is objectively documented. 
 


 
 
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Duration of stable disease: Stable disease is measured from the start of the treatment until the criteria for 
progression are met, taking as reference the smallest measurements recorded since the treatment started, 
including the baseline measurements. 
 
Permitted deviations from RECIST 
 
The study's efficacy objectives will be evaluated according to the standard, unmodified RECIST v1.1 criteria as 
described above. Within the context of this protocol, the only purpose of the modifications to the criteria is to 
allow certain patients to continue the study treatment despite meeting RECIST criteria for progression of disease. 
Response to immunotherapy may differ from the typical responses observed with cytotoxic chemotherapy 
including the following [68-70]: 
 
 
Response to immunotherapy may be delayed 
 
Response to immunotherapy may occur after POD by conventional criteria 
 
The appearance of new lesions may not represent POD with immunotherapy 
 
SD while on immunotherapy may be durable and represent clinical benefit. 
 
As long as they are receiving treatment on protocol, patients will be permitted to continue study treatment after 
RECIST v 1.1 criteria for PD are met if they meet all of the following criteria: 
 
 
Absence of symptoms and signs indicating unequivocal progression of disease 
 
No decline in ECOG performance status 
 
Absence of tumor growth at critical anatomical sites (e.g., leptomeningeal disease) that cannot be 
managed by protocol-allowed medical interventions 
 
Patients for whom approved therapies exist must provide written consent to acknowledge deferring these 
treatment options in favor of continuing study treatment at the time of initial apparent progression. Patients in 
whom radiographic disease progression is confirmed at the subsequent tumor assessment may be considered for 
continued study treatment at the discretion of the investigator if they continue to meet the criteria above and have 
evidence of clinical benefit. 
 
Modification of RECIST as described may discourage the early discontinuation of TPIV200 and provide a more 
complete evaluation of its anti-tumor activity than would be seen with conventional response criteria. 
Nonetheless, the primary efficacy analysis will be conducted by programmatically deriving each efficacy 
endpoint based on RECIST v 1.1 criteria. 
 
Progression Free Survival 
 
Progression-Free Survival (PFS) is defined as the duration of time from start of study treatment to time of 
recurrence, progression, or death, whichever occurs first. 
 
Survival 
 
Survival is defined as the duration of time from start of treatment to time of death, or patients will be censored 
on the date of last contact. Survival will continue to be followed quarterly until study completion. 
 
9.5. 
Data Analysis 
All subjects who received one dose of study drug will be included in the analysis of safety and tolerability. 
Summary statistics for each endpoint will be provided for each relevant comparison group including the results 


 
 
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of statistical tests. All subjects who have a result for the baseline and a follow-up and who have received at least 
one dose of study drug will be included for the analysis of efficacy.  
9.5.1. Demographics, Baseline and Other Characteristics 
Subject characteristics (demographic information and pre-treatment measurements) will be summarized. All 
medical history and physical examination findings will be coded as appropriate and listed by subject. The results 
of the screening and final weight will be listed by subject. 
9.5.2. Safety and Tolerability 
Adverse events will be coded for purposes of summary by body system and preferred term. The incidence of 
TEAEs will be summarized for each treatment and tabulated by severity and attribution. Serious adverse events 
and those leading to study withdrawal will also be tabulated. 
 
The results of laboratory tests results at each study visit will be listed by subject. Values outside the normal range 
will be identified, with special attention given to those values the PI or Medical Monitor flags as clinically 
significant. Shift tables or scatter plots of numeric laboratory parameters will be provided, depicting changes in 
values, as appropriate. Normal ranges will be incorporated. Laboratory data obtained at any time after the 
vaccination will not be used as Baseline data.  
 
The incidence of Grade 3 and higher AEs will be compared across treatment groups. 
 
9.5.3. Evaluation for Efficacy 
The primary clinical efficacy endpoint is PFS (inclusive of recurrence or any death), where disease progression 
is determined per RECIST v1.1 criteria. The primary method for analysis will use Cox proportional hazards 
regression, adjusted for stage of disease at diagnosis and debulking status (stage III cancer and maximal residual 
lesion diameter ≤1 cm vs. stage III cancer and maximal residual lesion diameter >1 cm vs. stage IV cancer) and 
disease status (tumor response at the last platinum containing regimen [CR, PR, or SD]), to estimate the hazard 
functions for time to disease progression in each treatment group and compare them using HRs.  
 
Cox models will be generated at an interim analysis when 50 PD events have occurred, and again at the end of 
the study when all patients are expected to have had disease progression or censorship or completed the study. 
The HRs will be evaluated using one-sided upper 90% confidence intervals and a p-value of <0.02 at the interim 
and a p-value of <0.094 for the final analysis will be considered statistically significant to define trial success of 
the primary efficacy endpoint. The DSMB will review the interim results to recommend whether the trial should 
be continued until all patients have been fully assessed. The model will be adjusted for potential confounding 
variables: stage of disease at diagnosis and debulking status and disease status. Additionally, the probability of 
disease progression will be estimated using Kaplan-Meier methods for each treatment group.  
 
The above stopping rules will only serve as the guidance for decision-making during this exploratory phase of 
development. To support the best decisions based on the totality of efficacy evidence and benefit-risk evaluation, 
other methods including Bayesian approaches may also be utilized at interim and final analyses. Furthermore, 
when interim data becomes available, the sponsor may opt to discuss with the regulatory authorities regarding 
the possibility of extending the trial to a Phase 3 pivotal design. 
 
Other secondary efficacy end-points are: 
 
 
Overall survival (OS) will be analyzed using a Cox model similar to that for PFS. The probability of 
death will be estimated using the method of Kaplan-Meier for each treatment group. 


 
 
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 
Best overall response (CR+PR) will be treated as a binary endpoint. Response rates will be reported 
and 90% CI will be estimated using exact binomial proportions. Treatment groups will be compared 
using Fisher’s exact test or other appropriate method.  
 
Duration of response will be summarized with descriptive statistics for subjects who have a baseline 
response or achieve a post-baseline response of CR or PR. 
 
Duration of stable disease will be summarized with descriptive statistics for subjects who achieve a 
post-baseline response of SD. 
 
Disease control rate (CR+PR+SD) will be analyzed like best overall response. 
 
Response by irRECIST criteria will be treated as a binary endpoint [69, 70]. Rates of response by 
irRECIST will be reported and 90% CI will be estimated using exact binomial proportions. Treatment 
groups will be compared using Fisher’s exact test. 
 
Cancer Antigen (CA) 125 response (Gynecologic Cancer InterGroup [GCIG] criteria) will be analyzed 
like PFS. 
 
The progression free rate (PFR) at 6 months will be treated as a binary endpoint [71]. Response rates 
will be reported and 90% CI will be estimated using exact binomial proportions. Treatment groups will 
be compared using Fisher’s exact test. 
 
The PFR and OS for each group will be determined at the interim analysis and reported to the Sponsor, as they 
do not impact further hypothesis testing. A secondary efficacy variable is the PFS by CA125 [67]. 
 
Patients who have received at least one cycle of therapy and have has their disease re-evaluated at least once 
after baseline will be considered evaluable for response and PFS. Patients without a post-baseline assessment 
of response will be included in a sensitivity analysis as non-responders for response rate and PFS rate.  
9.5.4. FRα tumor expression 
Tumor membrane staining intensity will be scored by a pathologist as negative (0), weak (1+), moderate (2+), 
and strong (3+). The percent of cells within each tissue core stained at each intensity will be recorded to calculate 
an H-score. The H-score is a weighted score that captured both the proportion of positive staining and intensity 
for each tumor. H-score values can range from zero (no membrane staining) to a maximum of 300 (100% 
membrane staining at 3+). The mean H-scores across treatment groups will compared using the Mann-Whitney 
test. 
9.5.5. Immune Monitoring 
To evaluate each treatment arm with respect to change from baseline in T cell response, descriptive statistics 
will be provided and statistical inference will be performed using the Wilcoxon signed rank test. To compare the 
low versus high vaccine dose groups, the Mann-Whitney test will be used after aligning ranks within each 
cyclophosphamide level (priming or no priming). To compare priming versus no priming, the Mann-Whitney 
test will be used after aligning ranks within each vaccine dose level. 
 
The emergence of a FRα-specific T cell responses (i.e. immune responder) will be defined as (1) a 2-fold or 
greater increase in FRα-specific T cell at the end of the vaccination period if pre-treatment levels are detectable, 
or (2) levels of FRα-specific T cells above the threshold of the assay at end of the vaccination period if pre-
treatment levels are non-detectable.  
 
A 90% binomial confidence interval will be constructed for percentage of patients who develop an immune 
response among those patients in each treatment groups and for the sub-group of patients in each H-score 
quartile.  


 
 
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9.5.6. Exploratory Correlative Research  
The goal of the correlative studies is to determine whether serum biomarkers or immune measurement or tissue 
marker may be a predictor of a robust FRα specific T-cell response after vaccination. Such a predictor of 
immune response may be used clinically to rapidly assess whether or not immune protection against recurrence 
will be established. Surrogate markers could be used to assess the need for booster immunizations that may be 
required if immunity wanes. 
 
The following markers may be evaluated as baseline predictors: i/ Tumor infiltration from immune-cell subsets 
such as TIL, CD4+ Treg, myeloid cells by immunofluorescence and expression of markers of T cell activations 
such as 4-1BB (CD137), OX40, GITR, CD40, and ICOS, as well as known pathway inhibitors such as PD-1/PD-
L1, IDO, B7, LAG3, TIM-3, CTLA-4; ii/ Tumor cell markers such as Ki and EGFR [72]; iii/ Circulating 
inhibitory T cells such as Tregs and MDSC; iv/ Tumor genotyping to identify ovarian cancer subtypes. 
 
10. MANAGEMENT AND REPORTING OF SAES AND SPECIAL SITUATIONS 
10.1. Definition of Serious Adverse Events 
A serious adverse event is defined in general as an untoward (unfavorable) adverse event which: 
 
1.  Is fatal or life-threatening (defined as an event in which the subject was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it were more 
severe); 
2.  Requires or prolongs hospitalization; 
3.  Is significantly or permanently disabling or incapacitating; 
4.  Constitutes a congenital anomaly or a birth defect; or 
5.  May jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed above (examples of such events include, but are not limited to, intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not 
result in hospitalization). 
 
Suspected transmission of an infectious agent (e.g., any organism, virus or infectious particle, pathogenic or non-
pathogenic) via the study drug is an SAE. 
 
Although pregnancy, overdose of the peptides or dosing above the label dose of GM-CSF, and cancer (other 
than the pre-existing ovarian cancer) are not always serious by regulatory definition, these events must be 
handled as SAEs for data transmission purposes. 
 
The following hospitalizations are not considered SAEs in TapImmune clinical studies: 
 
1. A visit to the emergency room or other hospital department < 24 hours, that does not result in admission 
(unless considered "important medical event" or event life threatening) 
2. Elective surgery, planned prior to signing consent 
3. Admissions as per protocol for a planned medical/surgical procedure 
4. Routine health assessment requiring admission for baseline/trending of health status (e.g., routine 
colonoscopy)  
5. Medical/surgical admission for purposes other than remedying ill health state and was planned prior to 
entry into the study. Appropriate documentation is required in these cases 
6. Admission encountered for another life circumstance that carries no bearing on health status and requires 
no medical/surgical intervention (e.g., lack of housing, economic inadequacy, care-giver respite, family 
circumstances, administrative). 


 
 
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10.2. Special Situations for Reporting 
10.2.1. Adverse Events of Special Interest 
While they may not be considered SAEs, certain situations require special documentation; these are called 
Adverse Events of Special Interest (AESIs). These can occur at any time during the trial and must be handled 
in the same manner as SAEs for data transmission purposes, whether they are considered related or not. 
Autoimmune diseases of new onset or that are exacerbated are a typical example for vaccine product 
development; a list of diseases that may be autoimmune related are included in Appendix 4. Any TEAE can be 
addressed in this fashion; the Sponsor will determine whether the event should be reported to FDA. 
10.2.2. Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., treatment with 
investigational agent/intervention, radiation or chemotherapy). A secondary malignancy is not considered a 
metastasis of the initial neoplasm. All secondary malignancies that occur following treatment with the study 
drug during the follow-up must be must be handled in the same manner as SAEs for data transmission purposes.  
10.2.3. Pregnancy 
Although pregnancy is not considered an AE or SAE by regulatory definition, for this study pregnancies must 
be handled in the same manner as SAEs for data transmission purposes. In the event that a pregnancy 
complication occurs or elective termination of a pregnancy is required for medical reasons, then the complication 
will be recorded as an AE or SAE as appropriate. 
 
