Clinical trial NCT02853604
Conditions: High Risk Cervical Cancer Advanced Cervical Cancer
Sponsor: Advaxis, Inc.
Start date: 2015-12-15; Completion date: 2019-07-31
Enrollment: 110 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Locally advanced cervical cancer at higher risk for recurrence (HRLACC) following concurrent chemotherapy and radiation therapy. This is a group of participants with a significant unmet need. The estimated probability of disease recurrence or death within 4 years of diagnosis is 50% and the prognosis is very grave for those who experience a recurrence.

The purpose of the study was to compare the disease free survival (DFS) of ADXS11-001 to placebo administered following cisplatin-based combination chemotherapy and radiation (CCRT) with curative intent in participants with HRLACC.

Detailed description:
This was a double-blind, placebo-controlled randomized study of ADXS11-001 administered in the adjuvant setting after completion of CCRT in participants with HRLACC, or death. All eligible participants had received CCRT administered with curative intent according to institutional/national guidelines as well as meeting the minimum standards defined in the protocol. Participants initiated the Screening period within 10 weeks after the completion of CCRT. Baseline radiographic assessments and clinical laboratory assessments were completed no longer than 28 days prior to and 3 days prior to the first study treatment infusion, respectively. Eligible participants were randomized 1:2 to receive either placebo or ADXS11-001. Participants received 1 infusion of study treatment administered every 3 weeks for 3 doses for the first 3 months. Thereafter, participants received study treatment every 8 weeks for a total of 5 doses or until disease recurrence. Participants received a 7-day course of an oral antibiotic or placebo starting 72 hours following the completion of study treatment administration.

Arms: arm 1: Participants with locally advanced cervical cancer at higher risk for recurrence (HRLACC) received ADXS11-001 matching placebo by intravenous infusion for approximately 60 minutes every 3 weeks for 3 doses (Weeks 1, 4 and 7) and thereafter, every 8 weeks for 5 doses (Weeks 15, 23, 31, 39, and 47) during treatment phase or until disease recurrence. Participants received a 7-day course placebo matching to either trimethoprim/sulfamethoxazole or ampicillin starting 72 hours post treatment in prime and maintenance phase. arm 2: Participants with HRLACC received ADXS11-001 at a dose of 1x10\^9 colony forming units (CFU) by intravenous infusion for approximately 60 minutes every 3 weeks for 3 doses (Weeks 1, 4 and 7) and thereafter, every 8 weeks for 5 doses (Weeks 15, 23, 31, 39, and 47) during treatment phase or until disease recurrence. Participants received a 7-day course of either trimethoprim/sulfamethoxazole or ampicillin starting 72 hours post treatment in prime and maintenance phase.
Interventions: intervention 1: ADXS11-001 intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
 
 
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PROTOCOL ADXS001-02 
PHASE 3 STUDY OF ADXS11-001 ADMINISTERED FOLLOWING 
CHEMORADIATION AS ADJUVANT TREATMENT FOR HIGH RISK LOCALLY 
ADVANCED CERVICAL CANCER:  
AIM2CERV (Advaxis IMmunotherapy 2 prevent CERVical recurrence) 
SPONSOR: 
Advaxis, Inc. 
 
305 College Road East 
 
Princeton, NJ 08540 
 
609-452-9813 (office) 
 
609-452-9818 (fax) 
PRINCIPAL INVESTIGATOR: 
 
 
 
 
 
 
 
 
STATISTICIANS: 
Cytel Inc.  
675 Massachusetts Ave.  
 
Cambridge, MA 02139 US 
 
 
 
Buffalo, NY 14623 
 
 
IND NUMBER: 
13712 
EudraCT NUMBER: 
2015-0048-4420 
Version: 
5 Dated 07Dec2020  
Confidentiality Statement 
This protocol was designed and developed by the GOG Foundation and Advaxis, Inc.  The information contained 
herein is confidential and proprietary and may not be disclosed, reproduced, or circulated without the prior written 
consent of Advaxis, Inc. 
 


 
 
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PROTOCOL APPROVAL 
Protocol Number:   ADXS001-02 
Title of Protocol:  
Phase 3 Study of ADXS11-001 Administered Following  
 
 
 
 
Chemoradiation as Adjuvant Treatment for High Risk Locally  
 
 
 
Advanced Cervical Cancer:  AIM2CERV 
Version: 
 
5 Dated 07Dec2020  
 
 
 
Approved by: 
 
 _____________________________________  
 _________________________ 
Date 
Advaxis, Inc. 
 
 
 
 


 
 
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INVESTIGATOR SIGNATURE PAGE 
Protocol No.: ADXS001-02 
Title:    
Phase 3 Study of ADXS11-001 Administered Following Chemoradiation as 
 
 
Adjuvant Treatment for High Risk Locally Advanced Cervical Cancer:   
 
 
AIM2CERV 
Version: 
5 Dated 07Dec2020  
 
 
By signing below, the Investigator agrees to adhere to the protocol as outlined and agrees that 
any changes to the protocol must be approved by Advaxis, Inc. and GOG prior to seeking 
approval from the approving Institutional Review Board (IRB)/Ethical Review Committee 
(ERC). 
This study will be conducted in accordance with Good Clinical Practices (GCP), 
International Conference on Harmonisation (ICH) Guidelines, the Declaration of Helsinki, 
and local ethical and legal requirements. 
 
Investigator Name:  
 _____________________________________  
 _________________________ 
Signature 
Date 
 
 
 
_____________________________________ 
Site #:  __________ 
Printed Name 
 
 
 
 
 


 
 
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TABLE OF CONTENTS 
PROTOCOL ADXS001-02 ...............................................................................................1 
Table Of Contents ..............................................................................................................4 
List of Tables ......................................................................................................................7 
List of Figures .....................................................................................................................8 
Synopsis ...............................................................................................................................9 
1 
OBJECTIVES ...........................................................................................................12 
1.1 
Primary Objective & Hypothesis .......................................................................12 
1.2 
Secondary Objectives...........................................................................................12 
1.3 
Exploratory Objective .........................................................................................13 
2 
BACKGROUND & RATIONALE .........................................................................13 
2.1 
Background ..........................................................................................................13 
2.1.1 
Locally Advanced Cervical Cancer ..............................................................13 
2.1.2 
Relationship between Cervical Cancer and Human Papilloma Virus ......13 
2.1.3 
Rationale for Study and Selected Subject Population ................................14 
2.1.4 
ADXS11-001 Immunotherapy ......................................................................16 
2.1.5 
ADXS11-001 Mechanism of Action ..............................................................16 
2.1.6 
Preclinical and Clinical Study Data .............................................................17 
2.1.7 
Summary of Safety of ADXS11-001 .............................................................17 
2.1.7.1 
Biofilm-Associated Bacteremia ...............................................................19 
2.1.8 
Summary of Efficacy for ADXS11-001 Studies in Cervical Cancer .........20 
2.1.8.1 
Lm-LLO-E7-01: Phase 1 Experience .....................................................20 
2.1.8.2 
Lm-LLO-E7-15: Phase 2 Study of ADXS11-001 vs ADXS11-001 
and Cisplatin in Recurrent, Refractory Cervical Cancer ....................21 
2.1.8.3 
GOG-0265: Phase 2 Evaluation of ADXS11-001 in Recurrent, 
Refractory Cervical Cancer ....................................................................22 
2.1.9 
Rationale for ADXS11-001 Dose Selection/Regimen/Modification ...........22 
2.2 
Rationale for Endpoints ......................................................................................23 
2.2.1 
Efficacy Endpoints .........................................................................................23 
2.2.2 
Safety Endpoints ............................................................................................24 
3 
SUBJECT ELIGIBILITY AND EXCLUSIONS ...................................................26 
3.1 
Inclusion Criteria .................................................................................................26 
3.2 
Exclusion Criteria ................................................................................................29 
4 
STUDY MODALITIES ............................................................................................31 
4.1 
ADXS11-001 (IND #13,712) ................................................................................32 
4.1.1 
Adverse Effects ...............................................................................................32 
4.1.2 
Drug Accountability.......................................................................................32 
4.1.3 
Drug Ordering and Distribution ..................................................................32 
4.1.4 
How Supplied, Storage and Stability ...........................................................32 
4.2 
Concomitant Therapies and Procedures (Allowed & Prohibited) ..................32 
4.2.1 
Acceptable Concomitant Therapies and Procedures ..................................33 
4.2.1.1 
Hematopoietic Growth Factors ..............................................................33 
4.2.1.2 
Major and Minor Surgeries and ADXS11-001 Treatment ..................33 
4.2.2 
Prohibited Concomitant Therapies ..............................................................33 


 
 
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4.3 
Diet/Activity/Other Considerations ....................................................................34 
4.3.1 
Diet ..................................................................................................................34 
4.3.2 
Contraception .................................................................................................34 
4.3.3 
Use in Pregnancy ............................................................................................35 
4.3.4 
Use in Nursing Women ..................................................................................35 
5 
TREATMENT PLAN AND ENTRY/REGISTRATION PROCEDURE ...........35 
5.1 
Subject Entry and Registration ..........................................................................35 
5.2 
Randomization and Treatment Plan ..................................................................35 
5.2.1 
Screening Period ............................................................................................36 
5.2.2 
Subjects Who Fail to meet Screening Criteria ............................................37 
5.2.3 
Treatment Period ...........................................................................................37 
5.2.3.1 
Pretreatment Prophylaxis Regimen .......................................................38 
5.2.3.2 
Administration of Study Treatment .......................................................39 
5.2.3.3 
Study Treatment Regimen ......................................................................40 
5.2.3.4 
Pre-Treatment Assessment and Study Therapy Administration ........40 
5.2.3.5 
Post-Treatment Monitoring ....................................................................40 
5.2.4 
Follow-up Period ............................................................................................40 
5.2.4.1 
Lm Surveillance .......................................................................................41 
5.2.4.2 
End of Study Visit ....................................................................................41 
5.3 
Stratification .........................................................................................................41 
6 
Treatment Modification Guidelines ........................................................................42 
6.1 
Treatment Delay/Discontinuation Guidelines ...................................................42 
6.2 
Supportive Care Guidelines Following Administration of Study 
Treatment .............................................................................................................42 
6.2.1 
Symptoms Related to Immune Cell Activation ...........................................43 
6.2.1.1 
Grading and Management Guidelines for Acute Hypotension, 
Hypoxia, Encephalopathy, Organ Toxicity, Fever and 
Constitutional Symptoms ........................................................................44 
6.2.2 
Nausea/Vomiting ............................................................................................50 
6.2.3 
Hypotension ....................................................................................................50 
6.2.4 
Listeriosis and Listeria Infection - Identification and Management.........50 
6.2.5 
Management of Listeria during Study Treatment Period .........................51 
6.2.5.1 
Management Immediately Following Completion of a Study 
Treatment Infusion ..................................................................................51 
6.2.6 
Management of Listeria During the Follow-up Period ..............................52 
6.2.7 
Management of Listeria in Subjects Who Withdraw Consent ..................53 
7 
STUDY PARAMETERS ..........................................................................................54 
7.1 
Schedule of Events ...............................................................................................54 
7.2 
Study Procedures .................................................................................................58 
7.2.1 
Administrative Procedures ...........................................................................58 
7.2.1.1 
Informed Consent ....................................................................................58 
7.2.1.2 
Eligibility Criteria ....................................................................................58 
7.2.1.3 
Subject Identification Card .....................................................................58 
7.2.1.4 
Demographics/Medical/Surgical History ...............................................59 
7.2.1.5 
Prior Cancer History ...............................................................................59 
7.2.1.6 
Prior/Concomitant Therapies and Procedures .....................................59 


 
 
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7.2.1.7 
Administer Prophylactic Medications....................................................59 
7.2.1.8 
Study Treatment Administration ...........................................................59 
7.2.1.9 
Administer Oral Prophylactic Antibiotics .............................................59 
7.2.2 
Clinical Procedures/Assessments ..................................................................60 
7.2.2.1 
Adverse Event Monitoring ......................................................................60 
7.2.2.2 
Physical Examination ..............................................................................60 
7.2.2.3 
Vital Sign Measurements ........................................................................61 
7.2.2.4 
Performance Status ..................................................................................61 
7.2.2.5 
Pelvic Examination ..................................................................................61 
7.2.3 
Laboratory Procedures/Assessments ...........................................................61 
7.2.5 
Efficacy Assessments .....................................................................................63 
7.2.5.1 
Histologic/Cytologic Assessment for Disease Recurrence ....................63 
7.2.5.2 
Radiographic Assessments for Disease Recurrence ..............................63 
7.2.5.2.1 
Unscheduled Radiographic Assessments .........................................63 
7.2.6 
Other Procedures ...........................................................................................64 
7.2.6.1 
Withdrawal/Discontinuation and End of Study Visit ...........................64 
7.2.6.1.1 
Discontinuation during Treatment Period Due to Disease 
Recurrence ..........................................................................................64 
7.2.6.1.2 
Early Discontinuation ........................................................................64 
7.2.6.1.3 
Discontinuation during the Follow-up Phase Due to Disease 
Recurrence ..........................................................................................65 
7.2.6.1.4 
Withdrawal of Informed Consent ....................................................65 
7.2.6.1.5 
Blinding/Unblinding ..........................................................................65 
8 
EVALUATION CRITERIA ....................................................................................66 
8.1 
Assessment of Disease ..........................................................................................66 
8.1.1 
Assessment of Disease Free Survival using Radiological Imaging 
Methodology ...................................................................................................66 
8.2 
Determination of Disease Recurrence ................................................................67 
8.2.1 
Definition of Recurrence ...............................................................................67 
8.2.1.1 
Pathologic Definition of Recurrence ......................................................67 
8.2.1.2 
Types of Radiographic Assessments.......................................................67 
8.2.1.2.1 
Date of Recurrence ............................................................................69 
8.2.1.2.2 
Assessment Date Conventions ...........................................................69 
8.2.1.3 
Definition of Non-Disease Recurrence ...................................................69 
8.2.1.4 
Radiographic Assessment of Time Point Response ..............................69 
9 
DURATION OF STUDY .........................................................................................71 
9.1 
Withdrawal/Discontinuation Criteria ................................................................71 
9.2 
Subject Replacement Strategy ............................................................................72 
10 ADVERSE EVENT MONITORING AND REPORTING PROCEDURES ......72 
10.1 
Definitions .............................................................................................................73 
10.2 
Assessing and Recording Adverse Events..........................................................74 
10.2.1 
Evaluating Adverse Events ...........................................................................74 
10.2.2 
Laboratory Test Abnormalities ....................................................................75 
10.2.3 
Reporting Abnormal Test Findings .............................................................75 


 
 
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10.2.4 
Reporting Events Related to Immune Cell Activation ...............................76 
10.2.5 
Immediate Reporting of Serious Adverse Events to the Sponsor..............76 
10.2.6 
Reporting Pregnancy and Lactation to the Sponsor ..................................76 
10.3 
Data Monitoring Committee ...............................................................................77 
11 STATISTICAL CONSIDERATIONS ....................................................................77 
11.1 
Sample Size Considerations ................................................................................78 
11.2 
Statistical Analysis Plan Summary.....................................................................79 
11.2.1 
Study Design ...................................................................................................79 
11.2.2 
Definition of Study Populations for Analyses ..............................................79 
11.2.3 
Measures of Efficacy and Safety ...................................................................80 
11.2.4 
Enrollment and Treatment Allocation .........................................................80 
11.2.5 
Primary Study Hypothesis ............................................................................80 
11.2.6 
Analytic Procedures for the Testing Hypothesis: Hp:E,DFS.....................80 
11.2.7 
Historical Information Used for Planning Purposes ..................................81 
11.3 
Interim & Final Analyses ....................................................................................83 
11.4 
Monitoring of Accrual and Event Rates ............................................................84 
11.5 
Estimated Study Duration ...................................................................................85 
11.6 
12 ADMINISTRATIVE AND REGULATORY DETAILS ......................................86 
12.1 
Confidentiality ......................................................................................................86 
12.2 
Compliance with Financial Disclosure Requirements ......................................86 
12.3 
Compliance with Law, Audit and Debarment ..................................................86 
12.4 
Compliance with Study Registration and Results Posting Requirements ......87 
12.5 
Quality Management System ..............................................................................87 
12.6 
Data Management ................................................................................................87 
13 ABBREVIATIONS ...................................................................................................88 
14 APPENDICES ...........................................................................................................91 
14.1 
2014 FIGO Staging System .................................................................................91 
14.2 
GOG Performance Status ...................................................................................95 
14.3 
14.4 
14.5 
14.6 
Flow Chart of the Independent Review Methodology ....................................101 
15 LIST OF REFERENCES .......................................................................................102 
16 SUMMARY OF CHANGES WITHIN PROTOCOL AMENDMENT .............107 
LIST OF TABLES 
 
Table 1 
Treatment-Related Adverse Events Reported in ≥5% (ADXS11-001) 
....................................................................................................................18 
Table 2 
Randomized Studies Evaluating Concomitant Chemoradiation in Cervical 
Cancer .......................................................................................................24 
Table 3 
Adequate Organ Function Laboratory Values .....................................28 
Table 4 
Study Treatment ......................................................................................31 


 
 
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Table 5 
Treatment Delay/Discontinuation Guidelines for Drug-Related  
Adverse Events .........................................................................................42 
Table 6.1 
Grading Scale for Hypoxia, Hypotension, and Organ Toxicity ..........44 
Table 6.2 
Management Guidelines for Acute Hypotension, Hypoxia,  
Organ Toxicity, Fever and Constitutional Symptoms ..........................44 
Table 6.3 
Grading Scale for Encephalopathy ........................................................48 
Table 6.4 
Management Guidelines for Encephalopathy .......................................48 
Table 7 
Laboratory Tests ......................................................................................62 
Table 8 
Imaging Time Point Assignment of Response Including Biopsy  
Information ...............................................................................................70 
Table 9 
Summary of Study Parameters and Targeted Sample Size .................78 
Table 10 
Subjects by Stage of Disease in Study GOG-219 Historical Subset ....81 
Table 11 
Definitions of 2014-FIGO Stage I ...........................................................91 
Table 12 
Definitions of 2014-FIGO Stage II..........................................................92 
Table 13 
Definitions of 2014-FIGO Stage III ........................................................93 
Table 14 
Definitions of 2014-FIGO Stage IV ........................................................94 
 
LIST OF FIGURES 
Figure 1 
Study Schema ...........................................................................................12 
Figure 2 
Kaplan Meier (KM) PFS curves by FIGO stage (GOG-120) ..............14 
Figure 3 
KM disease-specific survival divided by FIGO and  
PET lymph node status ............................................................................15 
Figure 4 
Progression-Free Survival (PFS) for Women Diagnosed with  
Stage IB2 or IIB2 (with pelvic node metastases; PN+) or Stage III or  
IV Cervical Cancer in Study GOG-219 .................................................82 
Figure 5 
Overall Survival (OS) for Women Diagnosed with Stage IB2 or IIB2 
 (with Pelvic Node Metastases, PN+) or Stage III or IV  
Cervical Cancer in Study GOG-219 .......................................................83 
  
 
 
 
 
 
 
 


 
 
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SYNOPSIS 
Study Title: 
A Phase 3 Study of ADXS11-001 Administered Following Chemoradiation 
as Adjuvant Treatment for High Risk Locally Advanced Cervical Cancer:  
AIM2CERV 
Study Phase 
Phase 3 
Clinical Indication 
High-risk locally advanced carcinoma of the cervix (HRLACC) following 
concurrent chemotherapy and radiation therapy.  This is a group of patients 
with a significant unmet need.  The estimated probability of disease 
recurrence or death within 4 years of diagnosis is 50% and the prognosis is 
very grave for those who experience a recurrence. 
Study Type 
Interventional 
Study Centers 
Multicenter, Global 
Route of Administration 
Intravenous (IV) 
Study Blinding 
Double blinded, placebo-controlled 
Number of Study Subjects 
Approximately 450 
Estimated Duration of Study 
Approximately 55 months of recruitment, 1 year of treatment, and 1 year 
Lm surveillance follow up 
Duration of Participation 
Approximately 2 years 
Reference Treatment Group  
Placebo (Arm A) 
Experimental Treatment Group  
ADXS11-001 (Arm B) 
Randomization Ratio 
1:2 Arm A to Arm B  
Primary Objective 
Disease free survival (DFS) 
Secondary Objectives 
Safety & tolerability 
Overall survival (OS) 
Exploratory Objective 
Key Inclusion Criteria 
• 
Subjects with: 
o 
Histological diagnosis of squamous cell, adenocarcinoma 
or adenosquamous carcinoma of the cervix who have 
undergone definitive therapy with a curative intent* 
• 
Subjects may have: 
o 
2014 FIGO-Stage IB2, IIA2, IIB with any of the 
following pelvic lymph node metastases criteria: 
▪ 
Biopsy proven pelvic node(s) 
▪ 
2 or more positive nodes by MRI/CT ≥1.5 cm 
shortest dimension 
▪ 
2 or more positive pelvic nodes by PET with 
standard uptake value ≥2.5 
OR 
o 
All Stage IIIA, IIIB, IVA 


 
 
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OR 
o 
Any FIGO stage with para-aortic lymph node metastases 
criteria (defined by 1 of the following): 
▪ 
Biopsy proven para-aortic node(s) 
▪ 
1 or more positive para-aortic node(s) by 
MRI/CT >1.5 cm shortest dimension 
▪ 
1 or more positive para-aortic node(s) by PET 
with SUV >2.5 
Subjects must have received definitive therapy with curative intent, which 
consist of at least 4 weeks of treatment with cisplatin and a minimum of 40 
Gy external beam radiation therapy (EBRT). NOTE: Brachytherapy is 
permitted. 
• 
Subjects must be: 
o 
Age 18 years or older 
o 
GOG performance status 0 – 1 
o 
ANC ≥1000 x 109/L 
o 
Platelets ≥75 x 109/L 
o 
Bilirubin ≤1.5 x ULN 
o 
AST or ALT ≤2.5 x ULN 
o 
Serum creatinine or measured creatinine clearance ≤1.5 x 
ULN 
o 
Toxicities resulting from definitive therapy must resolve 
to ≤Grade 1 prior to randomization, with the exception of 
peripheral neuropathy (sensory and motor) which must 
resolve to ≤Grade 2. 
Key Exclusion Criteria 
• 
Subjects who have not achieved disease-free status (e.g. no 
evidence of measurable disease or non-measurable disease per 
RECIST 1.1) after completion of CCRT administered with 
curative intent.   
• 
Subjects with FIGO stage IVB 
• 
Histologies other than described above (neuroendocrine cancers 
are excluded) 
• 
Has undergone a previous hysterectomy (defined as removal of the 
entire uterus), following neoadjuvant chemotherapy.   
• 
Has implanted medical device(s) that pose a high risk for 
colonization and/or cannot be easily removed (e.g., prosthetic 
joints, artificial heart valves, pacemakers, orthopedic screw(s), 
metal plate(s), bone graft(s), or other exogenous implant(s)).  
NOTE: More common devices and prosthetics which include 
arterial and venous stents, dental and breast implants and venous 
access devices (e.g. Port-a-Cath or Mediport) are permitted.  
Sponsor must be contacted prior to consenting any subject who has 
any other device and/or implant.  
• 
Who are receiving, plan, or anticipate on receiving PI3K or TNF𝛼 
inhibitors. 






