A Pilot Clinical Trial Assessing the Safety and Feasibility of Intramuscular Administration of the TA-CIN Vaccine as Adjuvant Therapy for Patients With History of HPV16 Associated Cervical Cancer
Phase: PHASE1
Conditions: HPV16 Associated Cervical Cancer
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

A Pilot Clinical Trial Assessing the Safety and Feasibility of Intramuscular Administration 
of the TA-CIN Vaccine as Adjuvant Therapy for Patients with History of HPV16 
Associated Cervical Cancer 
Coordinating Center: 
Sidney Kimmel Comprehensive Cancer Center 
Johns Hopkins University 
Coordinating Center Principal Investigator:       
Other Site: 
 Stéphanie Gaillard, M.D. (Protocol Chair) 
 Charles Leath, M.D. 
 Johns Hopkins SKCCC 
 Univ. of Alabama at Birmingham 
Statistician: 
Lead Research Nurse: 
Lead Regulatory Specialist: 
JHM SKCCC: 
SKCCC J1553 
IND: 
IND  17238 
IND Sponsor:  
Richard Roden, Ph.D. 
Protocol Version: 
October 21, 2022 
NCT02405221

TA-CIN Vaccine as Adjuvant Therapy in HPV16-Associated Cervical Cancer 
Protocol Chair:  Stephanie Gaillard, M.D. 
Johns Hopkins/SKCCC J1553 
 
 
 
 Version:  October 21, 2022 
 
Page 2  
A Pilot Clinical Trial Assessing the Safety and Feasibility of Intramuscular Administration 
of the TA-CIN Vaccine as Adjuvant Therapy for Patients with History of HPV16 
Associated Cervical Cancer 
- PROTOCOL REVISION RECORD - 
 
 
Original Protocol: 
 
January 30, 2015 (Version 1.0) 
April 20, 2015 (Version 1.1) 
Revisions: 
 
 
Amendment #1: 
February 7, 2016 
 
Sections revised: 
Schema, Sections 1-2, 3.9, 4-5, 6.2, 6.5-6.6, 7 (title only), 8.5.2, 8.5.3.1,  
9.1, 10.2 (new), 11, 12.3, Appendix D, and Appendix E (removed).  
 
 
 
Amendment # 2:            November 16, 2016 
 
Sections Revised:  
Title, Schema, Section 1, Section 2.3, Section 3.6, Section 4.1, Section 6,  
Section 9, Section 10, Section 12, Appendix D 
 
Amendment # 3:            April 25, 2018 
 
Sections Revised:  
All to reflect change in dose 
 
 
Amendment #4: 
February 7, 2019 
 
Sections Revised: 
 
 
Amendment #5:  
October 4, 2019 
 
Sections Revised: 
Schema, Section 10 (Footnote #5), Appendix C, Exclusion Criteria 
 
Amendment #5.1:  
February 6, 2020 
 
Sections Revised: 
Change in PI (1st page, header, Appendix C) 
 
Amendment #5.2:  
June 10, 2020 
 
Sections Revised: 
DSMB 
 
Amendment #5.3:  
July 26, 2020 
 
Sections Revised: 
 
 
 
Amendment #6: 
October 21, 2022 
 
Sections Revised: 
Change in Statistician, first page, enrollment total updated to 15 
 
 
 
 

TA-CIN Vaccine as Adjuvant Therapy in HPV16-Associated Cervical Cancer 
Protocol Chair:  Stephanie Gaillard, M.D. 
Johns Hopkins/SKCCC J1553 
 
 
 
 Version:  October 21, 2022 
 
Page 3  
SCHEMA 
 
 
Eligible:   
Women With HPV16-Associated Stage IB1-IV Cervical Cancer;  
Completed Definitive Treatment Within 12 Months. 
 
 
Study Design: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment Groups/Cohorts 
Group 
TA-CIN Route of 
Administration 
Volume 
(mL) 
Dose  
(µg) 
Treatment Frequency/Weeks 
# of 
Patients 
1 
Intramuscular Arm 
0.53  
100  
3 administrations per subject; 
Weeks 1, 5, and 9 
7 
2 
Intramuscular Thigh 
7 
 
 
 
 
 
Week 
11-13 
Week 9 
Day 1 
Week 1 
Day 1 
Within 60 Days of Day 1  
(8 weeks for imaging assessments) 
Week 5 
Day 1 
Month 
6 
TA-CIN Administration 
Clinical Exam, Safety Laboratories; 
Research Blood Testing 
Month 
24 
Month 
12 
Adverse Event Evaluation/Management, Including Vaccine Site Assessment 
Follow-Up Period 
Clinical Exam, Safety Laboratories, Imaging 
(Months 6, 12, 24); Research Blood Testing 
Eligibility/Screening 
Clinical Exam/History, Imaging, etc.; 
Research Blood and Tissue Testing 

TA-CIN Vaccine as Adjuvant Therapy in HPV16-Associated Cervical Cancer 
Protocol Chair:  Stephanie Gaillard, M.D. 
Johns Hopkins/SKCCC J1553 
 
 
 
 Version:  October 21, 2022 
 
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Table of Contents 
 
 
SCHEMA...................................................................................................................................................................... 3 
1. 
SUMMARY.................................................................................................................................................... 6 
2. 
OBJECTIVES................................................................................................................................................ 7 
2.1 
PRIMARY OBJECTIVES ...................................................................................................................................... 7 
2.2 
SECONDARY OBJECTIVES ................................................................................................................................. 7 
2.3 
EXPLORATORY OBJECTIVE(S) .......................................................................................................................... 7 
3. 
BACKGROUND ............................................................................................................................................ 7 
3.1 
CERVICAL CANCER .......................................................................................................................................... 7 
3.2 
HUMAN PAPILLOMAVIRUS AS AN ETIOLOGIC FACTOR IN A DISTINCT SUBSET OF CERVICAL CANCERS ........... 8 
3.3 
IMPORTANCE OF CELL-MEDIATED IMMUNE RESPONSES IN CONTROLLING HPV-ASSOCIATED TUMORS ......... 8 
3.4 
HPV ONCOGENIC PROTEINS, E6 AND E7, AS POTENTIAL TARGETS FOR IMMUNOTHERAPY AGAINST HPV-
ASSOCIATED CERVICAL CANCER .............................................................................................................................. 9 
3.5 
THERAPEUTIC EFFECTS OF THE STANDARD CARE OF CHEMORADIATION FOR CERVICAL CANCER MAY BE 
IMPROVED BY THERAPEUTIC HPV VACCINES ........................................................................................................... 9 
3.6 
SAFETY OF TA-CIN VACCINE ........................................................................................................................ 10 
3.7 
RATIONALE FOR THE CLINICAL TRIAL DESIGN .............................................................................................. 11 
4. 
PARTICIPANT SELECTION ................................................................................................................... 15 
4.1 
INCLUSION CRITERIA ..................................................................................................................................... 15 
4.2 
EXCLUSION CRITERIA .................................................................................................................................... 15 
4.3 
INCLUSION OF WOMEN AND MINORITIES ....................................................................................................... 16 
5. 
REGISTRATION PROCEDURES ........................................................................................................... 17 
5.1 
GENERAL GUIDELINES ................................................................................................................................... 17 
5.2 
REGISTRATION PROCESS ................................................................................................................................ 17 
6. 
TREATMENT PLAN ................................................................................................................................. 18 
6.1 
AGENT ADMINISTRATION .............................................................................................................................. 18 
6.2 
BLINDING AND RANDOMIZATION ................................................................................................................... 18 
6.3 
DOSE LEVELS ................................................................................................................................................. 18 
6.4 
RE-TREATMENT CRITERIA ............................................................................................................................. 19 
6.5 
DOSE MODIFICATIONS AND DELAYS .............................................................................................................. 19 
6.6 
UNACCEPTABLE TOXICITY AND EARLY STOPPING RULES ............................................................................. 19 
6.7 
GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES ............................................... 19 
6.8 
CONTRACEPTION, USE IN PREGNANCY, USE IN NURSING ............................................................................... 20 
6.9 
DURATION OF THERAPY ................................................................................................................................. 20 
6.10 DURATION OF FOLLOW-UP ............................................................................................................................ 21 
7. 
ADVERSE EVENTS ................................................................................................................................... 21 
7.1 
DEFINITIONS .................................................................................................................................................. 22 
7.2 
RELATIONSHIP ............................................................................................................................................... 23 
7.3 
EXPECTEDNESS .............................................................................................................................................. 23 
7.4 
HANDLING OF EXPEDITED SAFETY REPORTS ................................................................................................. 24 
7.5 
REPORTING PROCEDURES .............................................................................................................................. 24 
8. 
PHARMACEUTICAL INFORMATION ................................................................................................. 25 
8.1 
TA-CIN ......................................................................................................................................................... 25 

TA-CIN Vaccine as Adjuvant Therapy in HPV16-Associated Cervical Cancer 
Protocol Chair:  Stephanie Gaillard, M.D. 
Johns Hopkins/SKCCC J1553 
 
 
 
 Version:  October 21, 2022 
 
Page 5  
9. 
CORRLEATIVE STUDIES ....................................................................................................................... 26 
9.1 
BLOOD SAMPLES FOR IMMUNOLOGIC ASSAYS AND VIRAL DNA ................................................................... 26 
9.2 
SAMPLES FOR HPV16 .................................................................................................................................... 27 
9.3 
OTHER ASSESSMENTS .................................................................................................................................... 27 
10. 
STUDY CALENDAR .................................................................................................................................. 28 
11. 
DATA AND SAFETY MONITORING ..................................................................................................... 31 
11.1 DATA MANAGEMENT ..................................................................................................................................... 31 
11.2 SAFETY MEETINGS ......................................................................................................................................... 32 
11.3 MONITORING.................................................................................................................................................. 32 
12. 
STATISTICAL CONSIDERATIONS ....................................................................................................... 34 
12.1 STUDY DESIGN AND ENDPOINTS .................................................................................................................... 34 
12.2 SAMPLE SIZE .................................................................................................................................................. 34 
12.3 ACCRUAL RATE ............................................................................................................................................. 34 
12.4 EARLY STOPPING RULES ................................................................................................................................ 34 
12.5 STATISTICAL ANALYSIS ................................................................................................................................. 35 
REFERENCES .......................................................................................................................................................... 36 
APPENDICES ............................................................................................................................................................ 39 
APPENDIX A:  FIGO 2009 CANCER STAGING ....................................................................................................... 40 
APPENDIX B:  PERFORMANCE STATUS CRITERIA ................................................................................................. 41 
APPENDIX C:  PATHOLOGY REVIEW ..................................................................................................................... 42 
APPENDIX D:  SERIOUS ADVERSE EVENT REPORTING FORM ............................................................................... 43 
 
 
 

TA-CIN Vaccine as Adjuvant Therapy in HPV16-Associated Cervical Cancer 
Protocol Chair:  Stephanie Gaillard, M.D. 
Johns Hopkins/SKCCC J1553 
 
 
 
 Version:  October 21, 2022 
 
Page 6  
1. SUMMARY 
This is a randomized, multi-center, open label pilot study.  The primary goal of this study is to 
determine the safety of TA-CIN vaccine as adjuvant therapy, and to assess evidence of induction 
of HPV antigen-specific immunologic response when administered at different locations. TA-
CIN has proven to be well-tolerated in healthy humans when administered three times monthly 
intramuscularly in the deltoid at a 533µg dose. In this pilot study, a single dose level (100µg) 
assessment of the safety and tolerability of administering TA-CIN vaccine three times to either 
the arm versus the thigh of patients who have previously been treated for HPV16-related cervical 
cancer in the past year and are documented to have no evidence of disease recurrence based on 
standard-of-care imaging and/or clinical assessment upon eligibility. Since TA-CIN 
administration is likely to have low toxicity, an important element of this study is to analyze 
immunologic parameters to examine whether one of the two immunization sites induces greater 
HPV-specific immunogenicity. The immunogenicity analyses include: 1) assessment of T cell-
mediated immune responses of peripheral blood lymphocytes to HPV16 E7E6 stimulation by 
ELISPOT, and if not discriminatory then 2) by T cell proliferation assays, or 3) by measurement 
of HPV16 L2E7E6-specific antibodies by ELISA (Section 10),. These analyses will be 
combined with toxicity data to select a vaccination site for a future clinical trial(s).  
 