While elective and uncomplicated induced abortion not required for medical reasons does not constitute an AE 
or SAE (even if the subject is hospitalized to undergo abortion), spontaneous abortion is considered a fatal event 
and must be reported as an AE and SAE as appropriate.  
 
Any pregnancy complication or elective termination of a pregnancy for medical reasons will be recorded as an 
AE or, if appropriate, as an SAE. A spontaneous abortion is always considered an SAE and should be reported 
as described below. 
 
Women of childbearing potential enrolled in this study will have pregnancy tests administered during screening 
and before each treatment. Female subjects must either be of non-reproductive potential (i.e. post-menopause by 
history: >60 years old and no menses for >12 months naturally or secondary to radiation/chemotherapy; OR 
serum FSH, LH and estradiol levels in the post-menopausal range; OR history of hysterectomy; OR history of 
bilateral tubal ligation; OR history of bilateral oophorectomy), or must have a negative serum or urine pregnancy 
test upon study entry. Subjects who are pregnant or are breast feeding must not be entered into the study. 
 
If any pregnancy and/or suspected pregnancy occurs during the study in a female patient or a female partner of 
a male patient should be reported. Any pregnancy and/or suspected pregnancy will be followed for outcome.  
 
The Investigator must notify the Sponsor immediately after the pregnancy is confirmed. If the subject has 
received the investigational drug prior to becoming pregnant, the subject will continue the efficacy assessment 
and follow-up periods and measures of safety and efficacy will be obtained. 
 
The subject will be followed until the outcome of the pregnancy is determined. It is the responsibility of the 
Investigator to obtain and document pregnancy information on the most recent InClin Pregnancy Report Form. 
Furthermore, any SAE occurring as outcome of the pregnancy must be reported to the Sponsor’s Medical 
Monitor. 


 
 
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10.3. Reporting Procedures 
SAEs are collected from the time the patient signs consent until they come off study, whether or not considered 
to be related to study drug, as booster doses will continue during follow-up. Deaths must all be reported to the 
Sponsor within 24 hours of knowledge of the event, whether or not considered to be related to study drug, 
although deaths due to ovarian cancer will not be considered as SAEs.  
 
Any SAE that occurs greater than 30 days after the patient’s last dose of study drug and is considered to be at 
least possibly related to the study drug requires reporting within 24-hours to InClin Drug Safety. Unrelated SAEs 
that occur more than 30 days after a dose of study drug should be reported as soon as is convenient. These events 
will be followed until resolution, stabilization or until the Investigator provides sufficient evidence that no further 
information can be obtained. 
 
The Investigator or healthcare professional must send the InClin Serious Adverse Report Form by e-mail, e-
facsimile or telephone to: 
 
Contact Methods for SAEs & Pregnancy Reports 
E-mail: (primary) 
drugsafety@inclin.com 
eFacsimile: (back-up) 
+1 (877) 669-1618 
Telephone: (emergency) 
+1 (415) 870-7682 
 
Although not all information required for a complete InClin Serious Adverse Event Form may be readily 
available at the time of the event, the Investigator must include sufficient information on the InClin Serious 
Adverse Report Form to allow for a complete medical assessment. This should include at a minimum the subject 
number, site number, detailed description of the event, seriousness criteria, and causality/relationship to study 
drug.  
 
The InClin Drug Safety Team will acknowledge the receipt of the SAE via e-mail to the clinical site. After 
submission of the initial report, the Investigator will provide follow-up information to the InClin Drug Safety 
Team as requested (eg, concomitant medications, hospital discharge summary) to further evaluate the event and 
assure that all appropriate information is received. Once all information is received and the SAE has been deemed 
appropriate for closure, the InClin Serious Adverse Report Form must be signed and dated by the Investigator.  
 
The Investigator is responsible for informing the Institutional Review Board/Independent Ethics Committee 
(IRB/IEC) of the SAE in accordance with institutional policies and procedures including relevant initial and 
follow-up information about the SAE. 
 
11. ETHICAL ASPECTS 
11.1. Ethics and Good Clinical Practice 
This trial will be conducted in compliance with the appropriate protocol, ICH GCP guidelines, the principles of 
the Declaration of Helsinki, and all other applicable regulatory requirements. Participating sites must obtain 
written approval of the study protocol, consent form, other supporting documents, and any advertising for 
participant recruitment from their local institutional review board (IRB) in order to participate in the study. Prior 
to study initiation, the protocol and the informed consent documents will be reviewed and approved by an 


 
 
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appropriate Ethics Review Committee (ERC) or IRB. Any amendments to the protocol or consent materials must 
be approved before they are implemented. 
 
11.2. Regulatory files 
The regulatory files should contain all required regulatory documents, study-specific documents, and all 
important communications. Regulatory files will be checked at each participating site for regulatory compliance 
prior to study initiation, throughout the study, as well as at the study closure. 
 
11.3. Confidentiality Regarding Study Subjects 
Investigators must assure that the privacy of subjects, including their personal identity and all personal medical 
information, will be protected at all times, as required by law. Study sites may be required by their institutions 
to obtain authorization from participants for use of protected health information. Sites will be responsible for 
communicating with their IRBs or Privacy Boards and obtaining the appropriate approvals or waivers to be in 
regulatory compliance with HIPAA.  
 
Participant records will be held confidential by the use of study codes for identifying participants on eCRFs, 
secure storage of any documents that have participant identifiers, and secure computing procedures for entering 
and transferring electronic data. 
 
11.4. Financial Disclosure 
All investigators will comply with the requirements of 42 CFR Part 54, Subpart F to ensure that the design, 
conduct, and reporting of the research will not be biased by any conflicting financial interest. Everyone with 
decision-making responsibilities regarding the protocol will have an up-to date signed financial disclosure form 
on file with the sponsor. 
 
11.5. Institutional Review Board/Independent Ethics Committee 
Before implementing this study, the protocol, the proposed ICF, and other information provided to subjects must 
be reviewed by an IRB/IEC. A signed and dated statement that the protocol, and ICF, subject recruitment 
materials/process (e.g., advertisements), and any other written information to be provided to subjects have been 
approved by the IRB/IEC must be given to TapImmune before study initiation. The name and occupation of the 
chairperson and the members of the IRB/IEC (preferred) or the IRB’s Health and Human Safety Assurance 
number must be supplied to TapImmune or its designee. This committee, as required by local law or procedure, 
will approve any amendments to the protocol that need formal approval. The IRB/IEC will also be notified of 
all other administrative amendments (i.e., administrative changes). The investigator or sponsor should also 
provide the IRB/IEC with a copy of the Investigator Brochure or product labeling, information to be provided to 
subjects and any updates. The investigator or sponsor should provide the IRB/IEC with reports, updates and 
other information (eg, expedited safety reports, amendments and administrative letters) according to regulatory 
requirements or institution procedures.  
 
11.6. Informed Consent 
The informed consent form is a means of providing information regarding the trial to a prospective participant 
and allows for an informed decision about participation in the study. All participants must read, sign, and date a 
consent form(s) prior to undergoing any study-specific procedures and participating in the study. The informed 


 
 
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consent form must be updated or revised whenever important new safety information is available, or whenever 
the protocol is amended in a way that may affect study participation. A copy of the informed consent(s) form 
will be given to a prospective participant to review during the consent process and to keep for reference. The 
participant will be informed that their participation is voluntary and they may withdraw from the study at any 
time, for any reason without penalty. Study sites will be responsible for maintaining signed consent forms as 
source documents for quality assurance review and regulatory compliance. 
 
12. ADMINISTRATIVE REQUIREMENTS 
12.1. Monitoring Procedures 
Investigators will host periodic visits by TapImmune or CRO Clinical Monitors who will ensure all study 
procedures are conducted and that study data are generated, documented and reported in compliance with the 
protocol, GCP, and applicable regulations. These monitors will audit, at mutually agreed upon times, regulatory 
documents, case report forms (CRFs), and corresponding source documents for each participant. 
 
12.2. Protocol Deviation 
A protocol deviation is any departure from procedures and requirements outlined in the protocol. Protocol 
deviations are departures that may compromise the participant safety, participant rights, inclusion/exclusion 
criteria or study data and could be cause for corrective actions if not rectified or prevented from re-occurrence. 
Protocol deviations will be monitored at each site for (1) significance, (2) frequency, and (3) effects on the study 
objectives, to ensure that site performance does not compromise the integrity of the trial.  
 
All protocol deviations will be recorded in the EDC via the Protocol Deviations eCRF. Additionally, each site is 
responsible for tracking and reporting Protocol Deviations to their IRB as required by IRB regulations. The 
TapImmune Clinical Monitor must be contacted immediately if an unqualified/ineligible participant is 
randomized into the study. 
 
12.3. Investigational Site Training 
TapImmune may provide investigational staff training prior to study initiation. Training topics will include but 
are not limited to: GCP, AE reporting, study details and procedures, electronic CRFs, study documentation, 
informed consent, and enrollment of WOCBP as applicable.  
 
12.4. Recording of Data and Retention of Documents 
Study sites will collect data on eCRFs. All information required by the protocol should be provided. These forms 
will be completed on an ongoing basis during the study. Instructions will be provided for the site personnel to 
instruct the participant in the use of the eCRFs. However, the local investigative team is responsible for 
maintaining accurate, complete and up-to-date records, and progress notes are required by the protocol and the 
SOPs. The investigative team is also responsible for maintaining any source documentation related to the study. 
 
Essential documents, as listed below, will be retained by the Investigator for the maximum period required to 
comply with national and international regulations, or institutional procedures. The investigator must contact 
TapImmune prior to destroying any records associated with the study. If the investigator withdraws from the 
study (eg, relocation, retirement), the records shall be transferred to a mutually agreed upon designee (eg, another 
investigator, IRB). Notice of such transfer will be given in writing to TapImmune.  
 


 
 
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Essential documents include: 
1. Signed protocol and all amendments;  
2. IRB/IEC approvals for the study protocol and all amendments;  
3. All source documents and laboratory records;  
4. Subjects’ ICF/HIPAA authorization; and  
5. Any other pertinent study documents.  
 
12.5. Disclosure and Confidentiality 
By signing the protocol, the Investigator agrees to keep all information generated in connection with the study 
or provided by TapImmune or its designee in strict confidence and to request similar confidentiality from his/her 
staff and the IRB/IEC. Study documents provided by TapImmune (protocols, Investigators’ Brochures, eCRFs, 
and other material) will be stored appropriately to ensure their confidentiality. Such confidential information 
may not be disclosed to others without direct written authorization from TapImmune, except to the extent 
necessary to obtain informed consent/HIPAA authorization from subjects who wish to participate in the study. 
 
12.6. Discontinuation of Study 
TapImmune reserves the right to discontinue any study for any reason at any time. 
 
13. DATA MANAGEMENT 
13.1. Data Collection 
Electronic Data Capture (EDC) system will be deployed, eCRF will be completed by the authorized study site 
personnel. An electronic version of the final eCRF book for each subject will be forwarded to the study sites for 
record keeping at the study site closure.  
 
13.2. Data clarification 
Obvious eCRF data errors may be corrected by Data Management. Other errors, omissions, or requests for 
clarification will be queried; queries will be returned to the study site for resolution.  
 