 
 
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• To evaluate the overall survival (OS) of ADXS11-001 administered in the adjuvant 
setting following definitive therapy of CCRT in subjects with HRLACC. 
1.3 
Exploratory Objective 
2 BACKGROUND & RATIONALE 
2.1 
Background 
2.1.1 
Locally Advanced Cervical Cancer 
Cervical cancer is the fourth most common cancer and the most common cause of mortality 
in women worldwide with 528,000 new cases reported annually, and an estimated 266,000 
deaths in 2012 [1]. Early detection by routine screening of pre-neoplastic lesions has led to a 
large decline in mortality from cervical cancer in the Western hemisphere; however, cervical 
cancer is still the leading cause of cancer death in women worldwide and a significant cause 
of cancer death for poor and for uninsured women in the US. Approximately 13,000 cases of 
invasive cervical cancer FIGO stages IA-IVB are diagnosed annually in the US, 30% of 
which will present with bulky or locally advanced disease defined by FIGO (FIGO stage IIB-
IVA) at the time of diagnosis that is not amendable to high cure rates with surgery or 
radiation therapy [2, 3]. 
Based on the results of multiple Phase 3 studies [4-8], the well-established standard of care 
for the treatment of locally advanced cervical cancer (LACC) is concurrent cisplatin-based 
CCRT [9]. Despite the widespread adoption of CCRT, a significant proportion of subjects 
will recur and ultimately die from their disease.  Five-year survival rates decrease with stage 
of disease (e.g., IA~100%, IB2 and IIB ~50-75%; III ~30-50%, and IV ~15%). While FIGO 
staging is a useful predictor of both DFS and OS in subjects with LACC [10], additional 
factors such as presence or absence of lymph node metastases have emerged as more 
accurate predictors of prognosis. Taking into account FIGO stage and the presence or 
absence of lymph node metastases, we are better able to identify subjects who are at high risk 
for recurrence and for whom new therapeutic options are needed. 
2.1.2 
Relationship between Cervical Cancer and Human Papilloma Virus 
Squamous cell carcinoma of the cervix is largely the result of persistent infections with high-
risk types of human papillomavirus (HPV). Ninety-five to 98% of cervical cancers have 
detectable amounts of HPV DNA. There are multiple high-risk HPV types and more than 
half of cervical cancer is caused by infection with the oncogenic HPV-16 [11]. HPVs inhabit 


 
 
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the squamous epithelium of the mucocutaneous surface and often infections are either 
harmless or cause minor subclinical disease. Cervical HPV infections are largely 
immunologically quiescent, but it is clear that the immune system can be effective in 
eliminating HPV infected cells in healthy people. Nevertheless, a significant percentage of 
women are not protected against cervical cancer that occurs after HPV infection with a 
number of different types, possibly owing to the inability to mount an effective immune 
response to the virus. 
2.1.3 
Rationale for Study and Selected Subject Population 
Despite the widespread adoption of CCRT, a significant proportion of subjects will recur and 
ultimately die from their disease (5-year survival: IA~100% IB2 and IIb~50-75%; III~30-
50%, and IV~15%) [10]. For example, in GOG-120, the probability of surviving progression-
free decreased with increasing stage. As shown in (Figure 2), an analysis of only those 
subjects from GOG-120 treated with cisplatin-based chemotherapy and radiotherapy, reveals 
that the estimated probability of surviving recurrence-free for at least 3 years is 69%, 33%, 
56% and 10% for subjects with stage 2B, 3A, 3B and 4A disease, respectively. 
Figure 2 
Kaplan Meier (KM) PFS curves by FIGO stage (GOG-120) 
 
While FIGO staging is a useful predictor of both PFS and OS in subjects with LACC [10], 
lymph node metastases is the most important prognostic factor in early stage cervical cancer 
[12-15]. 
In subjects with advanced cervical cancer who are surgically staged and then treated with 
radiotherapy, 5-year PFS was 57% for node-negative subjects but decreased to 34% and 12% 
for subjects with pelvic and para-aortic lymph node (PALN) metastases, respectively [16].  
An additional study evaluated 560 subjects with cervical cancer who underwent fluorodeoxy-
glucose positron emission tomography (FDG-PET) lymph node staging. Treatment included 
surgery alone, surgery and postoperative radiation therapy, and definitive radiation or 
combination radiation and chemotherapy. Overall, 47% of subjects had lymph node 
involvement by FDG-PET at diagnosis. The frequency of lymph node metastasis increased 


 
 
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with clinical stage and was similar to that in historical surgical series. Within a stage, 
subjects with PET-positive lymph nodes had significantly worse disease specific survival 
than those with PET-negative lymph nodes (P<0.001) (Figure 3) [17]. 
Figure 3 
KM disease-specific survival divided by FIGO and PET lymph 
node status 
 
stage I, PET negative (dark blue triangle); stage I, PET positive (light blue triangle); 
stage II, PET negative (gray square); stage II, PET positive (gold square); stage III, PET 
negative (red circle); and stage III, PET positive (blue circle) 
Further evaluation of standard uptake value (SUV) revealed important differences in the 
degree of “positivity.” An analysis of 130 subjects with FIGO stage IB to IIA was undertaken 
to better understand the utility of pre-operative FDG-PET to predict recurrence in this 
population. Receiver operating characteristic (ROC) analysis identified that pelvic lymph 
nodes with a SUV >2.36 as the most significant cut-off value for predicting recurrence.  
Univariate analyses showed a significant association between recurrence and SUVLN 
(P=0.001). 
Finally, the presence of PALN metastases has been associated with even poorer prognosis.  
The percentage of LACC subjects with PALN metastases ranges from 2%-21% and is 
associated with FIGO disease stage [18]. An analysis of recurrence-free survival (RFS) and 
disease-specific survival based on location of nodes by stage reveals that subjects with PALN 
metastases demonstrate inferior survival to subjects with pelvic nodes (Figure 3) [17]. 
The FIGO staging system is sub-optimal towards accurately assessing the relative risk of 
recurrence in subjects with LACC because it does not take into account the presence or 
absence of lymph node metastases. Because of the importance of lymph node metastases, the 
National Comprehensive Cancer Network (NCCN) guideline recommends that the initial 
work-up of subjects with LACC include assessment of nodal disease by technologies such as 
computer tomography (CT), PET and/or magnetic resonance imaging (MRI). Because of the 
superiority of PET to MRI and/or CT in detecting nodal metastasis, the US Centers for 
Medicare and Medicaid Services has issued a national coverage determination paying for 
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diagnosed cervical cancer subsequent to conventional imaging that is negative for extra 
pelvic metastasis [19]. 
As noted above, subjects with nodal disease, either pelvic or para-aortic, and subjects with 
FIGO stage III and IV represent a subset of subjects with LACC who are at greatest risk for 
recurrence and death from the disease and represent the population of LACC with the highest 
unmet need. Therefore, by restricting the study population to high risk disease, as determined 
by conventional and accepted diagnostic standards, we are focusing our evaluation of 
ADXS11-001 on those subjects who would have the highest potential to benefit and where 
the benefit/risk ratio is acceptable for treatment with experimental therapies. 
2.1.4 
ADXS11-001 Immunotherapy 
ADXS11-001 is a live attenuated Listeria monocytogenes (Lm) bacteria bioengineered to 
secrete an antigen-adjuvant fusion protein (tLLO-HPV-E7) consisting of a truncated 
fragment of the listeriolysin O (tLLO) fused to the full length E7 peptide of HPV-16. 
2.1.5 
ADXS11-001 Mechanism of Action 
ADXS11-001 is rapidly taken up by antigen presenting cells (APC) within the subject. This 
causes activation of the APC and results in a multi-factorial stimulation of innate immunity.  
To the subject, this activation can manifest as flu-like symptoms or symptoms associated 
with cytokine release syndrome (CRS) that occur during or in the hours immediately 
following administration. Once inside the APC, ADXS11-001 can escape the phagolysosome 
into the cytoplasm where it secretes the HPV-E7-tLLO fusion protein. This peptide, along 
with other Lm peptides, is very rapidly ubiquitinated and transported to the proteasome where 
the peptides are broken down and cross-presented through major histocompatibility complex 
(MHC) class 1 and class 2 pathways. This cross-presentation, in immunologic context of 
responding to a “perceived” acute infection, stimulates the development of adaptive 
immunity culminating in HPV-specific effector T-cells that can infiltrate into the tumor 
microenvironment (TME) and destroy tumor cells immunologically. 
Advaxis Lm-LLO immunotherapies have broad effects on the immune system and the ability 
to neutralize mechanisms of immune tolerance. These Lm-LLO immunotherapies take 
advantage of the ability of Lm to present target antigens in the cytoplasm of APCs that 
generate a target-specific T-cell immunity. High avidity T-cells are generated where possible, 
but when they are not, Lm stimulates an up-regulation of T-cell responses to sub-dominant 
epitopes. Advaxis Lm-LLO immunotherapies secrete tumor peptides fused to LLO from 
multiple copies of plasmids. This increased LLO secretion triggers endocrine and exocrine 
signaling of the immune system that results in a relative reduction in the number and function 
of regulatory T-cells and myeloid-derived suppressor cells (MDSC) in the TME which 
enables tumor cell killing, even when the T-cells are of lower avidity. Tumor antigen specific 
T-cell immunity generated in the context of Lm-LLO immunotherapies can be effective even 
when targeting self-antigens or viral targets that are partially cross reactive.  Preclinical and 
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against multiple types of high-risk HPV, including cross-reactivity activity where there are 
minor differences in HPV E7 T-cell epitopes. 
As an investigational drug product, ADXS11-001 has no direct effect on the tumor tissue but 
is designed to stimulate the subject’s own immune system to generate an effective immune 
response targeting the tumor-associated antigen like HPV-E7. 
2.1.6 
Preclinical and Clinical Study Data 
Refer to the Investigator’s Brochure (IB) for detailed preclinical and clinical data. 
2.1.7 
Summary of Safety of ADXS11-001 
Clinical investigation of ADXS11-001 is ongoing. Additionally, because ADXS11-001 
shares the same attenuated Lm parental strain, vector backbone, and mechanisms of action 
with other Lm-based immunotherapies, a description of all clinical studies evaluating 
Advaxis’ Lm-based immunotherapies is provided. 


 
 
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2.1.7.1 
Biofilm-Associated Bacteremia 
ADXS11-001 has been attenuated over
more in comparison to the wild-type (wt)-Lm.  
ADXS11-001 bacteremia (listeremia) is confirmed only after isolation of Lm from a normally 
sterile site, such as blood or spinal fluid (in the setting of nervous system involvement).  
Stool samples are of limited use as ADXS Lm strains are not shed. Listeriosis (as opposed to 
listeremia with attenuated Lm) is a systemic organ infection caused by invasive Lm infection 
and is highly unlikely to occur during study treatment due to the method of attenuation used 
in the Advaxis Lm platform. In a Phase 1 clinical study, in the absence of antibiotics, Lm was 
rapidly cleared from the blood. 
 
 
 
 
  
wt-Lm is known to form and persist within biofilms especially on medical devices despite 
antibiotic treatment [22]. Although rare, medical device–related infections such as 
ventriculo-peritoneal shunt infection, peritoneovenous shunt infection, and prosthetic joint 
infection have been reported after systemic listeriosis caused by wt-Lm [23-26]. ADXS11-
001 is highly sensitive to antibiotics such as ampicillin and sulfamethoxazole/trimethoprim 
which can be an effective treatment regimen for listeria infection. This systemic organ 
infection caused by wild-type, invasive Lm, is highly unlikely to occur during study 
treatment with Advaxis Lm constructs due to the method of attenuation.  However, subjects 
with a fixed medical device may be at risk for ADXS11-001 attachment to the surface of the 
device by establishing a biofilm. Therefore, subjects with implanted medical device(s) that 
pose a high risk for colonization and/or cannot be easily removed are excluded from this 
study. In addition, all subjects, will receive a course of oral antibiotics beginning on Day 4 
(approximately 72 hours) after each dose of ADXS11-001 and for 3 weeks following the last 
dose of ADXS11-001 to help ensure the clearance of the ADXS11-001 bacteria. In addition, 
as the PI3K signaling pathway may be directly involved in the regulation of TNFα 
production, inhibition of the PI3K pathway may block the TNFα-mediated signaling pathway 
that could reduce resistance to bacterial infections [27, 28]. 
In the Phase 1 Lm-LLO-E7-01 study, in the absence of antibiotics administered to assist in 
Lm clearance following the completion of each dose administration, the attenuated bacteria 
Lm was shown to be rapidly cleared from the blood. No Lm bacteria was detected in the 
blood of any subject beyond 48 hours post-dosing in doses of up to 1 x 1010 CFU [21]. 
Importantly, there has not been any report of person-to-person transmission associated with 
use of Lm-based therapy in completed or ongoing clinical studies [21]. 


 
 
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2.1.8 
Summary of Efficacy for ADXS11-001 Studies in Cervical Cancer 
2.1.8.1 
Lm-LLO-E7-01: Phase 1 Experience 


 
 
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2.1.8.2 
Lm-LLO-E7-15: Phase 2 Study of ADXS11-001 vs ADXS11-001 and 
Cisplatin in Recurrent, Refractory Cervical Cancer 


 
 
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2.1.8.3 
GOG-0265: Phase 2 Evaluation of ADXS11-001 in Recurrent, 
Refractory Cervical Cancer 
2.1.9 
Rationale for ADXS11-001 Dose Selection/Regimen/Modification 
The dose regimen for both placebo and ADXS11-001 consists of a Prime Phase followed by 
a Maintenance Phase: 
• Prime Phase = 1 dose administered q3 weeks for a total of 3 doses followed by; 
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Those subjects who complete the 12-month treatment period (Prime + Maintenance Phases) 
may receive a total of 8 doses of ADXS11-001 at 1 x 109 CFU or placebo. 
The recommended Phase 2 dose and the Prime Phase schedule were determined by safety 
and efficacy results from the Phase 1 and 2 studies (described in Section 2.1.8.1 and 2.1.8.2, 
respectively). The Maintenance Phase of the study was included based on the 2 fundamental 
actions of Lm-LLO immunotherapy; (1) the generation of antigen specific lymphocytes; (2) 
and a reduction in the immune tolerance of the TME resulting from a reduction in the relative 
percentage and immune-suppressive function of Tregs and MDSCs in the TME. 
 In addition, the beneficial reduction of 
immune tolerance within the TME, attributable to the secretion of LLO, decreases as well.  It 
is not known how long this effect persists after a single treatment with ADXS11-001, but 
clinical data suggest that this effect is not permanent.
Furthermore, a completed study in 
the adjuvant treatment of canine osteosarcoma demonstrated that after 2 months the antigen-
specific T-cell response returns to baseline and that doses administered every 2 months were 
able to maintain elevated levels of T-cells [29]. Based on the previous studies completed in 
LACC the events of progression or recurrence, particularly in subjects with high risk disease, 
often occur within the first 12 months so therefore the Prime and Maintenance Phase dosing 
over a 12-month treatment period is hypothesized to be sufficient and able to potentially 
provide additional benefit to the subject. 
2.2 
Rationale for Endpoints 
2.2.1 
Efficacy Endpoints 
The primary endpoint for this study is DFS measured from the time of randomization to 
recurrence or death. DFS was selected as the primary endpoint since only subjects who 
achieve disease-free status without evidence of measurable or non-measurable disease after 
definitive CCRT are eligible to participate.  
DFS is the appropriate primary endpoint for this study based on the eligible study population 
because it is closely aligned with progression-free survival as a reliable surrogate endpoint 
for OS. An evaluation of PFS and OS of 14 randomized studies conducted in HRLACC 
between 1999 and 2014 is shown in (Table 2). In the 9 studies where both PFS and OS were 
available, 8 demonstrated that PFS and OS were closely correlated. PFS is also believed to be 
a more accurate endpoint and one that has been used as the primary endpoint for many 
studies in HRLACC. The RECIST 1.1 criteria which will be used in this study have been 
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Table 2 
Randomized Studies Evaluating Concomitant Chemoradiation in 
Cervical Cancer 
 
Treatments 
Stage 
of 
Disease 
No. of 
Subject
s 
PFS 
HR (95% CI) 
OS 
HR (95% CI) 
Control 
Experimental 
Thomas-1998 
RT 
RT+5FU 
Ib-IVa 
234 
0.49 (0.25-0.97) 
NA 
Whitney-1999 
RT+Hyd 
RT+Cis+5FU 
IIb-IVa 
368 
0.79 (0.60-1.04) 
0.74 (0.55-
0.99) 
Rose-1999 a 
RT+Hyd 
RT+Cis 
IIb-IVa 
353 
0.57 (0.42-0.78) 
0.61 (0.44-
0.85) 
Rose-1999 b 
RT+Hyd 
RT+Cis+5FU+Hy
d 
IIb-IVa 
350 
0.55 (0.40-0.75) 
0.58 (0.41-
0.81) 
Keys-1999 
RT 
RT+Cis 
Bulky 
Ib 
369 
0.51 (0.34-0.75) 
0.54 (0.34-
0.86) 
Roberts-2000 
RT 
RT+MitoC 
Ib2-IVa 
160 
NA 
NA 
Brundage-2002 
RT 
RT+Cis 
Ib-IVa 
259 
NA 
1.10 (0.75-
1.62) 
Lorvidhaya-2003 
RT 
RT+MitoC+5FU 
IIb-IVa 
475 
NA 
NA 
Eifel-2004 
RT 
RT+Cis+5FU 
Ib-IVa 
389 
0.49 (0.36-0.66) 
0.48 (0.36-
0.66) 
Lanciano-2005 
RT+Cis 
RT+5FU(PVI) 
IIb-IVa 
316 
1.29 (0.93-1.80) 
1.37 (0.96-
1.97) 
Duenas-Gonzalez-
2011 
RT+Cis 
RT+Cis+Gem 
IIb-IVa 
515 
0.68 (0.49-0.95) 
0.68 (0.49-
0.95) 
Nagy-2012 
RT+Cis(wkl
y) 
RT+Cis(q3wk) 
IIb-IIIb 
326 
NA 
NA 
DiSilvestro-2014 
RT+Cis 
RT+TPZ 
Ib2-IVa 
379 
1.06 (0.65-1.71) 
1.17 (0.65-
2.11) 
Sugiyama-2014 
RT+placebo 
RT+Z100 
IIb-IVa 
249 
0.86 (0.57-1.29) 
0.65 (0.40-
1.04) 
The utilization of DFS as the primary endpoint in this study will more efficiently evaluate the 
treatment effect and clinical benefit while limiting the number of study participants and 
reducing the time to reach an overall study conclusion. Overall survival will be evaluated as a 
secondary endpoint. 
2.2.2 
Safety Endpoints 
The safety objective of this study is to determine and compare the frequency and severity of 
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The safety of ADXS11-001 administration will be assessed according to the NCI CTCAE v 
4.03 criteria which will be used to define the grades and levels of toxicity. These criteria will 
be applied to: 
• Observation of the infusion site for swelling, irritation, immune reaction or other 
abnormalities 
• Changes from baseline in physical examination findings and vital signs 
• Changes from baseline in laboratory parameters (hematology, serum chemistry and 
urinalysis) 
• Evidence of allergic and constitutional symptoms 
• Other adverse events 
Safety evaluations will be performed throughout the study. All subjects who received at least 
1 dose of study treatment (placebo or ADXS11-001) will be evaluated for safety. The AE 
grade, attribution to drug, date of onset, duration of the event, outcome, impact on study 
treatment, any concomitant medications, procedures and/or therapies administered will be 
recorded. 