A total of 15 patients will be enrolled to assess the safety of TA-CIN vaccine via different 
injection sites as adjuvant therapy. Patients with HPV16-associated stage IB1-IV cervical cancer 
who completed definitive cancer treatment within 1 year before the initiation of vaccination and 
are documented to have no evidence of disease recurrence based on standard-of-care imaging 
and/or clinical assessment will be eligible. This population was chosen because women with 
HPV-associated cervical cancer may potentially benefit from the vaccination strategy as adjuvant 
therapy as compared to healthy volunteers with respect to prevention or delay in the development 
of HPV16 associated cervical cancer recurrence.  One dose level of TA-CIN (100µg) delivered 
via one of two different intramuscular injection sites is planned (Section 6).  
 
Safety assessments will continue for a period for 1 month after the last vaccination; reporting 
requirements, exclusions, and stopping rules are outlined (Sections 7 and 8). Subjects who 
withdraw from the study for reasons other than toxicity may be replaced at the discretion of the 
Principal Investigator and/or IND sponsor. 
 
Few or no serious adverse events (SAEs) are expected from this regimen and routes of 
administration. The motivation for the design is to confirm that the dose and site of injection 
implemented here has minimal or no systemic toxicity, as well as determining the preferred 
injection site that can elicit more potent immune response.  
 
Patient immune and clinical responses in cohorts with different injection sites will be evaluated 
through the following methods: 1) peripheral blood lymphocytes (PBL) to assess HPV16 E6 and 
E7-specific CD8+ T cell ELISPOT and lymphocyte proliferative responses to HPV16  antigenic 
stimulation and T cell receptor sequencing; 2) serum for HPV16 L2, E6, and E7 and neutralizing 
antibody responses; 3) plasma for residual HPV viral load; and, 4) imaging scans per standard-of-
care (i.e., every 6-12 months) and as clinically indicated to assess time to disease recurrence. 
 

TA-CIN Vaccine as Adjuvant Therapy in HPV16-Associated Cervical Cancer 
Protocol Chair:  Stephanie Gaillard, M.D. 
Johns Hopkins/SKCCC J1553 
 
 
 
 Version:  October 21, 2022 
 
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2. OBJECTIVES 
2.1 
Primary Objectives 
2.1.1 To determine the safety and feasibility of intramuscular administration of TA-CIN 
vaccine via arm or thigh in patients with a history of HPV16 associated IB1-IV 
cervical cancer 
2.2 
Secondary Objectives 
2.2.1 To evaluate the levels of circulating antibody to HPV16 E6, E7, and L2 in the 
peripheral blood pre- and post-vaccination by ELISA 
2.2.2 To evaluate the levels of circulating HPV16 E6- and E7- specific CD8+ T cells and/or 
CD4+  T cells in the peripheral blood pre- and post-vaccination using the ELISPOT 
assay and/or  cell surface staining with multi-parameter flow cytometry analysis 
2.2.3 To evaluate the proliferative responses of peripheral blood mononucleocytes pre- and 
post-vaccination in response to stimulation by HPV16 E6, E7 and L2 
2.3 
Exploratory Objective(s) 
2.3.1 To evaluate the levels of circulating HPV16 E6- and E7-specific CD8+ T cells in the 
peripheral blood pre- and post-vaccination using T cell receptor sequencing 
2.3.2 To evaluate the levels of HPV-specific neutralizing antibodies in the peripheral blood 
pre- and post-vaccination  
2.3.3 To assess residual HPV16 viral load in plasma 
2.3.4 To assess time to disease recurrence as a measure of clinical response that may be 
associated with vaccine-induced immune responses 
 
3. BACKGROUND 
3.1 
Cervical Cancer 
Globally, cervical cancer accounted for an estimated 530,000 new cancer cases 
worldwide and for 275,000 deaths in 2013 (1). The most common histologic types of 
cervical cancer are squamous cell (69 percent of cervical cancers) and adenocarcinoma 
(25 percent). In countries that do not have access to cervical cancer screening and 
prevention programs, cervical cancer remains the second most common type of cancer  
and cause of cancer deaths among all types of cancer in women (2). In the United States 
(U.S.), an estimated 12,000 women diagnosed with cervical cancer each year (3). It is 
less common in the U.S. because of the routine use of Pap smear testing in intervention 
via ablation on high grade cervical intraepithelial neoplasia (CIN). Prior to the 
introduction of the Pap test in the 1940s, cervical cancer was one of the leading causes of 

TA-CIN Vaccine as Adjuvant Therapy in HPV16-Associated Cervical Cancer 
Protocol Chair:  Stephanie Gaillard, M.D. 
Johns Hopkins/SKCCC J1553 
 
 
 
 Version:  October 21, 2022 
 
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cancer death for women in the United States. But after routine cervical cancer screening 
was initiated, cervical cancer incidence was reduced by 70 percent and deaths from 
cervical cancer by 90 percent. Despite treatment advances over the past several decades 
including radiotherapy, cisplatin-based chemotherapy and/or surgery, the overall 5-year 
survival in the U.S. has not changed significantly and remains approximately 30% 
(http://www.cancer.org/Cancer/CervicalCancer/DetailedGuide/cervical-cancer-survival). 
The human papillomavirus (HPV) is central to the development of cervical dysplasia and 
cancer is detected in 99.7 percent of cervical cancers. 
3.2 
Human Papillomavirus as an Etiologic Factor in a Distinct Subset of Cervical 
Cancers 
Human papillomaviruses (HPV) are small, non-enveloped DNA viruses that induce self-
limited epithelial lesions of the skin or mucosa. Of the more than 150 genotypes of HPV 
that have been identified, a dozen have been found to induce lesions that may progress to 
cancer. Persistent infection with one of about 14 genotypes of carcinogenic human 
papillomavirus (HPV) causes almost all cases, and 70% of cervical cancer cases in the 
U.S. are associated with HPV 16 or 18 (4). The International Agency for Research on 
Cancer (IARC) concluded that there is sufficient evidence in humans to establish the 
carcinogenicity of HPV in causing cervical cancer and a subset of head and neck cancers. 
HPV DNA has been detected in the tumor nuclei of up to approximately 99% of all 
cervical cancers. HPV type 16 (HPV16) is the most prevalent HPV type detected in 
cervical cancers, involved in approximately 50-60%. Given the causative role of HPV16 
in at least half of cervical cancer cases, prophylactic vaccines targeting HPV16 have been 
developed for the prevention of HPV-related cervical malignancies. Unfortunately, the 
licensed preventive HPV vaccines (Gardasil® and Cervarix®) have no documented 
therapeutic activity for the treatment of cervical cancer. Therefore, there is an urgent need 
for new targeted treatments for cervical cancer to complement existing modalities such as 
radiation and/or cisplatin chemotherapy. 
3.3 
Importance of Cell-Mediated Immune Responses in Controlling HPV-Associated 
Tumors 
Several lines of evidence highlight the importance of cell-mediated immune responses in 
controlling both HPV infections and HPV-associated neoplasms (for review, see (5)). 
First, the prevalence of HPV-related diseases (infections and neoplasms) is increased in 
transplant recipients on immunosuppressive therapies (6) and HIV-infected patients (7, 
8), both of whom are known to have impaired cell-mediated immunity. HIV-infected 
women with baseline CD4+ T-cells of ≥350, 200-349, and <200 cells per microliter had a 
2.3, 3.0, and 7.7 times increase in invasive cervical cancer incidence, respectively, 
compared with HIV-uninfected women (9). HPV16 associated oropharyngeal cancer has 
been reported in the post-transplant setting (10) and the incidence of HPV16 associated 
tonsillar cancer in HIV infected men has been reported to be 2.6 fold greater (11) than in 
non-HIV infected individuals. In addition, when patients on immunosuppressive 
therapies discontinue their treatment, their HPV-associated lesions regress (for review, 
see (12)). Infiltrating CD4+ (T helper cells) and CD8+ (cytotoxic T cells) T cells have 
been observed in spontaneously regressing HPV-associated lesions (13). Lastly, 

TA-CIN Vaccine as Adjuvant Therapy in HPV16-Associated Cervical Cancer 
Protocol Chair:  Stephanie Gaillard, M.D. 
Johns Hopkins/SKCCC J1553 
 
 
 
 Version:  October 21, 2022 
 
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preclinical studies have demonstrated that vaccinated animals are protected from 
papillomavirus infection and from the development of neoplasms, and vaccination also 
facilitates the regression of existing lesions (14-16). The link between HPV16-associated 
lesions and/or carcinoma and cell-mediated immunity presents the possibility of 
eradicating these lesions or cancers through vaccines which enhance HPV-specific T cell 
immune responses. 
3.4 
HPV Oncogenic Proteins, E6 and E7, as Potential Targets for Immunotherapy 
Against HPV-Associated Cervical Cancer 
In the cellular progression from viral infection to malignant transformation, the episomal 
viral DNA can integrate into the host genome with a resultant deletion of non-critical 
viral genes. Expression of late genes (L1 and L2) and some early genes (E1 and E2) is 
typically lost, and E6 and E7 are often the only open reading frames consistently 
expressed in cancer cell lines (17) and in HPV-associated cancers (18), although they are 
expressed in productive precursor lesions. E6 and E7 are necessary for viral 
transformation through their inactivation of two human tumor suppressor proteins, p53 
and pRb, respectively, resulting in dysregulated cell cycle proliferation, delayed cellular 
differentiation, increased frequency of spontaneous and carcinogenic-induced mutations, 
and increased chromosomal instability (19).  
 