 


 
 
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14. REFERENCES 
 
1. 
Chobanian, N. and C.S. Dietrich, 3rd, Ovarian cancer. Surg Clin North Am, 2008. 88(2): p. 285-99, vi. 
2. 
Armstrong, D.K. and M.F. Brady, Intraperitoneal therapy for ovarian cancer: a treatment ready for prime 
time. J Clin Oncol, 2006. 24(28): p. 4531-3. 
3. 
Dizon, D.S., et al., Retrospective analysis of carboplatin and paclitaxel as initial second-line therapy for 
recurrent epithelial ovarian carcinoma: application toward a dynamic disease state model of ovarian 
cancer. J Clin Oncol, 2002. 20(5): p. 1238-47. 
4. 
Markman, M., et al., Duration of response to second-line, platinum-based chemotherapy for ovarian 
cancer: implications for patient management and clinical trial design. J Clin Oncol, 2004. 22(15): p. 
3120-5. 
5. 
Hope, J.M. and S.V. Blank, Current status of maintenance therapy for advanced ovarian cancer. Int J 
Womens Health, 2010. 1: p. 173-80. 
6. 
Sabbatini, P., et al., Consolidation strategies in ovarian cancer: observations for future clinical trials. 
Gynecol Oncol, 2010. 116(1): p. 66-71. 
7. 
Hess, L.M., et al., Continued chemotherapy after complete response to primary therapy among women with 
advanced ovarian cancer: a meta-analysis. Cancer, 2010. 116(22): p. 5251-60. 
8. 
Burger, R.A., Experience with bevacizumab in the management of epithelial ovarian cancer. J Clin Oncol, 
2007. 25(20): p. 2902-8. 
9. 
Burger, R.A., et al., Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J 
Med, 2011. 365(26): p. 2473-83. 
10. Perren, T.J., et al., A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med, 2011. 365(26): p. 
2484-96. 
11. Aghajanian, C., et al., OCEANS: a randomized, double-blind, placebo-controlled phase III trial of 
chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial 
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12. Pujade-Lauraine, E., et al., Bevacizumab combined with chemotherapy for platinum-resistant recurrent 
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13. Bixel, K. and J.L. Hays, Olaparib in the management of ovarian cancer. Pharmgenomics Pers Med, 2015. 
8: p. 127-35. 
14. Mutch, D.G., et al., Randomized phase III trial of gemcitabine compared with pegylated liposomal 
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16. Kelemen, L.E., The role of folate receptor alpha in cancer development, progression and treatment: cause, 
consequence or innocent bystander? Int J Cancer, 2006. 119(2): p. 243-50. 
17. Kalli, K.R., et al., Folate receptor alpha as a tumor target in epithelial ovarian cancer. Gynecol Oncol, 
2008. 108(3): p. 619-26. 
18. Siu, M.K., et al., Paradoxical impact of two folate receptors, FRalpha and RFC, in ovarian cancer: effect 
on cell proliferation, invasion and clinical outcome. PLoS One, 2012. 7(11): p. e47201. 
19. Bottero, F., et al., Gene transfection and expression of the ovarian carcinoma marker folate binding protein 
on NIH/3T3 cells increases cell growth in vitro and in vivo. Cancer Res, 1993. 53(23): p. 5791-6. 
20. Kane, M.A., et al., Influence on immunoreactive folate-binding proteins of extracellular folate 
concentration in cultured human cells. J Clin Invest, 1988. 81(5): p. 1398-406. 
21. Figini, M., et al., Reversion of transformed phenotype in ovarian cancer cells by intracellular expression 
of anti folate receptor antibodies. Gene Ther, 2003. 10(12): p. 1018-25. 
22. Toffoli, G., et al., Overexpression of folate binding protein in ovarian cancers. Int J Cancer, 1997. 74(2): 
p. 193-8. 
23. Toffoli, G., et al., Expression of folate binding protein as a prognostic factor for response to platinum-
containing chemotherapy and survival in human ovarian cancer. Int J Cancer, 1998. 79(2): p. 121-6. 
24. Rothenberg, S.P., et al., Autoantibodies against folate receptors in women with a pregnancy complicated 
by a neural-tube defect. N Engl J Med, 2004. 350(2): p. 134-42. 
25. Ramaekers, V.T., et al., Autoantibodies to folate receptors in the cerebral folate deficiency syndrome. N 
Engl J Med, 2005. 352(19): p. 1985-91. 
26. Peoples, G.E., et al., Vaccine implications of folate binding protein, a novel cytotoxic T lymphocyte-
recognized antigen system in epithelial cancers. Clin Cancer Res, 1999. 5(12): p. 4214-23. 
27. Knutson, K.L., et al., T-cell immunity to the folate receptor alpha is prevalent in women with breast or 
ovarian cancer. J Clin Oncol, 2006. 24(26): p. 4254-61. 
28. Butterfield, L.H., Cancer vaccines. BMJ, 2015. 350: p. h988. 
29. Gajewski, T.F., H. Schreiber, and Y.X. Fu, Innate and adaptive immune cells in the tumor 
microenvironment. Nat Immunol, 2013. 14(10): p. 1014-22. 
30. Kreiter, S., et al., Mutant MHC class II epitopes drive therapeutic immune responses to cancer. Nature, 
2015. 520(7549): p. 692-6. 
31. Reed, C.M., et al., Vaccination with Melanoma Helper Peptides Induces Antibody Responses Associated 
with Improved Overall Survival. Clin Cancer Res, 2015. 21(17): p. 3879-87. 
32. Slingluff, C.L., Jr., et al., A randomized phase II trial of multiepitope vaccination with melanoma peptides 
for cytotoxic T cells and helper T cells for patients with metastatic melanoma (E1602). Clin Cancer Res, 
2013. 19(15): p. 4228-38. 


 
 
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33. Tran, E., et al., Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial 
cancer. Science, 2014. 344(6184): p. 641-5. 
34. Hunder, N.N., et al., Treatment of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. 
N Engl J Med, 2008. 358(25): p. 2698-703. 
35. Galaine, J., et al., Interest of Tumor-Specific CD4 T Helper 1 Cells for Therapeutic Anticancer Vaccine. 
Vaccines (Basel), 2015. 3(3): p. 490-502. 
36. Korn, T., et al., Th17 cells: effector T cells with inflammatory properties. Semin Immunol, 2007. 19(6): p. 
362-71. 
37. Sakaguchi, S., Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological 
tolerance to self and non-self. Nat Immunol, 2005. 6(4): p. 345-52. 
38. Kim, H.J. and H. Cantor, CD4 T-cell subsets and tumor immunity: the helpful and the not-so-helpful. Cancer 
Immunol Res, 2014. 2(2): p. 91-8. 
39. Kennedy, R. and E. Celis, Multiple roles for CD4+ T cells in anti-tumor immune responses. Immunol Rev, 
2008. 222: p. 129-44. 
40. Ikeda, H., L.J. Old, and R.D. Schreiber, The roles of IFN gamma in protection against tumor development 
and cancer immunoediting. Cytokine Growth Factor Rev, 2002. 13(2): p. 95-109. 
41. Quezada, S.A., et al., Tumor-reactive CD4(+) T cells develop cytotoxic activity and eradicate large 
established melanoma after transfer into lymphopenic hosts. J Exp Med, 2010. 207(3): p. 637-50. 
42. Xie, Y., et al., Naive tumor-specific CD4(+) T cells differentiated in vivo eradicate established melanoma. 
J Exp Med, 2010. 207(3): p. 651-67. 
43. Matsuzaki, J., et al., Nonclassical antigen-processing pathways are required for MHC class II-restricted 
direct tumor recognition by NY-ESO-1-specific CD4(+) T cells. Cancer Immunol Res, 2014. 2(4): p. 
341-50. 
44. Fridman, W.H., et al., The immune microenvironment of human tumors: general significance and clinical 
impact. Cancer Microenviron, 2013. 6(2): p. 117-22. 
45. Zhang, Z., et al., Infiltration of dendritic cells and T lymphocytes predicts favorable outcome in epithelial 
ovarian cancer. Cancer Gene Ther, 2015. 22(4): p. 198-206. 
46. Slingluff, C.L., Jr., et al., Randomized multicenter trial of the effects of melanoma-associated helper 
peptides and cyclophosphamide on the immunogenicity of a multipeptide melanoma vaccine. J Clin 
Oncol, 2011. 29(21): p. 2924-32. 
47. Slingluff, C.L., Jr., et al., Helper T-cell responses and clinical activity of a melanoma vaccine with multiple 
peptides from MAGE and melanocytic differentiation antigens. J Clin Oncol, 2008. 26(30): p. 4973-80. 
48. Woods, K. and J. Cebon, Tumor-specific T-cell help is associated with improved survival in melanoma. 
Clin Cancer Res, 2013. 19(15): p. 4021-3. 


 
 
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49. Disis, M.L., et al., Concurrent trastuzumab and HER2/neu-specific vaccination in patients with metastatic 
breast cancer. J Clin Oncol, 2009. 27(28): p. 4685-92. 
50. Brunsvig, P.F., et al., Telomerase peptide vaccination in NSCLC: a phase II trial in stage III patients 
vaccinated after chemoradiotherapy and an 8-year update on a phase I/II trial. Clin Cancer Res, 2011. 
17(21): p. 6847-57. 
51. Kyte, J.A., Cancer vaccination with telomerase peptide GV1001. Expert Opin Investig Drugs, 2009. 18(5): 
p. 687-94. 
52. Middleton, G., et al., Gemcitabine and capecitabine with or without telomerase peptide vaccine GV1001 
in patients with locally advanced or metastatic pancreatic cancer (TeloVac): an open-label, randomised, 
phase 3 trial. Lancet Oncol, 2014. 15(8): p. 829-40. 
53. Hu, Y., et al., Immunologic hierarchy, class II MHC promiscuity, and epitope spreading of a melanoma 
helper peptide vaccine. Cancer Immunol Immunother, 2014. 63(8): p. 779-86. 
54. Inderberg-Suso, E.M., et al., Widespread CD4+ T-cell reactivity to novel hTERT epitopes following 
vaccination of cancer patients with a single hTERT peptide GV1001. Oncoimmunology, 2012. 1(5): p. 
670-686. 
55. Necela, B.M., et al., Folate receptor-alpha (FOLR1) expression and function in triple negative tumors. 
PLoS One, 2015. 10(3): p. e0122209. 
56. Zhang, Z., et al., Folate receptor alpha associated with triple-negative breast cancer and poor prognosis. 
Arch Pathol Lab Med, 2014. 138(7): p. 890-5. 
57. Hartmann, L.C., et al., Folate receptor overexpression is associated with poor outcome in breast cancer. 
Int J Cancer, 2007. 121(5): p. 938-42. 
58. O'Shannessy, D.J., et al., Folate receptor alpha (FRA) expression in breast cancer: identification of a new 
molecular subtype and association with triple negative disease. Springerplus, 2012. 1: p. 22. 
59. Zhang, L., et al., Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med, 
2003. 348(3): p. 203-13. 
60. Sato, E., et al., Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell 
ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci U S A, 2005. 
102(51): p. 18538-43. 
61. Perez, S.A., et al., AE37 peptide vaccination in prostate cancer: a 4-year immunological assessment 
updates on a phase I trial. Cancer Immunol Immunother, 2013. 62(10): p. 1599-608. 
62. Jackson, D., et al., Preliminary report of a clinical trial supporting the sequential use of an attenuated E39 
peptide (E39') to optimize the immunologic response to the FBP (E39+GM-CSF) vaccine. Journal for 
ImmunoTherapy of Cancer, 2015. 3(2): p. P156. 
63. Armstrong, D.K., et al., Farletuzumab (a monoclonal antibody against folate receptor alpha) in relapsed 
platinum-sensitive ovarian cancer. Gynecol Oncol, 2013. 129(3): p. 452-8. 


 
 
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64. Moore, K.N., et al., Safety and Activity of Mirvetuximab Soravtansine (IMGN853), a Folate Receptor 
Alpha-Targeting Antibody-Drug Conjugate, in Platinum-Resistant Ovarian, Fallopian Tube, or Primary 
Peritoneal Cancer: A Phase I Expansion Study. J Clin Oncol, 2016: p. JCO2016699538. 
65. Roby, K.F., et al., Development of a syngeneic mouse model for events related to ovarian cancer. 
Carcinogenesis, 2000. 21(4): p. 585-91. 
66. Eisenhauer, E.A., et al., New response evaluation criteria in solid tumours: revised RECIST guideline 
(version 1.1). Eur J Cancer, 2009. 45(2): p. 228-47. 
67. Rustin, G.J., et al., Definitions for response and progression in ovarian cancer clinical trials incorporating 
RECIST 1.1 and CA 125 agreed by the Gynecological Cancer Intergroup (GCIG). Int J Gynecol Cancer, 
2011. 21(2): p. 419-23. 
68. Wolchok, J.D., et al., Guidelines for the evaluation of immune therapy activity in solid tumors: immune-
related response criteria. Clin Cancer Res, 2009. 15(23): p. 7412-20. 
69. Nishino, M., et al., Developing a common language for tumor response to immunotherapy: immune-related 
response criteria using unidimensional measurements. Clin Cancer Res, 2013. 19(14): p. 3936-43. 
70. Nishino, M., et al., Optimizing immune-related tumor response assessment: does reducing the number of 
lesions impact response assessment in melanoma patients treated with ipilimumab. J Immunother 
Cancer, 2014. 2: p. 17. 
71. Verweij, J., Other endpoints in screening studies for soft tissue sarcomas. Oncologist, 2008. 13 Suppl 2: 
p. 27-31. 
72. de Mascarel, I., et al., Comprehensive prognostic analysis in breast cancer integrating clinical, tumoral, 
micro-environmental and immunohistochemical criteria. Springerplus, 2015. 4: p. 528. 
 