 
 
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3 SUBJECT ELIGIBILITY AND EXCLUSIONS 
3.1 
Inclusion Criteria 
1. Prior to receiving CCRT with curative intent: 
a. Subjects must have a biopsy confirmed diagnosis of squamous cell, adenocarcinoma, 
or adenosquamous carcinoma of the cervix. Histologic confirmation of the original 
primary tumor is required. 


 
 
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b. FIGO Stage IB2, IIA2, IIB with any of the following pelvic lymph node metastases 
criteria (2014 FIGO Staging) 
i. 
Biopsy proven pelvic node metastases 
ii. 
2 or more pelvic node(s) by CT or MRI measuring >1.5 cm in shortest 
dimension 
iii. 
2 or more pelvic node(s) by PET with SUV >2.5 cm 
OR 
c. All FIGO Stage IIIA, IIIB, IVA 
OR 
d. Any FIGO Stage (except stage IVB) with para-aortic lymph node metastases 
criteria (as defined by any of the following) 
i. 
Biopsy proven para-aortic node 
ii. 
1 or more positive para-aortic node by CT or MRI >1.5 cm shortest 
dimension 
iii. 
1 positive para-aortic node by PET with SUV >2.5 cm 
2. Must have received CCRT with curative intent according to either institutional or 
national guidelines (e.g., NCCN) with a minimum of at least 4 weeks exposure with 
cisplatin and a minimum of 40 Gy external beam radiation therapy (EBRT) (NOTE: 
Carboplatin-based CCRT is permitted; Neoadjuvant therapy is permitted).  
3. Completed CCRT, defined as the last dose of radiation (including brachytherapy) or 
chemotherapy, must be completed by no more than 14 weeks prior to the initiation of the 
Screening Period (date of signed Informed Consent). Have performance status of 0 or 1 
on the GOG Performance Scale 
4. Demonstrate adequate organ function as defined in (Table 3). (NOTE: All screening labs 
should be performed within 3 days of treatment initiation.) 
 
NOTE: Toxicities resulting from CCRT must resolve to ≤ Grade 1 prior to 
randomization, with the exception of alopecia. Peripheral neuropathy (sensory and 
motor) must resolve to ≤ Grade 2. 


 
 
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Table 3 
Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematologica 
Absolute neutrophil count (ANC) 
≥1,000/mcL 
Platelets 
≥75,000/mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L 
Renal 
Serum creatinine OR 
 
Measured or calculatedb creatinine clearance 
(GFR can also be used in place of creatinine or 
CrCl) 
≤1.5 x upper limit of normal (ULN) OR 
 
≥50 mL/min for subject with creatinine levels >1.5 x 
institutional ULN 
Hepatic 
Serum total bilirubin 
≤1.5 x ULN OR 
Direct bilirubin ≤ULN for subjects with total bilirubin levels 
>1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤2.5 x ULN  
 
Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
≤1.5 x ULN (NOTE: Subject is eligible if receiving 
anticoagulant therapy and PT or INR is within 
therapeutic range of intended use of anticoagulant 
therapy.) 
Activated Partial Thromboplastin Time (aPTT) 
≤1.5 X ULN (NOTE: Subject is eligible if receiving 
anticoagulant therapy and aPTT is within therapeutic 
range of intended use of anticoagulants.) 
 
a Hematologic requirement cannot be met with the use of recent transfusions, or growth factor support (G-CSF, 
erythropoietin, etc.) within two weeks prior to treatment initiation. 
b Creatinine clearance should be calculated per institutional standard. 
5. Must be ≥18 years old at time of giving written informed consent 
6. Subjects of childbearing potential must have a negative urine or serum pregnancy test 
prior to the study entry and be practicing 2 methods of study doctor approved birth 
control or be surgically sterile or abstain from heterosexual activity for the course of the 
study from Screening through 120 days after the last dose of study medication. Subjects 
of childbearing potential are those who have not been surgically sterilized or have not 
been free from menses for >1 year. 
7. Cannot be breast-feeding  
 
 


 
 
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3.2 
Exclusion Criteria 
The subject must be excluded from participating in the study if the subject: 
1. Has not achieved disease-free status (e.g. no evidence of measurable disease or non-
measurable disease per RECIST 1.1) after completion of CCRT administered with 
curative intent.   
2. Has FIGO Stage IVB (e.g. the cancer has spread to other parts of the body [any T, any N, 
M1]).  
3. Has histologies other than squamous cell, adenocarcinoma, or adenosquamous carcinoma 
of the cervix. 
o Note: neuroendocrine cancers are excluded. 
4. Is currently participating in or has participated in a study of an investigational agent or an 
investigational device within 4 weeks of the first dose of treatment. 
5. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of' immunosuppressive therapy within 7 days prior to the first dose of study 
treatment. 
6. Had any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for 
other invasive malignancy(ies) within 2 years. Concurrent use of hormones for non-
cancer-related conditions (e.g., insulin for diabetes and hormone replacement therapy) is 
acceptable. 
o Note:  Local treatment of isolated lesions for palliative intent (e.g., by local 
surgery or radiotherapy), basal cell carcinoma of the skin, squamous cell 
carcinoma of the skin, or ductal carcinoma in situ of the breast that has/have been 
surgically cured is acceptable. 
7. Has an active autoimmune disease requiring systemic treatment within the past 3 months 
or a documented history of clinically severe autoimmune disease, or a syndrome that 
requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or 
resolved childhood asthma/atopy would be an exception to this rule. Subjects who require 
intermittent use of inhaled steroids or local steroid injections would not be excluded from 
the study. Subjects with hypothyroidism stable on hormone replacement or Sjorgen’s 
syndrome will not be excluded from the study. 
8. Has an active infection requiring systemic therapy. (NOTE: Prior to dosing with study 
treatment, the subject must be at least 5 half-lives from their last dose of antibiotic.) 
9. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the subject’s participation for 


 
 
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the full duration of the study, or is not in the best interest of the subject to participate, in 
the opinion of the treating Investigator. 
10. Has implanted medical device(s) that pose a high risk for colonization and/or cannot be 
easily removed (e.g., prosthetic joints, artificial heart valves, pacemakers, orthopedic 
screw[s], metal plate[s], bone graft[s], or other exogenous implant[s]).  NOTE: More 
common devices and prosthetics which include arterial and venous stents, dental and 
breast implants and venous access devices (e.g. Port-a-Cath or Mediport) are permitted.  
Sponsor must be contacted prior to consenting any subject who has any other device 
and/or implant.  
11. Currently receiving or have a known plan to receive in the future a PI3K or TNF𝛼 
inhibitors. 
12. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the study. 
13. Has a clinically active bacterial, fungal, parasitic or viral infection which require therapy, 
or who are HIV positive.  
14. Has a contraindication (sensitivity or allergy) to trimethoprim/sulfamethoxazole. 
15. Has a known allergy to any component of the study treatment(s) formulations. 
16. Has undergone a major surgery, including surgery for a new artificial implant and/or 
device, within 6 weeks prior to the initiation of ADXS11-001 treatment. (NOTE: All 
toxicities and/or complications must have recovered to baseline or Grade 1 prior to the 
initiation of ADXS11-001 study therapy.) Consult with the Sponsor prior to enrolling 
subjects on the study who recently had a major surgery or have new artificial implant, 
and/or devices. 
17. Has received a live vaccine within 30 days prior to the first dose of study treatment. 
18. Has a history of other invasive malignancies within 3 years of randomization, with the 
exception of non-melanoma skin cancer and in situ melanoma. Subjects with other 
malignancies diagnosed more than 3 years ago who are relapse-free for at least 3 years 
may be enrolled. Subjects are also excluded if their previous cancer treatment 
contraindicates this protocol therapy. 
19. Has bilateral hydronephrosis unless at least one side has been stented and renal function 
fulfils the required inclusion criteria. 
20. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.  
21. Has an uncontrolled intercurrent illness including, but not limited to ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 


 
 
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arrhythmia, or psychiatric illness/social situations that would limit compliance with study 
requirements. 
22. Has liver cirrhosis or any other impaired hepatic function as determined by serum 
enzymes. 
23. Has undergone a previous hysterectomy (defined as removal of the entire uterus), 
following neoadjuvant chemotherapy.   
24. Has a medical history or conditions not otherwise previously specified which in the 
opinion of the Investigator should exclude participation in this study.  The Investigator 
should feel free to consult the Sponsor for any question regarding eligibility.  
25. Is or has an immediate family member (spouse or children) who is directly involved with 
this study, that is employed by the investigational site or Sponsor, unless prospective 
Institutional Review Board (IRB) approval (by chair or designee) is given allowing 
exception to this criterion for a specific subject. 
4 STUDY MODALITIES 
The treatments to be used in this study are outlined below in (Table 4). 
Table 4 
Study Treatment 
Arm 
Drug 
Dose 
Route of 
Administration 
Regimen 
A 
ADXS11-001  
Placebo 
NA 
IV infusion over 
 
 
1 dose administered every 3 weeks 
(Weeks 1, 4 and 7) for 3 doses 
(Prime Phase), thereafter, subjects 
will receive 1 dose every 8 weeks 
(Weeks 15, 23, 31, 39, and 47) 
(Maintenance Phase) 
A 
Placebo matching 
trimethoprim/sulfamethoxazole 
NA 
Oral 
trimethoprim/sulfamethoxazole 
placebo administered once daily for 
7 consecutive days1  
B 
ADXS11-001 
1 x 109 CFU 
IV infusion over 
 
 
1 dose administered every 3 weeks 
(Weeks 1, 4 and 7) for 3 doses 
(Prime Phase), thereafter, subjects 
will receive 1 dose every 8 weeks 
(Weeks 15, 23, 31, 39, and 47) 
(Maintenance Phase) 
B Trimethoprim/sulfamethoxazole 
80 mg trimethoprim / 
400 mg 
sulfamethoxazole  
Oral 
trimethoprim/sulfamethoxazole 
administered once daily for 7 
consecutive days1  
1Subjects will receive a 3-week course of antibiotics or placebo at the indicated dosage following the final dose 
of study treatment or upon discontinuation of study drug, whichever occurs first. 


 
 
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4.1 
ADXS11-001 (IND #13,712) 
Details on the preparation, handling, administration and destruction are provided in the 
Pharmacy Manual. 
4.1.1 
Adverse Effects 
Please refer to Section 2.1.7 for summary information on the ADXS11-001 AE profile and 
the ADXS11-001 IB for complete information regarding AEs. 
4.1.2 
Drug Accountability 
The Investigator is responsible for keeping accurate records of the clinical supplies received 
from Advaxis or designee, the amount administered to subjects, and the amount remaining at 
the conclusion of the study. 
4.1.3 
Drug Ordering and Distribution 
Drug will be supplied by Advaxis and distributed by Almac Clinical Services LLC. No 
supplies will be shipped to any site until regulatory approval has been obtained. There will 
NOT be an initial drug supply forwarded to any investigational site(s) until initial regulatory 
approval. Details regarding drug ordering and distribution are provided in the Pharmacy 
Manual. 
4.1.4 
How Supplied, Storage and Stability 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label. 
Details on the drug supply, storage and stability are provided in the Pharmacy Manual. 
4.2 
Concomitant Therapies and Procedures (Allowed & Prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the course of the study. If there is a clinical indication for one of these or other 
medications or vaccinations specifically prohibited during the study, then discontinuation 
from study therapy may be required. The Investigator should discuss any questions regarding 
this with the Sponsor. The final decision on any supportive therapy or vaccination rests with 
the Investigator and/or the subject's primary physician. However, the decision to continue the 
subject on study therapy requires mutual agreement of the Investigator, the Sponsor, and the 
subject. 


 
 
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4.2.1 
Acceptable Concomitant Therapies and Procedures 
All treatments that the Investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the Investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the electronic case report form 
(eCRF) including all prescription, over-the-counter (OTC), herbal supplements, and IV 
medications and fluids. If changes occur during the study period, documentation of drug 
dosage, frequency, route, and date should also be included on the eCRF. 
4.2.1.1 
Hematopoietic Growth Factors 
While it is not expected that administration of ADXS11-001 may lead to neutropenia, 
hematopoietic growth factors may be used to treat emergent neutropenia as indicated by the 
current ASCO guidelines. 
4.2.1.2 
Major and Minor Surgeries and ADXS11-001 Treatment 
No formal studies of the effect of ADXS11-001 on wound healing have been conducted.  
However, based on its mechanism of action it is not expected that administration of 
ADXS11-001 would complicate wound healing. Therefore, a subject may initiate or resume 
study treatment 2 weeks after minor surgery (i.e., surgery involving little risk to the life of 
the subject; specifically, an operation on the superficial structures of the body or a 
manipulative procedure that does not involve a serious risk) if the wound has completely 
healed and there are no wound healing complications. A subject who has wound healing 
complications following minor surgery, received major surgery or requires new implants 
and/or devices (permitted by the protocol) during the course of the study, must wait a 
minimum of 6 weeks and must have recovered from any toxicity (e.g., return to baseline or 
Grade 1) and/or complication before the next infusion of study treatment. Sponsor 
consultation is required prior to resuming study treatment for these subjects. If the treatment 
is delayed due to concomitant surgery beyond 12 weeks the subject may be discontinued 
from the study.   
4.2.2 
Prohibited Concomitant Therapies 
Subjects are prohibited from receiving the following therapies during the screening and 
treatment period of this study: 
• Anti-cancer therapy including, hormonal therapy, chemotherapy, radiation therapy, 
treatment with targeted agents (e.g., tyrosine kinase inhibitors). 
• Immunotherapy (e.g., therapies for the treatment of rheumatoid arthritis) not specified 
in this protocol. However, immunotherapy for the treatment of allergies is allowed. 
• Investigational agents other than ADXS11-001. 
• PI3K and TNF inhibitors  


 
 
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• Live vaccines (e.g., measles, mumps, rubella, chicken pox, yellow fever, BCG, rabies 
and typhoid) must not be given concomitantly with ADXS11-001. 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. 
• Chronic use of systemic glucocorticoids since these have the potential to reduce the 
immune response. However, glucocorticoids should be considered to manage 
symptoms from an event of suspected immunologic etiology (eg, symptoms associated 
with CRS, hypotension occurring during infusions). (NOTE: The use of occasional 
inhaled corticosteriods for the treatment of COPD and/or asthma is allowed.) 
Subjects who, in the assessment by the Investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the study.  
Subjects may receive other medications that the Investigator deems to be medically 
necessary. 
The Exclusion Criteria (Section 3.2) describe other therapies and procedures that are 
prohibited during this study. 
4.3 
Diet/Activity/Other Considerations 
4.3.1 
Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
4.3.2 
Contraception 
ADXS11-001 may have adverse effects on a fetus in utero. Furthermore, it is not known if 
ADXS11-001 has transient adverse effects on the composition of sperm. Prior to enrollment, 
all study candidates with reproductive potential must be advised of the importance of 
avoiding pregnancy during study participation and the potential risk factors for an 
unintentional pregnancy. Women of childbearing potential is defined as females who have 
experienced menarche and who have not undergone successful surgical sterilization 
(hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or, are not postmenopausal 
(defined as amenorrhea 12 consecutive months or women on hormone replacement therapy 
with a documented serum follicle stimulating hormone level >35 mIU/ml). Even women who 
are using oral, implanted, or injectable contraceptive hormones or mechanical products, such 
as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent 
pregnancy, who are practicing abstinence, and who have a sterile partner (e.g., vasectomy) 
should be considered of childbearing potential. 
The following are considered adequate barrier methods of contraception: diaphragm, condom 
(by the partner), copper intrauterine device, sponge, or spermicide. Appropriate hormonal 
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estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents). 
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study. In order to participate in 
the study, all female study candidates of reproductive potential must adhere to the 
contraception requirement (described above) from Visit 1 through 120 days after the last 
study treatment administration. If there is any question that a subject will not reliably comply 
with the requirements for contraception, that subject should not be entered into the study. 
4.3.3 
Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment, the subject will immediately 
be removed from the study. The site will contact the subject by phone at least monthly and 
document the subject’s status until the pregnancy has been completed or terminated. The 
outcome of the pregnancy will be reported to the Sponsor without delay and within 24 hours 
if the outcome is a SAE (e.g., death, abortion, congenital anomaly, or other disabling or life-
threatening complication to the mother or newborn). The study Investigator will make every 
effort to obtain permission to follow the outcome of the pregnancy and report the condition 
of the fetus or newborn to the Sponsor. 
4.3.4 
Use in Nursing Women 
The effects of ADXS11-001 on human milk are unknown. Therefore, subjects who are 
breast-feeding are not eligible for enrollment. 
5 TREATMENT PLAN AND ENTRY/REGISTRATION PROCEDURE 
5.1 
Subject Entry and Registration 
An Interactive Response Technology (IRT) system will be used for this study to register drug 
dispensation visits (ADXS11-001/placebo and antibiotics/placebo), obtain subject drug 
assignments, and manage site drug inventory. A blinded user manual will be provided to site 
personnel in the study manual. An unblinded manual will be provided in the pharmacy 
manual. 
Additional details on subject entry and registration can be found in the study Administrative 
Binder. 
5.2 
Randomization and Treatment Plan 
Subjects must initiate the Screening period within 14 weeks after the completion of CCRT 
(inclusive of brachytherapy, when applicable). The Screening Period is 28 days in duration 
and all examinations and assessments required by the protocol are expected to be completed 
within this period. Clinical laboratory assessments must be completed no more than 3 days 
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Eligible subjects will be randomized 1:2 to Arm A (placebo) or Arm B (ADXS11-001).  
Study treatment (ADXS11-001or placebo) will be administered on Day 1 of the Week 1 visit. 
Study treatment may be administered ±3 days within Day 1 of each scheduled infusion for 
subsequent visits (e.g. Week 4, Day1 and Week 7, Day 1 visits). 
• Arm A: Placebo administered IV over approximately 
 every 3 weeks 
(Weeks 1, 4 and 7 only) for 3 doses (Prime Phase), thereafter, subjects will receive an 
additional dose every 8 weeks (Weeks 15, 23, 31, 39, and 47) for 5 doses 
(Maintenance Phase). The total treatment period will be approximately 1 year. 
• Arm B: ADXS11-001 administered IV over approximately 
 every 3 weeks 
(Weeks 1, 4 and 7 only) for 3 doses (Prime Phase), thereafter, subjects will receive an 
additional dose every 8 weeks (Weeks 15, 23, 31, 39, and 47) for 5 doses 
(Maintenance Phase). The total treatment period will be approximately 1 year. 
5.2.1 
Screening Period 
The following evaluations will be performed to confirm subjects’ eligibility: 
• Informed consent 
• Demographic information 
• Medical, surgical, and cancer history 
• Concomitant therapy review 
• Adverse events review (collected from the time informed consent is obtained) 
• Full physical examination  
• Vital signs, height, weight 
• Pelvic exam inclusive of cervical and vaginal cytology (NOTE: Exam should include 
a speculum examination with bi-manual pelvic and rectal examinations.) 
• GOG performance status 
• Routine Laboratory tests (hematology, coagulation profile, blood chemistry, 
urinalysis, pregnancy test): Subjects whose pre-treatment CBC reveals leukocytosis 
may need additional evaluation (e.g., UA, etc.) to rule out an active infection.  
Confirmed infection will result in a delay of study treatment and must be treated with 
appropriate antibiotic treatment. Screening labs must be performed within 3 days of 
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• Tumor Imaging: Baseline scans must be performed within 28 days of first study 
treatment infusion and must include contrast-enhanced CT of the chest, abdomen and 
a contrast-enhanced MRI or PET/CT of the pelvis. If a contrast-enhanced CT of the 
pelvis is performed, an MRI of the pelvis is still required. 
o The modality selected for a patient for imaging of the pelvis (either contrast-
enhanced CT and MRI or PET/CT) must be used consistently for the patient 
throughout the study. 
o For subjects who have a medical contraindication to IV contrast, a contrast-
enhanced MRI or PET/CT of the abdomen and pelvis may be performed.  In 
these subjects, a non-contrast CT scan of the chest must also be performed. 
NOTE: Please refer to the Imaging Manual for details regarding imaging 
requirements, including but not limited to, image acquisition, collection 
and submission of scans for independent radiology review. 
• Inclusion/Exclusion Review: Results of all screening evaluations must be 
reviewed by the principal Investigator or qualified designee to ensure that all 
eligibility criteria have been satisfied prior to subject randomization. 
5.2.2 
Subjects Who Fail to meet Screening Criteria 
A subject who has a laboratory test results(s), vital signs, or other finding(s) that does not 
satisfy the eligibility criteria may have the test(s) repeated once. These tests may be repeated 
as soon as the Investigator believes the retest result is likely to be within the acceptable range 
to satisfy the entrance criteria but must be completed within the 28-day screening period. 
The subject will not be required to sign another informed consent form (ICF), and the 
original subject identification number will be used. In the event that the laboratory test(s) 
cannot be performed within the Screening period, or the re-test(s) does not meet the entrance 
criteria or the subject’s medical condition has changed significantly during the Screening 
Period so that inclusion/exclusion criteria are no longer met, the subject is considered a 
Screen failure, and must be withdrawn from the study. 
5.2.3 
Treatment Period 
During the treatment period, the following assessments will be performed prior to study 
treatment infusion: 
• Physical examination (NOTE: A “focused” physical examination will be performed 
during the Prime Phase on Weeks 4 and 7 and during the Maintenance Phase on the 
Week 23 visit. Full physical exams should be performed on all other visits during the 
treatment period.  (See Section 7.1, Schedule of Events). 
• Vital signs and weight 
• GOG performance status 