Since E6 and E7 are constitutively expressed in most HPV-associated cancers, they 
represent promising targets for the development of antigen-specific therapeutic vaccines. 
There are several advantages to targeting the E6 and/or E7 proteins. They are foreign 
viral proteins, and, therefore, are more immunogenic than a self-protein that is genetically 
altered (such as a mutated p53) or aberrantly reactivated (such as the embryonic protein, 
MAGE-1). Furthermore, since E6 and E7 are required for the induction and maintenance 
of the malignant phenotype of cancer cells (20), tumor cells cannot evade a directed 
immune response through antigen loss of E6 or E7. Lastly, preclinical studies suggest 
that vaccines targeting these early papillomavirus proteins can generate therapeutic as 
well as protective effects in vivo (21). Therefore, the E6 and E7 proteins represent logical 
targets for developing antigen-specific immunotherapies or vaccines directed against 
HPV-associated cervical cancers. Various forms of vaccines, such as vector-based 
vaccines, tumor-based vaccines, DNA-based vaccines and protein/peptide-based 
vaccines, have been described in experimental systems targeting the HPV16 E6 and/or 
E7 proteins (22-32). 
3.5 
Therapeutic Effects of the Standard Care of Chemoradiation for Cervical Cancer 
May be Improved by Therapeutic HPV Vaccines 
The current standard of care for advanced HPV-associated cervical cancer includes the 
use of a chemotherapeutic drug, cisplatin, in conjunction with local radiation therapy. 
Despite improvements noted with combination therapy, five-year survival in most 
patients affected by advanced cervical cancer is approximately 30% (33). Thus, an 
innovative treatment strategy, via a distinct mechanism, that can improve outcomes in 
patients with advanced cervical cancer is needed.  We have previously demonstrated that 
administration of a therapeutic HPV vaccine following chemotherapy with cisplatin or 

TA-CIN Vaccine as Adjuvant Therapy in HPV16-Associated Cervical Cancer 
Protocol Chair:  Stephanie Gaillard, M.D. 
Johns Hopkins/SKCCC J1553 
 
 
 
 Version:  October 21, 2022 
 
Page 10  
radiation was able to improve the therapeutic antitumor effect in a preclinical model 
compared to vaccination, chemotherapy or chemoradiation alone (34-36). These data 
suggest that a therapeutic HPV vaccine may have value in improving the therapeutic 
effect of the standard care of chemoradiation for cervical cancer. 
3.6 
Safety of TA-CIN Vaccine 
TA-CIN is a single fusion protein comprised of HPV16 E6, E7 and L2 proteins linked in 
tandem. Vaccination with TA-CIN induces immunity to HPV16 E6/E7-specific T cell 
mediated immune responses and L2-specific neutralizing antibodies in mice. Importantly, 
vaccination of HPV16 infected-patients with TA-CIN is also designed to trigger 
therapeutic immunity targeting the E6, E7 and L2 of HPV16. A placebo-controlled, 
double-blinded phase I dose escalation study provided preliminary evidence that serial 
vaccination with up to 533μg of TA-CIN for a total of three doses in the absence of an 
adjuvant is safe, well-tolerated and immunogenic in healthy volunteers (37). However, 
vaccination of patients produced only low titers of L2-specific cross-neutralizing 
antibodies and weak E6/E7-specific interferon (IFN)-γ and proliferative T cell responses 
following a TA-CIN dose response (37, 38). In a phase II clinical study, 29 patients with 
predominantly HPV16+ high grade vaginal or vulval intraepithelial neoplasia (VAIN or 
VIN), were vaccinated with 533 μg of TA-CIN followed by a single dose boost with 
recombinant vaccinia virus expressing both HPV16 and HPV-18 E6 and E7 genes (TA-
HPV) (2.5 x 105 pfu). Combination TA-CIN and TA-HPV vaccination failed to induce an 
improved rate of lesion regression as compared to earlier studies utilizing either TA-HPV 
alone or TA-CIN alone in 30 VIN patients (39).  
 
Another clinical trial tested TA-CIN vaccination following treatment with an 
immunomodulatory drug, imiquimod. Twenty women aged 18–70 years with 
biopsy-proven VIN grades 2 and 3 were recruited (19 evaluated) in a clinical trial 
examining combination treatment with topical imiquimod followed by 3 doses of 
TA-CIN vaccination (40). Exclusion criteria were pregnancy, invasive disease, 
immunosuppression, history of severe allergy and previous HPV vaccination. Imiquimod 
5% cream was self-administered topically for 8 weeks, escalating from one application in 
week 1 to two in week 2 and three applications in weeks 3–8. This was followed by three 
intramuscular doses of TA-CIN (128 μg) at weeks 10, 14 and 18. The primary objective 
was to measure treatment effect on VIN by lesion size and histology and the secondary 
objectives were to assess lesion HPV status, symptoms, immune responses as well as 
safety, toxicity and tolerability. Women were reviewed at weeks 0, 10, 14, 18, 20, 26 and 
52, the primary end point. Punch biopsies were taken for histology and HPV typing at 
weeks 0, 10, 20 and 52. Heparinized blood was obtained for immunological assays at 
weeks 0, 10 and 20. TA-CIN, which was administered intramuscularly into the deltoid 
muscle, was well tolerated with no side effects or adverse events (40). 
 
The vaccination strategy of boosting with TA-CIN recombinant protein following 
priming with a different therapeutic HPV vaccine was investigated in a phase I clinical 
trial (41). 10 women with HPV16+ high grade VIN were primed with TA-HPV vaccinia 
vaccine followed by boosting with TA-CIN (533 μg/0.5 mL) three times at 1 month 

TA-CIN Vaccine as Adjuvant Therapy in HPV16-Associated Cervical Cancer 
Protocol Chair:  Stephanie Gaillard, M.D. 
Johns Hopkins/SKCCC J1553 
 
 
 
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intervals 7-15 months after TA-HPV priming vaccination. The results showed that the 
prime-boost vaccination strategy elicited strong HPV16-specific proliferative T cell and 
serological responses. Furthermore, lesion shrinkage or symptom relief was observed in 3 
patients. Importantly, vaccination with TA-CIN was shown to be safe and well tolerated 
with no reported adverse events.  In sum, the four clinical trials involving the use of TA-
CIN in over 90 patients provide strong support for the safety and feasibility of three 
monthly intramuscular  TA-CIN vaccinations at doses as high as 533µg. 
3.7 
Rationale for the Clinical Trial Design 
3.7.1 TA-CIN is highly effective in tumor bearing mice but not in healthy mice 
In a recent pre-clinical study, we have compared the HPV16-specific CD8 T cell 
immune responses elicited by three vaccinations with TA-CIN in the naïve or tumor 
bearing mice.  
 
 
As shown in Figure 1, vaccination three times with TA-CIN alone is poorly 
immunogenic in healthy naïve mice. However, as shown in Figure 2, administration 
of TA-CIN to mice bearing HPV16 E6 and E7 expressing TC-1 tumor generated 
remarkably higher HPV16-specific CD8+ T cell responses as compared to the 
untreated mice. This was also associated with a potent therapeutic effect against the 
TC-1 tumor that had metastasized to lung. These results suggest that TA-CIN alone 
can be highly immunogenic and effective when administered into subject with 
preexisting exposure to HPV16-associated tumor. 
Figure 1. TA-CIN is not immunogenic in healthy mice. A. Schematic illustration of the experiment. Briefly, 5~8 weeks old female C57BL/6 mice (5 
mice/group) were injected with vaccinated with either 25 g/mouse of TA-CIN or PBS on day 0. The mice were boosted twice with the same regimen 
in 2 week interval. On day 35, the mice were sacrificed and the spleens were harvested. B. Flow cytometry analysis of HPV16 E6 and E7-specific 
CD8+ T cell responses analyzed by IFN- intracellular staining. Briefly, splenocytes were collected, stimulated with 1 g/ml HPV16 E6aa50-57, or 
E7aa49-57 peptide at the presence of GolgiPlug (1l/ml) overnight at 370C. The cells were then stained with anti-mouse CD8 followed by intracellular 
IFN-. The data were acquired with FACSCalibur and analyzed with CellQuest. C. Summary of the flow cytometry data. 

TA-CIN Vaccine as Adjuvant Therapy in HPV16-Associated Cervical Cancer 
Protocol Chair:  Stephanie Gaillard, M.D. 
Johns Hopkins/SKCCC J1553 
 
 
 
 Version:  October 21, 2022 
 
Page 12  
 
 
 
3.7.2 Site of Vaccination Affects the Anti-Tumor Immunity 
In another pre-clinical study, we explored whether the site of vaccination will impact 
anti-tumor immunity, specifically whether intramuscular vaccination of the leg will 
generate better anti-tumor immunity than vaccination on the arm against cervical 
HPV disease. As a model for vaccination of cervical cancer patients in the arm versus 
the leg, we vaccinated mice bearing cervicovaginal, luciferase-expressing TC-1 tumor 
with a therapeutic HPV16 DNA vaccine pNGVL4A-CRT/E7(detox), administered 
either in the front leg (which drains to a lymph node distal to the cervical tumor) or 
the hind leg (which drains to the proximal lymph node shared with the cervical 
tumor).  
 
Figure 2. Therapeutic effect of TA-CIN against HPV16 E6E7-expressing TC-1 lung metastasis. A. Schematic illustration of the experiment. 
Briefly, 5~8 weeks old female C57BL/6 mice (5 mice/group) were injected with 5  104 TC-1 cells intravenously on day 0. On day 3, the mice were 
vaccinated with either 25 g/mouse of TA-CIN via subcutaneous injection or left untreated. The mice were boosted twice with the same regimen. On 
day 21, the mice were sacrificed, lungs and spleens were harvested. The weight of the lungs was weighed, and the number of nodules of the tumor was 
counted. B. Images of lungs of the mice from the experiment. C. Summary of the weight of the lungs of the mice from the experiment. D. Summary of 
the number of TC-1 metastasis nodules. E. Flow cytometry analysis of HPV16 E6 and E7-specific CD8+ T cell responses analyzed by IFN- 
intracellular staining. Briefly, splenocytes were collected, stimulated with 1 g/ml HPV16 E6aa50-57, or E7aa49-57 peptide at the presence of 
GolgiPlug (1l/ml) overnight at 370C. The cells were then stained with anti-mouse CD8 followed by intracellular IFN-. The data were acquired with 
FACSCalibur and analyzed with CellQuest. F. Summary of the flow cytometry data. 

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As shown in Figure 3, tumor bearing mice that received hind leg vaccination 
demonstrated a significantly greater reduction in luminescence signal as compared to 
the tumor bearing mice vaccinated at the front leg or tumor bearing mice with no 
vaccination, corresponding to a greater reduction in tumor volume. Furthermore, 
100% of the tumor bearing mice with hind leg vaccination survived for at least 80 
days while 80% of the tumor bearing mice with front leg vaccination and 100% of the 
tumor bearing mice with no vaccination died within 50 days after tumor challenge, 
demonstrating a significantly better anti-tumor effect against cervicovaginal tumor 
elicited by the therapeutic vaccination when administered at the hind leg of the tumor 
bearing mice. 
 
To examine the impact of the site of vaccination upon antigen-specific immune 
response in mice bearing cervicovaginal tumor, we harvested the tumor and lymph 
nodes from the tumor bearing mice that received no vaccination, vaccination in front 
leg, or vaccination in hind leg 7 days after the last vaccination and analyzed each 
sample for E7-Specific CD8+ T cells. As shown in Figure 4 A-B, mice vaccinated at 
the hind leg generated significantly larger amount of E7-specific CD8+ tumor 
infiltrating lymphocyte as compared to mice vaccinated at the front leg.  
When comparing the T cell populations in the lymph nodes, vaccination in the hind 
leg generated a significantly higher amount of E7-specific CD8+ T cells in the 
inguinal and iliac lymph node as compared to the axillary lymph node, while 
vaccination in the front leg generated comparable amount of E7-specific CD8+ T 
cells in the axillary, inguinal, and iliac lymph nodes (Figure 4 C-D). These results 
suggest that administration of a therapeutic HPV vaccine such as TA-CIN at a site 
adjacent to tumor-draining lymph nodes can enhance the generation of antigen-
specific T cells and improve treatment outcome. 
 