 
 


 
 
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15. APPENDIX 1: ECOG / KARNOFSKY PERFORMANCE STATUS 
 
Grade 
 
 
0 
Fully active, able to carry on all pre-disease activities without restriction (Karnofsky 90-100). 
 
 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light housework, office work (Karnofsky 70-80). 
 
 
2 
Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about 
more than 50 percent of waking hours 
 
 
(Karnofsky 50-60). 
 
 
3 
Capable of only limited self-care, confined to bed or chair 50 percent or more of waking hours 
(Karnofsky 30-40). 
 
 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair (Karnofsky 10-
20). 
 
 
5 
Dead 
 


 
 
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16. APPENDIX 2: IMMUNE MONITORING METHODS 
16.1. Background  
 
The goal of the immunologic studies is to determine whether the potential exists for an immune measurement 
or tissue marker to act as a surrogate marker of protection against disease recurrence in patients immunized 
with the FRα vaccine. While the clinical response (e.g. disease free period in the current proposal) remains the 
endpoint of choice for many different types of therapeutic modalities, validated surrogate endpoints are useful 
for vaccines for a number of reasons.  
 
• 
Prediction of clinical benefit: Surrogate immunologic endpoints can be used clinically to rapidly assess 
whether or not protection against disease exists in the absence of clinical symptoms or other biologic 
features of infection or disease. Surrogates are used to determine protection following immunization 
against a number of infectious agents including Polio virus and Streptococcus pneumonia.  
 
• 
Decisions for ongoing therapy: Surrogate markers could be used to assess the need for booster 
immunizations that may be required if immunity wanes.  
 
• 
Vaccine improvements and lot variations 
 
16.2. Methods 
16.2.1. FRα-specific antibody enzyme-linked immunosorbent assay 
The FRα vaccine in this protocol incorporates a known antibody recognition epitope of FRα. Testing will be 
done in an ELISA assay to detect response toward the FRα peptide-mix and/or FRα protein. 
 
A vaccine-induced increase in FRα-specific antibody responses will be defined as (1) a 2-fold or greater increase 
in FRα-specific antibody at any point during treatment if there were detectable pre-treatment levels of FRα-
specific T cells or (2) FRα-specific antibodies at any point during treatment if pre-treatment levels of FRα-
specific antibodies are non-detectable. 
 
16.2.2. Flow cytometric analysis of circulating regulatory T cells (Tregs) and MDSC 
Treg and MDSC will be counted at baseline either from fresh blood (K3 EDTA tube) or from the PBMC obtained 
from the heparin tubes.  


 
 
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17. APPENDIX 3 – TISSUE IMMUNOCHEMISTRY METHODS 
 
FRα expression in the tumor will be examined as previously described [17]. Samples will be examined for FRα 
expression by assessing triplicate slides made from a full paraffin block. Tissues will be stained with a IgG 
antibody specific for human FRα purified.  
 
Five-micron sections will be cut and placed on positively charged slides. After rehydration, tissues will be 
subjected to antigen retrieval and blocking of endogenous peroxidases prior to staining with FRα Ab or a non-
specific isotype matched antibody as a negative control for 30 min. After washing the slides, signals will be 
detected using the mouse MACH3 system (Biocare Medical, Walnut Creek, CA). Slides will be counterstained 
with Modified Schmidt's Hematoxylin and permanently mounted. 
 
Slides will then be archived using digital imaging system. The staining intensity (strong, moderate, weak, or 
negative) and proportion of FRα-positive cells among the malignant cells and will be scored independently.  
 
Other testing may be done to evaluate the local immune response, including standard or multiplex 
immunohistochemistry for CD4, CD8, and Treg cells or transcript analysis. 
 


 
 
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18. APPENDIX 4 - DISEASES THAT MAY BE AUTOIMMUNE RELATED  
 
Acute disseminated 
encephalomyelitis 
Addison’s disease 
Alopecia universalis 
Ankylosing spondylitis 
Antiphospholipid antibody 
syndrome 
Aplastic anemia 
Asthma 
Autoimmune hemolytic anemia 
Autoimmune hepatitis 
Autoimmune 
hypoparathyroidism 
Autoimmune hypophysitis 
Autoimmune myocarditis 
Autoimmune oophoritis 
Autoimmune orchitis 
Autoimmune thrombocytopenic 
purpura 
Behcet’s disease 
Bullous pemphigold 
Celiac disease 
Chronic fatigue syndrome 
Chronic inflammatory 
demyelinating 
polyneuropathy 
Chung-Strauss syndrome 
Crohn’s disease 
Dermatomyositis 
Diabetes mellitus type 1 
Dysautonomia 
 
Eczema 
Epidermolysis bullosa acquista 
Gestational pemphigoid 
Giant cell arteritis 
Goodpasture’s syndrome 
Graves’ disease 
Guillain-Barré syndrome 
Hashimoto’s disease 
IgA nephropathy 
Inflammatory bowel disease 
Interstitial cystitis 
Kawasaki’s disease 
Lambert-Eaton myasthenia 
syndrome 
Lupus erythematosus 
Lyme disease - chronic 
Meniere’s syndrome 
Mooren’s ulcer 
Morphea 
Multiple sclerosis 
Myasthenia gravis 
Neuromyotonia 
Opsoclonus myoclonus 
syndrome 
Optic neuritis 
Ord’s thyroiditis 
Pemphigus 
Pernicious anemia 
Polyarteritis nodusa 
 
Polyglandular autoimmune 
syndrome 
Primary biliary cirrhosis 
Psoriasis 
Reiter’s syndrome 
Rheumatoid arthritis (but not 
osteoarthritis) 
Sarcoidosis 
Scleroderma 
Sjögren’s syndrome 
Stiff-Person syndrome 
Takayasu’s arteritis 
Ulcerative colitis 
Vitiligo 
Vogt-Kovanagi-Harada disease 
Vulvodynia 
Wegener’s granulomatosis 
 
 
 

SAP_001.pdf: 
 
 
STATISTICAL ANALYSIS PLAN 
PROTOCOL FRV-002 
A randomized multicenter Phase II trial to evaluate the safety and 
immunogenicity of two doses of vaccination with Folate Receptor Alpha 
peptides with GM-CSF in patients with Triple Negative Breast Cancer 
defined as primary tumor that is Her2-neu negative and low (≤10%) ER/PR 
nuclear staining 
 
Protocol Number: 
Protocol Version and Date: 
FRV-002 
Original Protocol: 07 October 2015 
Protocol Amendment 1 (Edition 02): 30 November 2015 
Protocol Amendment 2 (Edition 03): 16 June 2016 
Protocol Amendment 3: 30 November 2016 
Protocol Amendment 4 (Edition 04): 05 December 2016 
Protocol Amendment 5 (Edition 05): 24 April 2017 
Protocol Amendment 6 (Edition 06): 04 February 2019 
Name of Test Drug: 
TPIV200 (hu-FRα peptide vaccine with GM-CSF adjuvant) 
Phase: 
Phase II 
Methodology: 
Open-label, Randomized, Parallel groups trial 
Sponsor: 
Marker Therapeutics, Inc. 
3200 Southwest Freeway, Suite 2240 
Houston, TX 77027 
Sponsor Representative: 
Richard T. Kenney, MD, FACP 
Marker Therapeutics Medical Monitor 
Analysis Plan Date: 
31 October 2019 
Analysis Plan Version: 
Version 1.0 
Confidentiality Statement 
The information contained herein is confidential and the proprietary property of Marker 
Therapeutics, Inc. and any unauthorized use or disclosure of such information without 
the prior written authorization of Marker Therapeutics Inc. is expressly prohibited. 




Marker Therapeutics, Inc. 
Statistical Analysis Plan, Protocol FRV-002 
31 October 2019, Version 1.0 
 
 
 
CONFIDENTIAL 
3
TABLE OF CONTENTS 
Section 
Page 
1. 
INFORMATION FROM THE STUDY PROTOCOL .............................. 8 
1.1 
Introduction and Objectives ....................................................................... 8 
1.1.1 
Introduction ................................................................................................ 8 
1.1.2 
Study Objectives ........................................................................................ 8 
1.2 
Study Design .............................................................................................. 9 
1.2.1 
Summary of Study Design ......................................................................... 9 
1.2.2 
Randomization Methodology................................................................... 10 
1.2.3 
Stopping Rules ......................................................................................... 10 
1.2.4 
Study Procedures ..................................................................................... 11 
1.2.5 
Efficacy and Safety Parameters ............................................................... 15 
2. 
PATIENT POPULATION ....................................................................... 17 
2.1 
Population Definitions ............................................................................. 17 
2.2 
Protocol Violations .................................................................................. 17 
3. 
GENERAL STATISTICAL METHODS ................................................ 18 
3.1 
Sample Size Justification ......................................................................... 18 
3.2 
General Methods ...................................................................................... 18 
3.3 
Computing Environment .......................................................................... 19 
3.4 
Baseline Definitions ................................................................................. 19 
3.5 
Methods of Pooling Data ......................................................................... 20 
3.6 
Adjustments for Covariates...................................................................... 20 
3.7 
Multiple Comparisons/Multiplicity ......................................................... 20 
3.8 
Subpopulations ......................................................................................... 20 
3.9 
Withdrawals, Dropouts, and Loss to Follow-up ...................................... 20 
3.10 
Missing, Unused, and Spurious Data ....................................................... 21 
3.11 
Visit Windows ......................................................................................... 21 
3.12 
Interim Analyses ...................................................................................... 22 
4. 
STUDY ANALYSES .............................................................................. 23 
4.1 
Patient Disposition ................................................................................... 23 


Marker Therapeutics, Inc. 
Statistical Analysis Plan, Protocol FRV-002 
31 October 2019, Version 1.0 
 
 
 
CONFIDENTIAL 
4
Section 
Page 
4.2 
Demographics and Baseline Characteristics ............................................ 23 
4.3 
Efficacy Evaluation .................................................................................. 24 
4.3.1 
Primary Efficacy Endpoint – Immune Response ..................................... 24 
4.3.2 
Additional Efficacy Endpoints ................................................................. 25 
4.4 
Safety Analyses ........................................................................................ 27 
4.4.1 
Primary Safety Endpoint .......................................................................... 27 
4.4.2 
Additional Safety Endpoints .................................................................... 27 
4.4.3 
Adverse Events ........................................................................................ 27 
4.4.4 
Clinical Laboratory Evaluations .............................................................. 28 
4.4.5 
Vital Sign Measurements and Physical Examinations............................. 29 
4.4.6 
Concomitant Medications ........................................................................ 29 
4.4.7 
Overall Survival ....................................................................................... 30 
5. 
CHANGES TO PLANNED ANALYSES ............................................... 31 
6. 
REFERENCES ........................................................................................ 33 
7. 
REVISION HISTORY............................................................................. 34 
7.1 
Statistical Analysis Plan Version 0.1: 20 November 2018 ...................... 34 
7.2 
Statistical Analysis Plan Version 0.2: 12 February 2019 ........................ 34 
7.3 
Statistical Analysis Plan Version 1.0: 31 October 2019 .......................... 34 
8. 
APPENDIX 1: RANDOMIZATION PLAN ........................................... 35 
 


Marker Therapeutics, Inc. 
Statistical Analysis Plan, Protocol FRV-002 
31 October 2019, Version 1.0 
 
 
 
CONFIDENTIAL 
5
TABLES INCLUDED IN THE TEXT 
 
Page 
Table 1-1 Schedule of Assessments ..............................................................................12 
Table 3-1 Evaluation Intervals for Efficacy Analysis ...................................................22 
 
 


Marker Therapeutics, Inc. 
Statistical Analysis Plan, Protocol FRV-002 
31 October 2019, Version 1.0 
 
 
 
CONFIDENTIAL 
6
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
AE 
Adverse event 
ALT  
Alanine aminotransferase  
ANA 
Antinuclear antibody 
AST  
Aspartate aminotransferase  
ATC 
Anatomic Therapeutic Chemical 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CI 
Confidence interval 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DSMB 
Data Safety Monitoring Board 
eCRF 
Electronic case report form 
EGFR 
Epidermal growth factor receptor 
ER 
Estrogen receptor 
FRα 
Folate receptor alpha 
GM-CSF 
Granulocyte-macrophage colony-stimulating factor 
huFR 
Humane folate receptor 
ICH 
International Conference on Harmonisation 
IHC 
Immunohistochemistry 
IRB 
Institutional Review Board 


Marker Therapeutics, Inc. 
Statistical Analysis Plan, Protocol FRV-002 
31 October 2019, Version 1.0 
 
 
 