 
 
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• Routine laboratory tests (hematology profile, blood chemistry, urinalysis, pregnancy 
test). Lab tests must be completed within 3 days of study treatment dosing.* 
• Prophylactic medication administration within the approximate pre-infusion window 
• AE review 
• Concomitant therapy/procedures review 
• 
• Tumor imaging and pelvic examination will be performed at Weeks 12, 24, 36, and 
48 in all subjects who have not experienced disease recurrence, even those who have 
discontinued treatment prior to early study termination.  
o Note: Cervical and vaginal cytology will be performed at Screening only unless 
deemed necessary by the treating physician. 
*Prior to each study treatment, a subject must be thoroughly screened for an ongoing or 
active infection.  Any subject whose pre-treatment CBC reveals leukocytosis may need 
additional evaluation (e.g. urinalysis, etc.) to rule out an active infection. Confirmed 
infection will result in a delay of study treatment and appropriate antibiotic treatment. Study 
treatment may resume following at least 5 half-lives from the subject’s final antibiotic dose. 
5.2.3.1 
Pretreatment Prophylaxis Regimen 
Mild to moderate cytokine release symptoms (e.g., fever, chills, rigors, fatigue, headache, 
nausea, vomiting, tachycardia, shortness of breath, hypotension and rash) are commonly seen 
and typically occur 2-4 hours after ADXS11-001 infusion and often resolve within 12-24 
hours. Prophylactic medications are intended to reduce the inflammatory response and 
minimize the occurrence of post-treatment symptoms. Therefore, it is strongly recommended 
that subjects receive the following pretreatment prophylaxis regimen: 
 
 


 
 
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IV Fluid Hydration: 
• Normal saline (NOTE: A recommended fluid amount is 500 mL administered IV over 
approximately one hour but investigator discretion should be used to determine an 
individual subject’s need based on her medical condition. Appropriate hydration has 
been determined to be a key component in helping to minimize post-treatment 
symptoms related to an immune-mediated response.) 
Premedication Regimen: 
• Antihistamine - PO or IV (e.g., diphenhydramine 25 mg or equivalent) 
prior 
to the procedure, once   
• NSAIDs - PO (e.g., naproxen 220 mg or ibuprofen 400 mg) 
prior to the 
procedure, once 
o NOTE: Acetaminophen is prohibited for prophylaxis because it does not have 
anti-inflammatory properties required to assist in reducing adverse events 
associated with ADXS11-001 administration. When naproxen and ibuprofen are 
contraindicated an alternative anti-inflammatory should be used. Acetaminophen 
may be used for supportive care measures. Sponsor consultation is recommended. 
• Antiemetic - PO or IV (e.g., promethazine or ondansetron) 
 prior to the 
procedure, once 
• Histamine H2-receptor antagonist - PO or IV (e.g., famotidine 20 mg or equivalent) 
prior to the procedure, once 
IV fluids and pretreatment medications should be given on the day of dosing and completed 
at least 
 prior to the start of the assigned study treatment infusion. Do not 
substitute acetaminophen for the selected NSAID for prophylactic treatment since 
acetaminophen does not have similar anti-inflammatory properties that could ameliorate 
symptoms related to an immune-mediated response. 
5.2.3.2 
Administration of Study Treatment 
ADXS11-001 and all other study medications must be administered through a temporary 
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5.2.3.3 
Study Treatment Regimen 
The treatment period consists of the Prime Phase (dosing every 3 weeks (± 3 days) for 3 total 
doses in the first 12 weeks and the Maintenance Phase (dosing every 8 weeks (± 3 days) for a 
total of 5 doses). Study treatment will be administered as an IV fusion over approximately 
 
 in 250 mL of normal saline. Vital signs will be taken immediately before each study 
treatment infusion. Treatment is to be done on an outpatient basis. 
5.2.3.4 
Pre-Treatment Assessment and Study Therapy Administration 
The investigator or research staff must ensure that the subject’s vital signs, laboratory results 
and physical condition are within normal limits with consideration given to the subject’s 
prior medical history as well as information available based on her current participation in 
the study prior to the administration of study therapy. Study therapy must not be 
administered until all of the subject’s assessments are within acceptable limits in the opinion 
of the investigator. In the situation where one or more of the subject’s assessments are not 
within the normal limits for that subject, but in the opinion of the investigator study therapy 
dosing may proceed, then documentation must be made to note baseline values and the 
investigator’s assessment that the findings were not clinically or medically significant. 
5.2.3.5 
Post-Treatment Monitoring 
After study treatment administration, subjects will remain in the clinic to be monitored for 
safety for at least 4 hours. Vital signs will be taken
following each study treatment infusion. Four hours after the study treatment, the investigator 
must ensure the subject is in stable medical condition and in the investigator’s opinion can be 
safely discharged before being released. The investigator must take action to provide 
appropriate medical care. After the completion of study treatment an NSAID and/or 
antiemetic may be given on Day 1 and Day 2, as needed. The prescribed dosage of the 
selected NSAID and antiemetic will be at the discretion of the Investigator. 
5.2.4 
Follow-up Period 
Subjects who complete the one-year treatment period: The Follow-up period is defined as the 
portion of the study that begins after completion of the treatment period and will last for 1 
year. The treatment period will be considered complete once the subject receives his/her last 
dose of study treatment in either the Prime or Maintenance phases. During the Follow-up 
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they have experienced for several days, the following symptoms that could potentially be 
associated with delayed listeremia: fever or chills, headache, nausea, confusion or changes in 
alertness. As part of the End of Study procedures, upon completing the Lm Surveillance 
period, site staff should instruct subjects to contact the site if they experience any of these 
symptoms, as applicable (refer to Section 6.2.6).  
Subjects who discontinue early for reasons other than disease recurrence: Subjects will 
immediately enter the Follow-up Period (refer to Section 7.2.6.1.2), which will last for a total 
of 1 year Lm Surveillance period. 
 
5.2.4.1 
Lm Surveillance 
Surveillance monitoring for the detection of Lm will be performed during the Follow-Up 
period. Surveillance will be initiated at the completion of study treatment according to the 
protocol or at the time of study discontinuation if earlier. See Section 6.2.6 Management and 
Surveillance of Listeria during Study Participation and Section 9 for further information. 
Medications and antibiotics administered during the Lm surveillance period should also be 
captured in the eCRF along with any new procedures which are performed during this time. 
Adverse events and serious adverse events experienced that are potentially associated with 
listeremia during the 1-year Lm surveillance monitoring phase will be reported and recorded 
in the eCRF. Adverse experiences will be graded and recorded throughout the study 
andfollow-up according to CTCAE V 4.03 (see Section 5.2.4 and 6). 
5.2.4.2 
End of Study Visit 
The EOS visit will be performed on the last scheduled study visit day of the Follow-up phase 
(± 5 days), or earlier if the subject meets a reason for discontinuation during the Follow-up 
phase due to disease recurrence. All study procedures that are included for the scheduled visit 
and EOS visit will need to be performed. This can be done remotely. The following 
procedures will be performed for the EOS visit: 
• Record adverse events 
• Completion of end of Lm Surveillance Monitoring visit (can be done remotely) 
 
5.3 
Stratification 
Treatment arms will be stratified based on the: 
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• Region (US vs Rest of World) 
• FIGO stage (Stages I-II or III-IV) (2014 FIGO Staging) 
6 TREATMENT MODIFICATION GUIDELINES 
6.1 
Treatment Delay/Discontinuation Guidelines 
The study treatment dose will not be modified (i.e., reduced or increased).  However, 
treatment may be delayed or discontinued for drug related severe and life-threatening 
toxicities, as shown below in (Table 5). 
Table 5 
Treatment Delay/Discontinuation Guidelines for Drug-Related 
Adverse Events 
Toxicity 
Grade 
Hold Treatment 
Timing for 
Restarting 
Treatment 
Discontinue Study 
Treatment 
Hematologic 
1,2,3 
No  
N/A 
N/A 
4 
Yes 
Toxicity resolves to 
≤Grade 1 or baseline 
Toxicity does not 
resolve to ≤Grade 1 
or baseline within 3 
weeks of AE onset 
Non-
hematologic, 
excluding 
cytokine 
release 
symptoms  
1 
No 
N/A 
N/A 
2-3 
Yes 
Toxicity resolves to 
≤Grade 1 or baseline 
Toxicity does not 
resolve to ≤Grade 1 
or baseline within 3 
weeks of AE onseta 
4 
N/A 
Permanent 
discontinuation from 
study treatment 
Permanent 
Discontinuation from 
study treatment 
aWith investigator and sponsor agreement, subjects with a non-hematologic  AE (e.g., alopecia, neuropathy) 
still at Grade 2 after 3 weeks may continue treatment if subject is asymptomatic and well-controlled.  
 
Treatment may also be delayed at the discretion of the investigator for adverse events that 
are not drug-related, but which would either put the subject at risk from treatment, adversely 
affect the efficacy of study treatment, confound the interpretation of study results, or prevent 
the assessment of study results. 
6.2 
Supportive Care Guidelines Following Administration of Study 
Treatment 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
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6.2.1 
Symptoms Related to Immune Cell Activation 
A subject may experience inflammatory symptoms associated with T-cell engagement and 
proliferation following the administration of ADXS11-001. Symptoms may include 
constitutional symptoms such as fever, chills, rigors, fatigue, headache, nausea, vomiting, 
rash tachycardia, hypotension, and shortness of breath which usually present several hours 
after the infusion and may last for up to 24 hours. These symptoms which are caused by an 
increase in cytokines such as IL- 6, TNFα and IFNγ occur after ADXS11-001 administration. 
This is the result of the body’s immune response to the therapy. In most cases, the symptoms 
are usually CTCAE Grade 1 and 2, transient and resolve with appropriate medical 
management within 30 minutes to1 hour. The guidelines for the grading and management of 
symptoms related to immune cell activation are shown in Table 6.1-6.4 
 


 
 
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6.2.1.1 
Grading and Management Guidelines for Acute Hypotension, 
Hypoxia, Encephalopathy, Organ Toxicity, Fever and Constitutional Symptoms 
Table 6.1 
Grading Scale for Hypoxia, Hypotension, and Organ Toxicity 
Grade 
Description of Severity 
1 
Fever (temperature > 38○C) or Grade 1 organ toxicity 
2 
Symptoms require and respond to moderate intervention 
Oxygen requirement FiO2 < 40% and/or subject requires intermittent supplemental oxygen,  
              OR 
Hypotension responsive to IV fluids or low-dose of one vasopressor to maintain systolic blood 
pressure > 90 mmHg,  
 
OR 
Grade 2 organ toxicity  
3 
Needs oxygen to maintain O2 saturation > 90% Oxygen requirement FiO2 ≥ 40% and/or 
requiring BiPAP,  
 
OR 
Hypotension refractory to management for Grade 2 or where hospitalization is required,  
 
OR 
Grade 3 organ toxicity or Grade 4 transaminitis per CTCAE v5.0 criteria 
4 
Life-threatening signs and symptoms 
 
OR 
Requirement for ventilator support to maintain O2 saturation > 90%   
 
OR 
Grade 4 organ toxicity (excluding Grade 4 transaminitis) per CTCAE v5.0 criteria 
Table 6.2 
Management Guidelines for Acute Hypotension, Hypoxia, Organ 
Toxicity, Fever and Constitutional Symptoms 
Toxicity 
Grade 
Sign/Symptom 
Treatment 
Instructions for 
Interruption of  
ADXS11-001 
Modification for Subsequent 
infusions 
1 
Hypotension 
• Supportive care 
 
Not applicable 
• Increase pretreatment IV fluids 
(e.g., 500 ml -1L normal 
saline) 
1 
Fever; Constitutional 
symptoms; Grade 1 
organ toxicity 
• Symptomatic management of 
constitutional symptoms and 
organ toxicity 
• Acetaminophen and 
hypothermia blanket as needed 
for fever 
• Ibuprofen if fever is not 
controlled with above, use with 
Not applicable • No modification 


 
 
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caution or avoid if 
thrombocytopenic 
• IV fluids as needed 
2 
Hypotension 
• Fluids (500 – 1000 mL normal 
saline to keep systolic blood 
pressure > 90 mmHg)  
• If hypotension persists after IV 
fluid bolus, administer a 
vasopressor (e.g., epinephrine 
0.3 mg IM)  
• If hypotension persists despite 
IV fluid bolus ± a low dose 
pressor, administer the IL-6 
antagonist tocilizumab (8 
mg/kg IV over 1 hour), and 
consider transfer to ICU 
• If hypotension persists despite 
these measures, treat with a 
high-dose corticosteroid.  
•  If there are signs of hypo-
perfusion or if there is rapid 
deterioration in the opinion of 
the clinician, consider the use 
of corticosteroids 
• Increase frequency of 
monitoring vital signs 
• Immediately 
interrupt 
ADXS11-001 
until AE(s) 
resolve to 
Grade ≤ 1 but 
for no less than 
72 hours 
 
• Permanently 
discontinue 
ADXS11-001 if 
there is no 
improvement of 
AE(s) to ≤ 
Grade 1 within 
7 days. 
• Extend infusion time to 2 hours 
• Increase pretreatment IV fluids 
(e.g. 500 mL – 1L normal 
saline)  
• Upon evaluation, 
Glucocorticoid- 
Hydrocortisone or equivalent- 
50 mg, IV, may be 
incorporated as premedication 
2 
Hypoxia 
• Use supplemental oxygen as 
needed 
• Use tocilizumab 8 mg/kg IV 
with or without corticosteroids 
as with Grade 2 hypotension 
(described above) 
• Increase frequency of 
monitoring vital signs 
• Restrict the administration of 
IV fluid, if possible 
• Immediately 
interrupt 
ADXS11-001 
until AE(s) 
resolve to 
Grade ≤ 1 but 
for no less than 
72 hours 
 
• Permanently 
discontinue 
ADXS11-001 if 
there is no 
improvement of 
AE(s) to ≤ 
Grade 1 within 
7 days. 
• No modifications 
• Discussion with Sponsor 
recommended 
2 
Fever, 
Constitutional 
symptoms; Grade 2 
organ toxicity 
• Appropriate supportive care 
• Manage organ toxicity as per 
standard guidelines 
• If no improvement with 
supportive care, use 
tocilizumab 8 mg/kg IV with 
or without corticosteroids as 
described above for Grade 2 
hypotension 
• Manage fever and 
constitutional symptoms as 
• Immediately 
interrupt 
ADXS11-001 
until AE(s) 
resolve to 
Grade ≤ 1 but 
for no less than 
72 hours 
 
• Permanently 
discontinue 
ADXS11-001 if 
• Extend infusion time to 2 hours 
• Consider increasing doses of 
prophylactic medications 
• Discussion with Sponsor 
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noted above for Grade 1 
toxicity 
there is no 
improvement of 
AE(s) to ≤ 
Grade 1 within 
7 days. 
3 
Hypotension  
• IV fluid bolus (as for Grade 2 
hypotension) and tocilizumab 
(8mg/kg IV over 1 hour) 
o 
If an IV fluid bolus was 
previously administered it 
may be repeated, 
depending on the 
subject’s hemodynamic 
status.  However, IV fluid 
administration in the 
presence of hypoxia may 
lead to increased 
pulmonary edema (see 
guidance for hypoxia 
above) 
o 
If no improvement, 
tocilizumab 8 mg/kg IV  
can be repeated every 8 
hours for a total of 3 doses 
• Transfer subject for inpatient 
management 
• High dose vasopressors (e.g., 
Dopamine 10 µg/kg/min)   
• If hypotension worsens or is 
unresponsive to above 
measures, administer high dose 
corticosteroids 
(methylprednisolone or 
dexamethasone)  
• Monitor for neurologic signs 
and symptoms.  Consult 
neurology to assess for signs 
of elevated intracranial 
pressure (e.g., papilledema) 
/cerebral involvement. See 
Table 6.3 and Table 6.4 below 
for grading and management of 
encephalopathy  
• Increase frequency of 
monitoring vital signs 
• Immediately 
interrupt  
ADXS11-001 
• Permanently 
discontinue  
ADXS11-001 if 
there is no 
improvement in 
AE(s) to ≤ 
Grade 2 within 
5 days or AE ≤ 
Grade 1 within 
7 days 
• Discuss with Sponsor 
3 
Hypoxia 
• Use supplemental oxygen  
• Use tocilizumab 8 mg/kg IV 
with or without corticosteroids 
(as for Grade 3 hypotension) 
• Increase frequency of 
monitoring vital signs 
• Restrict the administration of 
IV fluid if possible 
• Immediately 
interrupt  
ADXS11-001 
 
• Discuss with Sponsor 


 
 
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Note: Tocilizumab is a humanized, immunoglobulin G1k (IgG1k) anti-human IL-6R mAb approved by the 
FDA for treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) who have 
had an inadequate response to Disease-Modifying Anti-Rheumatic Drugs (DMARDs), for the treatment of 
active polyarticular juvenile idiopathic arthritis (PJIA), and active systemic juvenile idiopathic arthritis (SJIA) 
in patients 2 years of age and older, and for the treatment of adults and pediatric patients 2 years of age and 
older with chimeric antigen receptor (CAR) T cell-induced severe or life-threatening cytokine release 
syndrome. Tocilizumab works by preventing IL-6 binding to both cell-associated and soluble IL-6 receptors.  
Dosing guidelines for tocilizumab are provided below. 
 