Figure 3. Characterization of therapeutic antitumor effect of therapeutic HPV vaccine administered at different site in cervicovaginal 
tumor model. 5~8 weeks old female C57BL/6 mice (5 mice/group) were injected with 5  104 of TC-1/ luciferase cells at the intravaginal cavity on 
day 0. The mice were vaccinated with 20 g/mouse of pNGVL4a-CRT/E7 DNA via intramuscular injection follow by electroporation at different 
site on day 4 and boosted once 4 days later. (A) Bioluminescence images of the cervicovaginal TC-1/luciferase tumor-bearing mice. (B) Kaplan-
Meier survival of the TC-1/luciferase tumor-bearing mice. 

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Figure 4. Characterization of E7-Specific CD8+ T cells in tumor and lymph node microenvironment produced by different vaccination sites in 
TC-1 tumor-bearing mice. 5~8 weeks old female C57BL/6 mice (5 mice/group) were injected with 5  104 of TC-1/ luciferase cells at the 
intravaginal cavity on day 0. The mice were vaccinated with 20 g/mouse of pNGVL4a-CRT/E7 DNA via intramuscular injection follow by 
electroporation at different site on day 4 and boosted once 4 days later. 7 days after the last vaccination, lymph nodes and tumors from different groups 
(both treated and untreated) were harvested, processed, and analyzed for HPV16 E7-specific CD8+ T cells by HPV16 E7 peptide-loaded tetramer 
staining followed by flow cytometry analysis. (A-B) Representative flow cytometry image and Bar graph showing E7-specific CD8+ T cells in TC-1 
tumor tissues. (C-D) Representative flow cytometry image and Bar graph showing E7-specific CD8+ T cells in inguinal lymph nodes, iliac lymph 
nodes and axillary lymph nodes. (* = p < 0.05, ** = p < 0.01, ns = not significant). 

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4. PARTICIPANT SELECTION 
4.1 
Inclusion Criteria 
4.1.1 Females, age ≥ 18 years  
4.1.2 Diagnosis of HPV16 related stage IB1-IV cervical cancer (Appendix A); completed 
definitive treatment within the past 12 months   
4.1.3 No evidence of disease recurrence based on imaging and clinical assessments within 
8 weeks of enrollment  
4.1.4 Documented to have HPV16 nucleic acid within the cervical tumor specimen as 
determined by in situ hybridization.  NOTE:  HPV16 nucleic acid testing may be 
done as part of a “pre-screening” consent at any time prior to enrollment on the 
primary study.  To be eligible for HPV16 testing, patients must have stage IB1-IV 
cervical cancer and have completed definitive treatment such that enrollment within 
12 months of diagnosis would be possible if testing is positive.   
4.1.5 Fresh-frozen or paraffin-embedded material must be available for in situ 
hybridization testing for HPV16 nucleic acid for central confirmation.  
4.1.6 Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
(Appendix B) 
4.1.7 Adequate organ function as defined by the following parameters:  
− white blood cell count  
 ≥ 3,000  
− lymphocyte number  
 ≥ 500  
− absolute neutrophil count  
 ≥ 1,000  
− platelets 
 ≥ 90,000  
− hemoglobin  
 ≥ 9  
− total bilirubin  
 <1.5 X upper limit of normal (ULN) 
 
 
 
(<3 x ULN if Gilbert’s disease)  
− AST(SGOT)/ALT(SGPT)  
<3 X ULN  
− creatinine  
 < 1.5X ULN or estimated creatinine clearance ≥ 60 
ml/min per Modified Cockcroft-Gault Formula  
4.1.8 Ability to understand and the willingness to sign a written informed consent 
document 
4.1.9 Subject is able to adhere to the study visit schedule and other protocol requirements 
4.2 
Exclusion Criteria 
4.2.1 Patients with a diagnosis of immunosuppression or prolonged, active use of 
immunosuppressive medications such as systemic steroids 

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4.2.2 Patients who have had chemotherapy, radiation, biological cancer therapy, or other 
investigational agents within 28 days prior to the first dose of study drug 
4.2.3 Patients who have had surgery within 28 days of dosing of investigational agent, 
excluding minor procedures (dental work, skin biopsy, etc) 
4.2.4 Patients with an uncontrolled intercurrent illness including, but not limited to, 
ongoing or active infection, symptomatic congestive heart failure, unstable angina 
pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit 
compliance with study requirements 
4.2.5 Patients who have an active autoimmune disease (e.g., rheumatoid arthritis, systemic 
lupus erythematosus (SLE), ulcerative colitis, Crohn's Disease, multiple sclerosis 
(MS), ankylosing spondylitis) 
4.2.6 Patients being chronically treated with immunosuppressive drugs such as cyclosporin, 
adrenocorticotropic hormone (ACTH), or systemic corticosteroids 
4.2.7 Patients with a recognized immunodeficiency disease including cellular 
immunodeficiencies, hypogammaglobulinemia or dysgammaglobulinemia; patients 
who have acquired, hereditary, or congenital immunodeficiencies 
4.2.8 Women of child-bearing potential (i.e., those who have had fertility-sparing 
procedures for the management of cervical cancer) will be excluded 
4.2.9 Patient with active or chronic infection of HIV, HCV, or HBV (tested at baseline; see 
Study Calendar) 
4.2.10 Patients with non-healed wounds 
4.2.11 A history of current or recent concurrent malignancy (≤5 years) except basal cell 
cancer.  
4.2.12 Inability to understand or unwillingness to sign an informed consent document 
4.3 
Inclusion of Women and Minorities 
Only women are eligible for this trial as cervical cancer does not afflict males. Women of all 
races and ethnic groups are eligible for this trial. 
 
 
 

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5. REGISTRATION PROCEDURES 
5.1 
General Guidelines 
 
Pre-Screening:  Patients eligible for HPV16 testing must be entered on study 
centrally at the Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins 
University.  All sites should call the Lead Study Coordinator/designee at the 
Coordinating Center.  The fax cover sheet, Pre-Screening Registration Form, and Pre-
Screening Eligibility Worksheet will be supplied to each participating site. 
 
Primary Study:  Eligible patients will be entered on study centrally at the Sidney 
Kimmel Comprehensive Cancer Center at the Johns Hopkins University.  All sites 
should call the Lead Study Coordinator/designee at the Coordinating Center to verify 
drug availability.  The fax cover sheet, Registration Form, and Eligibility Worksheet 
will be supplied to each participating site. If a patient does not receive protocol 
therapy following registration, the patient’s registration on the study may be canceled.  
The Study Coordinator should be notified of cancellations as soon as possible. 
5.2 
Registration Process 
 
Pre-Screening:  To register a patient, the following documents should be completed 
and faxed or e-mailed to the Coordinating Center: 
• Fax Cover Sheet 
• Pre-Screening Registration Form 
• Signed Patient Consent Form – Pre-Screening 
• HIPAA Authorization Form 
• Pre-Screening Eligibility Screening Checklist 
 
Once eligibility is verified, to complete the registration process, the Coordinating 
Center will: 
• Assign/confirm a pre-screening patient study number 
• Register the patient on the study for pre-screening 
• Fax or e-mail the patient study number to the participating site 
• Call the research nurse or data manager at the participating site and verbally 
confirm registration (if needed) 
 
Primary Study:  To register a patient, the following documents should be completed 
and faxed or e-mailed to the Coordinating Center: 
• Fax Cover Sheet 
• Registration Form 
• Signed Patient Consent Form 
• HIPAA Authorization Form 
• Eligibility Screening Checklist 
• Copy of Required Screening Tests and Scans 

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Once eligibility is verified, to complete the registration process, the Coordinating 
Center will: 
• Assign a patient study number 
• Register the patient on the study 
• Fax or e-mail the patient study number to the participating site 
• Call the research nurse or data manager at the participating site and verbally 
confirm registration. 
6. TREATMENT PLAN 
6.1 
Agent Administration 
Treatment will be administered on an outpatient basis.  Reported adverse events and 
potential risks are described in Section 8.1.  
 
There is a possible risk of anaphylaxis and the vaccine should be administered in a setting 
where emergency treatment is available. Administration should be immediately 
discontinued and the appropriate therapy instituted per institutional guidelines if there is a 
serious allergic reaction. The patient must be observed in the clinic for at least 60 minutes 
after each vaccine. If an anaphylactic reaction is suspected, this must be discussed with 
the IND Sponsor before the subject is given another dose of vaccine. 
6.2 
Blinding and Randomization 
This is a non-blinded, non-placebo controlled, randomized, prospective study. Eligible 
patients will be randomized in a 1:1 ratio to receive TA-CIN in either the arm or the 
thigh. Randomization will occur after registration and prior to the planned first dose of 
TA-CIN. All participants and providers will know the arm to which subjects are 
randomized.   
 
A master list of randomization assignments will be generated and will be delivered to the 
Research Pharmacy at each participating site and to other key personnel, as identified.  
Upon successful registration of a subject, randomization will occur by the appropriate 
study staff.   
6.3 
Dose Levels 
The dose of TA-CIN is fixed. The site of administration is as assigned by randomization 
(as above). 
 
Treatment Groups/Cohorts 
Group 
TA-CIN Route of 
Administration 
Volume 
(mL) 
Dose  
(µg) 
Treatment Frequency/Weeks 
# of 
Patients 
1 
Intramuscular Arm 
0.53  
100  
3 administrations per subject; 
Weeks 1, 5, and 9 
7 
2 
Intramuscular Thigh 
7 

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6.4 
Re-Treatment Criteria  
Subjects must maintain the following in order to receive each additional dose of study 
medication: 
 
• ECOG performance status 
 
0 - 1 
• white blood cell count  
 
≥ 3,000  
• lymphocyte number   
 
≥ 500  
• absolute neutrophil count  
 
≥ 1,000  
• platelets 
 
 
 
≥ 90,000  
• hemoglobin   
 
 
≥ 9  
• total bilirubin  
 
 
<1.5 X upper limit of normal (ULN) 
 
 
 
 
(<3 x ULN if Gilbert’s disease)  
• AST(SGOT)/ALT(SGPT)   
<3 X ULN  
• creatinine  
 
 
 
< 1.5X ULN or estimated creatinine   
 
 
 
 
 
clearance ≥ 60 ml/min per Modified   
 
 
 
 
 
Cockcroft-Gault Formula 
 
In addition, subjects must not have any acute grade 3 or higher hematologic and/or non-
hematological adverse event that is judged possibly, probably or definitely related to the 
investigational drug agent and/or administration occurring on or after the first day of 
vaccine administration. 
6.5 
Dose Modifications and Delays 
Dose reduction or dose increase of TA-CIN will not be permitted. The dose in this study 
is fixed.   
 