CONFIDENTIAL 
7
Abbreviation 
Definition 
ITT 
Intent-to-treat 
IV 
Intravenous 
MDSC 
Myeloid-derived suppressor cells 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-Treat 
NCI 
National Cancer Institute 
OS 
Overall survival 
PD 
Progressive disease 
PR 
Progesterone receptor 
PT 
Preferred term 
RFS 
Relapse-free survival 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SI 
International System of Units 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
TNBC 
Triple-negative breast cancer 
Treg 
Regulatory T-cell 
TSH 
Thyroid-stimulating hormone 
WHO 
World Health Organization 


Marker Therapeutics, Inc. 
Statistical Analysis Plan, Protocol FRV-002 
31 October 2019, Version 1.0 
 
 
 
CONFIDENTIAL 
8
1. 
INFORMATION FROM THE STUDY PROTOCOL 
1.1 
Introduction and Objectives 
1.1.1 
Introduction 
This document is the statistical analysis plan (SAP) for study FRV-002, a randomized, 
multicenter Phase II trial evaluating the safety and immunogenicity of 2 doses of vaccination 
with Folate Receptor Alpha (FRα) peptides with granulocyte-macrophage colony-stimulating 
factor (GM-CSF) in patients with triple negative breast cancer (TNBC) defined as primary 
tumor that is Her2-neu negative and low (≤ 10%) estrogen receptor (ER)/progesterone receptor 
(PR) nuclear staining. This document is based on Protocol FRV-002, Edition 6, dated 04 
February 2019. 
1.1.2 
Study Objectives 
The primary study objectives are: 
• To evaluate high- and low-dose hu-FRα peptide vaccine with GM-CSF administered 
every month for 6 months (the vaccination phase) to elicit a FRα-specific T cell 
response. 
• To evaluate cyclophosphamide priming prior to vaccinations to elicit a FRα-specific 
T cell response. 
• To evaluate the safety and tolerability of high- and low-dose hu-FRα peptide vaccine 
with GM-CSF. 
• To evaluate the long-term safety and tolerability of booster vaccination of hu-FRα 
peptide vaccine with GM-CSF. 
The secondary study objectives are: 
• To determine FRα expression status of primary tumors when available as a formalin-
fixed, paraffin-embedded material and whether expression correlates with the emergence 
of a FRα-specific T cell response.  
• To determine the relapse-free survival (RFS) of patients with TNBC after treatment with 
hu-FRα peptide vaccine with GM-CSF. 
This SAP is designed to outline the methods to be used in the analysis of study data in order to 
answer the study objectives. Populations for analysis, data handling rules, statistical methods, 
and formats for data presentation are provided. The statistical analyses and summary tabulations 
described in this SAP will provide the basis for the results sections of the clinical study report 
(CSR) for this trial. 
This SAP will also outline any differences in the currently planned analytical objectives relative 
to those planned in the study protocol. 


Marker Therapeutics, Inc. 
Statistical Analysis Plan, Protocol FRV-002 
31 October 2019, Version 1.0 
 
 
 
CONFIDENTIAL 
9
1.2 
Study Design 
1.2.1 
Summary of Study Design 
This is an open-label, randomized, parallel groups Phase II trial conducted at up to 20 clinical 
sites in the United States in 80 eligible female patients with TNBC who are ≥ 18 years of age. 
Patients will be randomized to 1 of 4 treatment groups in a 2×2 design: low-dose versus high-
dose FRα peptide vaccine and cyclophosphamide priming versus none. A total of 20 patients 
will be enrolled in each treatment group. 
The vaccine will be administered in 2 phases: a vaccination phase and a booster phase. The 
vaccination phase will include 6 administrations of the vaccine at 4-week intervals. The booster 
phase will include administration of the vaccine every 6 months (defined as approximately 180 
days) during a 3-year follow-up or until cancer recurrence.  
The total duration of the study will be 3.5 years. Assessment for disease recurrence will be 
conducted every 6 months from the end of treatment until documented disease progression. 
The vaccination will be administered intradermally with a low dose of 165 µg/peptide and a 
high dose of 500 µg/peptide. Cyclophosphamide will be administered intravenously (IV) at a 
dose of 300mg/m2. 
The study design is summarized in Figure 1: 


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Figure 1: 
Study Schema 
 
1.2.2 
Randomization Methodology 
This study will use an automated central randomization procedure to allocate patients in a 
1/1/1/1 ratio to each of the treatment groups. The randomization will be stratified based on the 
disease stage (ie, pretreatment clinical Stage I, II, or III), treatment (ie, neoadjuvant or just 
adjuvant), and outcome to last cycle of chemotherapy prior to randomization (ie, pathologic 
complete response: yes or no). 
1.2.3 
Stopping Rules 
The Medical Monitor and the study statistician will review the study periodically, after every 6 
months, to identify accrual, toxicity, and endpoint problems that might be developing. The study 
statistician will prepare a report containing accrual, adverse event (AE), and efficacy data that 
will be submitted to an independent data safety monitoring board (DSMB) every 3 months until 
all patients are off study Phase 1 (vaccination phase) and every 6 months thereafter. The DSMB 
will include no less than 3 members (2 physicians and a statistician). 
At any point in the vaccination phase, after 5 or more patients have been enrolled in each 
treatment group, if more than 20% of the enrolled patients develop a Grade 2 allergic reaction, 
Grade 2 autoimmune reaction, Grade 3 injection site reaction, Grade 2 neurologic problem, 
Grade 2 Proteinuria, Grade 3+ Hematologic AE, Grade 3+ Non-hematologic (excluding 


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alopecia), or any other  Grade 3+ toxicity, then enrollment to the trial will be suspended. All 
safety data will be reviewed; a trial recommendation will be formulated by the study team and 
presented to the independent DSMB and institutional review board (IRB) for approval. 
For example, assuming 22 patients have been treated in the study, using this stopping rule the 
probability of suspending enrollment for various hypothetical toxicity rates is as follows: 
Hypothetical toxicity rate (%) 
0 
5 
10 
15 
20 
25 
30 
Probability (%) of suspending 
enrollment 
0 
0.4 
6.2 
22.6 
45.7 
67.7 
83.5 
The frequency of toxicities will be tabulated. If toxicities are observed, the DSMB may estimate 
an upper bound on the underlying toxicity rate using standard statistical methods. For example, 
assuming 22 patients have been enrolled, the upper bound of the 90% confidence interval (CI) 
based on an exact binomial test is as follows: 
Number of patients observed 
with toxicity 
0 (0%) 
1 (4.5%) 
2 (9.1%) 
3 (13.6%) 
4 (18.2%) 
Upper bound of 90% CI for 
the underlying toxicity rate 
12.7% 
19.8% 
26.0% 
31.6% 
36.9% 
1.2.4 
Study Procedures 
The schedule of assessments, as outlined in the study protocol, is provided in Table 1-1. 


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Table 1-1 
Schedule of Assessments 
Tests and Procedures 
Prior 
Protocol 
Activity 
≤ 28 Days 
before 
Cycle 1 CYP IV 2 
PHASE 1 – Vaccination 1 
PHASE 2 
Cycle 1 
Cycle 2 ± 
4 days 
Cycle 3 ± 
4 days 
Cycle 4 ± 
4 days 
Cycle 5 ± 
4 days 
Cycle 6 ± 
4 days 
28 ± 4 
Days 
after 
Cycle 6 
Booster and 
Follow-up for 3 
years  
(q 6 months)1 
Screening 
X 
 
 
 
 
 
 
 
 
 
 
Administer informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion Exclusion Criteria 
 
X 
 
 
 
 
 
 
 
 
 
Submission of primary tumor 
specimen for FRα antigen 6 
X 
 
 
 
 
 
 
 
 
At recurrence X 
Demographics, Medical history, 
Disease staging, Breast cancer 
treatment history 
 
X 
 
 
 
 
 
 
 
 
 
Urine or Serum pregnancy test 5 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Height & weight 
 
X 
 
 
 
 
 
 
 
 
 
Clinical examination, vitals 
 
X 9 
X 10 
X 
X 
X 
X 
X 
X 
X 4 
X 4 
CYP IV 
 
 
X 
 
 
 
 
 
 
 
 
HuFR vaccination 
 
 
 
X 
X 
X 
X 
X 
X 
 
X 11 
Injection site tolerance 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
Adverse events12 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 12 
Concomitant medications13 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 13 
TSH and ANA 
 
X 
 
 
X 
 
X 
 
 
X 
 


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Tests and Procedures 
Prior 
Protocol 
Activity 
≤ 28 Days 
before 
Cycle 1 CYP IV 2 
PHASE 1 – Vaccination 1 
PHASE 2 
Cycle 1 
Cycle 2 ± 
4 days 
Cycle 3 ± 
4 days 
Cycle 4 ± 
4 days 
Cycle 5 ± 
4 days 
Cycle 6 ± 
4 days 
28 ± 4 
Days 
after 
Cycle 6 
Booster and 
Follow-up for 3 
years  
(q 6 months)1 
CBC with differential 
 
X 
 
 
X 
 
X 
 
X 
X 
X 4 
Metabolic panel 
 
X 
 
 
X 
 
X 
 
X 
X 
X 4 
Urinalysis for proteinuria 3 
 
X 
 
 
X 
X 
X 
X 
X 
X 
 
Primary tumor genotyping 6 
 
X 
 
 
 
 
 
 
 
 
 
Recurrence / RFS evaluation 4 
 
X 
 
 
 
 
 
 
 
X 
X 
Research Blood Samples 7 
 
X 
X 
X 
 
X 
 
 
X 
X 8 
Abbreviations: ANA = antinuclear antibody; CBC = complete blood count; CYP IV = cyclophosphamide infusion; FRα = folate receptor alpha; huFR = human 
folate receptor; RFS = relapse-free survival; NCCN = National Comprehensive Cancer Network; q = every; TSH = thyroid-stimulating hormone 
1. Each vaccination cycle will be 28 days ± 4 days in length. Booster doses start at 12 months ± 14 days after Cycle 1 dose. 
2. Cyclophosphamide IV - 300 mg/m2 – Done 3 days prior to Cycle 1 vaccine injection.  
3. All patients must have a urinalysis. If ≥ 2+ proteinuria, a 24-hour urine should be collected for protein quantification.  
4. Disease evaluation will occur during a meeting with a physician at each visit throughout the study. At a minimum, this will include per standard practice a 
history, physical examination, and hematology and chemistry group, per standard of care. Mammogram or breast ultrasound will be performed annually per 
standard of care. If there is suspicion of disease recurrence, further testing (e.g. imaging, etc.) should be performed per standard of care (NCCN guidelines) for 
women who have a history of breast cancer as part of their disease follow-up.  
5. Required for women of child-bearing potential only. Must be done ≤7 days prior to registration.  
6. Test does not need to be completed prior to enrollment.  
7. Refer to Table in Protocol Section 6.  
8. Samples taken at the 6-, 12-, 18-, and 24-months post vaccination phase visits.  
9. Complete Physical Examination at Baseline (≤ 28 days prior to cycle 1) only, as noted in Section 3.5 of the protocol. 
10. Symptom Directed Examination – Whenever the patient meets with the physician, per standard of care as noted in Protocol Section 5.4.4. Patients will have 
these at Cycles 2, 4, 6, and 28 days after cycle 6, as well as at all Booster and Follow-up visits. 
11. No booster vaccination at last visit. 


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12. After completion of cycle 6, TEAEs are capture during th e28-day time period following Booster Vaccinations. NOTE: All serious adverse events (SAEs) as 
defined in Protocol Section 10.1 of the protocol, Events of Special Interest (Protocol Section 10.2.1), Secondary Malignancies (Protocol Section 10.2.2) or 
Pregnancies (Protocol Section 10.2.3) are reported when they occur, regardless of the timing of last vaccine administration. 
13. After completion of cycle 6, new concomitant medications are capture from date of booster vaccination until 28 days post vaccination. New concomitant 
medications administered after the 28-day time point but prior to the next Booster vaccination do not need to be capture unless they are still ongoing at the time 
of the next Booster vaccination. 