Tocilizumab Dosing Guidelines [39] 
• 8 mg/kg IV; maximum dose/infusion = 800 mg. 
• If the subject’s condition does not improve or stabilize within 8 hours of the 
tocilizumab dose, administration of a second dose of tocilizumab should be 
3 
Fever, Constitutional 
symptoms; Grade 3 
organ toxicity 
• Appropriate supportive care 
• Manage organ toxicity as per 
standard guidelines 
• Use tocilizumab 8 mg/kg IV 
with or without  corticosteroids 
(as for Grade 3 hypotension) 
• Manage fever and 
constitutional symptoms above 
for Grade 1 toxicity 
• Immediately 
interrupt  
ADXS11-001 
 
• Discuss with Sponsor 
4 
Hypotension 
• IV fluid bolus (as for Grade 2 
hypotension) and tocilizumab  
• High-dose methylprednisolone 
• Immediately 
interrupt  
ADXS11-001 
• Permanently discontinue  
ADXS11-001 
4 
Hypoxia 
• Mechanical ventilation 
• Tocilizumab, high-dose 
methylprednisolone, and 
supportive care 
• Immediately 
interrupt  
ADXS11-001 
 
• Permanently discontinue  
ADXS11-001 
4 
Fever, Constitutional 
symptoms; Grade 4 
organ toxicity 
 
• Appropriate supportive care 
• Manage organ toxicity as per 
standard guidelines 
• Tocilizumab, high-dose 
methylprednisolone, and 
supportive care  
• Manage fever and 
constitutional symptoms as 
noted for Grade 1 above 
• Increase frequency of 
monitoring vital signs 
• Immediately 
interrupt  
ADXS11-001 
• Permanently discontinue  
ADXS11-001 


 
 
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considered.  A total of three doses can be administered in a 24-hour period (maximum 
800 mg/dose), and a maximum of 4 doses total can be administered. 
• Tocilizumab may be administered with corticosteroids. 
Table 6.3 
Grading Scale for Encephalopathy 
Grade 
Description of Severity 
1 
Neurological assessment score (see below) – Mild (7-9) 
2 
 Neurological assessment score (see below) – Moderate (3-6) 
3 
Neurological assessment score (see below) - Severe (0-2) 
OR 
Stage 1 or 2 papilledema1 with CSF opening pressure less than 20 mmHg 
4 
Neurological assessment score Critical / obtunded 
OR 
Stage 3, 4, or 5 papilledema1 or CSF opening pressure greater than or equal to 20 mmHg or 
cerebral edema 
CARTOX 10-point neurological assessment (Assign one point for each task performed correctly; score 
of 10 = normal) 
● Orientation to year, month, city, hospital, President: 5 points 
● Name 3 objects (point to clock, pen, button): 3 points  
● Ability to write a standard sentence (e.g., Our national bird is the bald eagle): 1 point 
● Count backwards from 100 by ten: 1 point 
1 Papilledema grading is performed according to Modified Frisén scale 
CSF = cerebrospinal fluid 
Table 6.4 
Management Guidelines for Encephalopathy 
Toxicity 
Grade 
Treatment 
Instructions for 
Interruption of 
ADXS11-001 
Modification for 
Subsequent 
Infusions 
1 
• 
Vigilant supportive care; aspiration precautions; 
IV hydration 
• 
Withhold oral intake of food/medicines/fluids 
and assess swallowing  
• 
Convert all oral medications and/or nutrition to 
IV if swallowing is impaired         
• 
Avoid medications that cause CNS depression     
• 
Low doses of lorazepam (0.25-0.5 mg IV every 8 
hours) or haloperidol (0.5 mg IV every 6 hours) 
may be used for agitated patients with careful 
monitoring 
• 
Neurology consultation 
• 
Daily CARTOX 10-point neurological 
assessment as in Table 6.3 
• 
Fundoscopic exam to assess for papilledema  
Not applicable 
Discuss with 
Sponsor 


 
 
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Toxicity 
Grade 
Treatment 
Instructions for 
Interruption of 
ADXS11-001 
Modification for 
Subsequent 
Infusions 
• 
MRI brain with and without contrast; diagnostic 
lumbar puncture with OP; MRI spine if focal 
signs exist; CT of brain may be performed if 
MRI brain is not feasible 
2 
• 
Supportive care and neurological workup as per 
Grade 1 
• 
IL-6 antagonist (tocilizumab1), if associated with 
other events such as refractory hypotension 
and/or hypoxia 
• 
Dexamethasone or methylprednisolone if 
refractory to tocilizumab1 therapy, when it is 
administered 
• 
Consider ICU transfer if associated with other 
events such as hypotension or hypoxia  
• Immediately 
interrupt 
ADXS11-001 
Discuss with 
Sponsor 
3 
• 
Supportive care and neurological workup as per 
Grade 1 
• 
ICU transfer is recommended 
• 
Tocilizumab1, if associated with concurrent 
refractory hypotension and/or hypoxia and if not 
administered previously 
• 
Dexamethasone or methylprednisolone around 
the clock, if symptoms worsen despite 
tocilizumab therapy. Continue corticosteroids 
until improvement to Grade 1 and then taper or 
stop. 
• 
Low grade (Stage 1 or 2) papilledema with CSF 
OP less than 20 mmHg, acetazolamide as per 
Institutional guidelines 
• 
Consider repeat neuro-imaging (CT or MRI) 
every 2-3 days if persistent event greater than or 
equal to Grade 3 
• Immediately 
interrupt 
ADXS11-001 
• Permanently 
discontinue 
ADXS11-001 
Not applicable 
4 
• 
Supportive care and neurological workup as per 
Grade 1 
• 
ICU monitoring; consider mechanical ventilation 
for airway protection 
• 
Tocilizumab1 and repeat neuro-imaging as per 
Grade 3 
• 
High dose methylprednisolone 
• 
For high-grade (Stage 3, 4, or 5) papilledema, 
CSF OP greater than or equal to 20 mmHg, or 
cerebral edema, follow Institutional guidelines 
for high dose steroids, hyperventilation, 
hyperosmolar therapy, metabolic profile; CT 
scan daily. 
• Immediately 
interrupt 
ADXS11-001 
• Permanently 
discontinue 
ADXS11-001 
Not applicable 
1IL-6 antagonist (tocilizumab) administration -  See Table 6.2 


 
 
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6.2.2 
Nausea/Vomiting 
Nausea and vomiting should be treated aggressively. In addition to the prophylactic 
antiemetic therapy subjects receive prior to each infusion, consideration should be given to 
subsequent administration of antiemetic therapy every 8 hours, as needed according to 
standard institutional practice. Subjects should also be strongly encouraged to maintain 
liberal oral fluid intake. 
6.2.3 
Hypotension 
In some instances (~7% of subjects receiving ADXS11-001) CTCAE Grade 3 and 4 
hypotension has been seen. The occurrence of hypotension may be related to increased levels 
of IL-6 which are strongly associated with capillary leak which manifests as hypotension due 
to the cytokines involved. Elevated IL-6 levels have been observed after infusion of 
ADXS11-001 with peak levels occurring 2-4 hours after infusion. Therefore, close 
monitoring of blood pressure is strongly recommended at baseline and during the post-
infusion period. 
 An updated algorithm for the grading and management of >Grade 3  
hypotension, hypoxia, encephalopathy, and other constitutional symptoms has been 
developed. 
Particularly, emerging evidence indicates that IL-6 antagonists, such as Tocilizumab, have 
demonstrated positive results in treating cytokine-induced hypotension [40-43]. Therefore, 
Tocilizumab is recommended for cases of hypotension which are refractory to supportive 
care (e.g., fluids and/or pressors; See Section 6.2.1). 
6.2.4 
Listeriosis and Listeria Infection - Identification and Management 
A person with wild type (wt) listeriosis usually presents with fever and muscle aches which 
may be preceded by diarrhea or other gastrointestinal symptoms. In most cases, a person who 
is diagnosed with listeriosis has an "invasive" infection in which the bacteria has spread 
beyond the gastrointestinal tract. However, the symptoms will vary with the infected person.  
Pregnant women are at a higher risk and typically experience fever and other non-specific 
symptoms such as fatigue and aches. Infections during pregnancy can lead to miscarriage, 
stillbirth, premature delivery, or life-threatening infection of the newborn.  In people other 
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and convulsions in addition to fever and muscle aches. Listeriosis can present in different 
ways. In older adults and people with a compromised immune system septicemia and 
meningitis are the most common clinical presentations [44].  In these extreme cases, 
appropriate medical management may include an immediate evaluation with a brain CT scan 
or MRI and a lumbar puncture with the analysis of spinal fluid to rule out meningitis. 
For symptomatic subjects, diagnosis is confirmed only after isolation of wt-Lm from a 
normally sterile site such as blood or spinal fluid (in the setting of nervous system 
involvement), or amniotic fluid/placenta (in the setting of pregnancy). Stool samples are of 
limited use and are not recommended. Wild-type Listeria monocytogenes can be isolated 
readily on routine media but care must be taken to distinguish this organism from other 
Gram-positive rods particularly diphtheroids. Selective enrichment media improve rates of 
isolation from contaminated specimens. Cultures will take approximately 1-2 days for 
growth. Importantly, a negative culture does not rule out infection in the presence of strong 
clinical suspicion. Serological tests are unreliable and not recommended at the present time 
[44].  
Listeriosis can be successfully treated using a wide range of antibiotics. In contrast, listeriosis 
which is a systemic organ infection caused by wild-type, invasive Lm infection, is highly 
unlikely to occur during study treatment with Advaxis Lm constructs due to the method of 
attenuation used in the Advaxis Lm constructs. Bacteremia with attenuated ADXS11-001 
(i.e., listeremia) can be documented in a blood culture taken within 24-72 hours after the 
infusion of ADXS11-001 and before the administration of antibiotics. It may or may not be 
associated with clinical signs and symptoms (e.g., fever, chills, headache, nausea, confusion 
or changes in alertness for several days) and it will limit itself by the time antibiotics are 
started (~72 h) (see Section 5.2.4). In preclinical studies, wt-Lm and ADXS11-001 are 
susceptible to the lowest tested concentration of the following antimicrobial agents:  
 
 
  
6.2.5 
Management of Listeria during Study Treatment Period  
6.2.5.1 
Management Immediately Following Completion of a Study 
Treatment Infusion 
Each subject will be given a 7-day supply of trimethoprim/sulfamethoxazoleor matching 
placebo to be taken beginning approximately 72 hours following the completion of each dose 
of study treatment, except for the last dose (see Section 6.2.6 for a description of post-
treatment antibiotics). Antibiotic treatment will consist of oral trimethoprim/ 
sulfamethoxazole (80 mg trimethoprim/400 mg sulfamethoxazole) administered once daily, 
or a matching placebo. Subjects who have an allergic reaction to or develop sensitivity to 
trimethoprim/sulfamethoxazole will be discontinued from the study. These subjects will be 
unblinded (Section 7.2.6.1.5) to confirm randomization to Arm B (ADXS11-001), and 
subjects confirmed randomized to Arm B will receive commercially available oral ampicillin 
500 mg four times daily. In the rare case that a subject also has a contraindication to 


 
 
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ampicillin, the subject may receive another antibiotic to which Listeria is sensitive to (refer to 
Section 6.2.4 and the Investigator’s Brochure) and there are no contraindications to 
administer it to the patient. Antibiotic treatment after each dose is intended to ensure 
elimination of ADXS11-001 and reduce the possibility of post-dose Lm persistence. 
In cases where a subject experiences a fever (CTCAE Grade 1 or greater) 24 hours following 
the completion of the study treatment infusion NSAIDs and other appropriate measures to 
treat the fever should be started. In the event that the fever persists or worsens 24 hours after 
starting NSAIDs and other appropriate measures then treatment with oral antibiotics (e.g., 
Bactrim) should be considered based on the subject’s medical condition. If the fever remains 
unresponsive to oral antibiotics after an adequate treatment course then the administration of 
IV antibiotics should be considered and a blood culture obtained to evaluate for listeremia in 
order to determine the appropriate treatment course for the subject. 
6.2.6 
Management of Listeria During the Follow-up Period  
After completion of study treatment, subjects will undergo extended antibiotic treatment and 
then begin Lm surveillance for a period of 1-year. Subjects will begin a 3-week course of 
antibiotics beginning 72 hours after the 8th dose of study treatment. The 3-week course of 
antibiotics will also begin after a decision has been made to discontinue further study 
treatment prior to the 8th dose. Antibiotic treatment will consist of 3 weeks of oral 
trimethoprim/ sulfamethoxazole (80 mg trimethoprim/400 mg sulfamethoxazole) 
administered once daily or a matching placebo. Subjects for whom trimethoprim/ 
sulfamethoxazole is contraindicated due to allergy or other reasons will be discontinued from 
the study. These subjects will be unblinded (Section 7.2.6.1.5) to confirm randomization to 
Arm B (ADXS11-001), any subjects confirmed randomized to Arm B will receive 
commercially available oral ampicillin 500 mg four times daily. In the rare case that a subject 
also has a contraindication to ampicillin, the subject may receive another antibiotic to which 
Listeria is sensitive to (refer to Section 6.2.5, 6.2.6 and the Investigator’s Brochure) and there 
are no contraindications to administer it to the patient. Extended treatment with 3-weeks of 
antibiotics is intended to reduce the possibility of post-treatment Lm persistence. Following 
the completion of the 3-week trimethoprim/sulfamethoxazole treatment, it is strongly 
recommended that a subject avoid having an implantable device which is not easily removed 
unless warranted based on the subject’s medical condition. In this case, the investigator, 
subject and the subject’s primary care provider should discuss the risk/benefit in order to 
make a well-informed decision. 
Lm surveillance will begin at 3 months (±2 weeks) after the 8th dose of study treatment or 
after early treatment discontinuation, and will consist of contacting subjects by phone every 3 
months (±1 week) to determine whether they have experienced the following symptoms that 
could potentially be associated with delayed listeremia: fever or chills, headache, nausea, 
confusion or changes in alertness for several days.  The contact will be made to all subjects 
who have received at least one dose of Study treatment for 1-year (see Section 5.2.4). If the 
subject’s response to having experienced any of the afore-mentioned symptoms is negative, 
the Lm surveillance would continue remotely through phone contacts. However, if the 
investigator, his/her research staff, other healthcare providers become aware of any positive 


 
 
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signs and symptoms of listeremia reported for a subject and listeremia is suspected, the 
subject should be tested for the presence of listeria in their blood culture, and treated as 
medically appropriate if a diagnosis of listeremia is made.  
It is extremely important that the investigator, his/her research staff, other healthcare 
providers involved in the care of the subject as well as each subject participating in this study 
are educated and made aware of the signs and symptoms of listeremia and the potential for 
delayed listeremia. Educational materials for the investigator, research staff, health care 
providers and subjects will be prepared and educational training performed. 
Thus, at the End of Study visit (which can be completed remotely via phone), subjects should 
be instructed to contact their primary care provider or the site if they experience any of the 
potential listeremia symptoms (i.e., fever or chills, headache, nausea, confusion or changes in 
alertness for several days).   
For subjects who have completed the Lm surveillance period, the subject’s primary care 
provider or the investigator should initiate evaluation of listeremia if suspected and treat 
accordingly. 
A subject should be treated as medically appropriate if a diagnosis of listeremia is made. 
Listeremia can be treated using IV antibiotics such as ampicillin and gentamycin (Note: 
ADXS11-001 is resistant to streptomycin and chloramphenicol). An infectious disease 
consult should be obtained to ensure optimal management of listeremia. Based on each 
individual subject’s case and at the discretion of the treating physician, the removal of any 
implanted device that has been present since treatment with ADXS11-001 was initiated may 
be warranted.  
6.2.7 
Management of Listeria in Subjects Who Withdraw Consent 
A subject who has received at least one dose of study treatment and withdraws consent at any 
time during her participation in the study should be reminded of the recommended course of 
action with respect to the detection and management of listeria as summarized above. 






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3 
Upon completion of the treatment period, subjects who have not had confirmed documented disease recurrence/recurrence, (as defined in Section 8.2.1 Definition of Recurrence) will continue with 
routine physical and pelvic examinations, tumor imaging and 
until documented disease recurrence or death during the Follow-up Phase.  
4 
Screening evaluations will be performed within the 28 day screening period, unless otherwise specified. 
5 
At every study treatment infusion, the indicated procedures will be performed within the specified window(s). 
6 
Informed Consent must be obtained prior to conducting screening evaluations. 
7 
Concomitant therapies and procedures will be collected from the time informed consent is signed through 30 days past last dose, and should be recorded in the eCRF. 
8 
Pretreatment prophylactic medication administration and IV hydration must be completed at least
before each study treatment infusion. The prescribed dosage of the selected 
prophylactic medications will be at the discretion of the Investigator. 
9 
Study treatment (ADXS11-001or placebo) may be administered ±3 days within Day 1 of each scheduled infusion. The assigned study treatment will be administered every 3 weeks for a total of 3 
doses during the Prime Phase and every 8 weeks for a total of 5 doses during the Maintenance Phase.   
10 All Subjects will receive a 7-day course of oral antibiotic therapy starting 72 hours after administration of each ADX11-001 treatment, except for the last treatment where subjects will receive a 
3 week oral antibiotic course (instead of the 7-day course) to be initiated 72 hours following the last dose of study treatment (administered at Week 47) or immediately upon discontinuation of 
study treatment.  
11 All AEs/SAEs will be assessed from the time Informed Consent is obtained through 30 days past last dose. Beyond that point, report the signs and symptoms of listeremia during the Lm surveillance 
period. All AE/SAEs will be followed through resolution. All AEs/SAEs experienced must be recorded on the eCRF. 
12 Physical Examinations (PEs) will be performed up to 3 days prior to the administration of study treatment to confirm safety criteria for study treatment administration are met. Focused physical 
examination to be performed during the Prime Phase on Weeks 4 and 7, and during the Maintenance Phase on the Week 23 visit.  Full physical exams should be performed on all other visits 
during the treatment period.  In the follow-up phase, full physical exams should be performed if a blood culture positive for Lm is reported.  PEs may be performed more frequently, as clinically 
indicated. 
13 Height measurement will be obtained at screening only. Monitor vital signs immediately
 for the first 4 hours following the completion of every 
study treatment infusion. Weight will be taken prior to each study treatment infusion. 
14 Pelvic exam inclusive of speculum exam with bimanual pelvic and rectal examination and will occur during End of Study treatment period or Early Discontinuation from treatment period, as 
applicable. Cervical and vaginal cytology will be performed at Screening only unless deemed necessary by the treating physician. 
15 All laboratory procedures are to be completed and assessed by the Investigator no more than 3 days prior to the administration of study treatment to confirm safety criteria for study treatment 
are met. 
16 Prior to each study treatment, subjects must be thoroughly screened for an ongoing or active infection.  Subject’s whose pre-treatment CBC reveals leukocytosis may need additional evaluation 
(e.g. urinalysis, etc.) to rule out an active infection.  Confirmed infection will result in a delay of study treatment and must receive appropriate antibiotic treatment.  Study treatment may resume 
following at least 5 half-lives from the subject’s final antibiotic dose. 
17 Coagulation tests will only be required at Screening as a baseline value. 
18  Urine pregnancy tests must be performed within 3 days prior to each study treatment infusion for subjects of childbearing potential. If the urine test is positive or cannot be confirmed as negative, 
a serum pregnancy test will be required. 
19 Lm Surveillance Monitoring will include a 3-weeks course of oral antibiotics and routine monitoring of subjects via phone contact, and blood cultures if subjects report experiencing potential signs and 
symptoms of listeremia  All assessments will be performed beginning on the 3rd month after the last dose of study treatment during the 1-year Lm surveillance monitoring period or immediately at the 
time of study discontinuation unless a subject withdraws her consent  
20 Contrast-enhanced CT of the chest, abdomen and a contrast-enhanced MRI or PET/CT of the pelvis are required.  If a contrast-enhanced CT of the pelvis is performed, an MRI or PET/CT of the 
pelvis is still required, as described in the Advaxis Imaging Manual. The modality selected for a patient for imaging of the pelvis (either contrast-enhanced CT and MRI or PET/CT) must be 
used consistently for the patient throughout the study.  Baseline tumor imaging must be performed within 28 days prior to the first study treatment infusion. Imaging during the Treatment 
Period will occur at Weeks 12, 24, 36, and 48 as indicated provided a subject does not experience disease recurrence.   
21 


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22 
23 Subjects with documented disease recurrence will complete the 1 year Lm Surveillance Period, be contacted by phone every 3 months (±1 week) to collect status of signs and symptoms of 
listeremia (see Section 5.2.4 and 6.2.6). 
24 At the completion of therapy, or upon the decision to discontinue/withdraw a subject prior to study completion, all treatment assessments will be completed. Subjects will then be contacted by 
phone every 3 months (±1 week) for Lm Surveillance monitoring for 1-year (see footnote 23).   
25 After all screening procedures have been completed, Investigators should utilize the IRT for treatment assignment. Subsequently, the IRT should be utilized on an as-needed basis for study drug 
resupply purposes.