In the event that TA-CIN re-treatment criteria are not met, treatment may be delayed for 
up to 14 days. Future doses should be delayed accordingly such that at least 23 days is 
maintained between each dose of TA-CIN. The timing for the Month 6, 12, and 24 
assessments should be scheduled from the initial dose of TA-CIN.   
6.6 
Unacceptable Toxicity and Early Stopping Rules 
Unacceptable toxicities are defined as treatment-related ≥ grade 4 AEs, or treatment-related 
grade 3 AEs not improving to ≤ grade 2 under therapy within 2 weeks. Exceptions include: 
Grade 3 lymphopenia. Because this is a pilot study evaluating safety of immunization, the 
stopping rule for safety is the presence of vaccine attributable (either probably or definitely) 
systemic grade 3 or 4 toxicities or grade 4 local/skin toxicities in ≥20% of patients in the 
study. Patients will be withdrawn from study if they manifest Grade 3 or 4 systemic toxicity 
attributable to vaccination with TA-CIN or grade 4 local/skin toxicities attributable to 
vaccination with TA-CIN. In the event of two identical unexpected treatment-related Grade 
4 toxicities, accrual will be suspended pending further review. 
6.7 
General Concomitant Medication and Supportive Care Guidelines 
In general, concomitant medications and therapies deemed necessary for the supportive 

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Johns Hopkins/SKCCC J1553 
 
 
 
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care and safety of the subject are allowed, provided their use is documented in the 
medical records. Local vaccine site reaction may be treated with topical applications of 
aloe vera or vitamin E gel or lotion. Significant local inflammation that is causing the 
research participant severe pain or is interfering with the activities of daily living may be 
treated with cold packs and oral analgesics. Local toxicities of pruritus at the vaccine 
sites and systemic pruritus may be treated with topical or oral diphenhydramine 
hydrochloride (Benadryl) or topical aloe vera. If oral diphenhydramine hydrochloride is 
used the recommended dose shall be 25-50 mg every four to six hours as needed for 
pruritus, not to exceed 300 mg/day. Severe local inflammation or significant clinical 
autoimmunity will be managed on a case by case basis. 
 
Use the following medications are prohibited during the vaccination administration 
period and one month (28 days) after last vaccination received: 
 
• Any non-study anticancer or immunotherapy agent (investigational or non-
investigational) 
• Any other investigational agents 
• Live vaccines (examples of live vaccines include, but are not limited to: measles, 
mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid [oral] 
vaccine). Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed. However, intranasal influenza vaccines (e.g. Flu-Mist®) 
are live attenuated vaccines, and are not allowed. 
 
All concomitant medications will be reviewed and recorded by study staff during the 
study. 
6.8 
Contraception, Use in Pregnancy, Use in Nursing 
 
TA-CIN may have adverse effects on an embryo or fetus; therefore, women of 
 
childbearing potential with fertility sparing procedures will not be eligible for enrollment.  
6.9 
Duration of Therapy 
In the absence of treatment delays due to adverse event(s), treatment may continue for a 
total of three vaccinations or until one of the following criteria applies: 
• Disease recurrence, 
• Intercurrent illness that prevents further administration of treatment, 
• Unacceptable adverse event(s) (Section 6.6), 
• Patient or legal representative withdraws consent from the study, 
• Patient is lost to follow-up, 
• General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator, 
• Non-compliance with protocol or treatment,  

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• Use of systemic glucocorticoids or other immune-suppressive drugs for more than 
7 days required at any time after enrollment in the study, or 
• Termination of the study.  
6.10 
Duration of Follow-Up 
Patients will be followed for 24 months after initiation of study treatment or until death, 
whichever occurs first Patients who are discontinued from the study treatment due to an 
unacceptable drug-related AE will be monitored for safety until the resolution of the AE to 
≤ grade 1 or stabilization or until initiation of a new therapy for their cancer, whichever 
occurs first. 
 
7.  ADVERSE EVENTS 
This study will use the descriptions and grading scales found in the revised National Cancer 
Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 for 
adverse event reporting that can be found at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.   
 
Information about all adverse events, whether volunteered by the subject, discovered by 
investigator questioning, or detected through physical examination, laboratory test or other 
means, will be collected, recorded, and followed as appropriate.  
 
All adverse events experienced by subjects will be collected and reported from the time of 
consent, throughout the study, and will only be followed until month 24 unless related to the 
investigational vaccine.  All adverse events related to the vaccine will be followed until 
resolution.  
 
Subjects who have an ongoing adverse event related to the study procedures and/or 
medication(s) may continue to be periodically contacted by a member of the study staff until 
the event is resolved or determined to be irreversible by the investigator. 
 
Laboratory abnormalities: Laboratory abnormalities present at the screening visit will be 
recorded as pre-treatment signs and symptoms. After study treatment administration, all 
grade 3 and 4 clinical laboratory results that represent an increase in severity from baseline 
(pre-study) will be reported as adverse events. A grade 1 or 2 clinical laboratory 
abnormality should be reported as an adverse event only if it is considered clinically 
significant by the investigator. 
 
Vaccination site assessment: This study will use the CTCAE version 4.0 injection site 
reaction grading scale as it relates to vaccine administration associated adverse events. 
Patients are to have the site of vaccination examined for pain, erythema, warmth, pruritis, 
induration/fibrosis, and bruising. A follow-up phone call will be made to the patient 7 days 
after receiving the vaccine to obtain a self-assessment of the vaccination site. The vaccine 
site(s) will be assessed by the research nurse (or designated clinician) at each subsequent 
vaccination visit (Day 1 on Weeks 5 and 9) and at the follow-up visit between Weeks 11-13 

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for local reactions. An optional skin biopsy and/or photographs may be obtained based on 
the assessment by the principal investigator if the subject has a systemic rash, or an unusual 
vaccine reaction. In addition to sending this to pathology for diagnosis, we will use 
additional material from the biopsy for research purposes to understand the effects of the 
vaccine. We will follow these local reactions until complete resolution. 
7.1 
Definitions 
7.1.1 Adverse Event (AE) 
Adverse event is defined as any undesirable sign, symptom or medical condition 
occurring after starting the study drug (or therapy) even if the event is not considered 
to be related to the study. An undesirable medical condition can be symptoms (e.g., 
nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of 
an investigation (e.g., laboratory findings, electrocardiogram).  
 
Medical conditions/diseases present before starting the study treatment are only 
considered adverse events if they worsen after starting the study treatment (any 
procedures specified in the protocol). Adverse events occurring before starting the 
study treatment but after signing the informed consent form will be recorded. 
Abnormal laboratory values or test results constitute adverse events only if they 
induce clinical signs or symptoms or require therapy. 
7.1.2 Serious Adverse Event (SAE) 
A serious adverse event is an undesirable sign, symptom or medical condition which:  
 
• 
Results in death  
• 
Is 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)  
• 
Requires inpatient hospitalization or causes prolongation of existing 
hospitalization (see note below for exceptions) for ≥ 24 hours 
• 
Results in persistent or significant disability/incapacity  
• 
Is a congenital anomaly/birth defect (note: reports of congenital anomalies/birth 
defects must also be reported on the Pregnancy Supplemental Form)  
• 
Is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based upon 
appropriate medical and scientific judgment, may jeopardize the subject or may 
require intervention [e.g., medical, surgical] to prevent one of the other serious 
outcomes listed in the definition 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.)  
 
 
 

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Events not considered to be serious adverse events are hospitalizations for the:  
 
• 
Admissions as per protocol for a planned medical/surgical procedure  
• 
Routine health assessment requiring admission for baseline/trending of health 
status (e.g., routine colonoscopy)  
• 
Medical/surgical admission for purpose other than remedying ill health state and 
was planned prior to entry into the study. Appropriate documentation is required 
in these cases  
• 
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). 
 
The definition of serious adverse event (experience) also includes important medical 
event. Medical and scientific judgment should be exercised in deciding whether 
expedited reporting is appropriate in other situations, such as important medical 
events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the patient or may require intervention to prevent 
one of the other outcomes listed in the definition above. These should also usually be 
considered serious. 
7.2 
Relationship 
The Principal Investigator must assess whether AEs have a suspected causal relationship 
to the study drug. A suspected causal relationship is defined as possibly, probably or 
definitely related: 
 
Definite – The AE is clearly related to the study treatment. 
Probable – The AE is likely related to the study treatment. 
Possible – The AE may be related to the study treatment. 
Unlikely – The AE is doubtfully related to the study treatment. 
Unrelated – The AE is clearly NOT related to the study treatment. 
7.3 
Expectedness 
Expected adverse events are those which are expected to occur, according to previous 
clinical experience, and are listed in the Investigator Brochure. The expectedness of an 
AE will be assessed by the Principal Investigator: 
 
Unexpected adverse event: An adverse event, which varies in nature, intensity or 
frequency from information on the investigational drug/agent provided in the 
Investigator’s Brochure, package insert or safety reports. Any adverse event that is not 
included in the informed consent is considered “unexpected”.  
 
Expected (known) adverse event: An adverse event, which has been reported in the 
Investigator’s Brochure. An adverse event is considered “expected”, only if it is included 
in the informed consent document as a risk. 

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7.4 
Handling of Expedited Safety Reports 
In accordance with local regulations, the IND Sponsor will notify investigators of all 
SAEs that are unexpected (i.e., not previously described in the IB), and related to the 
vaccine. This notification will be in the form of an expedited safety report (ESR) that is 
to be faxed to the investigators and the study coordinators. Upon receiving such notices, 
the investigator must review and retain the notice with the IB and where required by local 
regulations, the investigator will submit the ESR to the appropriate IRB. The investigator 
and IRB will determine if the informed consent requires revision. The investigator should 
also comply with the IRB procedures for reporting any other safety information. 
7.5 
Reporting Procedures 
7.5.1 General 
All adverse events (both expected and unexpected) will be captured on the 
appropriate study-specific case report forms (CRFs). In addition, all serious adverse 
events, regardless of causality to study drug and/or administration device, will be 
reported promptly to the Sponsor (Dr. Roden, 
 
) within 24 hours of recognition of the adverse event (Appendix 
D). If this falls on a weekend or holiday, an email notification is acceptable but must 
be followed by an SAE reporting form on the next business day. Follow-up 
information will be submitted to the sponsor as soon as relevant information is 
available. 
7.5.2 Institutional Review Board (IRB) 
All serious adverse events will be reported to the Institutional Review Board (IRB) 
per institutional standards. If a serious adverse event requires modification of the 
study protocol and informed consent, these modifications will be provided to the IRB 
with the report of the adverse event. Follow-up information will be submitted to the 
IRB as soon as relevant information is available per institutional standards. 
7.5.3 Food and Drug Administration (FDA) 
7.5.3.1 
Expedited IND Safety Reports: 
7 Calendar-Day Telephone or Fax Report:   
The Sponsor is required to notify the FDA of any fatal or life-threatening adverse 
event that is unexpected and assessed by the investigator to be at least possibly 
related to the investigational agent.  Such reports are to be telephoned or faxed 
 to the FDA within 7 calendar days of first learning of the event. 
Follow-up information will be submitted to the FDA as soon as relevant 
information is available. 
 
15 Calendar-Day Written Report:   
The Sponsor is required to notify the FDA of any serious adverse event that is 
unexpected and possibly related to the investigational agent in a written IND 
Safety Report.   