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1.2.5 
Efficacy and Safety Parameters 
1.2.5.1 
Efficacy Parameters 
The primary efficacy endpoint of this study is maximum observed FRα-specific T cell response. 
A vaccine-induced increase in FRα-specific T cell responses will be defined as (1) a ≥ 3-fold 
increase in FRα-specific T cells at any point during treatment if there were detectable 
pretreatment levels of FRα-specific T cells or (2) levels of FRα-specific T cells above the 
threshold of the assay at any point in the vaccination phase if pre-treatment levels of FRα-
specific T cells are non-detectable. 
Other efficacy parameters include: 
• Immune response 
o Change from baseline in T cell response, using maximum observed FRα-specific 
T cell response. 
o Time to maximum observed FRα-specific T cell responses. 
o Slope of the FRα-specific T cell responses after the vaccination phase of the trial, 
determined from the terminal log-linear portion of the T cell response curve (as a 
measure of the persistence FRα-specific T cell immune response during the 
booster phase). 
o Immune response status per patient.  
• FRα tumor expression 
o Tumor membrane staining intensity, as scored by a pathologist (0 = negative, 
1+ = weak, 2+ = moderate, 3+ = strong). 
o Percent of cells within each tissue core stained at each intensity will be recorded 
to calculate an H-score. The H-score is a weighted score that captures both the 
proportion of positive staining and intensity for each tumor. 
• Duration of RFS, defined as the time from registration to any local, regional, or distant 
recurrence of breast cancer; the development of a contralateral breast cancer or 
secondary primary other than squamous or basal cell carcinoma of the skin, carcinoma in 
situ of the cervix, or lobular carcinoma in situ of the breast; or death from any cause 
without the documentation of 1 of these AEs. 
• Exploratory correlative research 
o Tumor infiltration from immune-cell subsets such as TIL, CD4+ regulatory T-
cell (Treg), myeloid cells by immunofluorescence and expression of T cell 
activations such as 4-1BB (CD137), OX40, GITR, CD40, and ICOS, as well as 
known pathway inhibitors such as PD-1/PD-L1, IDO, B7, LAG3, TIM-3, CTLA-
4. 
o Tumor cell markers such as Ki and epidermal growth factor receptor (EGFR). 
o Circulating inhibitory T cells such as Tregs and myeloid derived suppressor cells 
(MDSC). 


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o Tumor genotyping to identify TNBC subtypes. 
1.2.5.2 
Safety Parameters 
Safety evaluations performed during the study include physical examinations, measurement of 
vital signs; monitoring of injection site tolerance; clinical laboratory evaluations including 
hematology, chemistry, urinalysis, and measurement of thyroid-stimulating hormone (TSH) and 
antinuclear antibody (ANAs) values; and monitoring of AEs and concomitant medications. 
Adverse events are graded using the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03 grading scheme. If the CTCAE grading does not exist for an AE, the 
severity of mild (1), moderate (2), severe (3), life-threatening (4), and death related to an AE (5) 
will be used. 
The primary safety endpoint of this study is incidence of treatment-emergent AEs (TEAEs). 
Other safety endpoints include incidence of serious AEs, incidence of TEAEs leading to study 
withdrawal, and overall survival (OS). 


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2. 
PATIENT POPULATION 
2.1 
Population Definitions 
The following patient populations will be evaluated and used for presentation and analysis of 
the data: 
• Safety Population (SP): All patients who are enrolled, are randomized to treatment, and 
receive at least one dose of treatment (cyclophosphamide or study vaccine). 
• Modified Intent-to-Treat Population (mITT): All patients who are randomized to 
treatment, received at least 1 dose of study vaccine, and have a result for the baseline 
and at least 1 post-baseline immune response evaluation. 
The SP will be the primary population for analyses of safety and tolerability. The mITT is the 
primary population for the analysis of all efficacy endpoints, and for the analysis of the T cell 
immune response. It is expected that the SP and the mITT will not differ. 
All safety analyses and all efficacy analyses will be conducted according to the study treatment 
regimen received. Should a patient’s randomized study treatment regimen differ from their 
received study treatment, this will be evaluated on a case-by-case basis in the CSR. 
2.2 
Protocol Violations 
A protocol violation is any departure from procedures and requirements outlined in the protocol. 
Protocol violations and departures that may compromise the participant safety, participant 
rights, inclusion/exclusion criteria or study data and could be cause for corrective actions if not 
rectified or prevented from re-occurrence. Protocol violations will be monitored at each site for 
(1) significance, (2) frequency, and (3) effects on the study objects, to ensure that site 
performance does not compromise the integrity of the trial. 
All protocol violations will be recorded in the Protocol Violations electronic case report form 
(eCRF). Additionally, each site is responsible for tracking and reporting protocol violations to 
their IRB as required by IRB regulations. The Marker Therapeutics Clinical Monitor must be 
contacted immediately if an unqualified/ineligible participant is randomized to treatment in the 
study. 
All protocol violations will be listed by patient. 


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3. 
GENERAL STATISTICAL METHODS 
3.1 
Sample Size Justification 
The emphasis of this Phase II study is estimation of immune response effect size and incidence 
of AEs, rather than confirmatory hypothesis testing of clinical endpoints such as RFS. In study 
MC1015, patients treated with hu-FRα and GM-CSF had a mean (±standard deviation [SD]) 
increase from baseline in the T cell responses targeting the hu-FRα antigen of 175 (±200) 
T cells. Assuming the same mean (175) and SD (200) for the 2 low-dose groups in this study, a 
sample size of 20 patients per group, a doubling of the T cell response in the high-dose groups at 
the end of the vaccination phase, a drop-out rate of no more than 10%, and statistical testing 
using the Mann-Whitney test stratified by level of cyclophosphamide priming, the power to 
detect a difference between the combined low-dose groups versus the combined high-dose 
groups depends on the variability of the T cell response in the high-dose groups, as follows: 
Standard Deviation in High-Dose Groups of 
the Change from Baseline in T Cell Count at 
End of Vaccination Phase 
Statistical Power 
(%) 
200 
92 
225 
89 
250 
86 
275 
82 
300 
78 
325 
73 
350 
69 
375 
64 
400 
60 
3.2 
General Methods 
All data listings that contain an evaluation date will contain a relative vaccine start day. 
Pretreatment and on-treatment study days are numbered relative to the day of the first dose of 
study vaccine, which is designated as Day 0. The preceding day is Day -1, the day before that is 
Day -2, etc. Each data listing presenting an evaluation date will present the Rel Day variable, eg 
“Off Treatment Date (Rel Day).”  
All output will be incorporated into Microsoft Word files, sorted and labeled according to the 
International Conference on Harmonisation (ICH) recommendations, and formatted to the 
appropriate page size(s). 
Tabulations will be produced for appropriate demographic, baseline, efficacy, and safety 
parameters as described in Section 4. For categorical variables, summary tabulations of the 
number and percentage of patients within each category (with a category for missing data) of the 
parameter will be presented. Two-sided 90% CIs using the Clopper-Pearson exact method will 
be calculated for the proportion of patients achieving a T cell immune response in each of the 4 
treatment groups. For continuous variables, the number of patients, mean, median, SD, 
minimum, and maximum values will be presented along with the 90% CI of the mean where 


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appropriate. Time-to-event data will be summarized using Kaplan-Meier methodology using 
25th, 50th (median), and 75th percentiles with associated 2-sided 90% CIs, as well as percentage 
of censored observations.  
The following tests will be used for formal statistical hypothesis testing on the specified 
parameters: 
• Primary efficacy analysis: Mann-Whitney test comparing distributions of maximum T 
cell response between low and high vaccine dose groups, stratified by level of 
cyclophosphamide priming 
• Exploratory efficacy analysis: Mann-Whitney test comparing distributions of maximum 
T cell response between cyclophosphamide priming groups, stratified by level of vaccine 
dose received 
• Exploratory efficacy analysis: Wilcoxon signed rank test comparing change from 
baseline in maximum T cell response within each of the 4 treatment groups 
All tests will be conducted at the 1-sided, 0.10 level of significance. Summary statistics will be 
presented, as well as CIs on selected parameters, as described in the sections below. 
3.3 
Computing Environment 
All descriptive statistical analyses will be performed using SAS statistical software, version 9.4, 
unless otherwise noted. Medical history and TEAEs will be coded using Medical Dictionary for 
Regulatory Activities (MedDRA, version 19.0 or higher). Concomitant medications will be 
coded using World Health Organization (WHO) Drug Dictionary (March 2016 or later). The 
National Cancer Institute (NCI) CTCAE, version 4.03 will be used to determine TEAE severity 
grades where applicable. 
3.4 
Baseline Definitions 
For non-efficacy analyses, baseline will be defined as the most recent measurement before the 
first administration of study vaccine.  
For the efficacy analyses of FRα-specific T cell response and analyses stratified by immune 
response status, efficacy baseline value definition will be the same for all treatment groups. For 
any FRα parameter, the efficacy baseline value is the minimum pre-vaccination result. The 
minimum pre-vaccination result is calculated by first averaging Media results per date per 
patient for Media results prior to first vaccine dose; followed by averaging FRα parameter 
results per parameter per date per patient. Minimum pre-vaccination result is the difference 
between FRα parameter average and Media average; if the initial difference is a negative value, 
the result is set to 0. If there are multiple pre-vaccination dates for any parameter, the minimum 
difference of averages is used as the minimum pre-vaccination result for that FRα parameter and 
will be used as the baseline value. 


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3.5 
Methods of Pooling Data 
All analyses will primarily be conducted separately for each of the 4 treatment groups, unless 
otherwise specified. 
To evaluate the safety and tolerability of hu-FRα peptide vaccine with GM-CSF, data will be 
pooled by high dose and low dose vaccine groups.  
To evaluate the ability of the hu-FRα peptide vaccine with GM-CSF to elicit a FRα-specific T 
cell response, data will be pooled by high dose and low dose vaccine groups and compared via 
the Mann-Whitney test after aligning ranks within each cyclophosphamide level. An exploratory 
analysis to evaluate cyclophosphamide priming prior to hu-FRα peptide vaccinations to elicit a 
FRα-specific T cell response will pool data by cyclophosphamide use and no cyclophosphamide 
use and will compare these two groups via the Mann-Whitney test after aligning ranks within 
each vaccine dose level.  
3.6 
Adjustments for Covariates 
No formal statistical analyses that adjust for possible covariate effects are planned for tests of 
clinical efficacy. 
Exploratory correlative research will be conducted to determine whether an immune 
measurement or tissue marker may be a predictor of a robust FRα-specific T cell response after 
vaccination. Such a predictor of immune response may be used clinically to rapidly assess 
whether or not immune protection against recurrence will be established. Surrogate markers 
could be used to assess the need for booster immunizations that may be required if immunity 
wanes. 
3.7 
Multiple Comparisons/Multiplicity 
The primary analysis of this study is the comparison of high and low dose vaccine groups to 
elicit a FRα-specific T cell response, and thus multiplicity is not of concern for this study with a 
single primary efficacy analysis. All other analyses will be considered exploratory and/or 
hypothesis generating. 
3.8 
Subpopulations 
The SP will be the primary population for analyses of safety and tolerability. The mITT is the 
primary population for the analysis of all efficacy endpoints, and for the analysis of the T cell 
immune response.  
3.9 
Withdrawals, Dropouts, and Loss to Follow-up 
If a patient is withdrawn before completing the study, the reason for withdrawal will be entered 
on the End-of-Study Form and other appropriate eCRF pages will be completed. If the patient is 
not deceased, final physical examinations and clinical laboratory assays will be performed, if 
possible. All patient data collected before discontinuation will be made available to Marker 
Therapeutics, Inc. Patients who are withdrawn or discontinue from the study will not be 
replaced. 


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3.10 
Missing, Unused, and Spurious Data 
Patients in the mITT population who discontinue prior to the end of the vaccination phase will 
be considered non-immune responders, if immune response status cannot be determined by the 
end of the vaccination phase.  
In general, there will be no substitutions made to accommodate missing data points. All data 
recorded on the eCRF will be included in data listings that will accompany the CSR. No 
imputation will be performed for missing data elements and data will be analyzed as recorded in 
the eCRF. For the time-to-event distributions, patients will be censored at the time of the last 
known evaluation, should they have missing information regarding event endpoints, eg missing 
outcome data. 
When tabulating AE data, partial onset dates will be handled as follows. If the day of the month 
is missing, the onset day will be set to the first day of the month unless it is the same month and 
year as study treatment. In this case, in order to conservatively report the event as treatment-
emergent, the onset date will be assumed to be the date of treatment. If the onset day and month 
are both missing, the day and month will be assumed to be January 1, unless the event occurred 
in the same year as the study treatment. In this case, the event onset will be coded to the day of 
treatment in order to conservatively report the event as treatment-emergent. A missing onset 
date will be coded as the day of treatment initiation. 
3.11 
Visit Windows 
It is expected that all visits should occur according to the protocol schedule. All data will be 
tabulated per the evaluation visit as recorded on the eCRF even if the assessment is outside of 
the visit window. If the evaluation visit is missing in the database but there is data from an 
unscheduled or additional visit that is inside the visit window, the data from the unscheduled or 
additional visit will be used in data summaries. In data listings, the relative day to first study 
vaccine dose will be presented for all dates. 
If a patient presents with an acute illness (eg, cold, influenza), the vaccination will be withheld 
until the illness has resolved. Subsequent cycles will commence 24 to 32 days after the next 
cycle is initiated rather than according to the schedule established before the illness-induced 
delay. 
There will be no modifications to the planned vaccine dose. There may be allowances for the 
timing of the administration of vaccine to accommodate patient schedules or special 
circumstances. Such variations in the timing of vaccinations will be decided in advance on a 
case-by-case basis by the study Medical Monitor (see Protocol Section 5.4.1). 


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Table 3-1 
Evaluation Intervals for Efficacy Analysis 
Phase 
Evaluation 
Protocol-Specified Interval 
Interval for Analysis 
 
Prior Protocol 
Activity (Screening) 
Prior to Cycle 1 Day -28 
Prior to Cycle 1 Day -28 
 
≤ 28 days Prior to 
Cycle 1 (Baseline) 
Cycle 1 Day -28 to Day -1 
Cycle 1 Day -28 to Day -1 
 
CYP IV 
Cycle 1 Day -3 (72±10 hours) 
Cycle 1 Day -3 (72±10 hours) 
Phase 1 – 
Vaccination 
Cycles 1–6 
28 days ± 4 days 
28 days ± 4 days 
28±14 days after 
Cycle 6 
28 days ± 14 days after Cycle 6 
28 days ± 14 days after Cycle 6 
Phase 2 – 
Booster and 
Follow-up 
Over 3 
years (q6 
months) 
12 months after 
Cycle 1 injection 
(±14 days) and 
every 6 months ±14 
days for 3 years 
12 months after Cycle 1 injection 
(±14 days) and every 6 months ±14 
days for 3 years 
12 months after Cycle 1 injection 
(±14 days) and every 6 months 
±14 days for 3 years 
Abbreviation: CVP IV = cyclophosphamide infusion; q = every. 
3.12 
Interim Analyses 
There are no interim analyses planned for investigating primary endpoints. 
An informal analysis investigating FRα-specific T cell responses (secondary study objective) 
was performed by the Sponsor after n=24 patients had concluded Phase I (Vaccination Phase) of 
the trial. No formal statistical tests were conducted on the interim data. 
 


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4. 
STUDY ANALYSES 
4.1 
Patient Disposition 
Patient disposition will be tabulated and include the number of patients who:  
• Were enrolled 
• Were randomized to study treatment 
• Received at least 1 dose of cyclophosphamide or study vaccine 
• Received low-dose and high-dose FRα peptide vaccine alone 
• Received low-dose and high-dose FRα peptide vaccine after cyclophosphamide priming 
• Were in each patient population for analysis 
• Withdrew before completing the study; reason(s) for withdrawal will be tabulated 
• Completed Phase 1 (all 6 cycles of FRα peptide vaccine) 
• Completed Phase 2 (booster and 3 years of follow-up every 6 months)  
Study completion information, including dosing dates, dates of disease progression, treatment 
group, date of discontinuation/completion, and the reason for premature study withdrawal, if 
applicable, will be listed by patient. This listing will be presented for the overall study as well as 
by investigational site. 
4.2 
Demographics and Baseline Characteristics 
Demographics, baseline characteristics, and medical history (including disease staging and 
breast cancer treatment history) information will be summarized overall and stratified by 
treatment group and immune FRα-specific T cell responder status for the SP and mITT 
populations. No formal statistical comparisons will be performed. 
Demographic and baseline data, including medical history and physical examinations, will be 
listed by patient. In addition, results of screening evaluations and final weight measurements 
will be listed by patient. Age at informed consent will be listed with demographic data, and will 
be calculated as the integer part of (date of informed consent – date of birth + 1). 
The following evaluations will be performed before cyclophosphamide priming or first 
vaccination and collected data/results will be tabulated and listed: 
• Recent medical and surgical history (preceding 5 years or chronic conditions), including 
underlying breast cancer status and history. 
• Body weight (kg). 
• Vital sign measurements, including temperature and blood pressure. 
• Physical examination findings. 
• Clinical laboratory testing: 


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o Complete blood count (CBC) with differential and platelet count. 
o Serum chemistry (electrolytes, glucose, blood urea nitrogen [BUN], calcium, 
phosphorus, albumin, creatinine, bilirubin (total and direct), aspartate 
aminotransferase (AST)/alanine aminotransferase (ALT), alkaline phosphatase). 
o Urinalysis with proteinuria. 
o TSH and ANA. 
o Pregnancy test, if applicable. 
Note: for the purpose of this protocol the following criteria are used to determine 
reproductive potential: postmenopausal by history, defined as > 60-years-old and 
no menses for > 12 months naturally or secondary to radiation/chemotherapy; or 
serum follicle-stimulating hormone, luteinizing hormone, and estradiol levels in 
the postmenopausal range; or history of hysterectomy, history of bilateral tubal 
ligation; or of bilateral oophorectomy. 
• Collection of blood for exploratory correlative immune monitoring research, as detailed 
in Protocol Section 6. 
In addition, immunohistochemistry (IHC) findings based on review of the primary tumor 
specimen submitted to the IHC central laboratory (Protocol Section 16) for FRα 
antigen-expression testing will be listed.  
4.3 
Efficacy Evaluation 
4.3.1 
Primary Efficacy Endpoint – Immune Response 
Patients will have FRα-specific T cell response measurements to the following FRα parameters: 
FR30, FR56, FR56, FR76, FR113, FR238, and FRα protein. These parameters will also 
accompany a Media parameter as a control measurement. Each patient will have 3 
measurements per evaluation date per parameter. The 3 measurements will be averaged per date 
per parameter and will have the Media date-average subtracted: for each date, T cell response = 
(FRα parameter average – Media average); if the initial difference is a negative value, the T cell 
response value will be set to 0. The maximum on-study result for each patient will be the 
maximum difference of averages between any FRα parameter and Media average, following the 
first vaccination dose; each patient will have only one maximum on-study result. The 
distribution of maximum observed FRα-specific T cell response in the high dose group will be 
compared to the distribution of maximum observed FRα-specific T cell response low dose 
group (anticipated n=40 for each group) via a Mann-Whitney test using a one-sided alpha of 
0.10, stratified by level of cyclophosphamide priming. 
An exploratory analysis will be performed, comparing the distributions of maximum observed 
FRα-specific T cell response between cyclophosphamide priming groups (anticipated n=40 for 
each group) via a Mann-Whitney test using a one-sided alpha of 0.10, stratified by level of 
vaccine dose received.  
The mean (90% CI) and change from baseline in FRα-specific T cell responses will be 
computed at the end of the vaccination phase using the maximum T cell response per patient to 


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any FRα parameter; hypothesis testing will be done at the end of the vaccination phase using the 
maximum T cell response per patient to any FRα parameter.  
4.3.2 
Additional Efficacy Endpoints 
4.3.2.1 
Immune Response 
To evaluate each treatment arm with respect to change from baseline in FRα-specific T cell 
response, descriptive statistics of maximum T cell response per patient will be provided and 
statistical analysis will be performed using the Wilcoxon signed-rank test. 
The following parameters will be computed for each patient: change from baseline in T cell 
response, using maximum observed FRα-specific T cell response; time to maximum observed 
FRα-specific T cell response, defined as the time in days from date of first dose of FRα peptide 
vaccination to date of observed maximum FRα-specific T cell response; and slope of the 
FRα-specific T cell response after the vaccination phase of the trial (determined from the 
terminal log-linear portion of the T cell response curve as a measure of the persistence 
FRα-specific T cell immune response during the booster phase); immune response status. These 
parameters will be summarized for each treatment group. 
The emergence of a FRα-specific T cell response (ie, immune responder) will be defined as: 
1. 
A 3-fold or greater increase in FRα-specific T cells at any point during treatment if there 
were detectable pretreatment levels of FRα-specific T cells, or  
2. 
Levels of FRα-specific T cells above the threshold of the assay at any point in the 
vaccination phase if pre-treatment levels of FRα-specific T cells are non-detectable.  
Immunologic data are currently represented in spots/2.5 × 105 cells. The immunologic data will 
be multiplied by 4 for figures in order to be presented in spots/million cells.  
Immune response will be a categorical variable based on the following processes: 
• Immunologic and media measurements will be averaged by date per patient. 
• A difference of averages will be calculated by subtracting the media average from the 
immunologic parameter average per date. If the value is less than 0, the difference of 
averages will be set to 0. 
• If there are multiple pre-treatment dates, the baseline difference of averages will be the 
minimum difference of averages before treatment initiation per patient. 
• If there are multiple evaluation dates after vaccine start date, the on-study difference of 
averages will be the maximum of difference of averages after the vaccine start date per 
patient. 
• If the baseline value is detectable (≥ 12.5 spots/2.5 × 105 cells) and the on-study 
difference of averages is at least three times as great as the baseline difference of 
averages for any FRα parameter, the patient is a responder. 


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• If the baseline value is not detectable (< 12.5 spots/2.5 × 105 cells) and the on-study 
difference of averages is greater than 12.5 spots/2.5 × 105 cells for any FRα parameter, 
the patient is a responder. 
• If the baseline value is detectable (≥ 12.5 spots/2.5 × 105 cells) and all of the on-study 
difference of averages are less than three times the value of the baseline difference of 
averages for all FRα parameters, the patient is not a responder. 
• If the baseline value is not detectable (< 12.5 spots/2.5 × 105 cells) and all of the on-
study difference of averages are less than or equal to 12.5 spots/2.5 × 105 cells for any 
FRα parameter, the patient is not a responder. 
Calculation: 
𝐼𝑓 𝑃𝑅𝐸< 12.5 𝑡ℎ𝑒𝑛 𝑅𝑒𝑠𝑝𝑜𝑛𝑑𝑒𝑟= { 𝑌,
𝑖𝑓 𝑂𝑁𝑆𝑇𝐷𝑌> 12.5
𝑁,
𝑖𝑓 𝑂𝑁𝑆𝑇𝐷𝑌≤12.5,},  
𝐼𝑓 𝑃𝑅𝐸≥12.5 𝑡ℎ𝑒𝑛 𝑅𝑒𝑠𝑝𝑜𝑛𝑑𝑒𝑟= {
𝑌,
𝑖𝑓 𝑂𝑁𝑆𝑇𝐷𝑌
𝑃𝑅𝐸
≥3
𝑁,
𝑖𝑓 𝑂𝑁𝑆𝑇𝐷𝑌
𝑃𝑅𝐸
< 3,
} , 
𝑤ℎ𝑒𝑟𝑒 𝑂𝑁𝑆𝑇𝐷𝑌= 𝑀𝐴𝑋(𝐷𝐼𝐹𝐹𝐴𝑉𝐺𝑆𝑃𝑂𝑆𝑇𝑉1), 𝑃𝑅𝐸 = 𝑀𝐼𝑁(𝐷𝐼𝐹𝐹𝐴𝑉𝐺𝑆𝑃𝑅𝐸𝑇𝑅𝑇), 
             𝑎𝑛𝑑 𝐷𝐼𝐹𝐹𝐴𝑉𝐺𝑆= 𝐴𝑉𝐺(𝑃𝐴𝑅𝐴𝑀) −𝐴𝑉𝐺(𝑀𝐸𝐷𝐼𝐴) 
A 90% binomial CI will be constructed for percentage of patients who develop an immune 
response among those patients in each treatment group. 
4.3.2.2 
FRα Tumor Expression 
Tumor membrane staining intensity will be scored by a pathologist as negative (0), weak (1+), 
moderate (2+), and strong (3+). The percent of cells within each tissue core stained at each 
intensity will be recorded to calculate an H-score on the pre-baseline tumor sample. The H-score 
is a weighted score that captures both the proportion of positive staining and intensity for each 
tumor. H-score values can range from zero (no membrane staining) to a maximum of 300 
(100% membrane staining at 3+). The staining intensity, percent of cells, and H-score will be 
listed by patient. Mean H-scores will be presented in a table by treatment group. 
4.3.2.3 
Duration of RFS 
The RFS distributions will be estimated using the Kaplan-Meier method for each treatment 
group using the mITT population. Time-to-event data will be summarized using Kaplan-Meier 
methodology using 25th, 50th (median), and 75th percentiles with associated 2-sided 90% CIs, as 
well as percentage of censored observations.  
4.3.2.4 
Exploratory Correlative Research 
Correlative data analyses are included to determine whether an immune measurement or tissue 
marker may be a predictor of a robust FRα-specific T cell response after vaccination. Such a 