 
 
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7.2 
Study Procedures 
The Schedule of Events (Section 7) summarizes the study procedures to be performed at each 
visit.  Individual study procedures are described in detail below. It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
Investigator. 
7.2.1 
Administrative Procedures 
7.2.1.1 
Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to 
participating in the study. Consent must be documented by the subject’s dated signature on 
the most current Institutional Review Board/Independent Ethics Committee (IRB/IEC) 
approved ICF or ICF addendum document along with the dated signature of the person 
conducting the consent discussion. 
A copy of the signed and dated ICF should be given to the subject before participation in the 
study. 
The initial ICF, any subsequent revised written ICF/ICF addendum and any written 
information provided to the subject must receive the IRB/IEC’s approval/favorable opinion 
in advance of use. The subject should be informed in a timely manner if new information 
becomes available that may be relevant to the subject’s willingness to continue participation 
in the study. The communication of this information will be provided and documented via a 
revised consent form or addendum to the original consent form that captures the subject’s 
dated signature. 
The ICF will adhere to IRB/IEC requirements, applicable laws and regulations, and Sponsor 
requirements. 
7.2.1.2 
Eligibility Criteria 
All inclusion and exclusion criteria will be reviewed by the Investigator or qualified designee 
to ensure that the subject qualifies for the study. 
7.2.1.3 
Subject Identification Card 
A subject will be given a Subject Identification Card identifying them as participants in a 
research study. The card will contain study site contact information (including direct 
telephone numbers) to be utilized in the event of an emergency. The Investigator or qualified 
designee will provide the subject with a Subject Identification Card after the subject provides 
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7.2.1.4 
Demographics/Medical/Surgical History 
Demographic information, medical and surgical history, including surgical history for cancer 
will be obtained by the Investigator or qualified designee. Medical history will include all 
active conditions and any condition diagnosed within the prior 10 years that are considered to 
be clinically significant by the Investigator. 
7.2.1.5 
Prior Cancer History 
The Investigator or qualified designee will obtain prior and current details regarding disease 
status, including histopathologic confirmation of cancer, all prior cancer treatments and best 
response(s), if applicable (e.g., systemic, radiation and surgeries). 
7.2.1.6 
Prior/Concomitant Therapies and Procedures  
The Investigator or qualified designee will review all prescription and nonprescription 
medication (excluding vitamins and nutritional supplements) taken by the subject from 
screening up to and including 30 days after the last administration of assigned study 
treatment when a subject discontinues her participation in the study; Protocol-mandated 
prophylactic medications and antibiotics administered during the 3-year Lm surveillance 
phase should also be captured in the eCRF along with any new procedures which are 
performed during this time. All of this information will be recorded in the subject’s medical 
record and on the eCRF.  Any addition, deletion, or change in the dose of these medications 
will also be recorded. Generic names should be used to eliminate confusion that may result 
from trade names.   
7.2.1.7 
Administer Prophylactic Medications 
See Section 5.2.3.1 Pretreatment Prophylactic Regimen. 
7.2.1.8 
Study Treatment Administration 
See Section 5.2.3.2 Placebo or ADXS11-001 Regimen. 
7.2.1.9 
Administer Oral Prophylactic Antibiotics  
(1) During Study Treatment Period - All subjects will receive a 7-consecutive day course 
of oral antibiotic therapy starting approximately 72 hours (Day 4) after administration of 
each study treatment, except for the final dose of study treatment (either as per the Schedule 
of Events or upon discontinuation of study drug), at which time all subjects will receive a 3-
week course of oral antibiotic therapy starting approximately 72 hours later (see (2), Post 
Study Treatment, below). Antibiotic therapy should consist of 80 mg trimethoprim/400 mg 
sulfamethoxazole tablet or matching placebo to be administered once daily for 7 consecutive 
days. Subjects who are not able to tolerate trimethoprim/ sulfamethoxazole will be 
discontinued from the study. These subjects will be unblinded (Section 7.2.6.1.5) to confirm 
randomization to Arm B (ADXS11-001), and subjects confirmed randomized to Arm B will 
receive commercially available oral ampicillin 500 mg four times daily. In the rare case that a 
subject also has a contraindication to ampicillin, the subject may receive another antibiotic to 


 
 
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which Listeria is sensitive to (refer to Section 6.2.5 and the Investigator’s Brochure) and 
there are no contraindications to administer it to the patient. See Section 6.2.6 “Management 
and Surveillance of Listeria during Study Treatment Phase” for additional information. 
(2) Post Study Treatment – All subjects will receive a 3-week course of oral trimethoprim/ 
sulfamethoxazole as defined in Section 7.2.1.9 (1) above to be initiated approximately 72 
hours following the last dose of study treatment or immediately at the time of study 
discontinuation from the treatment period of the study. The dose and dosing instructions are 
also defined in Section 7.2.1.9 (1) above.  
7.2.2 
Clinical Procedures/Assessments 
7.2.2.1 
Adverse Event Monitoring 
The Investigator or qualified designee will assess each subject to evaluate for potential new 
or worsening AEs as specified in the Schedule of Events and more frequently if clinically 
indicated. AEs will be recorded starting from the time that the first dose of study treatment is 
administered through the completion of the Lm surveillance period. Adverse and serious 
adverse events experienced during this period will be reported and recorded in the eCRF. 
Adverse experiences will be graded according to NCI CTCAE v 4.03 (see Section 10.2).  
Toxicities will be characterized in terms regarding seriousness, causality, toxicity grading, 
and action taken with regard to study treatment. 
7.2.2.2 
Physical Examination 
The Investigator or qualified designee will perform focused physical examinations (PE) 
during the Prime Phase on Weeks 4 and 7, and during the Maintenance Phase on the Week 
23 visit.  Full physical exams should be performed on all other visits.  
The “full” PE will include the following organ or body system assessments: skin; head, eyes, 
ears, nose, and throat; thyroid; lungs; cardiovascular; abdomen (liver, spleen); extremities; 
groin, axillary and neck lymph nodes; assessment for edema and/or ascites, and a brief 
neurological exam; Gynecologic exam: external genitalia, speculum exam of the vagina, 
digital exam of the vagina and digital exam of the rectum/anus.  
The “focused” PE will include the following assessments: examination of all symptomatic 
areas as well as skin; head; lungs; cardiovascular; abdomen (liver, spleen); extremities; groin, 
axillary and neck lymph nodes; assessment for edema and/or ascites; neurological exam. 
A clinically significant finding or a worsening in a PE finding from the previous visit in the 
opinion of the Investigator or qualified designee will be recorded in the eCRF and reported as 
an AE.  
PEs may be performed more frequently, as clinically indicated. An “Unscheduled Visit” form 
will be used to record this information in the eCRF.  


 
 
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7.2.2.3 
Vital Sign Measurements 
The Investigator or qualified designee will measure and record vital signs (including blood 
pressure, pulse rate, respiratory rate, and temperature) at the Screening Visit, prior to each 
assigned study treatment administration and
following each study treatment infusion. Weight will be collected prior to each study 
treatment infusion. Height will be measured at Screening Visit only. 
A clinically significant finding or a worsening in a PE finding from the previous visit in the 
opinion of the Investigator or qualified designee will be recorded in the eCRF and reported as 
an AE.  
7.2.2.4 
Performance Status 
The Investigator or qualified designee will assess GOG performance status (see Section 14.2 
GOG Performance Scale). 
7.2.2.5 
Pelvic Examination 
The investigator or qualified designee will perform a pelvic exam which will include a 
speculum exam with bimanual pelvic and rectal examination.  Cervical and vaginal cytology 
will be performed at Screening only unless deemed necessary by the treating physician. 
7.2.3 
Laboratory Procedures/Assessments 
Laboratory tests will be performed within 3 days prior to each dose of study treatment 
administered.  The laboratory results must be reviewed by the Investigator or qualified 
designee and found to meet all defined dosing criteria in order for a subject to receive 
study treatment (See Table 7 
Laboratory Tests). 
Subjects must also be thoroughly screened for an ongoing or active infection prior to each 
treatment infusion. Subjects whose pre-infusion CBC reveals leukocytosis may need 
additional evaluation (e.g. a urinalysis) to rule out an active infection.  Subjects with 
documented ongoing or active infection must receive appropriate antibiotic treatment for 
their underlying infection and return to ≤ CTCAE Grade 1 prior to dosing with study 
treatment. The Investigator should call the Sponsor to discuss a specific subject’s case if 
there appears to be special circumstances which could result in resuming study treatment. In 
addition, the subject must also be at least 5 half-lives from their last dose of antibiotic. 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in (Table 7). 
Surveillance monitoring for the detection of Lm will be initiated at the completion of study 
treatment according to the protocol or at the time of study discontinuation, if earlier.  See 
Section 5.2.4 Follow-up Period for further details. All blood cultures that grow Lm will be 
reported to FDA as part of the Adverse Event and Serious Adverse Event monitoring during 
the Lm surveillance period.


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Table 7 
Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
  (β-hCG)† 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
Lm Surveillance blood cultures* 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
Specific gravity  
 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
Microscopic exam (If abnormal) 
 
Absolute Neutrophil Count 
C-Reactive Protein (CRP)* 
Carbon Dioxide ‡ (CO2 or bicarbonate) 
Urine pregnancy test † 
 
 
Creatinine 
 
 
 
Calcium 
 
 
 
Chloride 
Erythrocyte Sedimentation Rate (ESR)* 
Glucose 
 
 
 
Potassium 
 
 
 
Sodium   
 
 
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of normal) 
 
  
 
Total Protein 
 
  
 
Blood Urea Nitrogen 
 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required.   
‡ If considered standard of care in your region. 
*Lm surveillance Monitoring will include routine monitoring of CBC, CMP (including CRP, ESR) and blood cultures.  All blood cultures positive for Lm will 
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7.2.5 
Efficacy Assessments 
The efficacy endpoints of the study are Disease Free Survival (DFS) and Overall Survival 
(OS). They will be assessed as follows: 
7.2.5.1 
Histologic/Cytologic Assessment for Disease Recurrence 
Suspicion of recurrence can be based upon multiple clinical factors such as an abnormal 
physical and/or pelvic exam, including cytology and/or imaging. A biopsy and histologic 
examination and/or cytologic examination of a Fine Needle Aspirate (FNA) of a new 
suspected lesion is required to confirm disease recurrence when it is feasible in the opinion of 
the investigator. 
A cytologic examination of a PAP smear is not acceptable to make a determination of 
recurrence however a cytologic examination of a Fine Needle Aspirate (FNA) of a new 
suspected lesion is acceptable to make a determination of recurrence. 
7.2.5.2 
Radiographic Assessments for Disease Recurrence 
Baseline scans must be performed within 28 days of first study treatment infusion and must 
include contrast-enhanced CT of the chest and abdomen, plus a contrast-enhanced MRI of 
the pelvis; or a fluorodeoxyglucose (FDG) PET/CT of the chest, abdomen and pelvis.  When 
PET/CT is used, the CT component of the PET/CT must be of diagnostic quality. Each 
anatomic area must be assessed using the same method at all time points (baseline and post-
baseline) for each subject. 
Note: The only acceptable methods of imaging the pelvis are MRI and PET/CT. 
For subjects who have a medical contraindication to IV iodinated CT contrast, a non-contrast 
CT of the chest is acceptable; however, the abdomen must be imaged using a contrast-
enhanced MRI. A non-contrast CT of the abdomen is not acceptable. 
7.2.5.2.1 
Unscheduled Radiographic Assessments 
The schedule for radiographic assessments is detailed in Section 7.1 - Schedule of Events.  
Unscheduled radiographic assessments can occur and are based upon the clinical judgment of 
the investigator. Reasons for an unscheduled assessment may include, but are not limited to, 
clinical deterioration, subject complaint and/or findings stemming from a physical 
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Any unscheduled imaging assessment should be analyzed by the site for recurrence and 
labelled in the eCRF as an “Unscheduled Visit.” This assessment will also be submitted to 
the central imaging laboratory for evaluation. If the unscheduled imaging assessment occurs 
within 2 weeks of a scheduled visit, the unscheduled images should be evaluated with the 
nearest scheduled timepoint images. If disease recurrence is not confirmed on the evaluation 
of the images obtained at an unscheduled timepoint and within 2 weeks of a scheduled 
timepoint assuming all of the required scans were performed during the Unscheduled Visit 
then performing an additional radiographic assessment the next scheduled timepoint is not 
necessary. 
7.2.6 
Other Procedures 
7.2.6.1 
Withdrawal/Discontinuation and End of Study Visit 
7.2.6.1.1 
Discontinuation during Treatment Period Due to Disease 
Recurrence 
When a subject meets a reason for discontinuation due to disease recurrence prior to the 
completion of the Treatment Period (Prime + Maintenance Phases), an End of Study (EOS) 
visit will be conducted and all applicable assessments, including physical examination, vital 
signs, performance status, pelvic examination, hematology and chemistry profile, urine 
dipstick, pregnancy test, as applicable, tumor imaging, dispense course of oral antibiotic, and 
should be performed. Any AEs that are present at the time of 
discontinuation should be followed in accordance with the safety requirements outlined in 
Section 10. The subject will enter the Post-Disease Recurrence Period and Lm Surveillance 
Period will be initiated at this time. 
7.2.6.1.2 
Early Discontinuation 
Early discontinuation is defined as discontinuation during the treatment period for a reason 
other than disease recurrence. During the Study Treatment Period, when a subject meets a 
reason for discontinuation other than disease recurrence prior to the completion of the 
Treatment Period (Prime + Maintenance Phases) all applicable DFS assessments (i.e.: tumor 
imaging, pelvic examinations, and
) should be performed in accordance 
with the Visit Schedule until early study termination, 6 years from the date of enrollment, 
disease recurrence, or death, whichever comes first. Any AEs that are present at the time of 
discontinuation should be followed in accordance with the safety requirements outlined in 
Section 10. The subject will enter the Follow-up Phase and the Lm Surveillance period will 
be initiated. Oral prophylactic antibiotics will be administered. 
In subjects who have not experienced disease recurrence, physical exams, pelvic exams, and 
tumor imaging will occur at Weeks 12, 24, 36, and 48 during the first year (from date of 
enrollment) on trial, until early study termination, whichever comes first. During the second 
year, pelvic exams and tumor imaging will occur every 3 months (±1 week), and then every 6 
months (±1 week) thereafter for four years, or until early study termination, whichever comes 
first.  
 so they 
coincide with the scheduled visits to assess tumor imaging and pelvic exams and with the 


 
 
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End of Study visit, which will occur 6 years from date of enrollment, or until early study 
termination, whichever comes first.  
7.2.6.1.3 
Discontinuation during the Follow-up Phase  
During the Study Treatment phase, when a subject meets a reason for discontinuation from 
treatment, the EOS Visit should be conducted, after which the subject will enter the Lm 
Surveillance Period and will continue in accordance with the protocol requirements. During 
the Follow-up Phase, reasonable efforts should be made to have the subject contacted 
remotely  and report any AEs that may occur during this phase.  
7.2.6.1.4 
Withdrawal of Informed Consent 
In the event that any subject withdraws from the study treatment prior to completion, 
regardless of reason, reasonable efforts should be made to have the subject return for an EOS 
visit to have applicable assessments completed. The date the subject discontinued the study 
and specific reason for discontinuation will be recorded in the eCRF. 
7.2.6.1.5 
Blinding/Unblinding 
Blinding of treatment assignment is critical to the integrity of this clinical study. However, in 
the event of a medical emergency or pregnancy in an individual subject in which knowledge 
of the investigational product is critical to the subject's management, the blind for that subject 
may be broken by the investigator during the study. The subject’s safety takes priority in 
determining if a treatment assignment should be unblinded during the study. 
Before breaking the blind of an individual subject's treatment, the investigator should 
determine that the unblinded information is necessary (i.e. that it will alter the subject's 
immediate management, as in the case with subjects who discontinue due to the development 
of sensitivity to Bactrim). In many cases, the problem may be properly managed by assuming 
that the subject is receiving active product (ADXS11-001) and treated accordingly. It is 
highly desirable that the decision to unblind treatment assignment during the study be 
discussed with the Medical Monitor, but the investigator always has ultimate authority for the 
decision to unblind during the course of the study. The Principal Investigator should only call 
for emergency unblinding during the study AFTER the decision to discontinue the subject 
has been made. 
For subjects who are receiving treatment and have not progressed, the Sponsor, subjects, 
investigator and site staff will be blinded to the study drug. Each investigative site must 
assign an unblinded pharmacist/designee, and an unblinded site monitor will be assigned by 
sponsor to provide oversight of drug supply and other unblinded study documentation. The 
Sponsor’s central protocol team (including but not limited to clinical, statistics, data 
management) will remain blinded. 
For this study, the method of unblinding is through the IVRS. For information on how to 
unblind for emergency, please consult the IVRS manual. In cases of accidental unblinding 
during the study, contact the Medical Monitor and ensure every attempt is made to preserve 


 
 
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the blind my minimizing the total amount of individuals that may become unblinded. Any 
request to unblind a subject for non-emergency purposes during the blinded portion of the 
study is required to be discussed with the Medical Monitor. 
8 EVALUATION CRITERIA 
8.1 
Assessment of Disease 
Assessment of disease will be performed to evaluate for the development of new disease, and 
will include: 
• Physical exam 
• Pelvic exam  
• Tumor imaging  
• Confirmatory biopsy (when it can be safely achieved in the opinion of the 
investigator) 
8.1.1 
Assessment of Disease Free Survival using Radiological Imaging 
Methodology 
The primary endpoint of the study is DFS; therefore, the use of contrast-enhanced CT and 
MRI or PET/CT scans is to achieve the primary objective of identifying disease recurrence.  
RECIST 1.1 criteria is an accepted method for determining PFS in patients with metastatic 
disease where a primary goal of the study is to assess the ability of a drug to reduce or 
eradicate a tumor which was identified using radiological imaging. However, the patients 
who will be enrolled in this study will be unlike those enrolled in the majority of the studies 
which have used RECIST 1.1 because they must have no measurable or non-measurable 
disease at the baseline imaging assessment in order to be eligible to participate in the study. 
In addition, a primary objective of the study is to prevent tumor recurrence in accordance 
with the definitions provided in the following sections and not to achieve a tumor “response.” 
Therefore, this study will only evaluate the ability of ADXS11-001 to prevent tumor 
recurrence and accordingly the only relevant designation for each timepoint measured by 
radiological imaging will be either “recurrence” or “no recurrence.” As a result, 
modifications to the way that the RECIST 1.1 criteria will be implement are needed. The 
modifications to the way the RECIST criteria are applied are justified because this study 
population has: (1) has already received treatment for their cancer; (2) has no measurable or 
non-measurable disease by RECIST 1.1 criteria following CCRT with curative intent to 
follow during the study; (3) will be evaluated only for disease recurrence and (4) the results 
from a biopsy of the tumor being evaluated will be used as confirmation of disease. The 
intended “spirit” of RECIST 1.1 will be employed by using the terms and measurement 
criteria when they apply to this study and patient population. 
A detailed description of tumor imaging assessments is provided below as well as in the 
Imaging Review Charter. 


 
 
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8.2 
Determination of Disease Recurrence 
The following criteria define the methodology which can be used to define disease 
recurrence.  
• Clinical deterioration alone cannot be utilized as the sole determinant of recurrence and 
needs to be confirmed by either imaging or confirmatory biopsy. 
• Results from the physical and/or pelvic exam, including cytologic assessment of a PAP 
smear, cannot be utilized as the sole determinant of recurrence and need to be confirmed 
by either radiographic imaging or confirmatory biopsy/fine needle aspirate of a suspected 
lesion.   
• Results from biopsy/FNA of a suspected lesion can be utilized as the sole determinant of 
recurrence. However, results from radiographic imaging as determined by independent 
radiology review can only be utilized as the sole determinant of recurrence in the event 
that a tissue confirmation is not medically feasible in the opinion of the investigator. In 
cases where radiologic imaging confirms disease recurrence and a biopsy/FNA was 
obtained of the tumor being evaluated by imaging which is negative, then the subject will 
be considered to have disease recurrence. Histopathologic or cytologic assessment of 
tumor can occur by local lab. 
8.2.1 
Definition of Recurrence 
The determination of recurrence must occur by definitive pathologic tissue confirmation 
(e.g., biopsy/fine needle aspirate). However, in those cases where it is not medically feasible 
to obtain a tissue sample then radiographic evidence, when confirmed by independent 
radiology review, will be used to determine recurrence. 
8.2.1.1 
Pathologic Definition of Recurrence 
If a suspected lesion, especially in a previously irradiated field, is evaluated by 
histopathologic or cytologic examination and determined to be positive by biopsy/fine needle 
aspirate then the subject will be deemed to have progressed.  Evaluation of suspected tumor 
material will occur at the site by a qualified pathologist. 
8.2.1.2 
Types of Radiographic Assessments 
Three types of radiologic assessments will be performed in this study. 
(1) Site Reads – These are performed on all subjects at baseline and follow-up 
time points.  The site reads are used primarily for subject management.  
(2) Confirmation of Recurrence Reads – These reads are performed by a small, 
limited pool of independent radiologists trained on the criteria and with 
expertise in radiologic evaluation of this subject group.  If the results of the 
Site Read demonstrate recurrent disease (RD,) the images are electronically 
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results of an independent Confirmation of Recurrence (COR) will be 
transmitted to the site.  The role of this reader is very targeted – to ONLY 
confirm or not confirm disease recurrence.  The purpose of this assessment is 
to prevent subjects from being removed too early before true recurrence has 
actually occurred. 
(3) Blinded Independent Read – Each subject will be separately evaluated by two 
readers for the RD parameters.  When the two readers disagree on the 
presence or date of recurrence, a third expert reviewer (the Adjudicator) will 
review all results and select to agree with either reader A or B.  The purpose 
of this read is to confirm RD. A separate radiology charter provides detailed 
information on all aspects of the radiographic assessments to be utilized for 
this protocol including adjudication. An independent radiology review will be 
conducted to confirm recurrence for all subjects. The independent radiology 
review will both an independent efficacy review and an independent review of 
COR. 
In summary:  
• The objective of the independent efficacy review is to prospectively determine when 
a subject enrolled in the study has developed a new tumor(s) that qualifies them for 
the recurrence determination.  Expert and trained independent efficacy reviewers will 
interpret the images for the radiology review with no clinical information available. 
The independent efficacy review will provide the Sponsor with an assessment of the 
Time Point Response (TPR; NOTE: TPR will be limited to Recurrent Disease, [RD], 
non-RD, or Unable to Evaluate [UE] only; refer to Section 8.2.1.4) and the Date of 
Recurrence (if applicable) for each subject enrolled in the study. 
• Separately, the independent COR review will provide the Sponsor and the 
investigator with a rapid confirmation of site-determined radiographic disease 
recurrence in instances when radiographic disease recurrence is suspected by the site 
radiologist. The purpose of this COR process is to provide the site PI with the best 
possible information regarding radiographic disease recurrence 
• The population under evaluation by the independent efficacy reviewers will include 
all subjects enrolled on the ADXS001-02 study. For the purposes of the COR review, 
the population under evaluation by the independent COR reviewers will be all 
subjects suspected of having radiographic disease recurrence by the site radiologist 
and whose images were submitted to the central imaging lab for expedited COR 
review. 
 
All treatment decisions remain the responsibility of the investigator. 
A flow chart for the Independent Radiology Review Methodology can be found in 
Appendix 14.6. 


 
 
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8.2.1.2.1 
Date of Recurrence 
The Date of Recurrence is defined as the date of the first time point when RD is determined. 
8.2.1.2.2 
Assessment Date Conventions 
It is acknowledged that an assessment may include several methods of evaluation performed 
over a period of several days within a window of time around an expected assessment date. 
The convention to be followed when assessing each time point will be to assign a single date 
to evaluations performed within that time point. The Time Point Response (TPR) date will be 
recorded as the date of the first radiographic evaluation included in the series for that 
assessment. 
8.2.1.3 
Definition of Non-Disease Recurrence 
An assessment of non-recurrent disease (Non RD) will be made when the criteria for RD has 
not been met and the TPR is neither UE nor NA. 
8.2.1.4 
Radiographic Assessment of Time Point Response 
Radiographic assessments at each time point will be based on the presence or absence of new 
lesions. The time point assessment will be classified as either non-RD, RD or UE.  This TPR 
is assessed with reference to Baseline for the evaluation of RD. The TPR for each time point 
will still be determined even in cases where the prior time point demonstrates RD. In 
addition, if an identified new lesion subsequently becomes UE it will continue to be 
considered present and classified as a RD. 
Table 8 shows “Imaging Time Point Assignment of Response Including Biopsy 
Information.” In situations where a biopsy result is negative for tumor, but results from 
imaging demonstrate disease recurrence then the final determination of RD will be based on 
the imaging results. In situations where a biopsy result is positive for tumor, but results from 
imaging do not demonstrate disease recurrence, then the final determination of RD will be 
based on the biopsy results. 
 
 




 
 
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9 DURATION OF STUDY 
Subjects can receive assigned study treatment for up to 1 year. Subjects may refuse the study 
treatment at any time. Subjects who complete the Treatment Period or discontinue study 
treatment, will enter the Follow-up Phase (Section 5.2.4) for a total 1 year. During the 
Follow-up Period, all subjects will be contacted by phone every 3 months (±1 week) to 
determine whether they have experienced for several days, the following symptoms that 
could potentially be associated with delayed listeremia: fever or chills, headache, nausea, 
confusion or changes in alertness (see Section 6.2.6 for Management of Listeria During the 
Follow-up Period).       
9.1 
Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be discontinued from study 
treatment at the discretion of the Investigator should any untoward effect occur.  In addition, 
a subject may be withdrawn by the Investigator or the Sponsor if enrollment into the study is 
inappropriate, the study plan is violated or for administrative and/or other safety reasons.  
Specific details regarding discontinuation or withdrawal are provided in Section 9.1. 
A subject may be discontinued from the study with no further follow-up or data collection for 
any of the following reasons: 
• Screen Failure 
• Subject Lost to Follow-Up 


 
 
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• Death 
• Withdrawal of Consent by Subject 
• Other (specify) 
A subject may be discontinued from study treatment, but will continue to be followed for any 
of the reasons listed below: 
• Confirmed Disease Recurrence 
• Clinical Deterioration  
• Adverse Event/Serious Adverse Event 
• Sponsor Decision to Stop Study 
• Withdrawal of Consent by Subject 
• Investigator Decision  
• Study Non-Compliance by Subject 
• Subject has Positive Pregnancy Test 
In all cases, the reason for and date of study discontinuation must be recorded in the eCRF 
and in the subject's medical records. The subject must be followed up to establish whether 
the reason was an AE, and, if so, this must be reported and monitored through resolution. 
The Investigator must make every effort to contact subjects who discontinue the study 
prematurely or are lost to follow-up in order to schedule the end of therapy assessments.  
These attempts to contact such subjects must be documented in the subject’s records. It is 
expected that three phone calls and sending a certified letter will be sufficient to establish 
diligence in efforts to contact the subjects. 
All subjects who discontinue study treatment will continue to be followed and evaluated for 
recurrence as outlined in Section 7.1, Schedule of Events, for up to 5 years or death. 
9.2 
Subject Replacement Strategy 
Subjects will not be replaced. 
10 ADVERSE EVENT MONITORING AND REPORTING 
PROCEDURES 
All Investigators have the primary responsibility for AE identification, documentation, 
grading, and assignment of attribution to the study treatment. It is the responsibility of the 


 
 
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Investigator to supply the medical documentation needed to support expedited AE reports in 
a timely manner. 
10.1 Definitions 
Adverse event (AE): any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding, for example), symptom, or 
disease temporally associated with the use of a medicinal product or protocol-specified 
procedure, whether or not considered related to the medicinal product or protocol-specified 
procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or 
intensity) of a preexisting condition that is temporally associated with the use of study 
treatment (ADXS11-001 or Placebo) is also an AE. 
AE(s) may occur during the course of the study, from overdose (whether accidental or 
intentional), or from abuse and withdrawal. 
AE(s) may also occur in screened subjects during any pre-allocation baseline period as a 
result of a protocol-specified intervention, including washout or discontinuation of usual 
therapy, diet, placebo treatment or a procedure. 
Serious adverse event (SAE): any AE occurring at any dose or during any use of ADXS11-
001 or Placebo that: 
• Results in death 
• Is life threatening 
• Results in persistent or significant disability/incapacity 
• Results in or prolongs an existing inpatient hospitalization 
• Is a congenital anomaly/birth defect 
• Is a new cancer (that is not a condition of the study) 
• Is associated with an overdose 
• Is another important medical event 
Recurrence of the cancer under study is not considered an AE unless it results in 
hospitalization or death. 
Overdose: any dose exceeding the prescribed dose by 100%.  No specific information is 
available on the treatment of overdose of ADXS11-001. In the event of an overdose, the 
subject should be observed closely for signs of toxicity. Appropriate supportive treatment 


 
 
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should be provided if clinically indicated. If an AE(s) results from the overdose of 
ADXS11-001, the AE is reported as a SAE(s), even if no other seriousness criteria are met.  
An overdose without any associated clinical symptoms or abnormal laboratory results is 
reported as an AE. 
10.2 Assessing and Recording Adverse Events 
AEs will be recorded and assessed from the time the informed consent form is signed 
through 30 days past last dose. Beyond that point, AEs related to the signs and symptoms of 
listeremia should be assessed and reported during the Lm surveillance period. Events will be 
recorded on the AE eCRF. AEs will also be assessed to determine if it meets the definition of 
“serious.” In the event that an AE meets the criteria for “serious” the appropriate SAE form 
will be completed and the event reported in accordance with the required time period. The 
reporting timeframe for SAEs is described in Section 10.2.5.  
10.2.1 
Evaluating Adverse Events 
An Investigator who is a qualified physician will evaluate all AEs according to the NCI 
CTCAE v 4.03. Any AE that changes CTCAE grade over the course of a given episode will 
have each change of grade recorded on the AE eCRF. In these cases, when the intensity of an 
AE changes over time for a reporting period (e.g., between visits) each change in intensity 
will be reported as an adverse event until the AE resolves. For example, 2 separate AEs will 
be reported if a subject experiences Grade 1 diarrhea for 3 days, meeting the definition of an 
AE, and then after 3 days the AE increases to a Grade 3 intensity that lasts for 2 days and 
then resolves. The Grade 1 event will be reported as an AE with a start date equal to the day 
the event met the AE definition and a stop date equal to the day that the event increased in 
intensity from Grade 1 to Grade 3. The Grade 3 event will also be reported as an AE with the 
start date equal to the day the event changed in intensity from Grade 1 to Grade 3 and a stop 
date on the day that the event changed intensity again or resolved. For analysis purposes, this 
will be considered one AE for this subject and the maximum intensity will be recorded. 
When possible, AEs should be described in terms of a change in the baseline status or with a 
diagnosis or summary term rather than as individual symptoms. 
Criteria for Determining AE Severity: The descriptions and grading scales found in the 
revised NCI CTCAE v 4.03 will be utilized for AE reporting. 
Criteria for Determining AE Causality: The following attribution categories must be used in 
assessing the relationship between the AE and the study treatment: If the Investigator does 
not know whether or not the investigational agent caused the event, then the event will be 
handled as “related to investigational agent.” 
 


 
 
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RELATIONSHIP 
ATTRIBUTION 
DESCRIPTION 
Unrelated to investigational 
agent/intervention 
Unrelated 
The AE is clearly NOT related to the study treatment 
Unlikely 
The AE is doubtfully related to the study treatment 
Related to investigational 
agent/intervention 
Possible 
The AE may be related to the study treatment 
Probable 
The AE is likely related to the study treatment 
Definite 
The AE is clearly related to the study treatment 
10.2.2 
Laboratory Test Abnormalities 
Laboratory abnormalities that constitute an AE in their own right (are considered clinically 
meaningful, induce clinical signs or symptoms, require concomitant therapy or require 
changes in study treatment), should be recorded on the AE CRF. Whenever possible, a 
diagnosis, rather than a symptom should be provided (e.g., anemia instead of low 
hemoglobin). Laboratory abnormalities that meet the criteria for AEs should be followed 
until they have returned to normal or an adequate explanation of the abnormality is found. 
When an abnormal laboratory or test result corresponds to a sign or symptom of a previously 
reported AE, it is not necessary to separately record the laboratory/test result as an additional 
event. 
Laboratory abnormalities that do not meet the definition of an AE should not be reported as 
AEs. A Grade 3 or 4 (severe) event, as per CTCAE V4.03, does not automatically indicate a 
SAE unless it meets the definition of serious, as defined in Section 10.1 “Definitions” and/or 
as per the Investigator’s discretion. 
10.2.3 
Reporting Abnormal Test Findings 
The criteria for determining whether an abnormal test finding should be reported as an AE 
are as follows: 
• Test result is associated with accompanying symptoms; and/or 
• Test result requires additional diagnostic testing or medical/surgical intervention: 
and/or 
• Test result leads to a change in study dosing or discontinuation from the study, 
significant additional concomitant drug treatments, or other; and or 
• Test result is considered to be an AE by the Investigator or sponsor 
Merely repeating an abnormal test, in the absence of any of the above conditions does not 
constitute an AE.  An abnormal test result that is determined to be an error does not require 
reporting as an AE. 


 
 
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10.2.4 
Reporting Events Related to Immune Cell Activation  
The most relevant AEs to consider under this category are high-grade hypotension (refractory 
to fluids and vasopressors) and high-grade hypoxia. In the prior version of this protocol, 
these events were included under the term “cytokine release syndrome” (CRS) along with 
nausea, headache, tachycardia, rash, and shortness of breath as per NCI CTCAE v 4.03 
criteria. However, the description and grading scales for CRS in the NCI CTCAE v. 4.03 are 
not adequate to appropriately capture the toxicity associated with ADXS11-011, as per a 
recent communication from FDA. Investigators therefore are discouraged from using 
umbrella terms such as “cytokine release syndrome” or “infusion reaction” and are instead 
strongly encouraged to list each symptom and associated Grade individually.  
Considering these communications with FDA, > Grade 3 hypotension and >Grade 3 hypoxia, 
along with other high-grade organ toxicities, will be considered Events of Special Interest 
and for which new guidelines for grading and management have been developed 
 (Table 6.1-6.4). These are intended to be guidelines for the investigators, who will treat 
patients according to institutional recommendations. 
10.2.5 
 Immediate Reporting of Serious Adverse Events to the Sponsor 
Any SAE, or follow up to a SAE, including death due to any cause other than recurrence  of 
the cancer under study that occurs to any subject from the time the consent is signed through 
30 days past last dose, , whether or not related to ADXS11-001. Beyond that point, SAEs 
related to the signs and symptoms of listeremia should be assessed and reported during  the 
1-year  Lm surveillance period.  SAEs must be reported within 24 hours to the Sponsor at 
Syneos Health Clinical Pharmacovigilance (Attn:  Syneos SAE Reporting; FAX 866-880-
9343 or email: i3drugsafetyPV@syneoshealth.com  
Additionally, any SAE, considered by an Investigator who is a qualified physician to be 
related to ADXS11-001 that is brought to the attention of the Investigator at any time outside 
of the time period specified above also must be reported immediately to the Sponsor. 
SAE reports and any other relevant safety information are to be forwarded to Syneos Health 
Clinical Pharmacovigilance (Attn: Syneos SAE Reporting; FAX 866-880-9343 or email: 
i3drugsafetyPV@syneoshealth.com). 
All reports of overdose with AE(s) must be reported within 24 hours to Syneos Health 
Clinical Pharmacovigilance (Attn: Syneos SAE Reporting; FAX 866-880-9343 or email: 
i3drugsafetyPV@syneoshealth.com). 
10.2.6 
Reporting Pregnancy and Lactation to the Sponsor 
Although pregnancy and lactation are not considered AEs, it is the responsibility of 
Investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them), that occurs during the study or within 120 days of 
completing the study, or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier.  All subjects who become pregnant must be 


 
 
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followed to the completion/termination of the pregnancy. Pregnancy outcomes of 
spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal 
death, intrauterine death, miscarriage and stillbirth must be reported as an SAE (Important 
Medical Events). If the pregnancy continues to term, the outcome (health of infant) must also 
be reported. 
Such events must be reported within 24 hours of awareness to Syneos Health Clinical 
Pharmacovigilance (Attn: Syneos SAE Reporting; FAX 866-880-9343 or email: 
i3drugsafetyPV@syneoshealth.com). 
10.3 Data Monitoring Committee 
Details on safety monitoring, modifying or stopping the study early are found in the Data 
Monitoring Committee Charter. In general, consideration will be given to modifying the 
treatment or stopping the study early based on the reports of the DMC if: 
1. the futility boundary is crossed in the planned, formal interim analysis (See Section 11.3) 
2. a clearly more effective therapy becomes available 
3. the toxicity associated with ADXS11-001 treatment appears to outweigh the potential 
benefit to the subjects 
The toxicity would be considered excessive if in the ADXS11-001 arm there is a 
significantly higher than expected rate of life-threatening (Grade 4) AEs. The DMC will 
formally evaluate unblinded study reports which will provide detailed tabulations of all AEs 
by grade and treatment group on a regular, ongoing basis in accordance with the schedule as 
defined in the DMC Charter. 
11 STATISTICAL CONSIDERATIONS 
In the original study design (Protocol Version 1.1 – Version 4.1), a total of 450 subjects were 
to be randomly assigned (1:2) to Placebo (Arm A; control arm) or ADXS11 001 (Arm B; 
experimental arm). However, after the 110th subject was randomized, the Sponsor terminated 
the study and further enrollment early for reasons other than safety and efficacy.  Therefore, 
the assessments and analyses in the Statistical Analysis Plan will apply only to the 110 
subjects randomized by the time of early study termination. 
All subjects enrolled in the study will be moved to the End of Treatment (EoT) visit by 31 
July 2019 (except for 1 subject whose last dose occurring by 4 September 2019) and will not 
receive study treatment thereafter.  
As per the original protocol, Lm surveillance will begin for all patients at 3 months (±2 
weeks) after treatment discontinuation, and will consist of Lm safety evaluations only, as 
described in the protocol, for all subjects who have received at least one dose of study 
treatment.  


 
 
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However, efficacy evaluations will no longer be performed on any subjects after the early 
study termination date, e.g., 31 July 2019. 
11.1 Sample Size Considerations 
For a study involving a sample of subjects with the same distribution of stage as listed in 
(Table 9), the estimated probability of surviving disease-free for at least 4 years is 
approximately 50%. Thereafter, the probability of recurring or dying increases very slowly 
(2-3% per year). This study will be considered sufficiently mature for a final analysis when 
there are at least 184 subjects reported as having experienced either recurrence of their 
cancer or death due to any cause. This number of events provides 85% power for detecting a 
treatment hazard ratio (HR) of 0.620. The type I error will be set to 0.025 (accounting for 
interim analysis) for a one-tail test of the null hypothesis (HR=1) using stratified logrank 
procedure. A treatment hazard ratio of 0.620 is comparable to increasing the expected 
proportion alive and disease-free for at least 4 years from 0.500 to 0.651. 
Table 9 
Summary of Study Parameters and Targeted Sample Size 
Design Parameter 
 
Type I error (1-sided) 
0.025 
Statistical power 
0.85 
Treatment: Reference allocation ratio 
2:1 
Interim analysis * 
 
50% IT 
 
Hazard ratio | HA 
0.620 
Percent increase in DFS at 4 yrs. | HA 
0.151 
Number of DFS events required** 
184 
Target accrual (N of subjects)*** 
450 
Accrual duration**** 
55 months 
Post-accrual follow-up duration**** 
20 months 
*An interim analysis of safety and efficacy planned at 50% of the information time (IT)  
**East version 5.4, HA is the alternative hypothesis for power calculations. 
***Assumes cumulative probability of recurring or dying on the reference treatment during the first 4 years is 
approximately 50%, and thereafter this probability does not increase. See Note on Target Accrual (below). 
****The estimated duration of accrual and post-accrual follow-up  depend on the expected average accrual rate and the 
number of investigative sites participating in the study. It is estimated that ~ 450 subjects will be enrolled in 55 months.   
 
A Note on Target Accrual: The statistical power of this study is a function of the expected 
number of subjects experiencing either recurrence or death observed in each treatment group 
at the time of final analysis. The anticipated DFS event rate in this population is relatively 
high during the first 4 years of enrollment but declines considerably thereafter. Specifically, 
the cumulative probability of recurrence or death with the first 4 years is expected to be at 
least 50% (see Figure 4). However, for those who have not recurred during the first 4 years, 
the cumulative probability of recurrence or death during the subsequent 4 years is expected 
to be less than 10%. It is anticipated that about 30-40% will not experience a recurrence of 


 
 
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their cancer within their lifetime. The targeted accrual for this study is based on the expected 
(mean) number of recurrences or deaths that will be observed under the alternative 
hypothesis after following each subject for at least 4 years. However, the number of subjects 
experiencing either recurrence or death within 4 years of for a particular study is actually a 
random number. By chance alone, the actual number of DFS events in this study could be 
less than expected. Moreover, it is possible for more than planned low-risk subjects could 
be enrolled.  Therefore, it is prudent to enroll slightly more subjects than the minimum. 
Assuming that there are no subjects who recur after the first 4-years of follow-up, as was 
done for this study to determine the target accrual, provides some protection for 
underestimating the actual proportion of subjects recurring in the study sample. It is worth 
noting that this study will include criteria, which were not used in GOG-219, to clinically 
determine node involvement (e.g., minimum size of nodes) that are intended to reduce the 
frequency of false-positives. Therefore, the DFS event rate observed in this study could be 
slightly higher than predicted by the historical data from GOG-219 (see Section 11.2.7). 
11.2 Statistical Analysis Plan Summary 
The full statistical analysis plan is detailed in a separate document, with information 
presented in this section adjusted as applicable to allow data analysis up to the time of early 
study treatment termination [i.e., after 110th subject was randomized, the Sponsor terminated 
the study and further enrollment, and all subjects moved to the End of Treatment (EoT) visit 
by 31 July 2019 (except for 1 subject whose last dose occurred on 2 September 2019)]. 
11.2.1 
Study Design 
This is a 2-arm, placebo-controlled, randomized (2:1 ADXS11-001/placebo), Phase 3 clinical 
study.  The treatment for each enrolled subject will consist of either: 
• Placebo (P) 
• ADXS11-001 (E) 
The general objective of this study is to evaluate the relative efficacy and safety of adding 
ADXS11-001 in the adjuvant setting following CCRT with curative intent for the treatment 
of women with HRLACC. 
11.2.2 
Definition of Study Populations for Analyses 
The primary analysis population for the primary efficacy endpoints will be based upon the 
intention to treat (ITT) principle population. The ITT population includes all subjects 
enrolled into this study regardless of their eligibility or compliance with their assigned 
treatment. Secondary efficacy endpoints will be reported for the ITT population. Analyses of 
adverse events will include all subjects enrolled into this study who initiated their assigned 
study treatment. 


 
 
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11.2.3 
Measures of Efficacy and Safety 
The principal observations for evaluating the therapeutic efficacy and safety of the study 
regimens are: 
1. Primary efficacy endpoint: DFS  
2. Secondary efficacy endpoint: OS 
Safety endpoints: frequency and severity of related AEs as defined by CTCAE v 4.03, 
changes in physical examinations, vital signs measurements, and clinical laboratory 
evaluations. An external DMC will evaluate and analyze accrued subject data periodically 
throughout the study. 
For the analyses of the primary endpoint, the DFS duration for each subject will be assessed 
from the date of randomization to the date of first recurrence as determined by independent 
radiology review or death (due to any cause). For those subjects who have not recurred or 
died, the duration at risk of recurrence will be calculated up to the date of the subject’s last 
disease assessment. 
11.2.4 
Enrollment and Treatment Allocation 
Subjects are enrolled onto the study via a web-based enrollment and treatment randomization 
procedure. Treatments will be sequentially allocated from predetermined concealed lists 
consisting of randomly permuted study treatments balanced within blocks. The 
randomization procedure will allocate approximately twice as many subjects to ADXS11-001 
than placebo within the 8 subgroups defined by the following factors: 
1. Para-aortic node metastases (yes vs no/unknown). 
2. Region (USA vs Rest of World) 
3. FIGO Tumor Stage (Stage I, II vs Stage III, IV) (2014 FIGO Staging) 
11.2.5 
Primary Study Hypothesis 
Disease-free survival is the primary endpoint of the study. The null hypotheses for the 
primary endpoint of DFS is: 
Hp:E,DFS: ADXS11-001 following chemoradiation does not increase the duration of DFS 
compared with placebo in subjects with HRLACC. 
11.2.6 
Analytic Procedures for the Testing Hypothesis: Hp:E,DFS 
The logrank procedure will be used to evaluate the primary study hypothesis.  The logrank 
calculation will be stratified by 2014-FIGO tumor stage (I or II vs III or IV) system, region 
(US vs Rest of World), para-aortic node metastases (yes vs no/unknown). The analysis of 
DFS will consider all deaths as events, regardless of the cause of death. The impact of the 


 
 
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other potential prognostic/predictive factors will be explored in multivariate and/or subgroup 
analyses and will include, but not necessarily limited to, prior brachytherapy and radiation 
field at baseline. A sensitivity analysis will be performed to evaluate subjects who were 
determined to meet the criteria for recurrence based on radiographic imaging, but the results 
from biopsy were negative. The SAP will provide details for the sensitivity/supportive 
analyses which will be performed. 
For the primary analysis, subjects will be grouped according to their randomly assigned 
treatment and subjects will be included in the analysis, regardless of their compliance with 
their assigned treatment plan. The primary analyses will use the duration of DFS as it is 
determined by the Independent Radiology Reviewer. 


 
 
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11.3 Interim & Final Analyses 
As a result of early study termination, no interim analysis is to occur and the plans below 
described as per the original protocol are adjusted accordingly. The final analysis is clarified 
and detailed in the full statistical analysis plan in a separate document (see Section 11.2).  
An independent Data Monitoring Committee (DMC) will periodically assess the safety data 
during the treatment phase.  A description of the roles and responsibilities and details of the 
review processes are provided in a separate DMC charter.  
An administrative analysis is planned prior to completing the enrollment of the targeted 
number of subjects onto this study. In this assessment the DMC will be given the opportunity 
to recommend an adjustment to the targeted total accrual (N = 450 subjects) when the 
Sponsor has positively determined that the number of DFS events required for study maturity 
will not be attained within a reasonable time closely associated with the projected follow-up 
period (e.g., 20 months). In this case, the Sponsor will provide the DMC with the following 
information from their analysis: 
1- DFS events estimate using the Kaplan Meier method 
2- A revised enrollment and DFS events projection based on the actual current rates 
compared with those used in the original assumptions 
3- Other information as requested by the DMC 
No treatment unblinding will be performed as part of this analysis. The Sponsor will perform 
the analysis when a sufficient number of subjects have been enrolled in order to ensure a 
robust sample size and allow the DMC time to review the information provided to them and 
make a recommendation for increasing the sample size. Based on the current enrollment 
assumptions it is estimated that the analysis will be performed after the 300th subject is 


 
 
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enrolled and the initial 12-week post-baseline imaging assessment are reviewed. The Sponsor 
will maintain close communication with the DMC to ensure the committee is aware of the 
current status of enrollment and the timing for the planned analysis. The DMC will prepare a 
document which will detail their recommendation and supporting rationale and provide it to 
the Sponsor. Any output supporting their recommendation will also be included.  
A formal interim analysis which will only assess futility will be performed when there is at 
least, and as close to as administratively possible to, one-half the number of events (92 events) 
required for full maturity of the study. At this time the logrank test of the null hypothesis will 
be calculated as described in Section 4.3.1 of SAP and futility will be assessed. An O’Brien 
and Fleming-like spending function will be used. The O’Brien-Fleming-like alpha (and 
beta) spending function used in EAST has the functional form α(t)=2 -2Φ(Z∝/2/√t*) for 
one-sided tests, where Φ denotes the standard normal distribution function and t* the 
information fraction. These functions require that the percent of information time be 
specified at the time of the interim analyses. The percent of information time (information 
fraction) will be calculated as the number of enrolled individuals who have reported 
experiencing disease recurrence or death, relative to the required number for the final 
analysis. The futility analysis will be “non-binding”. 
The interim analysis will be performed by an independent Study Reporting Statistician, 
otherwise unaffiliated with the study, who will provide the results only to the DMC.  As 
detailed in the DMC charter, the DMC may consider making a recommendation to the 
Sponsor to discontinue the study if the p-value from the logrank test of the primary study 
hypothesis falls outside of the boundary for futility indicated by the O’Brien and Fleming-
like boundary proposed by Lan and Demets [50] and computed using by East (Cytel). 
The statistical boundary only serves as a trigger for the DMC to consider stopping the study. 
A complete assessment for stopping a study will involve considerations for the adverse 
events profile, impact on other study endpoints, and possibly external information. In the 
event the criteria for stopping are met, the interim results will be shared only with the 
Steering Committee members. The Sponsor in consultation with the DMC, Steering 
committee and other relevant individuals will have the authority to make the final decision 
regarding the outcome of the study. All members privy to the results as well as the results 
shared, and the sponsor’s final decision will be documented and made available for 
regulatory review. In the event that additional individuals outside the steering committee are 
involved in the decision, the information shared and the individuals involved will also be 
documented. 
 
11.4 Monitoring of Accrual and Event Rates 
Administrative monitoring of accrual and event rate based on blinded data will be performed 
periodically by the Sponsor’s blinded statistical team prior to completing the enrollment of 
the targeted number of subjects onto this study. The team will analyze the following 
information: 


 
 
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4- DFS events estimate using the Kaplan Meier method 
5- A revised enrollment and DFS events projection based on the actual current rates 
compared with those used in the original assumptions 
On the basis of this information, if the Sponsor determines that the number of DFS events 
required for study maturity will not be reached within reasonable time, then the Sponsor 
might consider increasing the targeted accrual beyond 450 subjects. 
11.5 Estimated Study Duration 
With an average accrual rate of 5 patients per month for the first 26 months and 11 patients 
per months thereafter, enrollment of 450 subjects will be completed in approximately 55 
months. If the DFS event rate among those randomized to placebo is as displayed in Figure 4 
and the true treatment HR is 0.62, the study will reach full maturity with 184 DFS events 
approximately 35 months after enrollment is complete. 


 
 
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12 ADMINISTRATIVE AND REGULATORY DETAILS 
12.1 Confidentiality 
The confidentiality of records and information that could identify subjects must be protected, 
respecting privacy and confidentiality rules in accordance with applicable regulatory 
requirements. 
The Investigator will agree to maintain in confidence all information furnished by the 
Sponsor and all data generated in the study, except as provided or required by law, and will 
divulge such information to the IRB/IEC with the understanding that confidentiality will be 
maintained by the committee. 
The identity of all subjects in this study must remain confidential, and only the initials of said 
subjects will appear on the eCRF.  Qualified representatives from the relevant regulatory 
agencies, the Sponsor, or its agents may inspect the subject/study records.  Subject data 
obtained during the study may be presented in scientific publications, but at no time will 
subject names be used. 
12.2 Compliance with Financial Disclosure Requirements 
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
(FDA) Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the Investigator's/Sub Investigator’s 
responsibility to comply with any such request. The Investigator/Sub Investigator(s) agree, if 
requested by the Sponsor in accordance with 21 CFR Part 54, to provide his/her financial 
interests in and/or arrangements with the Sponsor to allow for the submission of complete 
and accurate certification and disclosure statements. 
The Investigator/Sub Investigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor or through a secure password-protected electronic portal provided by the 
Sponsor. The Investigator/Sub Investigator(s) also consent to the transmission of this 
information to the Sponsor in the US for these purposes. 
12.3 Compliance with Law, Audit and Debarment 
International Conference on Harmonisation (ICH) Guidance on Good Clinical Practice 
([GCP] CPMP/ICH/135/95) and the Sponsor require the Investigator to be aware of his/her 
obligations in the conduct of this study. 
Representatives of the Sponsor must be allowed to visit all study site locations periodically to 
assess data quality and study integrity. On site, they will review study records and directly 
compare them with the original source documents, discuss the conduct of the study with the 
Investigator, and verify that the facilities remain acceptable. 


 
 
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In addition, the study may be evaluated by auditors designated by the Sponsor and by 
government inspectors who must be allowed access to CRFs, source documents, and all other 
study files. Sponsor audit reports will be kept confidential. 
THE INVESTIGATOR MUST NOTIFY THE SPONSOR PROMPTLY OF ANY 
INSPECTIONS SCHEDULED BY REGULATORY AUTHORITIES AND PROMPTLY 
FORWARD COPIES OF INSPECTION REPORTS TO THE SPONSOR. 
12.4 Compliance with Study Registration and Results Posting Requirements 
Under the terms of the FDA Modernization Act (FDAMA) and the FDA Amendments Act 
(FDAAA), the Sponsor of the study is solely responsible for determining whether the study 
and its results are subject to the requirements for submission to the Clinical Study’s Data 
Bank, http://www.clinicaltrials.gov.  Information posted will allow subjects to identify 
potentially appropriate studies for their disease conditions and pursue participation by calling 
a central contact number for further information on appropriate study locations and study site 
contact information. 
12.5 Quality Management System 
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
functional area standard operating procedures (SOPs) to ensure that studies are conducted 
and data are generated, documented, and reported in compliance with the protocol, accepted 
standards of GCP, and all applicable federal, state, and local laws, rules and regulations 
relating to the conduct of the clinical study. 
12.6 Data Management 
The Investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data. By signing this protocol, the Investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature. By entering 
his/her electronic signature, the Investigator confirms that all recorded data have been 
verified as accurate. 
Detailed information regarding Data Management procedures for this protocol will be 
provided separately. 


 
 
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13 ABBREVIATIONS 
 
AEs 
Adverse Events 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
APC 
Antigen Presenting Cell 
ASCO 
American Society for Clinical Oncology 
AST 
Aspartate aminotransferase 
BCG 
Bacillus Calmette–Guérin 
BRM 
Biologic Response Modifier 
CCRT 
Combination chemotherapy and radiotherapy 
CFU 
Colony Forming Unit 
CIN 
CMP 
Cervical Intraepithelial Neoplasia 
Comprehensive metabolic panel  
CNS 
Central nervous system 
COPD 
Chronic obstructive pulmonary disease 
CTEP 
Cancer Treatment Evaluation Program 
CR 
CRP 
Complete response 
C-reactive Protein 
CRS 
Cytokine release syndrome 
CT 
Computed tomography 
CTCAE 
Comprehensive Terminology Criteria for Adverse Events 
DCR 
Disease Control Rate 
DFS 
DLT 
Disease Free Survival 
Dose limiting toxicity 
DMC 
Data monitoring committee 
EBRT 
External beam radiation therapy 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
ERC 
ESR 
Ethical Review Committee 
Erythrocyte sedimentation rate 
FDA 
Food and Drug Administration 
FDG-PET 
Flurodeoxyglucose-positron emission tomography 
FFPE 
Formalin-fixed, paraffin-embedded 
FIGO 
International Federation of Gynecology and Obstetrics 
GCP 
Good Clinical Practice 
GGT 
Gamma glutyltransferase 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
GOG 
Gynecologic Oncology Group 
Gy 
Gray 
HBsAg 
Hepatitis B surface antigen 
HCC 
Hepatocellular cancer 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 


 
 
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HPV 
Human papilloma virus 
HR 
Hazard ratio 
HRLACC 
High risk locally advanced cervical cancer 
HRQOL 
Health related quality of life 
IA 
Interim Analysis 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
International Ethics Committee 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
irAE 
Immune related adverse event 
IV 
Intravenously 
LACC 
Locally advanced cervical cancer 
LFT 
Liver Function Test 
LLO 
Listeriolysin O 
Lm 
Listeria monocytogenes 
Lm-LLO 
Listeria monocytogenes Listeriolysin O 
MDSC 
myeloid-derived suppressor cells 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHC 
Major Histocompatibility Complex 
MRI 
Magnetic resonance imaging 
MTD 
Maximum Tolerated Dose 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NSAID 
Non-Steroidal Anti Inflammatory Drugs 
OS 
Overall survival 
OTC 
Over the counter 
PALN 
Para-aortic lymph node 
PET 
Positron emission tomography 
 
PI3K 
 
Phosphoinositide 3-kinase  
PR 
Partial response 
PWB 
Physical Well Being 
RBC 
Red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RFS 
Relapse free survival 
ROC 
Receiver operating characteristic 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SOC 
Standard of Care 
SOP 
Standard operating procedure 
SUV 
Standard uptake value 
tLLO 
Truncated LLO 
TME 
TNF 
Tumor microenvironment 
Tumor necrosis factor alpha 


 
 
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TOI 
Study Outcome Index 
TSE 
Treatment side effects 
Tregs 
Regulatory T cells 
ULN 
Upper limit of normal 
US 
United States 
WBC 
White blood cell 
wt-Lm 
wild type Listeria monocytogenes 










 
 
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14.2 GOG Performance Status 
Grade 
Karnofsky Scale 
Performance 
0 
90 & 100 
Fully active 
1 
70 & 80 
Restricted in physically strenuous activities, but ambulatory 
2 
50 & 60 
Ambulatory; capable of self-care; unable to work; up to 50% if waking hours 
3 
30 & 40 
Limited self-care; confined to bed or chair 50% of waking hours 
4 
10 & 20 
Completely disabled; no self-care 
 


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14.6 Flow Chart of the Independent Review Methodology 
 
Images QC’d 
Pass 
QC? 
Images prepared for 
Independent Reviewers  
Site queried for 
resolution 
Site submits images 
for eligible patients 
N 
Y 
Image login/processing 
Site submits new 
images 
Independent Efficacy Reviewer 
completes assessment 
N 
Adjudicate
? 
Y 
Adjudicator 
selects R1 
or R2 
Accepted read logged 
in database 
Advaxis 
Accepted read logged 
in database 
 
COR? 
Y 
COR Review completed 
by COR reviewer 
Images prepared for 
efficacy review 
Results of COR sent to 
Advaxis/site 
 


 
 
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15 LIST OF REFERENCES 
 
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Ferlay, J., et al., Cancer incidence and mortality worldwide: sources, methods 
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American Cancer Society 2015  [cited 2015 27 Apr 2015]; Available from: 
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Keys, H.M., et al., Cisplatin, radiation, and adjuvant hysterectomy compared with 
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Rose, P.G., et al., Concurrent cisplatin-based radiotherapy and chemotherapy for 
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Morris, M., et al., Pelvic radiation with concurrent chemotherapy compared with 
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Whitney, C.W., et al., Randomized comparison of fluorouracil plus cisplatin 
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Chen, Z., et al., Nasal immunization using a mimovirus vaccine based on the 
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Monk, B.J., et al., Which clinical/pathologic factors matter in the era of 
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Wheeler, C.M., et al., Human papillomavirus genotype distributions: implications 
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Delgado, G., et al., Prospective surgical-pathological study of disease-free 
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Tinga, D.J., et al., Prognostic significance of single versus multiple lymph node 
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Stehman, F.B., et al., Carcinoma of the cervix treated with radiation therapy. I. A 
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Narayan, K., et al., Patterns of failure and prognostic factor analyses in locally 
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Lanciano, R.M. and B.W. Corn, The Role of Surgical Staging for Cervical 
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Kidd, E.A., et al., Lymph node staging by positron emission tomography in 
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Hwang, L., et al., Para-aortic nodal metastases in cervical cancer: a blind spot in 
the International Federation of Gynecology and Obstetrics staging system: 
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16 
SUMMARY OF CHANGES WITHIN PROTOCOL 
AMENDMENT 
# 
Section 
Revision 
Rationale 
1 
Throughout 
Protocol was updated to reflect 
approved End of Study Procedures as 
part of early study termination 
notifications to sites and Health 
Authorities, which included collection 
of AEs and SAEs during the Lm 
surveillance period for all AE/SAEs 
associated with listeremia.  Further 
efficacy assessments post study 
termination in the Post-Treatment 
Follow-Up Period and Post-Disease 
Recurrence Period were deleted as no 
longer applicable. 
 
Change made 
consistent with 
already approved 
procedures per 
“Appendix 1 - Study 
Closure Guidance 
Clarification 
Document” in 
Sponsor’s early study 
termination 
notification 
submitted to 
authorities post 31 
July 2019.  
2 
Synopsis, 5.2.4, 6.2.5, 
6.2.6, 9 
The Lm surveillance duration changing 
from 3-years to 1-year, along with 
remote surveillance and assessment of 
listeremia signs and symptoms (i.e., 
fever or chills, headache, nausea, 
confusion or changes in alertness    
experienced for several days) via phone 
contact in place of routine blood 
culturing every 3 months (-/+ 1 week). 
Blood culture is to occur if subjects 
report having experienced any of these 
symptoms, followed by treatment for 
listeremia if suspected. 
   
Update made based 
on the Sponsor’s 
assessment of Lm 
surveillance data 
from about 171 
subjects participating 
across 7 Advaxis 
studies with Lm-
based therapies, 
followed by FDA 
agreement on 10 
November 2020 of 
this approach. 
3 
11, 11.2 ,11.3 Interim 
& Final Analyses 
In the previous protocol version, the 
planned final analysis was to be 
performed after “184 DFS events” had 
occurred (defined as the time from 
randomization until death or 
recurrence).  However, given the study 
treatment phase was terminated early, it 
is clarified that the data collected and 
analyzed up to the time of early study 
treatment termination will be analyzed 
[i.e., after 110th subject was 
randomized, the Sponsor terminated the 
study and further enrollment, and all 
subjects moved to the End of Treatment 
(EoT) visit by 31 July 2019 (except for 
1 subject whose last dose occurred on 2 
September 2019)]. 
Update made to 
reflect that SAP is 
provided as a 
separate document 
reflecting 
assessments up to the 
early study 
termination as of 31 
July 2019