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Written IND Safety Reports should include an Analysis of Similar Events in 
accordance with regulation 21 CFR § 312.32.  All safety reports previously filed 
with the IND concerning similar events should be analyzed.  The new report 
should contain comments on the significance of the new event in light of the 
previous, similar reports.   
 
Written IND safety reports with Analysis of Similar Events are to be submitted 
to the FDA within 15 calendar days of first learning of the event. Follow-up 
information will be submitted to the FDA as soon as relevant information is 
available. 
7.5.3.2 
IND Annual Reports 
In accordance with the regulation 21 CFR § 312.33, the Sponsor shall within 60 
days of the anniversary date that the IND went into effect submit a brief report of 
the adverse events and progress of the investigation.  Please refer to Code of 
Federal Regulations, 21 CFR § 312.33 for a list of the elements required for the 
annual report.  All IND annual reports will be submitted to the FDA by the 
Sponsor-Investigator. 
 
8. PHARMACEUTICAL INFORMATION  
Please refer to the Laboratory Manual for further details regarding storage, preparation, 
 
and administration of the product.  
8.1 
TA-CIN 
Product Description: The final formulated product TA-CIN (HPV16 L2E7E6 fusion 
polypeptide) contains 0.19 mg/mL TA-CIN in 5mM phosphate, 5mM glycine, 0.9mM 
cysteine at pH8.1  0.3. The product is supplied by the Waisman Biomanufacturing 
(Madison, WI). The vaccine will be supplied in 0.65mL aliquots. 
 
Storage Requirements: Vaccine supply is to be stored at ≤ -20°C. 
 
Solution Preparation: Thaw individual vials at ambient temperature. TA-CIN should be 
removed from –20C storage and allowed to defrost at room temperature for up to 30 
minutes.  Do not refreeze once defrosted. Gently invert the vial 5-6 times before dose is 
drawn up. Using a 25G (orange) or 23G (blue) needle and 1mL syringe, remove 0.53 mL 
of the clear solution. Administer a total volume of 0.53 mL by intramuscular vaccination 
within 2 hours of drawing up into the syringe. 
 
Stability:  Administer a total volume of 0.53 mL by intramuscular vaccination within 2 
hours of drawing up into the syringe.  
 
Route of Administration: The vaccine will be administered via one of two injection 
sites: 1) Intramuscular needle injection in the non-dominant medial deltoid (arm) region 

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using a 25 gauge needle, or 2) Intramuscular needle injection in the Vastus Lateralis 
(thigh) region using a 23 or 25 gauge needle. In the event that the specified arm or thigh 
is contraindicated, the other arm or thigh may be used respectively. A patient will receive 
all 3 injections in the arm if randomized to this group, or all 3 injections in the thigh if 
randomized to the alternate group. 
 
Known Adverse Effects: TA-CIN has been administered in over 90 adults (healthy 
adults and high grade VIN or AGIN 3 patients) across four clinical trials. To date, no 
patients with a history of advanced cervical cancer have received the TA-CIN vaccine. 
Based on the previous clinical safety data for TA-CIN, the following adverse events are 
expected when administering the TA-CIN vaccine:  
 
System/Organ 
Adverse Event 
Blood/Lymphatic  
Eosinophilia 
 
Constitutional 
Chills 
Flu-like symptoms 
 
Fatigue 
Flushing 
 
Fever 
Somnolence 
Dermatologic 
Rash 
Urticaria 
Gastrointestinal 
Abdominal Pain 
Nausea 
 
Anorexia 
Vomiting 
HEENT 
Dry Mouth 
Rhinitis 
Neurology 
Dizziness 
Headache 
 
Dreaming Abnormal 
Syncope 
Vaccine Site Reactions 
Bruising 
Pruritis 
 
Erythema  
Swelling 
 
Pain 
Tenderness 
Other 
Arm Weakness 
Myalgia 
 
Hypotension 
Pain in both arms 
 
Menstrual Disorder 
 
 
9. CORRLEATIVE STUDIES 
Please refer to the Laboratory Manual for further details regarding collection, processing and 
handling of specimens for the correlative studies. 
9.1 
Blood Samples for Immunologic Assays and Viral DNA 
Blood will be drawn at various time schedules as noted in the protocol. The volume of 
blood and container utilized will vary depending on the test to be performed, as detailed 
below:  
9.1.1 HPV16 L2, E6, E7 and HPV Neutralizing: Blood (1, 10cc SST [serum separator 
tube]) will be utilized for measurement of antibodies to HPV16 L2, E6, and E7 via 

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ELISA per routine laboratory methods and also the HPV in vitro neutralization assay.   
9.1.2 HPV16 E6- and E7-Specific T cells: Blood (1, 60cc heparinized syringe) will be 
collected to evaluate HPV16 antigen-specific T cell responses at the indicated time 
points during the vaccination series.  
9.1.3 Evaluation of the Proliferative Responses of Peripheral Blood Lymphocytes to 
Stimulation by HPV16 E6 and E7:  Evaluation of the proliferative responses of 
peripheral blood lymphocytes to stimulation by HPV16 E6 and E7 using heparinized 
blood sample (see 9.1.2). 
9.1.4 Evaluation of HPV16 DNA in Plasma. Plasma and cells will be separated from 
blood (1, 10cc EDTA) by standard protocol and stored at –70 ºC until processing. 
HPV DNA load in plasma samples will be quantified by use of real-time quantitative 
PCR and T cell receptor sequencing performed. 
9.2 
Samples for HPV16 
Tissue will be sent as part of a “pre-screening” consent process for eligibility purposes, as 
detailed below:       
9.2.1 HPV16 in situ Hybridization and p16 Immunohistochemistry Testing: Fresh-
frozen or paraffin-embedded material from the cervical cancer tumor specimen must 
be available for testing to confirm eligibility if this was not done per routine care.   
Samples will be sent to Johns Hopkins for analysis in a CLIA-certified environment 
and results will be returned to the study team/provider (Appendix C).  Sites will be 
provided with instructions on how to send samples to Johns Hopkins for testing at 
time of activation.   
In the event that standard of care HPV16 testing was done and is positive, and is felt to be 
adequate by the Protocol Chair, repeat testing will not be needed for eligibility purposes 
prior to screening and enrollment on the primary treatment study. In these cases archival 
tissue specimens will still be obtained for research analyses. 
9.3 
Other Assessments 
 
Disease Status Evaluation: After completion of standard therapy, disease status will be 
determined by current standard of care. Disease assessment after vaccine administration is to 
be performed as per current clinical care standards. Imaging studies, specifically a PET/CT, 
CT, or MRI scan (whichever is clinically indicated and/or preferred by the treating 
physician), will be performed per standard of care and/or based on the discretion of the 
treating physician.   

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10. STUDY CALENDAR 
 
Test/Procedure 
Pre- 
Study17 
Week 1 
Day 1 
Week 2 
Day 1  
Week 5 
Day 1 
Week 6 
Day 1 
Week 9 
Day 1 
Week 10 
Day 1 
Week 
11-13 Month 6 Month 12 Month 24 
Visit Window (Days) 
-60 
 
+/- 2 
+/- 5 
+/- 5 
+/- 5 
+/- 5 
 
+/- 28 
+/- 28 
+/- 28 
TA-CIN Administration1 
 
X 
 
X 
 
X 
 
 
 
 
 
Tumor HPV Testing2 
X 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Class I and II HLA Typing3 
X 
 
 
 
 
 
 
 
 
 
 
HIV/Hepatitis Panel 4 
X 
 
 
 
 
 
 
 
 
 
 
Physical/Pelvic Examination5 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Vital Signs6 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Performance Status7 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Concomitant Med Review 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Vaccine Site Assessment8 
 
 
 
X 
 
X 
 
X 
 
 
 
Phone Call 
 
 
X 
 
X 
 
X 
 
 
 
 
CBC w/Diff, Plts9 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Serum Chemistry10 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
PET/CT, MRI or CT Scan11 
X 
 
 
 
 
 
 
 
 
 
 
Evaluation of HPV16 E6, E7-
Specific CD8+T Cells12 
X13 
 
 
X13 
 
X13 
 
X13 
X13 
X13 
X13 
Evaluation of HPV16 Antibody and 
DNA15 and HPV16 Viral Load 
X14 
 
 
X14 
 
X14 
 
X14 
X14 
X14 
X14 
Adverse Event Evaluation15 
 
 
 
Archived Tumor Tissue16 
 
 
 

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Research samples will be collected at the discretion of the PI based on availability of supplies and safety of patient and staff. 
In order to minimize the need for research-only in-person visits, telemedicine visits may be substituted for in-person clinical trial visits 
or portions of clinical trial visits where determined to be appropriate and where determined by the investigator not to increase the 
participants risks.  Prior to initiating telemedicine for study visits the study team will explain to the participant, what a 
telemedicine visit entails and confirm that the study participant is in agreement and able to proceed with this method.  
Telemedicine acknowledgement will be obtained in accordance with the Guidance for Use of Telemedicine in Research. In the 
event telemedicine is not deemed feasible, the study visit will proceed as an in-person visit.  Telemedicine visits will be conducted 
using HIPAA compliant method approved by the Health System and within licensing restrictions. 
 
1:   Administration site (arm or thigh), as assigned. 
2:   Formalin fixed paraffin embedded tumor sections will be tested for HPV16 DNA/RNA in situ hybridization and p16 
immunohistochemistry.  
 
NOTE:  This may be done as part of a pre-screening consent process and/or at any time prior to enrollment to the main study. 
Otherwise, there is no window for HPV16 testing for eligibility. Sites without the capability to conduct HPV16 testing will submit 
slides from archival tissue to Johns Hopkins  
3:   Peripheral blood will be drawn prior to Week1 Day 1 dosing to undergo HLA typing at study site.  
4:   HIV, Hepatitis C Antibody, and HBsAg. Consent will be obtained for HIV testing.  
5:   Complete physical exam, including pelvic exam, will be completed at baseline (pre-study); focused physical examinations will be 
conducted thereafter. The Week 1 Day 1 physical examination does not need to be completed if the screening physical 
examination was performed ≤ 7 days prior.  
6:   Including (1) heart rate; (2) respiratory rate; (3) body temperature (°C), (4) height (centimeters), and (5) weight (kilograms). 
Height is only to be obtained once during pretreatment evaluation. 
7:   Eastern Cooperative Oncology Group performance status, 0 to 5. 
8:   Vaccine site reactions include, but are not limited to: erythema, induration, pruritis, tenderness, warmth, blisters, and vaccine site 
flares. Vaccine site reactions should be followed until resolution. 
9:  Sodium, potassium, bicarbonate, chloride, blood urea nitrogen, serum creatinine, glucose, magnesium, calcium, total bilirubin, 
direct bilirubin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, albumin, total protein. Labs may be 
collected up to 3 days prior to dosing. 
10: CBC with differential including absolute eosinophil count, absolute neutrophils, absolute lymphocytes, and platelets. Labs may be 
collected up to 3 days prior to dosing. 
11: PET/CT or CT of the chest/abdomen/pelvis at baseline (within 8 weeks) and as clinically indicated. If a subject cannot have a CT 
scan (e.g., allergy to contrast dye), a non-contrast enhanced PET/CT scan or MRI should be performed. In the event the patient 
cannot undergo CT, PET/CT, or MRI, a Chest X-Ray should be performed. 
12: Patients will undergo phlebotomy for the detection of E6 and E7-specific CD8+ T cells.    
13: 60 cc of whole blood 

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14: 10cc of blood for serum (antibody assays) and 10cc of blood for plasma (for measurement of HPV16 DNA). 
15: Adverse events will be evaluated up to 30 days after the last vaccination. Any adverse events related to the vaccine will be 
followed until resolution or until investigator deems the adverse event as chronic and/or stable. An optional skin biopsy may be 
performed for any systemic rash or vaccine reaction at the site of administration. 
16: Attempts to obtain additional archival tumor samples in excess to diagnosis that were collected as part of routine clinical care. 
17: Pre-Study CBC with differential, platelets and serum chemistry do not need to be repeated in Week 1 if done ≤ 7 days prior 
 

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11. DATA AND SAFETY MONITORING 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
11.1 
Data Management 
All information will be collected on study-specific case report forms (CRFs) by study 
staff. These data will be reviewed for completeness and accuracy by the Principal 
Investigator as well as the Sidney Kimmel Comprehensive Cancer Center Clinical 
Research Office. 
 