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predictor of immune response may be used clinically to rapidly assess whether or not immune 
protection against recurrence will be established. Surrogate markers could be used to assess the 
need for booster immunizations that may be required if immunity wanes.  
The following markers may be evaluated as baseline predictors if the data is available:  
1. Tumor infiltration from immune-cell subsets such as TIL, CD4+ Treg, myeloid cells by 
immunofluorescence and expression of markers of T cell activations such as 4-1BB 
(CD137), OX40, GITR, CD40, and ICOS, as well as known pathway inhibitors such as 
PD-1/PD-L1, IDO, B7, LAG3, TIM-3, CTLA-4  
2. Tumor cell markers such as Ki and EGFR [1] 
3. Circulating inhibitory T cells such as Tregs and MDSC 
4. Tumor genotyping to identify TNBC subtypes [2] 
4.4 
Safety Analyses 
Safety analyses will be performed using the SP population. 
4.4.1 
Primary Safety Endpoint 
The primary safety endpoint is incidence of TEAEs by severity and attribution, as described in 
Section 1.2.5.2. The incidence of TEAEs will be summarized for each treatment group and 
tabulated by severity and attribution.  
4.4.2 
Additional Safety Endpoints 
4.4.2.1 
Study Drug Exposure 
Study drug exposure will be calculated as the number of days patients were administered study 
drug, as determined by (date of last FRα peptide vaccination – date of first FRα peptide 
vaccination), and will be summarized using descriptive statistics, including the number and 
percentage of patients completing each study vaccine cycle. Additionally, overall study duration 
from dose of cyclophosphamide to last follow-up visit will be provided using descriptive 
statistics. 
Duration of study drug exposure and number of study drug vaccinations received will be listed 
by patient. 
4.4.3 
Adverse Events 
All TEAEs will be coded using MedDRA and displayed in tables and data listings using system 
organ class (SOC) and preferred term (PT). Treatment-emergent AEs in the eCRF reported as 
having a severity of Grade 0 or those missing a severity will not be tabulated or listed. 
Treatment-emergent AEs will be summarized overall and by treatment group, severity, and 
causality (unrelated, related to cyclophosphamide, or related to study vaccine). All TEAEs 
considered to be possibly, probably, or definitely related to study drug and occurring after 


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initiating cyclophosphamide but before the first treatment with study vaccine (Cycle 1) will be 
considered treatment-related due to cyclophosphamide. Related TEAEs occurring after the first 
treatment vaccination are considered to be due to the vaccine (Cycle 1 through Phase 2 Booster 
Phase), unless clearly consistent with a known delayed reaction to cyclophosphamide. 
Symptoms collected on the baseline eCRF (such as fatigue, fever, erythema multiforme) will not 
be considered as TEAEs, as these were collected before the first dose of cyclophosphamide and 
will be summarized with the medical history. 
Adverse events will be summarized by patient incidence rates; therefore, in any tabulation, a 
patient will contribute only once to the count for a given SOC/PT. 
The following TEAE summaries will be provided overall and by treatment group. In these 
tabulations, each patient will contribute only once (ie, the most related occurrence or the most 
intense occurrence) to each of the incidence rates in the descriptive analysis, regardless of the 
number of episodes 
• All TEAEs 
• All Grade 3 or higher TEAEs 
• All serious TEAEs 
• All study drug-related TEAEs (possibly, probably, and definitely related)  
• All TEAEs leading to study withdrawal 
• Deaths (Grade 5 TEAEs) 
All AEs occurring on-study will be listed by patient. 
All TEAEs will be listed by patient; serious TEAEs and TEAEs leading to study withdrawal 
will be flagged.  
Additionally, TEAEs of injection site reaction will be listed by patient and tabulated by CTCAE 
grade. 
4.4.4 
Clinical Laboratory Evaluations 
Clinical laboratory values will be expressed using the International System of Units (SI). Values 
will be summarized for each clinical laboratory parameter, including hematology (CBC with 
differential and platelet count), serum chemistry (electrolytes, glucose, BUN, calcium, 
phosphorus, albumin, creatinine, bilirubin [total and direct], AST, ALT, and alkaline 
phosphate), urinalysis, TSH, and ANA. 
Local laboratory ranges are utilized, and will be converted to standard units for analysis. Age-
specific (age at informed consent/assent as applicable) and gender specific ranges (ie, adult or 
pediatric, male or female) will be used to flag out-of-range values and to categorize by CTCAE 
grade where applicable. 
All laboratory data will be listed by patient and compared with their corresponding normal 
ranges. Data outside the normal range and/or data noted by the Investigator or Medical Monitor 


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as clinically significant will be flagged. Normal ranges will be obtained from the Mayo Clinic 
Medical Laboratories website. 
The actual value and change from baseline (most recent result before Day 0) to each on-study 
evaluation will be summarized for each clinical laboratory parameter. In the event of repeat 
values, the last non-missing value per study day/time will be used. Laboratory data obtained at 
any time after the vaccination will not be used as baseline data.  
Shifts in toxicity grade from values collected at baseline to timepoints on study vaccine (see 
Table 1-1, Schedule of Assessments, for the timepoints at which each laboratory parameter is 
collected) and to the worst value on study will be summarized using CTCAE grading.  
4.4.5 
Vital Sign Measurements and Physical Examinations 
The actual value and change from baseline to each on-study evaluation will be summarized for 
clinical examinations, vital signs, and weight. 
Vital sign measurements will be listed by patient. 
Physical examination results at each timepoint will be summarized using shift tables to indicate 
change in status (normal/abnormal) from baseline to each post-baseline assessment. 
All physical examination findings will be listed by patient. 
Baseline and final weight measurements will be listed by patient. 
4.4.6 
Concomitant Medications 
Patients should receive full supportive care while in this study. This includes blood product 
support, antibiotic treatment, and treatment of other newly diagnosed or concurrent medical 
conditions. All blood products and concomitant medications given from the day of the first 
vaccine administration until 28 days after the Cycle 6 administration, and within 28 days after 
each Booster vaccination, will be collected for Adverse Events and recorded in the eCRFs. 
Medications given for planned procedures that are related to the patient’s history of breast 
cancer, such as breast reconstruction, or for planned procedures related to conditions recorded in 
Medical History, such as a knee replacement, do not need to be captured as TEAEs. Every effort 
should be made to collect and capture key concomitant medications given for the treatment of 
SAEs. However, as patients may be treated at outside facilities, it is understood that this 
information may be limited and not fully available. 
Concomitant medications will be coded using the latest version of the WHO Drug Dictionary. 
Results will be tabulated by Anatomic Therapeutic Chemical (ATC) class and PT. 
Medications recorded on the baseline concomitant medication eCRF will be considered both 
prior and concomitant. All other medications will be considered concomitant as identified by 
cycle, and tabulated by interval, including time between each vaccination cycle and during the 
observation phase, where any medications that did not end before the first dose of 


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cyclophosphamide or first dose of vaccine (depending on treatment assignment) will be 
included. 
Concomitant medications will be listed by patient. 
4.4.7 
Overall Survival 
Overall survival is defined as time from date of first FRα peptide vaccination (Rel Day 0) to 
date of death or censorship. Overall survival will be censored at the date of last follow-up if 
subject is alive. The OS rate at Cycle 6, Booster and follow-up 12 months, Booster and follow-
up 24 months, and Booster and follow-up 36 months will be reported.  
 


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5. 
CHANGES TO PLANNED ANALYSES 
In Protocol FRV-002 v06 Section 8, the document reads: 
“The Medical Monitor and the study statistician will review the study periodically (after every 5 
patients have completed the first vaccination cycle) to identify accrual, toxicity, and endpoint 
problems that might be developing. The study statistician will prepare a report containing 
accrual, adverse event, and efficacy data which will be submitted to an independent DSMB 
every 3 months until all patients are off study Phase 1 (vaccination phase) and every 6 months 
thereafter. The DSMB will include no less than 3 members (2 physicians and a statistician).” 
The periodical review by the study statistician after every 5 patients have completed the first 
vaccination cycle to identify accrual, toxicity, and endpoint problems was not followed per 
protocol. However, the reports for DSMB meetings every 3 months until all patients are off 
study Phase 1 and every 6 months thereafter were and are being completed per protocol.  
In Protocol FRV-002 v06 Section 9.4, the document reads: 
“All subjects who received one dose of vaccine will be included in the analysis of safety and 
tolerability.” 
The Safety Population for this study will include any patient who receives at least one dose of 
treatment, either cyclophosphamide or study vaccine. See Section 2.1. 
In Protocol FRV-002 v06 Section 9.4.3, the document reads: 
“The mean H-scores for each treatment group and the percentage of 0+, 1+, 2+ and 3+ staining 
will [be] compared by a Mann-Whitney test.” 
The comparison of mean H-scores through the Mann-Whitney test will not be included in the 
statistical analyses of this study. Mean H-scores will be presented for descriptive purposes. 
In Protocol FRV-002 v06 Section 9.4.4, the document reads: 
“To evaluate each treatment arm with respect to change from baseline in T-cell response, 
descriptive statistics will be provided and statistical inference will be performed using the 
Wilcoxon signed rank test. The primary efficacy endpoint is highest T-cell response in high 
dose group versus low dose group (anticipated n=40 for each group) using a two-sided alpha of 
0.10.” 
Prior to finalization of Protocol v6.0, discussion with Marker Therapeutics concluded with the 
decision to use one-sided alpha of 0.10 for this analysis. This decision is reflected in Section 
1.2.5.1, Section 3.2, Section 3.8, and Section 4.3.2.3  
In Protocol FRV-002 v06 Section 9.4.6, the document reads: 
“The clinical efficacy endpoint is the duration of disease-free survival (DFS). DFS is the time 
from registration to any local, regional, or distant recurrence of breast cancer; the development 
of a contralateral breast cancer or second primary other than squamous or basal cell carcinoma 
of the skin, carcinoma in situ of the cervix, or lobular carcinoma in situ of the breast; or death 
from any cause without the documentation of one of these adverse events. 
“The distribution of disease-free survival times will be estimated using the method of Kaplan-
Meier for each treatment group.”  
As RFS and DFS are both used throughout the protocol, it is not clear which of the two should 
be evaluated per protocol. After discussion with Marker Therapeutics, it was decided that RFS 
would be the clinical efficacy endpoint as discussed in Section 1.1.2, Section 1.2.5.1, Section 


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3.2, Section 3.8, and Section 4.3.1. 
 
 
 


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6. 
REFERENCES 
1. de Mascarel, I., et al., Comprehensive prognostic analysis in breast cancer integrating 
clinical, tumoral, micro-environmental and immunohistochemical criteria. Springerplus, 
2015. 4: p. 528. 
2. Lehmann, B.D., et al., Identification of human triple-negative breast cancer subtypes and 
preclinical models for selection of targeted therapies. J Clin Invest, 2011. 121(7): p. 
2750-67. 


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7. 
REVISION HISTORY 
7.1 
Statistical Analysis Plan Version 0.1: 20 November 2018 
Rationale of Revisions 
SAP v0.1 written. 
7.2 
Statistical Analysis Plan Version 0.2: 12 February 2019 
Rationale of Revisions 
SAP v0.2 updated to incorporate following protocol changes: 
• Reflected the company name change from TapImmune, Inc. to Marker Therapeutics, 
Inc, and updated the company address and contacts 
• Clarified TEAE and concomitant medications collection and reporting during the 
Booster Phase 
• Clarifies statistical analysis plan and primary efficacy endpoint 
o Removed H-score analyses and analyses stratified by H-score quartile 
o Updated efficacy parameters 
O Removed analyses comparing cyclophosphamide priming groups 
7.3 
Statistical Analysis Plan Version 1.0: 31 October 2019 
Rationale of Revisions 
SAP v1.0 included the following changes: 
• Added Mann-Whitney test comparing cyclophosphamide groups as an exploratory 
analysis 
• Removed all references to cyclophosphamide relative day; only vaccine relative day will 
be used 
• Clarified methods for primary and exploratory analyses 
• Revised baseline definitions for non-efficacy analyses. Baseline will be defined the same 
for all four treatment groups 
• Clarified methods of pooling data for primary and exploratory analyses 
• Revised immune response categorical variable derivation based on updated minimum 
number of spots detectable. 
• Lab scatterplots removed, as primary and shift values presented in tables are informative 
enough


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8. 
APPENDIX 1: RANDOMIZATION PLAN 
The Randomization Plan is saved as “TAP FRV-002_Randomization Plan final v2.0” in 
P:\Tapimmune\FRV002\Biostats\Random\Randomization Plan\Final on Veristat’s network 
drive.