Protocol Chair 
The Protocol Chair is responsible for performing the following tasks: 
• Coordinating, developing, submitting, and obtaining approval for the protocol as 
well as its subsequent amendments. 
• Assuring that all participating institutions are using the correct version of the 
protocol. 
• Taking responsibility for the overall conduct of the study at all participating 
institutions and for monitoring the progress of the study. 
• Reviewing and ensuring reporting of Serious Adverse Events (SAE) 
• Reviewing data from all sites. 
 
Coordinating Center 
The Coordinating Center is responsible for performing the following tasks: 
• Ensuring that IRB approval has been obtained at each participating site prior to 
the first patient registration at that site, and maintaining copies of IRB approvals 
from each site. 
• Managing central patient registration. 
• Collecting and compiling data from each site. 
• Establishing procedures for documentation, reporting, and submitting of AE’s and 
SAE’s to the Protocol Chair, and all applicable parties. 
• Facilitating audits by securing selected source documents and research records 
from participating sites for audit, or by auditing at participating sites. 
 
Participating Sites 
Participating sites are responsible for performing the following tasks: 
• Following the protocol as written, and the guidelines of Good Clinical Practice 
(GCP). 
• Submitting data to the Coordinating Center (at the request of the Coordinating 
Center and the frequency dependent on the rate of subject accrual and the 
progress of the study). 
• Registering all patients with the Coordinating Center by submitting patient 
registration form, and signed informed consent promptly. 
• Providing sufficient experienced clinical and administrative staff and adequate 
facilities and equipment to conduct a collaborative trial according to the protocol. 

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• Maintaining regulatory binders on site and providing copies of all required 
documents to the Coordinating Center. 
• Collecting and submitting data according to the schedule specified by the 
protocol. 
11.2 
Safety Meetings 
Scheduled meetings will take place weekly and will include the protocol principal 
investigator, study coordinator(s), data manager(s), sub-investigators (as appropriate), 
collaborators (as appropriate), and biostatisticians (as appropriate) involved with the 
conduct of the protocol. During these meetings, matters related to the following will be 
discussed: safety of protocol participants, validity and integrity of the data, enrollment 
rate relative to expectation, characteristics of participants, retention of participants, 
adherence to protocol (potential or real protocol violations), data completeness, and 
progress of data for objectives. 
11.3 
Monitoring 
Interim analysis of toxicity, outcome and ongoing scientific investigations will be 
performed every 6 months by the Sidney Kimmel Comprehensive Cancer Center Data 
Safety Monitoring Board (SKCCC DSMB). The SKCCC DSMB will review aspects of 
this trial that are outlined in the responsibilities section of the Data and Safety Monitoring 
Board (DSMB) Guidance. If the committee decides that amendments should be made to 
this trial, recommendations will be made in writing to the Study Principal Investigator.  
The study team will submit modifications to the IRB within 60 days of receipt from the 
DSMB.  The Associate Director of Clinical Research, will arbitrate any disagreements 
between the DSMB and the study Principal Investigator.  These changes may include 
early termination of accrual if deemed appropriate.  
 
Johns Hopkins SKCCC: The protocol will be monitored externally by the SKCCC CRO 
in accordance with SKCCC guidelines. Trial monitoring and reporting will be done 
through the Safety Monitoring Committee (SMC) at SKCCC.  
 
Participating site(s): The protocol will be monitored by the internal CRO at each site. A 
report of the reviews will be submitted to the Johns Hopkins principal investigator and 
SKCCC CRO. 
 
Authorized representatives of the Coordinating Center may visit the satellite sites to 
perform audits or inspections, including source data verification. The purpose of these 
audits or inspections is to systematically and independently examine all trial-related 
activities and documents to determine whether these activities were conducted and data 
were recorded, analyzed, and accurately reported according to the protocol, Good 
Clinical Practice (GCP), and any applicable regulatory requirements. 
 
The Medical Expert Committee (MEC) for this clinical study contains three medical 
oncologists (see below) from other disciplines who are not affiliated with this clinical 
trial protocol. The MEC will review safety data on at least a semi-annual basis. The MEC 

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will provide a written summary of each assessment to the IND Sponsor after each 
meeting. In turn, the study team will forward these summaries to the JHU IRB, and JHU 
SKCCC SMC. The operating plan of the MEC will be as follows: 
 
• Meetings will be held at least semi-annually, and potentially more frequently if 
needed.  
• Meetings will be conducted in-person or via video/teleconference, with a 
participant sign-in sheet collected at each meeting.  
• Approximately one week prior to each MEC meeting, the study team will submit 
the following items to MEC personnel for review and discussion at the meeting 
(The PI may join the MEC meeting in order to answer any questions the MEC 
might have):  
o A summary of the clinical trial’s progress to date; 
o The latest IRB-approved consent document; and, 
o A summary of all adverse events, serious adverse events, deaths, and 
withdrawals to date. 
 
Note that the MEC reserves the right to halt trial accrual or all study activity if, after 
review, serious safety concerns warrant this action. If the MEC halts study accrual or all 
study activity, then the study team must notify the JHU SKCCC SMC, JHU IRB, and the 
FDA immediately.  
 
Dr. Roden will be holding the IND for this study.  He will comply with all regulated 
reporting requirements to the FDA. 
 
 
 

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12. STATISTICAL CONSIDERATIONS 
12.1 
Study Design and Endpoints 
This pilot study is a single dose level assessment of the immunologic response as well as 
the safety and tolerability of administering TA-CIN vaccine via different sites in patients 
who have a history of HPV16-related cervical cancer. The primary goal is to determine 
the most favorable injection site for TA-CIN that exhibits the greater HPV-specific 
immunogenicity. The secondary goal is to evaluate the safety and tolerability profile of 
TA-CIN in HPV16 related cervical cancer patients. 
 
The primary endpoint is the immune response rate at the time of the fourth follow-up 
measurement. The measure of immune response to the regimen will be the antigen-
specific T cell response, the simulation index of T cell proliferation, and the titer of the 
antibody response in peripheral blood. Each patient will have one measurement at 
baseline and 4 measurements at 4 time points after treatment. For each individual patient, 
a significant immunologic response is defined as the maximum increase in antigen-
specific T cell number or proliferation index after administration of TA-CIN by greater 
than 1.8 times the standard deviation (SD) of the baseline values, and the increase is at 
least 2-fold. An increase by 1.8 SD establishes a statistically significant reduction at the 
two-sided .10 level. 
 
This study will evaluate two different sites, thigh and arm, for TA-CIN vaccine 
administration. 
12.2 
Sample Size  
A total of 15 patients with a history of advanced HPV16-related cervical cancer will be 
enrolled and randomized at 1:1 ratio to receive TA-CIN administrations via thigh (Group 
A) or arm (Group B). Each group will treat at most 7 patients. A previous study by Smyth 
et al. in non-cancer patients who did not receive chemo/radiotherapy showed that 9 out of 
25 patients had a detectable E6/E7-specific T cell response one month after TA-CIN 
vaccination. It is expected that the prior chemo/radiotherapy received by the cervical 
cancer patients enrolled on this study will prime the response to the TA-CIN such that the 
T cell response rate will be higher. If the true response rate is 65% for Group A and 45% 
for Group B, with 7 patients each group, there is about 70% chance of picking the correct 
injection site based on the observed number of responders in the two groups. Even if the 
true response rate is 60% for Group A and 45% for Group B, with 7 patients each group, 
there is still about 60% chance to correctly pick the winner. 
12.3 
Accrual Rate 
The Kelly Gynecologic Oncology service at JHU sees ~50 cervical cancer cases per 
annum and UAB 120 per annum. Assuming half are HPV16+ and 15% are eligible to 
join the study then enrollment using both sites should be completed in 1 year.  
12.4 
Early Stopping Rules 
This study will evaluate two different sites of TA-CIN vaccine to determine the safety 

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and effectiveness of TA-CIN in patients with a history of advanced cervical cancer. For 
each injection site, the SAE rate of 20% or more is deemed unsafe. A total of 15 patients 
will be enrolled, with 7-8 patients in each injection site cohort.  
 
The study will be stopped early if there are more than two patients with SAEs observed 
during the study. If the SAE rate is 20% or more, there is at least 55% chance to stop the 
study early with 15 patients. 
12.5 
Statistical Analysis 
Adverse events will be tabulated by type and grade for each dose cohort.  
 
The measure of immune response to the regimen will be the number of antigen-specific T 
cells detected by ELISPOT and/or ICC, or the simulation index of T cell proliferation, 
and the titer of the serum antibody as determined by ELISA. Each patient will have one 
measurement at baseline and 5 measurements at 5 time points after treatment. Descriptive 
statistics (mean and SD) and box plots will be used to summarize the immunogenicity by 
time point and dose cohort. Formal hypothesis testing will not be conducted to determine 
the ideal vaccination site. Instead, a “winner” will be picked based on the observed 
number of responses (42). Two-sample t-test will be used to compare the 
immunogenicity between two immunization sites. Data transformation will be applied if 
the distribution is not normal. In addition, the time course of outcomes will be 
investigated graphically by individual subject plots.  
 
Cox regression analysis will be conducted to explore the association between time to 
disease recurrence and vaccine-induced immune response status. Patient baseline 
characteristics including disease stage and history of treatment will be adjusted in the 
analysis. 
 
 
 

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31. 
G. R. Gunn et al., Two Listeria monocytogenes vaccine vectors that express different 
molecular forms of human papilloma virus-16 (HPV-16) E7 induce qualitatively different 

TA-CIN Vaccine as Adjuvant Therapy in HPV16-Associated Cervical Cancer 
Protocol Chair:  Stephanie Gaillard, M.D. 
Johns Hopkins/SKCCC J1553 
 
 
 
 Version:  October 21, 2022 
 
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T cell immunity that correlates with their ability to induce regression of established tumors 
immortalized by HPV-16. J Immunol 167, 6471-6479 (2001). 
32. 
M. Smahel, P. Sima, V. Ludvikova, V. Vonka, Modified HPV16 E7 Genes as DNA 
Vaccine against E7-Containing Oncogenic Cells. Virology 281, 231-238 (2001). 
33. 
A. C. Society. (American Cancer Society, http://www.cancer.org). 
34. 
C. W. Tseng et al., Pretreatment with cisplatin enhances E7-specific CD8+ T-Cell-
mediated antitumor immunity induced by DNA vaccination. Clin Cancer Res 14, 3185-
3192 (2008). 
35. 
C. W. Tseng et al., Low-dose radiation enhances therapeutic HPV DNA vaccination in 
tumor-bearing hosts. Cancer immunology, immunotherapy : CII 58, 737-748 (2009). 
36. 
T. H. Kang et al., Chemotherapy acts as an adjuvant to convert the tumor 
microenvironment into a highly permissive state for vaccination-induced antitumor 
immunity. Cancer Res 73, 2493-2504 (2013). 
37. 
A. de Jong et al., Enhancement of human papillomavirus (HPV) type 16 E6 and E7-specific 
T-cell immunity in healthy volunteers through vaccination with TA-CIN, an HPV16 
L2E7E6 fusion protein vaccine. Vaccine 20, 3456-3464 (2002). 
38. 
R. Gambhira et al., Vaccination of healthy volunteers with human papillomavirus type 16 
L2E7E6 fusion protein induces serum antibody that neutralizes across papillomavirus 
species. Cancer Res 66, 11120-11124 (2006). 
39. 
A. N. Fiander et al., Prime-boost vaccination strategy in women with high-grade, 
noncervical anogenital intraepithelial neoplasia: clinical results from a multicenter phase 
II trial. International journal of gynecological cancer : official journal of the International 
Gynecological Cancer Society 16, 1075-1081 (2006). 
40. 
S. Daayana et al., Phase II trial of imiquimod and HPV therapeutic vaccination in patients 
with vulval intraepithelial neoplasia. British journal of cancer 102, 1129-1136 (2010). 
41. 
E. J. Davidson et al., Effect of TA-CIN (HPV 16 L2E6E7) booster immunisation in vulval 
intraepithelial neoplasia patients previously vaccinated with TA-HPV (vaccinia virus 
encoding HPV 16/18 E6E7). Vaccine 22, 2722-2729 (2004). 
42. 
S. J. Mandrekar, D. J. Sargent, Pick the winner designs in phase II cancer clinical trials. J 
Thorac Oncol 1, 5-6 (2006). 
 
 
 
 

TA-CIN Vaccine as Adjuvant Therapy in HPV16-Associated Cervical Cancer 
Protocol Chair:  Stephanie Gaillard, M.D. 
Johns Hopkins/SKCCC J1553 
 
 
 
 Version:  October 21, 2022 
 
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APPENDICES  
 
Appendix A:  FIGO 2009 Cancer Staging 
Appendix B:  Performance Status Criteria 
Appendix C:  Pathology Review 
Appendix D:  Serious Adverse Event Reporting Form 
 
 
 
 

TA-CIN Vaccine as Adjuvant Therapy in HPV16-Associated Cervical Cancer 
Protocol Chair:  Stephanie Gaillard, M.D. 
Johns Hopkins/SKCCC J1553 
 
 
 
 Version:  October 21, 2022 
 
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APPENDIX A:  FIGO 2009 Cancer Staging  
 
 
Carcinoma of the Cervix 
IA1       Confined to the cervix, diagnosed only by microscopy with invasion of < 3 mm in depth 
and lateral spread < 7 mm 
IA2       Confined to the cervix, diagnosed with microscopy with invasion of > 3 mm and < 5 mm 
with lateral spread < 7mm 
IB1       Clinically visible lesion or greater than A2, < 4 cm in greatest dimension 
IB2       Clinically visible lesion, > 4 cm in greatest dimension 
IIA1      Involvement of the upper two-thirds of the vagina, without parametrial invasion, < 4 cm 
in greatest dimension 
IIA2      > 4 cm in greatest dimension 
IIB        With parametrial involvement 
IIIA      Tumor involves lower third of the vagina with no extension to the pelvic side wall 
IIIB      Tumor involves extension to the pelvic side wall and or hydronephrosis or 
nonfunctioning kidney 
IVA      The carcinoma has extended beyond the true pelvis or has involved (biopsy proven) the 
mucosa of the bladder or rectum. A bullous edema, as such, does not permit a case to be 
allotted to stage IV. 
IVB     Spread to adjacent organs  
 
 

TA-CIN Vaccine as Adjuvant Therapy in HPV16-Associated Cervical Cancer 
Protocol Chair:  Stephanie Gaillard, M.D. 
Johns Hopkins/SKCCC J1553 
 
 
 
 Version:  October 21, 2022 
 
Page 41  
APPENDIX B:  Performance Status Criteria 
  
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
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). 
80 
Normal activity with effort; some signs 
or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all self-
care, but unable to carry out any 
work activities.  Up and about more 
than 50% of waking hours. 
60 
Requires occasional assistance, but is 
able to care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any self-
care.  Totally confined to bed or 
chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes progressing 
rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 

TA-CIN Vaccine as Adjuvant Therapy in HPV16-Associated Cervical Cancer 
Protocol Chair:  Stephanie Gaillard, M.D. 
Johns Hopkins/SKCCC J1553 
 
 
 
 Version:  October 21, 2022 
 
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APPENDIX C:  Pathology Review 
 
Study Number: 
 
Patient ID: 
 
Specimen ID Number: 
 
Date Specimen Obtained: 
 
Study Site: 
____________________________________ 
Person Sending to Pathologist:   
 
Initials: 
 
 
 
 
Quality of Tissue (H&E):   
 Satisfactory 
 
 
 
 
 Not satisfactory 
Microscopic Diagnosis: 
 
 
 No Evidence of in situ or Invasive Carcinoma or SIL 
 Adenocarcinoma in situ 
 Invasive Adenocarcinoma 
 LSIL 
 HSIL 
 Invasive Squamous Cell Carcinoma 
 Other:   
 
 
 
 
 
 
 
 
 
Diagnostic Testing: 
 
 
p16 Immunohistochemistry: 
 
 
Performed:   Yes   No 
Quality of Staining:   Satisfactory   Not Satisfactory 
Result:   Positive (Diffuse Expression in 90-100% of Lesional Cells)   Negative (Non-Diffuse Pattern) 
 
 
HPV16 in situ Hybridization: 
 
Performed:   Yes   No 
Quality of Staining:   Satisfactory   Not Satisfactory 
Result:   Positive   Negative For HPV16 
 
Study Pathologist: 
_________________________ 
_________________________ 
_________________ 
 
Print Name 
Signature 
Date 
 
Fax Completed Form ASAP to Dr. Stephanie Gaillard (Study PI) 
 
 
Pathologist’s Recommendations: 
 
 
No further work up required:  proceed with study. 
 
Possible work up required:  review and discuss patient in multidisciplinary conference. 
 
Definite work up required:  allocate specimen for official review by the department of pathology; review and 
discuss patient in multidisciplinary conference. 
 
 
Site Investigator: 
_________________________ 
_________________________ 
_________________ 
 
Print Name 
Signature 
Date 
 
 
Subject Notified By:   
 
 
Date:   
  
 
Comments:   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

TA-CIN Vaccine as Adjuvant Therapy in HPV16-Associated Cervical Cancer 
Protocol Chair:  Stephanie Gaillard, M.D. 
Johns Hopkins/SKCCC J1553 
 
 
 
 Version:  October 21, 2022 
 
Page 43  
APPENDIX D:  Serious Adverse Event Reporting Form 
 
**Must Notify Dr. Roden Within 24 Hours of Study Team Knowledge of Serious Adverse Events** 
 
Protocol Title: 
 
 
A Phase I Clinical Trial Assessing the Safety and Feasibility of Administration of 
the TA-CIN Vaccine in HPV16 Associated Cervical Cancer Patients 
Report Type: 
 
  Initial    
  Follow-up #___ 
  Death 
  Addendum to: 
_____________ 
Serious Criteria (Check All 
That Apply): 
Death 
Life-Threatening 
Hospitalization or Prolongation of 
Existing Hospitalization 
Persistent or Significant Disability 
Congenital Anomaly 
Other Important Medical Event 
Adverse Event Onset Date: 
 
 
Date of 
Report: 
Adverse Event End Date: 
Date Event 
Discovered: 
Section A: Subject Information 
Subject ID: 
Subject Age at Event Onset: 
Subject Gender: 
Male 
Female 
Subject Initials: 
 
Section B: Event Information 
Event Diagnosis Or Symptom(s): 
 
Date of 1st Dose (TA-CIN): 
 
 
Action Taken With The 
Study Drug (TA-CIN): 
 
None 
Interrupted 
Discontinued 
Delayed 
 
Date of 2nd dose (TA-CIN): 
 
 
 
CTCAE Severity: 
 
 Grade 1 (Mild) 
 Grade 2 (Moderate) 
 Grade 3 (Severe) 
 Grade 4 (Life-Threatening) 
 Grade 5 (Death) 
 
Date of Last Dose (TA-CIN) Prior 
to Event: 
 
Outcome: 
 
 Ongoing 
 Recovering/Resolving 
 Recovered/Resolved 
 Recovered/Resolved with  
       Sequelae (specify): __________ 
 Fatal 
 Unknown 
 
Number of Total Doses (TA-CIN): 
 
 
 
Hospital Admission Date:  
 
Hospital Discharge Date:  

TA-CIN Vaccine as Adjuvant Therapy in HPV16-Associated Cervical Cancer 
Protocol Chair:  Stephanie Gaillard, M.D. 
Johns Hopkins/SKCCC J1553 
 
 
 
 Version:  October 21, 2022 
 
Page 44  
Relationship to: 
TA-CIN Vaccine 
Underlying Disease 
Other Causality 
_________________ 
(Please Specify) 
Unrelated 
 
 
 
Probably Unrelated 
 
 
 
Possible Related 
 
 
 
Probably Related 
 
 
 
Definitely Related 
 
 
 
Section C: Brief Description of the Event (Attach Additional Pages as Necessary) 
 
Section D: Relevant Medical History (Attach Additional Pages as Necessary) 
 
Section E: Concomitant Drug (Taken Prior to SAE Onset) (Attach Additional Pages as Necessary) 
Name of the Drug (Trade or Generic) 
Start Date 
Stop Date 
Route 
Dose 
Frequency 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

TA-CIN Vaccine as Adjuvant Therapy in HPV16-Associated Cervical Cancer 
Protocol Chair:  Stephanie Gaillard, M.D. 
Johns Hopkins/SKCCC J1553 
 
 
 
 Version:  October 21, 2022 
 
Page 45  
Section F: Relevant Labs (Attach Additional Pages as Necessary) 
Lab Test Name 
Date 
Value 
Unit 
Reference Range 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section G: Comments (Attach Additional Pages as Necessary) 
 
 
 
 
 
 
 
 
Section G: Additional Documents (Attach Additional Pages as Necessary) 
 Please specify: 
 
 
 
 
 
 
 
Reporter’s Name: 
Reporter’s Signature:_ 
 
Phone Number: 
Signature Date: 
 
 
Investigator’s Name: 
Investigator’s Signature:____ 
 
Phone Number: 
Signature Date: