Clinical trial NCT02399813
Conditions: Anal Cancer Rectal Cancer
Sponsor: Advaxis, Inc.
Start date: 2016-06-02; Completion date: 2019-01-03
Enrollment: 36 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a single arm Phase 2 study. Stage 1 and 2 of the study are monotherapy evaluations of ADXS11-001 in 31 and 24 participants, respectively with persistent/recurrent, loco-regional or metastatic squamous cell carcinoma (SCCA) of the anorectal canal that have received at least 1 regimen for the treatment of advanced disease.

Detailed description:

Arms: arm 1: Participants received intravenous (IV) infusion of axalimogene filolisbac administered over 60 minutes every 3 weeks at a dose of 1 x 10\^9 colony forming units (cfu) for up to 2 years or until a discontinuation criterion was met (documented progression, unacceptable adverse events, withdrawn due to investigator's discretion, participant withdraws consent, pregnancy or noncompliance with study procedures or treatments). A treatment cycle was defined as 9 weeks in duration.
Interventions: intervention 1: Axalimogene filolisbac
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Protocol ADXS001-06, Amendment 4 
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ADXS11-001 
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PROTOCOL ADXS001-06 
PHASE 2 STUDY OF ADXS11-001 IN SUBJECTS WITH 
PERSISTENT/RECURRENT, LOCO-REGIONAL OR METASTATIC 
SQUAMOUS CELL CARCINOMA OF THE ANORECTAL CANAL 
SPONSOR: 
  
 
ADVAXIS, INC.  
  
 
305 COLLEGE ROAD EAST 
  
 
PRINCETON, NJ 08540 
  
 
609-452-9813 (OFFICE)  
  
 
609-452-9818 (FAX) 
 
IND NUMBER: 
 
 
13712 
EudraCT NUMBER: 
 
2015-001053-33 
Original Version 1.0: 
 
March 9, 2015 
Version 2.0/Amendment 1:   
April 27, 2015 
Version 3.0/Amendment 2:   
July 31, 2015 
Version 4.0/Amendment 3:  
December 1, 2015 
Version 5.0/Amendment 4:   
March 8, 2016 
 
 
 
 
 
 
 
Confidentiality Statement 
The information contained herein is confidential and proprietary and may not be 
disclosed, reproduced, or circulated without the prior written consent of Advaxis 
Incorporated 
 
 
 




 
 
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INVESTIGATOR SIGNATURE PAGE 
 
Protocol No.:  
ADXS001-06 
Title: 
Phase 2 Study of ADXS11-001 In Subjects with 
Persistent/Recurrent, Loco-Regional or Metastatic Squamous Cell 
Carcinoma of the Anorectal Canal 
Original Version 1.0: 
 
March 9, 2015 
Version 2.0/Amendment 1:   
April 27, 2015 
Version 3.0/Amendment 2:   
July 31, 2015 
Version 4.0/Amendment 3:  
December 1, 2015 
Version 5.0/Amendment 4:   
March 8, 2016 
 
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. 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 (GCPs), 
International Conference on Harmonisation (ICH) Guidelines, the Declaration of 
Helsinki, and local ethical and legal requirements. 
 
Investigator Name:  
 
 _____________________________________  
______________________ 
Signature 
Date 
 
 _____________________________________  
______________________ 
PI Name (Printed) 
Site # 
 
 


 
 
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TABLE OF CONTENTS 
1 
Summary ...................................................................................................................10 
2 
Trial Design ...............................................................................................................11 
3 
Objectives & Hypothesis ..........................................................................................12 
3.1 
Primary Objectives & Hypothesis ......................................................................12 
3.2 
Secondary Objectives...........................................................................................13 
4 
Background & rationale ...........................................................................................13 
4.1 
Background ..........................................................................................................13 
4.1.1 
ADXS11-001 Immunotherapy ......................................................................13 
4.1.2 
Preclinical and Clinical Trial Data ...............................................................14 
4.2 
Rationale for Trial and Selected Subject Population .......................................14 
4.2.1 
Rationale for Dose Selection/Regimen/Modification ..................................15 
4.2.1.1 
Summary of Safety of ADXS11-001 .......................................................15 
4.2.2 
Delayed/Late Listeria Infection ....................................................................18 
4.2.2.1 
ADXS11-001 – Rationale for Dose Selection and Regimen ..................19 
4.2.3 
Rationale for Endpoints ................................................................................21 
4.2.3.1 
Efficacy Endpoints ...................................................................................21 
4.2.3.2 
Safety Endpoints ......................................................................................21 
4.2.4 
Study Stopping Rules .....................................................................................21 
5 
Methodology ..............................................................................................................22 
5.1 
Entry Criteria .......................................................................................................22 
5.1.1 
Inclusion Criteria ...........................................................................................22 
5.1.2 
Exclusion Criteria ..........................................................................................24 
5.2 
Trial Treatments ..................................................................................................26 
5.2.1 
Dose Selection/treatment Modification ........................................................26 
5.2.1.1 
Dose Selection ...........................................................................................26 
5.2.1.2 
Treatment Modification/Delay Due to Adverse Events ........................27 
5.2.2 
Administration of ADXS11-001 ....................................................................28 
5.2.3 
Timing of Dose Administration ....................................................................28 
5.2.4 
Pretreatment Prophylaxis Regimen .............................................................28 
5.2.5 
ADXS11-001 Dosing.......................................................................................29 
5.2.6 
Treatment Duration .......................................................................................29 
5.2.7 
Trial Blinding/Masking .................................................................................29 
5.3 
Randomization or Treatment Allocation ...........................................................29 
5.4 
Stratification .........................................................................................................30 
5.5 
Concomitant Therapies and Procedures (Allowed & Prohibited) ..................30 
5.5.1 
Acceptable Concomitant Therapies and Procedures ..................................30 
5.5.2 
Prohibited Concomitant Therapies ..............................................................30 
5.6 
Supportive Care Guidelines ................................................................................31 
5.6.1 
Cytokine Release Symptoms .........................................................................31 
5.6.2 
Nausea/vomiting .............................................................................................35 
5.6.3 
Infusion Reaction ...........................................................................................35 
5.6.3.1 
Listeriosis and Listeria Infection - Identification and 
Management .............................................................................................37 


 
 
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5.6.4 
Management and Surveillance of Listeria During Study 
Participation ...................................................................................................37 
5.7 
Diet/Activity/Other Considerations ....................................................................38 
5.7.1 
Diet ..................................................................................................................38 
5.7.2 
Contraception .................................................................................................38 
5.7.3 
Use in Pregnancy ............................................................................................39 
5.7.4 
Use in Nursing Women ..................................................................................39 
5.7.5 
Major and Minor Surgeries and ADXS11-001 Treatment ........................40 
5.8 
Withdrawal/Discontinuation Criteria ................................................................40 
5.9 
Subject Replacement Strategy ............................................................................41 
5.10 
Treatment after Initial Evidence of Radiologic Disease Progression ..............41 
5.11 
Clinical Criteria for Early Trial Termination...................................................42 
6 
Study Evaluations .....................................................................................................43 
6.1 
Schedule of Events ...............................................................................................43 
7 
Trial Procedures .......................................................................................................45 
7.1 
Trial Procedures...................................................................................................45 
7.1.1 
Administrative Procedures ...........................................................................45 
7.1.1.1 
Informed Consent ....................................................................................45 
7.1.1.2 
Eligibility Criteria ....................................................................................45 
7.1.1.3 
Subject Identification Card .....................................................................46 
7.1.1.4 
Demographic/Medical History ................................................................46 
7.1.1.5 
Prior Cancer History ...............................................................................46 
7.1.1.6 
Prior/Concomitant Therapies and Procedures .....................................46 
7.1.2 
Clinical Procedures/Assessments ..................................................................46 
7.1.2.1 
Adverse/Serious Adverse Event Monitoring .........................................46 
7.1.2.2 
Physical Examination ..............................................................................47 
7.1.2.3 
Vital Sign Measurement ..........................................................................47 
7.1.2.4 
Eastern Cooperative Oncology Group Performance Scale ..................47 
7.1.3 
Laboratory Procedures/Assessments ...........................................................47 
7.1.3.1 
Laboratory Safety Evaluations ...............................................................47 
7.1.4 
Efficacy Measurements .................................................................................49 
7.1.4.1 
Tumor Imaging and Assessment of Disease ..........................................49 
7.1.4.2 
Measurable and Non-Measurable Lesions and Disease .......................49 
7.1.4.3 
Target/Non-Target Lesions .....................................................................49 
7.1.4.4 
Response in Measurable Lesions (RECIST 1.1) ...................................50 
7.1.4.5 
Immune-Related Response in Measurable Lesions (irRECIST) .........50 
7.1.4.6 
Response in Non-Measurable Lesions (RECIST 1.1) ...........................51 
7.1.4.7 
Immune-Related Response in Non-Measurable Lesions 
(irRECIST) ...............................................................................................52 
7.1.4.8 
Overall Response ......................................................................................52 
7.1.5 
Other Procedures ...........................................................................................55 
7.1.5.1 
Withdrawal/Discontinuation ...................................................................55 
7.1.6 
Visit Requirements.........................................................................................55 
7.1.6.1 
Screening ...................................................................................................56 
7.1.6.2 
Treatment Period .....................................................................................56 
7.1.6.3 
Safety Follow-up/Post-Treatment Visits ................................................58 


 
 
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7.1.6.4 
Survival Follow-up ...................................................................................58 
7.2 
Assessing and Recording Adverse Events..........................................................58 
7.2.1 
Overdose .........................................................................................................59 
7.2.2 
Reporting of Pregnancy and Lactation to the Sponsor ..............................60 
7.2.3 
Immediate Reporting of Adverse Events to the Sponsor ...........................60 
7.2.3.1 
Serious Adverse Events ...........................................................................60 
7.2.4 
Evaluating Adverse Events ...........................................................................61 
7.2.5 
Sponsor Responsibility for Reporting Adverse Events ..............................62 
8 
Statistical Consideration ..........................................................................................62 
8.1 
General Consideration.........................................................................................62 
8.2 
Sample Size and the Design .................................................................................62 
8.3 
Analysis of Study Endpoints ...............................................................................63 
8.3.1 
Analysis of Primary Endpoints for Efficacy ................................................63 
8.4 
Safety Monitoring ................................................................................................64 
8.5 
Analysis of Safety Data ........................................................................................64 
9 
Labeling, Packaging, Storage and Return of Clinical Supplies............................65 
9.1 
Investigational Product .......................................................................................65 
9.2 
Packaging and Labeling Information ................................................................65 
9.3 
Clinical Supplies Disclosure ................................................................................65 
9.4 
Storage and Handling Requirements .................................................................65 
9.5 
Safety Precautions ................................................................................................65 
9.6 
Returns and Reconciliation .................................................................................67 
9.7 
Destruction of ADXS11-001 ................................................................................67 
10 Administrative and Regulatory Details ..................................................................67 
10.1 
Confidentiality ......................................................................................................67 
10.2 
Compliance with Financial Disclosure Requirements ......................................67 
10.3 
Compliance with Law, Audit and Debarment ..................................................68 
10.4 
Compliance with Trial Registration and Results Posting 
Requirements........................................................................................................68 
10.5 
Quality Management System ..............................................................................68 
10.6 
Data Management ................................................................................................69 
11 List of References ......................................................................................................70 
12 Appendices.................................................................................................................72 
12.1 
ECOG Performance Status .................................................................................72 
12.2 
Common Terminology Criteria for Adverse Events V4.0 (CTCAE) ..............72 
12.3 
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria 
for Evaluating Response in Solid Tumors .........................................................72 
13 Summary of Changes ...............................................................................................73 
 
 
 
 


 
 
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Table of Tables 
Table 1  Number (%) of Subjects with Adverse Events >5% Incidence (Safety Population, 
N=230) .......................................................................................................16 
Table 2  Number (%) of Subjects with Adverse Events >5% with Respect to Relationship 
(Possibly Related, Probably Related and Related) (Safety Population, N=230)
....................................................................................................................17 
Table 3  Adequate Organ Function Laboratory Values...............................................23 
Table 4  Trial Treatment .................................................................................................26 
Table 5  Treatment Delay/Discontinuation Guidelines for Drug-Related Adverse Events
....................................................................................................................27 
Table 6  Recommended Management Guidelines for Adverse Events Associated with 
Cytokine Release ......................................................................................33 
Table 7  Management Guidelines for Infusion Reactions ............................................36 
Table 8  Laboratory Tests ...............................................................................................48 
Table 9  Tumor Response Evaluation: Comparison of RECIST 1.1 and irRECIST 52 
Table 10  Best Overall Response (RECIST 1.1) ............................................................53 
Table 11  Immune-Related Best Overall Response (irBOR) .......................................54 
Table 12  Attribution Categories ....................................................................................61 
 
Table of Figures 
No table of figures entries found. 
 
 
 
 
 
 
 
 
 
 


 
 
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ABBREVIATIONS 
ADXS11-001 
Lm-LLO Immunotherapy for HPV associated diseases 
AEs 
Adverse Events 
APC 
Antigen Presenting Cell 
CD4 
Cytotoxic T cell, effector T cell, Memory T cell 
CD8 
Helper T cell, Regulatory T cell 
CAT 
chloramphenicol acetyl transferase 
CFU 
Colony Forming Unit 
CMP 
Comprehensive Metabolic Panel 
CR 
CRP 
Complete response 
C-Reactive Protein 
CTL 
Cytotoxic T lymphocyte 
DCR 
Disease Control Rate 
DLT 
Dose limiting toxicity 
DTH 
ESR 
delayed-type Hypersensitivity 
Erythrocyte Sedimentation Rate 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
GOG 
Gynecologic Oncology Group 
HPV 
Human papilloma virus 
HspE7 
Heat Shock Fusion Protein-Based Immunotherapy 
IV 
Intravenously 
IFN 
Interferon 
LFT 
Liver Function Test 
LLO 
Listeriolysin O 
Lm 
Listeria monocytogenes 
Lmdd 
An attenuated strain of Listeria monocytogenes with deletions in two genes (dal and 
dat) 
Lm-LLO 
Listeria monocytogenes Listeriolysin O 
MDSC 
myeloid-derived suppressor cells 
MHC 
Major Histocompatibility Complex 
MIC 
Minimum inhibitory concentration 
MMC 
Mitomycin C 
MTD 
Maximum Tolerated Dose 
NCCN 
National Comprehensive Cancer Network 
NSAID 
Non-Steroidal Anti Inflammatory Drugs 


 
 
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PI3K 
Phosphoinositide 3-kinase  
PR 
Partial response 
PSA 
Prostate-specific antigen 
RBC 
Red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
Recommended Phase 2 Dose 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SOC 
Standard of Care 
TAA 
Tumor Associated Antigen(s) 
TCR 
T-cell receptor 
TNFα 
Tumor necrosis factor alpha 
TIL 
Tumor infiltrating lymphocytes 
tLLO 
Truncated LLO 
Tregs 
Regulatory T cells 
wt-Lm 
wild type Listeria monocytogenes 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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1 SUMMARY 
Study Title: 
Phase 2 Study of ADXS11-001 In Subjects with 
Persistent/Recurrent, Loco-Regional or Metastatic Squamous Cell 
Carcinoma of the Anorectal Canal  
Trial Phase 
Phase II 
Clinical Indication 
Persistent/recurrent, loco-regional or metastatic squamous cell 
carcinoma (SCCA) of the anorectal canal 
Trial Type 
Interventional 
Study Centers 
Multicenter, USA 
Route of Administration 
Intravenous (IV) 
Trial Blinding 
Open label, unblinded 
Number of Trial Subjects 
Approximately  55 
• 
31 subjects in Stage 1 
• 
24 subjects in Stage 2 
Estimated Duration of Trial 
Approximately 6 years 
Duration of Participation 
Each subject will participate in the study for an average of 
approximately 6 years from the time the subject signs the informed 
consent form (ICF) through the final contact.  Treatment will 
continue for up to 2 years or until the subject meets a 
discontinuation criterion (e.g., has either documented progression, 
unacceptable adverse events (AEs), withdrawn due to investigator’s 
discretion, subject withdraws consent, pregnancy, or noncompliance 
with study procedures or treatments).  Subjects who have been on 
therapy for >6 months and who attain a complete response (CR) 
may consider stopping the trial.  Subjects who achieve a CR should 
receive at least 1 additional cycle of treatment.  The study duration 
includes an active study treatment phase which may last up to a 
maximum of 36 months and a 3 year Lm Surveillance Monitoring 
Phase, which includes 6 months of oral antibiotic administration to 
commence upon completion of the active study treatment phase or 
upon study discontinuation.  All subjects will be followed for 
adverse and serious adverse events (SAEs) for a minimum of 30 
days.  End of Study will be defined as 1 year after the last subject is 
enrolled on study.  However, any ongoing subject, subjects who are 
still deriving clinical benefit from ADXS11-001 therapy at the end 
of their 2 year treatment period or at the end of the study may be 
enrolled into a separate extension study, as available. 
Randomization Ratio 
None 
Methodology 
This is a single arm Phase 2 study.  Stage 1 and 2 of the study are 
monotherapy evaluations of ADXS11-001 in 31 and 24 subjects, 
respectively with persistent/recurrent, loco-regional or metastatic 
SCCA of the anorectal canal that have received at least 1 regimen 
for the treatment of advanced disease.  Additionally, those deemed 
by their investigator as not optimal candidates for chemotherapy 
would be considered eligible. 


 
 
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Study Title: 
Phase 2 Study of ADXS11-001 In Subjects with 
Persistent/Recurrent, Loco-Regional or Metastatic Squamous Cell 
Carcinoma of the Anorectal Canal  
 In addition, all subjects will participate in a 3 year Lm surveillance 
period. The surveillance period will begin following the last dose of 
study treatment or at the time of study discontinuation. This period 
is intended to help ensure the eradication of Lm bacteria. This period 
will also include a 6 month course of 
trimethoprim/sulfamethoxazole which will be initiated 
approximately 72 hours after the completion of the last dose of 
ADXS11-001 or immediately following study discontinuation.  
Objectives 
Primary: 
• 
To evaluate efficacy as measured by the overall response 
rate and rate of 6 month progression-free survival (PFS) in 
subjects with persistent/recurrent, loco-regional or 
metastatic SCCA of the anorectal canal as determined by 
RECIST 1.1. 
Secondary: 
• 
To evaluate efficacy as measured by the overall response 
rate and rate of 6 month PFS in subjects with 
persistent/recurrent, loco-regional or metastatic SCCA of 
the anorectal canal as determined by irRECIST. 
• 
To evaluate the safety and tolerability of ADXS11-001 in 
subjects with persistent/recurrent, loco-regional or 
metastatic SCCA anorectal canal SCCA of the anorectal 
canal by NCI CTCAE 4.0 
• 
To evaluate the additional parameters of efficacy (duration 
of response, PFS and overall survival) of ADXS11-001 in 
subjects with persistent/recurrent, loco-regional or 
metastatic SCCA of the anorectal canal as determined by 
RECIST 1.1 and irRECIST. 
Criteria for Evaluation 
Safety: recorded AEs, changes in physical examinations, vital signs 
measurements, clinical laboratory evaluations and Lm surveillance 
monitoring. 
Efficacy: Response rates as measured by RECIST 1.1 and 
irRECIST, duration of response, PFS 
2 TRIAL DESIGN 
Specific procedures to be performed during this trial, as well as the prescribed times and 
associated visit windows are outlined in the Schedule of Events- Section 6.1.  Details of 
each procedure are provided in Section 7.1 - Trial Procedures. 
This is a multi-center, open-label, 2 stage monotherapy study of ADXS11-001 in subjects 
with persistent/recurrent, loco-regional or metastatic SCCA of the anorectal canal that 
was previously treated in the metastatic setting.   Stage 1 of the study will evaluate the 
safety and efficacy of ADXS11-001.  After 31 evaluable subjects have been enrolled, 
further accrual will be temporarily stopped in Stage 1 to complete an interim efficacy 


 
 
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analysis evaluation.  If the efficacy from Stage 1 demonstrates a response rate >10% by 
either RECIST 1.1 or 6-month progression free survival (PFS) rate >20%, enrollment 
will re-open to Stage 2.  Enrollment will be complete in Stage 2 when an additional 24 
evaluable subjects have been accrued (total 55). 
Subjects will be treated with intravenous (IV) ADXS11-001 administered over 
 
every 3 weeks at a dose of 5 x 109 CFU for up to 2 years or until a 
discontinuation criterion is met.  A treatment cycle is defined as 9 weeks.  Tumor 
assessments will occur every 9 weeks (Week 8 of every Cycle).  Subjects will be 
monitored for adverse events (AEs) throughout the study; AEs will be graded in severity 
according to the guidelines outlined in the NCI Common Toxicity Terminology Criteria 
for Adverse Events (CTCAE) version 4.0. 
 
Safety follow-up will be conducted via telephone call 30 days (±5 days) after the last 
ADXS11-001 infusion to confirm the resolution of any ongoing AEs and SAEs.  Survival 
Follow-Up will be conducted at each visit during the Lm Surveillance period and via a 
telephone call every 3 months (± 2 weeks) after the Lm Surveillance period to determine 
survival status for all subjects.   
The end of the study will be defined as 1 year after the last subject has enrolled on study.  
However, any ongoing subjects, subjects who are still deriving clinical benefit from 
ADXS11-001 therapy at the end of their 2-year treatment period or at the end of the study 
may be enrolled into a separate extension study, as available. 
Safety and efficacy analysis will be performed for both parts of the study.  Subject 
disposition, demographic and baseline characteristics will be summarized separately for 
Stage 1 and Stage 2.  Adverse events will be classified and summarized by system organ 
class (SOC) and preferred term, incidence, severity, and causality.  All subjects who 
receive at least 1 dose of study treatment will be included in the safety analyses. 
Efficacy analysis will be performed for Stage 1 separately (interim analysis) and both 
parts of the study combined.  All subjects who have completed at least 1 cycle of study 
treatment will be included in the efficacy analyses. 
3 OBJECTIVES & HYPOTHESIS 
3.1 
Primary Objectives & Hypothesis 
Objective: To evaluate efficacy as measured by the overall response rate and rate of 6 
month PFS in subjects with persistent/recurrent, loco-regional or metastatic SCCA of the 
anorectal canal as determined by RECIST 1.1 
a. Hypothesis:  ADXS11-001 will produce response rates >10% or 6 month PFS 
rates ≥20% in subjects with persistent/recurrent, loco-regional or metastatic 
SCCA of the anorectal canal. 


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3.2 
Secondary Objectives 
Objective: To evaluate efficacy as measured by the overall response rate and rate of 6 
month PFS in subjects with persistent/recurrent, loco-regional or metastatic SCCA of the 
anorectal as determined by irRECIST 
Objective:  To evaluate the safety and tolerability of ADXS11-001 in subjects with 
persistent/recurrent, loco-regional or metastatic SCCA of the anorectal canal by NCI 
CTCAE 4.0. 
Objective: To evaluate the additional parameters of efficacy (duration of response, PFS 
and overall survival) of ADXS11-001 in subjects with persistent/recurrent, loco-regional 
or metastatic SCCA of the anorectal canal as determined by RECIST 1.1 and irRECIST. 
4 BACKGROUND & RATIONALE 
4.1 
Background 
4.1.1 
ADXS11-001 Immunotherapy ­
ADXS11-001 is a live attenuated Listeria monocytogenes (Lm)-LLO immunotherapy, 
developed for the treatment of human papilloma virus (HPV)-associated cancers.  
ADXS11-001 is 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. 
ADXS11-001 is phagocytized by antigen-presenting cells (APCs) and secretes 
Listeriolysin O (LLO)-tumor antigen fusion proteins within the cytoplasm of the APC 
thereby allowing the generation of a new population of tumor antigen specific cytotoxic 
T lymphocytes (CTLs) driven by the adjuvant properties of LLO.  These tumor-specific 
CTLs can then take advantage of the acute immunologic response to the live vector to 
facilitate infiltration into the tumor, enabling them to access and destroy tumor cells. 
The advantages that Lm possesses as a vector are rooted in its biology.  It is a beta 
hemolytic Gram positive facultative intracellular bacterium that has been used to study 
cell mediated immunity for decades.[1] Lm are preferentially taken up by APCs and, 
unlike other intracellular bacteria like Salmonella, Lm escapes into the cytoplasm of the 
host cell by disrupting the phagosomal membrane.  Also unlike Salmonella, Lm is a Gram 
positive organism, thus, does not release endotoxin, a rate limiting attribute of 
Salmonella.  Because Lm quickly leaves the circulation becoming an intracellular 
infection and because it replicates in the cytoplasm, humoral immunity does not play a 
major role in combating listerial infections. 
Lm has other useful properties, such as stimulating monopoiesis, stimulating the 
differentiation and maturation of APCs, and the generation of a particularly strong innate 
and adaptive cellular immune response.[1, 2]  The ability to deliver antigen to the 
cytosolic compartment of APCs in order to develop human leukocyte antigen Class I 


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presentation to induce CD8+ cytotoxic T-cell responses appears to be an important aspect 
of developing an effective therapeutic antitumor therapy.  Peptides derived from Lm in 
the phagolysosome and the cytosol can be presented by both the major histocompatibility 
complex (MHC) Class I and Class II molecules, inducing both CD4+ and CD8+ T cell 
responses.  There is evidence that Lm also gets into tumors, probably carried by infected 
macrophages and neutrophils.  One potential consequence of this is the observed ability 
of live Lm vector that secrete an LLO-antigen fusion, but not those that secrete only an 
antigen, to diminish regulatory T-cells (Tregs) within the tumor, but not in the spleen or 
normal peripheral tissues. 
As a drug product, ADXS11-001 is administered as an IV infusion given every 
3­4 weeks.  It has no direct effect on tumor tissue, but is designed to stimulate the 
subject’s own immune system to generate an effective immune response targeting a 
tumor-associated antigen like HPV-E7.  Clinical benefit can manifest as a slowing of 
tumor growth, a stabilization of tumors, or a partial or complete response of the 
tumors.[3]  Collectively, the spectrum of clinical benefits is captured as relative delays in 
tumor progression and/or apparent prolonged survival. 
4.1.2 
Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochure for detailed preclinical and clinical data. 
4.2 
Rationale for Trial and Selected Subject Population 
Human papilloma viruses are spread by direct human contact.  Infection of squamous 
mucosal epithelial cells by high risk strains of HPV can result in the transformation of 
squamous epithelial to a pre-malignant phenotype that can progress to malignancy.  High 
risk HPV strain E6 and E7 gene products interfere with the expression and function of the 
host tumor suppressor gene products of P53 and Rb in the host cell.  This process can 
occur in the uterine cervix and can lead to cervical cancer, the oropharyngeal mucosa of 
the tonsils or base of the tongue, and lead to squamous cell carcinoma of the oropharynx, 
or the mucosal epithelium of the anus leading to anorectal cancer. 
While it is estimated that 80% of sexually active individuals are exposed to oncogenic 
strains of HPV, the percentage that develop dysplastic or malignant lesions is 
considerably less.[4]  This is presumably because many individuals can clear the viral 
infection immunologically.  However, in some individuals, the virus is not cleared and 
expressions of viral gene products can lead to malignancy over time. 
Various mechanisms have been proposed for the resistance of human solid tumors to 
immune recognition and obliteration, including the recruitment of regulatory T cells 
(Tregs), myeloid-derived suppressor cells (MDSC), and local secretion of inhibitory 
cytokines that mediate immune tolerance in tissue or tumor microenvironments.  The 
occurrence of HPV-induced cancer is strongly associated with failure to mount a strong 
HPV-specific type 1 T-helper and cytotoxic T-lymphocyte response.[5-7] 


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However, the inhibitory action of HPV-specific Tregs within the tumor 
microenvironment is not the only mediator of immune tolerance contributing to the 
immunologic resistance of HPV-associated malignancy.  Recent evidence also suggests 
that tumors can co-opt physiologic mechanisms of tissue protection from inflammatory 
destruction via up-regulation of immune inhibitory ligands. 
The mechanism of oncogenesis from high-risk HPV infection in squamous mucosal 
epithelium is consistent, whether the site of infection is the cervix or the oral or anal 
mucosa.  Persistence of the virus and its inhibition of tumor suppressor functions can lead 
to the development of dysplasia or malignant carcinoma.  Anorectal cancer, although 
relative rare has been steadily increasing over the last 50 years.  And while both survival 
and locoregional control is good for patients with early stage anorectal cancer, for those 
patients with high risk  and/or recurrent metastatic disease the unmet medical need 
remains high.[8, 9]  The epidemiology of anorectal cancer demonstrates that high-risk 
HPV has been reported in approximatley 90% in patients with squamous cell cancer of 
the anorectal canal, with serotypes HPV 16 and 18 being the most common.[10]  Given 
the activity that ADXS11-001 has demonstrated in metastatic squamous cell cancer of the 
cervix,[3] which are histologically and epidemiologically similar to anorectal cancer, 
evaluation of ADXS11-001 in patients with anorectal cancer seem logical. 
Currently there is an ongoing clinical study in subjects with high-risk locally advanced 
squamous anal cancer which evaluates ADXS11-001 therapy prior to, and following 
standard of care radiotherapy and concurrent 5FU/mitomycin C (MMC) (NCT 
#01671488).  To date 10 subjects have been enrolled.  Preliminary safety data from this 
ongoing study are consistent with those observed with ADXS11-001 treatment to date.  
The current study seeks to evaluate ADXS11-001 in the metastatic population.  The 
standard of care for patients with metastatic disease was established several years ago 
with a combination regimen of 5FU and cisplatin.  Response rates with this combination 
range between 40-50% with median overall survival of 34.5 months.[11, 12] While 
efficacious, patients will recur and eventually succumb to their disease.  The need to 
evaluate new therapies, particularly those targeted at HPV, such as ADXS11-001 is 
warranted. 
4.2.1 
Rationale for Dose Selection/Regimen/Modification 
4.2.1.1 
Summary of Safety of ADXS11-001 


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4.2.2 
Delayed/Late Listeria Infection 
In a Phase 1 clinical study, in the absence of antibiotics, Lm was rapidly cleared from the 
blood. No Lm was detected in the blood, urine or feces of any subject beyond 48 hours 
post-dosing and at the highest dose of ADXS11-001 tested  (1 x 1010 CFU).[13] 
wt-Lm is known to form and persist within biofilms especially on medical devices despite 
antibiotic treatment.[14] Although rare, medical device–related infections such as 
ventriculo-peritoneal shunt infection, peritoneovenous shunt infection, and prosthetic 
joint infection have been reported.[15-18] ADXS11-001is highly sensitive to antibiotics 
such as ampicillin and trimethoprim/sulfamethoxazole which can be an effective 
treatment regimen for listeria infection. 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 6 
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4.2.2.1 
ADXS11-001 – Rationale for Dose Selection and Regimen 
ADXS11-001 is a live attenuated strain of Listeria monocytogenes (Lm) that has been 
The AEs associated with this class of agents seem to be directly related to innate immune 
effects associated with the infusion of the live attenuated bacteria.  These typically 
consist of Grade 1 and 2 cytokine release symptoms (e.g., fever, chills, rigors, headache, 
nausea, vomiting, tachycardia, shortness of breath, hypotension, and rash) which 
typically occur 2-4 hours after ADXS11-001 infusion and usually resolve within 12-24 
hours. The symptoms appear to be related to the number of CFU infused over 
time.  Pretreatment with hydration, oral nonsteroidal anti-inflammatory drugs (NSAIDs), 
antihistamines, histamine H2-receptor antoagonists and antiemetics may reduce the 
incidence of these symptoms.  
With ADXS11-001, live bacteria has not been recovered from subjects after 48 hours 
following completion of the infusion.  A 7-day course of oral antibiotics is given 
beginning on  Day 4 post dose to help ensure clearance of the vector.  There is no specific 
target blood level that needs to be achieved in order for ADXS11-001 to compete with a 
target or bind to a receptor. Therefore, maximum concentration (Cmax), minimum 
concentration (Cmin), and half-life of ADXS11-001 are not relevant based on 
pharmacology.   


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The complex mechanism of action of ADXS11-001 includes elements that may be dose 
related. For example, the generation of T-cells may require a minimum effective dose in 
order for the body to respond. In previously completed, as well as ongoing clinical 
studies, a dose of 1 x 109 CFU has demonstrated clinical responses and appears to meet 
this minimum requirement. Additionally, in patients with advanced disease there may be 
an added benefit to treating with higher doses and repeating treatments until progression 
or complete response 
Patients with metastatic or recurrent anorectal cancer have advanced disease, extremely 
limited treatment options and a poor long-term prognosis.  Therefore, these patients 
should receive the most aggressive treatment that can be administered safely to optimize 
their opportunity for clinical benefit.  Since the results from the ongoing Phase 1 study 
have shown that a dose of 1 x 1010 CFU can be safely adminstered and is well-tolerated 
by patients with an advanced HPV-related disease (cervical cancer), a dose of 5 x 109 
CFU of ADXS11-001 has been selected for use in this clinical study. This dose has also 
be shown that it can be safely administered and was well-tolerated in a clinical study of 
patients with advanced HPV disease. It is also a dose level below the dose (1 x 1010 CFU) 
which has been established as the RP2D in a clinical study in an advanced disease HPV 
population. Finally, this dose was selected to offer patients with advanced anal cancer the 
greatest opportunity to receive clinical benefit during their participation in the study.  The 
safety and tolerability of this dose will be evaluated in this population on an individual 
and cumulative subject basis. Defined stopping rules are in place which require safety 
data to be evaluated and the study ‘stopped’ if specific individual patient and/or 
cumulative patient criteria are met. The 5 x 109 dose will be evaluated when the study is 
‘stopped’ based on meeting the protocol-defined criteria in order to determine if it is safe 
to proceed at this dose level or a lower dose should be considered. All subjects will 


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receive treatment for up to two years, until confirmed disease progression or until a 
complete clinical response is achieved.  
4.2.3 
Rationale for Endpoints 
4.2.3.1 
Efficacy Endpoints 
The evaluation of efficacy for both the parts of the study will utilize CT or magnetic 
resonance imaging (MRI) to assess tumor response as well as PFS measured by RECIST 
1.1 and irRECIST.  These endpoints are well established and commonly used  to evaluate 
signs of clinical activity and efficacy. 
4.2.3.2 
Safety Endpoints 
The safety objective of this trial is to characterize the safety and tolerability of ADXS11-
001 in subjects with metastatic SCCA of the anorectal canal.  The safety analysis will be 
based on subjects who experience toxicities as defined by NCI CTCAE v 4.0.  Safety will 
be assessed by quantifying the toxicities and grades experienced by subjects who have 
received ADXS11-001, including SAEs. 
The attribution to drug, time-of-onset, duration of the event, its resolution, and any 
concomitant medications administered will be recorded.  AEs will be analyzed including 
but not limited to all AEs, SAEs, fatal AEs, changes in physical examinations, vital sign 
measurments and clinical laboratory changes. 
4.2.4 
Study Stopping Rules 
Rules for temporary suspension of study for death due to non-progressive disease, 
hematologic and non-hematologic events related to ADXS11-001 treatment 
The Advaxis medical monitor and Project Manager as well as other key personnel 
associated with the trial (e.g. CRO Medical Monitor, Primary Investigator), as 
appropriate, will monitor death due to non-progressive disease and hematologic and non-
hematologic toxicities for individual subjects in real-time and trial-level cumulative 
toxicities on a monthly basis. These events must be deemed by the Investigator at the site 
to have some degree of “relatedness” to ADVXS11-011 treatment (e.g. definitely, 
probably or possibly related) in order to be considered for evaluation. The assessment of 
cumulative trial-level toxicities will not begin until at least 5 subjects have received a 
dose of ADXS11-001 and evaluated for death and individual toxicity events following 
the completion of the initial 3-week treatment period. The guidelines below will be used 
to determine the threshold of cumulative events that will result in temporary suspension 
of enrollment for new subjects and dosing for any active subject until a thorough of the 
cumulative information is evaluated and a risk/benefit assessment conducted.   
•
Death (other than death related to disease progression) that occurs within 30
days of the ADXS11-001 infusion


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•
>30% Grade 3 or greater non-hematologic adverse events that are at least
possibly related to ADXS11-001
•
>30% Grade 4 or greater hematologic adverse events that are at least possibly
related to ADXS11-001
The assessment of an individual subject event which meets the criteria as defined above 
and has been determined by the investigator to be related to ADXS11-001 treatment will 
begin as soon as all required and relevant information is received. The same project team 
personnel will review all of the information and determine an appropriate course of 
action (e.g., temporarily suspending enrollment and ongoing treatment in active subjects; 
temporarily suspending enrollment and allowing treatment in active subjects to continue) 
based on a thorough review pertaining to the event.  
The Sponsor will send a written communication to the investigative sites when a decision 
is made based on all available information from an individual subject or the cumulative 
data to temporarily suspend future enrollment and/or the continued doing of active 
subjects. The communication will contain information about the event(s) and the 
immediate steps which must be taken in order to comply with the Sponsor’s 
decision.  The investigative sites will also receive written notification from the Sponsor 
when the enrollment of new subjects and dosing for active subjects may resume.  
5 METHODOLOGY 
5.1 
Entry Criteria 
5.1.1 
Inclusion Criteria 
This study will include subjects with  persistent/recurrent, loco-regional or metastatic 
SCCA of the anorectal canal. 
For subjects to be eligible they: 
1.
Must have histopathologic diagnosis of squamous cell cancer of the anorectal
canal.
2.
Must have received at least one line of therapy for their metastatic disease.
However patients deemed by their investigator as not optimal candidates for
chemotherapy (e.g., drug allergy, ototoxicity, renal insufficiency) would be
considered eligible.
3.
Be willing and able to provide written informed consent for the trial.
4.
Be ≥18 years of age on day of signing informed consent.
5.
Have measurable disease based on RECIST 1.1
6.
Have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
7.
Demonstrate adequate organ function as defined in Table 3.


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Table 3  Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
Absolute neutrophil count (ANC)a 
≥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 OR 
≤5.0 X ULN for subjects with liver metastases 
Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT)  
≤1.5 X ULN unless subject is receiving 
anticoagulant therapy 
as long as PT or INR is within therapeutic range 
of intended use of anticoagulants 
Activated Partial Thromboplastin Time 
(aPTT) 
≤1.5 X ULN unless subject is receiving 
anticoagulant therapy 
as long as aPTT is within therapeutic range of 
intended use of anticoagulants 
a    ANC, Platelets, Hemoglobin requirement cannot be met by the use of recent transfusions, or growth 
factor support (G-CSF, erythropoietin, etc) within 2 weeks prior to treatment initiation.
b    Creatinine clearance should be calculated per institutional standard. 
8.
Female subjects of childbearing potential must not be breastfeeding and have a
negative urine or serum pregnancy test within 72 hours prior to receiving the first
dose of study medication.  If the urine test is positive or cannot be confirmed as
negative, a serum pregnancy test will be required.
9.
Female subjects of childbearing potential should be willing to use 2 methods of
birth control for the course of the study through 120 days after the last dose of
study medication (see Section 5.7.2).
10.
Male subjects should agree to use an adequate method of contraception starting
with the first dose of study therapy through 120 days after the last dose of study
therapy.
11.
Must have a washout period of the following prior to first dose of study treatment:


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a.
14 days from completing prior standard of care therapy, with the
exception of MMC and palliative radiation therapy for disease-related
pain.
b. 6 weeks from the last dose of MMC, given the delayed bone marrow
suppression that can be experienced with MMC.
c.
28 days from treatment with investigational device/therapy or 3 times the
half-life in the case of monoclonal antibodies, whichever is longer
d. 7 days from treatment with systemic steroid therapy or any other form of
immunosuppressive therapy
e.
30 days from treatment with live vaccine
Note:  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, chicken pox, yellow fever, rabies, 
BCG, typhoid, and intranasal influenza vaccines (e.g., Flu Mist®).  
Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed. 
5.1.2 
Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. Has not recovered (e.g., Grade ≤1 or at baseline) from AEs, with the exception of
alopecia or Grade ≤2 neuropathy, due to a previously administered agent.
2. Has a diagnosis of immunodeficiency.
3. Has known additional malignancy that is progressing or requires active treatment.
Treatment of an additional malignancy with chemotherapy, immunotherapy, biologic
or hormonal therapy must have occurred 2 years prior.   Concurrent use of hormones
for non-cancer-related conditions (e.g., insulin for diabetes and hormone replacement
therapy) is acceptable.
a.
Note:  Local treatment of isolated lesions for palliative intent (e.g., by local
surgery or radiotherapy), basal cell carcinoma of the skin, or squamous cell
carcinoma of the skin, or ductal carcinoma in situ of the breast that has/have been
surgically cured is acceptable.
4. Has known active CNS metastases and/or carcinomatous meningitis.  Subjects with
previously treated brain metastases may participate provided the metastases are stable
(without evidence of progression by imaging for at least 4 weeks prior to the first
dose of study treatment and any neurologic symptoms have returned to baseline),
have no evidence of new or enlarging brain metastases, and are not using steroids for
at least 7 days prior to the first dose of study treatment.


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5. Has concurrent unstable or uncontrolled medical condition (e.g. active uncontrolled
systemic infection, poorly controlled hypertension or history of poor compliance with
an anti-hypertensive regimen, unstable angina, congestive heart failure, uncontrolled
diabetes) or other chronic disease, which in the opinion of the investigator, could
compromise the patient or the study. 
6. 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.
a.
Subjects with vitiligo or resolved childhood asthma/atopy would be an exception
to this rule.
b. Subjects that require intermittent use of inhaled steroids, bronchodilators or local
steroid injections may be allowed with sponsor approval.
c.
Subjects with hypothyroidism stable on hormone replacement or Sjorgen’s
Syndrome will not be excluded from the study.
7. Has an active infection requiring systemic therapy.  Prior to dosing with study
treatment(s), the subject must be at least 5 half-lives from their last dose of antibiotic.
8. Has any other serious or uncontrolled physical or mental condition/disease that, as
judged by the investigator, could place the patient at higher risk derived from his/her
participation in the study, could confound results of the study, or would be likely to
prevent the patient from complying with the requirements of the study or completing
the study.
9. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
10. Subject 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)).
a.
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. Subjects with any other devices or implants must be
approved by Sponsor prior to participation.
11. Any patient currently requiring or anticipated to require tumor necrosis factor (TNF)
blocking agent (e.g., infliximab) therapy for diagnosis of rheumatologic disease or
inflammatory bowel disease (e.g., ankylosing spondylitis, Crohn disease, plaque
psoriasis, psoriatic arthritis, rheumatoid arthritis or ulcerative colitis).
12. Patients who are currently receiving or who have received any PI3K inhibitor within
30 days prior to registration.


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13. Subject has a contraindication (e.g. sensitivity/allergy) to
trimethoprim/sulfamethoxazole and ampicillin.
14. Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies).
15. Has known active hepatitis B or hepatitis C.
16. Has a known allergy to any component of the study treatment(s) formulations.
17. Has contraindication to administration of NSAIDs.
18. Has undergone a major surgery, including surgery for a new artificial implant and/or
medical device which is permitted by the protocol, within 6 weeks prior to the
initiation of ADXS11-001 treatment
a.
Note: If the subject had a major surgery, all toxicities and/or complications from
the intervention must have recovered to at least the 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 a new
artificial implant and/or medical device.
19. In the opinion of the investigator has rapidly progressing disease, OR has life
expectancy of <6 months, OR would be unable to receive at least 1 cycle of therapy.
5.2 
Trial Treatments 
The treatment to be used in this trial is outlined below in Table 4. 
Table 4  Trial Treatment 
Drug 
Dose 
Regimen 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
ADXS11-
001 
5 x 109 
CFU 
Q3W 
IV infusion 
9-week cycle
Experimental 
5.2.1 
Dose Selection/treatment Modification 
The dose to be used in each stage of the trial is described above.  Treatment Modification 
Guidelines are described below in Section 5.2.1.2. 
5.2.1.1 
Dose Selection 
The rationale for selection of doses to be used in this trial is provided in Section 4.2.2.1.  
The dose of ADXS11-001 will be 5 x 109 CFU, however the sponsor reserves the right to 
change the dose up to 1 x 1010 CFU based on emerging data from ongoing clinical 
studies.  If the dose is escalated, subjects who initiated therapy at 5 x 109 CFU may be be 
escalated up to 1 x 1010 CFU only after consultation with the sponsor. 


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The dose of 5 x 109 CFU will not be reduced for individual subject, however, the dose 
may be reduced for all subjects based on the stopping rules outlined in Section 4.2.4 
Details on the dose calculation, preparation and administration are provided in the 
Pharmacy Manual. 
5.2.1.2 
Treatment Modification/Delay Due to Adverse Events 
The most likely AEs associated with ADXS11-001 are comprised primarily of individual 
flu-like symptoms (e.g., fatigue, lethargy and low grade fever) or cytokine release 
symptoms (e.g., constitutional symptoms such as fever, chills, rigors, headache, nausea, 
vomiting tachycardia, shortness of breath, hypotension, and rash).  These symptoms 
usually present within 2-4 hours after the completion of infusion and are often mild to 
moderate and transient in nature or respond quickly to symptomatic treatment.  In rare 
instances they may last up to 24 hours. No cumulative or delayed toxicity has been 
observed. 
Less likely AE’s include increase heart rate, low blood pressure, muscle aches, 
headaches, allergic reaction, changes in blood chemistry, changes in blood counts, and 
short term changes in liver function. 
Rare but serious AEs include high fever, difficulty breathing and hypotension. 
 ADXS11-001 has a tropism for the liver.  Transient asymptomatic 
elevations of ALT and alkaline phosphatase were observed after dosing in the Phase 1 
trial without prophylactic medication administration.  For that reason, patients with 
significant liver disease are excluded, and particular attention is to be paid to hepatic 
abnormalities. 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 subject 
Hematologic 
1,2,3 
No 
N/A 
N/A 
4 
Yes 
Toxicity resolves to 
≤Grade 1or baseline 
Toxicity does not 
resolve to ≤Grade 
1or baseline within 3 
weeks 
1 
No 
N/A 
N/A 
2-3
Yes 
Toxicity resolves to 
≤Grade 1 or baseline 
Toxicity not 
resolved to ≤Grade 1 
or baseline within 3 
weeks of last 
infusiona 


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Non-
hematologic, 
excluding 
cytokine 
release 
symptoms 
and DLTs 
4 
N/A 
Permanent 
discontinuation 
Permanent 
Discontinuation 
from Study 
a With investigator and sponsor agreement, subjects with a non-heme  AE (eg  alopecia, neuropathy) still at grade 2 after 3 weeks, may continue treatment if only 
asymptametic and controlled   
With Investigator and Sponsor agreement, subjects with a laboratory AE still at Grade 2 
after 2 weeks may continue treatment in the trial only if asymptomatic and controlled.  
For information on the supportive care of AEs, see Section 5.6. 
Subjects who experience a recurrence of the same severe or life-threatening event at the 
same grade or greater with re-challenge of ADXS11-001 should be discontinued from 
trial participation. 
5.2.2 
Administration of ADXS11-001 
5.2.3 
Timing of Dose Administration 
ADXS11-001 should be initiated on Cycle 1/Day 1 after all procedures/assessments have 
been completed as detailed on the Schedule of Events (Section 6.1).  Trial treatment may 
be administered up to 7 days before or after the scheduled treatment day due to 
administrative reasons but only after consultation with the Sponsor. 
All trial treatments will be administered on an outpatient basis. 
5.2.4 
Pretreatment Prophylaxis Regimen 
Mild to moderate cytokine release symptoms (e.g., constitutional symptoms such as 
fever, chills, rigors, 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.  Subjects should receive the following 
pretreatment prophylaxis regimen: 
IV Fluid Hydration: 
•
Normal saline (e.g., 500mL over 30 minutes)


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Premedication Regimen: 
•
Antihistamine- PO or IV (e.g., diphenhydramine 25 mg or equivalent), once
•
NSAIDs- PO, (e.g., naproxen, 220 mg or ibuprofen, 400 mg), once
•
Antiemetic- PO or IV, (e.g., promethazine or ondansetron ), once
•
Histamine H2-receptor antagonist- PO or IV (e.g., famotidine 20 mg or
equivalent ), once
Pretreatment medication should be given on the day of dosing and completed at least 30 
minutes prior to the start of the assigned study treatment. Additional NSAID doses and 
antiemetic administration should be given per label or package insert post initial 
administration 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.  
Do not substitute acetaminophen for the selected NSAID for prophylactic treatment since 
acetaminophen does not have similar anti-inflammatory properties that could ameliorate 
cytokine release symptoms. 
5.2.5 
ADXS11-001 Dosing 
The dose for ADXS11-001 will be 5 x 109 CFU administered in 250 mL of normal saline 
infused over 
 Q3W in repeating 9-week treatment cycles.   
The Pharmacy Manual contains specific instructions for ADXS11-001 storage, handling, 
dose calculation, reconstitution, destruction and ordering. 
All subjects will also receive a 7 day course of oral antibiotics following each 
ADXS11-001 treatment.  Specific details of the antibiotic regimen are provided in 
Section 7.1.6.2. 
5.2.6 
Treatment Duration 
The study begins when the first subject signs informed consent. 
The treatment duration is approximately 2 years. 
5.2.7 
Trial Blinding/Masking 
This is an open-label trial.  Therefore, the Sponsor, investigator and subject will know the 
treatment administered. 
5.3 
Randomization or Treatment Allocation 
All subjects will receive ADXS11-001. 


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5.4 
Stratification 
There is no stratification. 
5.5 
Concomitant Therapies and Procedures (Allowed & Prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not 
allowed during the ongoing trial.  If there is a clinical indication for one of these or other 
medications or vaccinations specifically prohibited during the trial, discontinuation from 
ADXS11-001 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 ADXS11-001 therapy requires the mutual 
agreement of the Investigator, the Sponsor, and the subject. 
5.5.1 
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, therapies and procedures will be 
recorded on the electronic case report form (eCRF) including all prescription, over-the-
counter (OTC), herbal supplements, and IV medications and fluids.  Protocol-mandated 
prophylactic medications and antibiotics should also be captured in the eCRF.  If changes 
occur during the trial period, documentation of drug dosage, frequency, route, and date 
should be included on the CRF.  Only generic names should be used.  Do not use trade 
names. 
All concomitant medications received within 28 days before the first dose of trial 
treatment and up to 30 days after the last dose of trial treatment should be recorded. 
5.5.2 
Prohibited Concomitant Therapies 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this trial: 
•
Anti-cancer therapy including but not limited to, hormonal, chemotherapy,
radiation therapy, treatment with targeting agents (eg, Tyrosine kinase inhibitors).
However occasional radiation therapy for palliation of pain is allowed
o
Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may
be allowed after consultation with Sponsor.  Radio-pharmaceuticals (e.g.,
radium, strontium, etc.) are not acceptable.
•
Immunotherapy not specified in this protocol
•
Investigational agents other than ADXS11-001




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IL-6, all of which have been shown to occur after ADXS11-001 administration, resulting 
from the body’s immune response to the therapy. Although, symptoms are often grade 1-
2 and transient, resolving with symptomatic management within 30 minutes-1 hour, in 
rare instances (~1%) grade 3-4 hypotension has been seen.  Therefore, close monitoring 
of blood pressure is strongly recommended at baseline, and during the post-infusion 
period. Increased levels of IL-6, has been strongly associated with capillary leak which 
manifests as hypotension due to the cytokines involved. We have observed elevated IL-6 
levels after infusion of ADXS11-001, with peak levels occurring 2-4 hours after infusion. 
Emerging evidence indicates that IL-6 antagonists, such as Tocilizumab, has 
demonstrated good results in treating cytokine-induced hypotension [19-22] and is 
therefore recommended for cases of severe hypotension refractory to supportive care (e.g. 
fluids and/or pressors). 
The management of cytokine release symptoms and guidelines for subsequent treatment 
for patients who have experienced these adverse events are shown in Table 6. 


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Table 6  Recommended Management Guidelines for Adverse Events Associated with Cytokine Release 
Toxicity 
NCI CTCAE Grade 
or Severity 
Treatment 
Modification for Subsequent infusions 
Hypotension 
1 
Mild 
•
Supportive care
•
Increase pretreatment IV fluids (e.g., 500 ml -
1L normal saline)
Fever, 
Constitutional symptoms 
1 
•
Supportive care
•
No modification
Hypotension 
2 
Moderate 
•
Fluids and 1 dose of pressor (e.g. 0.3 mg epinephrine IM)
•
Increase monitoring of vital signs
•
If hypotension persist for more than one hour consider
low dose corticosteroids (e.g. hydrocortisone 100 mg IV
over 30 seconds
•
Extend infusion time to 2 hours. Increase
pretreatment IV fluids (e.g. 500 ml -1L
normal saline)
•
Incorporate Glucocorticoid- Hydrocortisone
or equivalent- 50 mg, IV, as premedication
All other cytokine release 
symptoms (e.g. chills, rigors, 
fever, nausea, vomiting) 
2 
•
Appropriate supportive care measure
•
Extend infusion time to 2 hours.
•
Consider increasing doses of prophylactic
medications
Hypotension 
3 
Severe 
•
Fluids, high dose pressors (e.g. Dopamine 10 µg/kg/min)
+1 dose tocilizumab*(4mg/kg over 1 hour)
•
If hypotension worsens or is unresponsive to above
measures, administer corticosteroids
•
If the patient’s condition does not improve or stabilize
within 24 hours of the tocilizumab dose, administration of
a second dose of tocilizumab +/- corticosteroids should be
considered.
•
Discuss with Sponsor


 
 
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Toxicity 
NCI CTCAE Grade 
or Severity 
Treatment 
Modification for Subsequent infusions 
All other cytokine release 
symptoms (e.g. chills, rigors, 
fever, nausea, vomiting) 
3 
• Appropriate supportive care  measures 
• 
Extend infusion time to 2 hours.  
• 
Consider increasing doses of prophylactic 
dose of NSAID, or antiemetic as appropriate 
Hypotension/Organ toxicity, 
mechanical ventilation 
4 
Life threatening 
• Vigilant supportive care 
• Fluids,  
• High dose  pressors,  
• Tocilizumab (4mg/kg over 1 hour) +/- corticosteroids 
(hydrocortisone 100 mg IV infused over 30 seconds 
administered every 2 hours until symptoms resolve to 
<Grade 1) 
• 
Permanently discontinue 
* Tocilizumab is a humanized, immunoglobulin G1k (IgG1k) anti-human IL-6R mAb approved 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. Tocilizumab works by preventing IL-6 binding to both cell-associated and soluble IL-6Rs. Although, it is not indicated for the treatment of cytokine release symptoms emerging clinical experience at 
several institutions has concluded that tocilizumab is an effective treatment for severe or life-threatening cytokine release symptoms.[19-22] 


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5.6.2 
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. 
5.6.3 
Infusion Reaction 
While there is some overlap between infusion reactions symptoms and cytokine release 
symptoms, infusion reactions symptoms, typically occur during the infusion, while 
cytokine release symptoms typically occur after the infusion and are mediated by a 
different mechanism of action.  Signs/symptoms of infusion reactions may include: 
allergic reaction/ hypersensitivity (including drug fever); arthralgia (joint pain); 
bronchospasm; cough; dizziness; dyspnea (shortness of breath); fatigue (asthenia, 
lethargy, malaise); headache; hypertension; hypotension; myalgia (muscle pain); nausea; 
pruritic/itching; rash/ desquamation; rigors/chills; sweating (diaphoresis); tachycardia; 
tumor pain (onset or exacerbation of tumor pain due to treatment); urticaria (hives, welts, 
wheals); and vomiting.  Table 7 below shows the management guidelines for subjects 
who experience an infusion reaction associated with administration of the study 
treatment. 


 
 
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Table 7  Management Guidelines for Infusion Reactions 
 
NCI CTCAE Grade 
Treatment 
Grade 1 
 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as medically indicated until the 
subject is deemed medically stable in the opinion of the investigator. 
Grade 2 
 
Requires infusion interruption 
but responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hrs. 
1. Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may include but is 
not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
2. Increase monitoring of vital signs as medically indicated until 
the subject is deemed medically stable in the opinion of the 
investigator. 
If symptoms resolve within one hour of stopping drug 
infusion, the infusion may be restarted at 50% of the original 
infusion rate (e.g. from 100 mL/hr to 50 mL/hr).  Otherwise 
dosing will be held until symptoms resolve and the subject 
should be premedicated for the next scheduled dose. 
Grades 3 or 4 
 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae (e.g., 
renal impairment, pulmonary 
infiltrates) 
 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
1. Stop Infusion. 
Additional appropriate medical therapy may include but is 
not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
2. Increase monitoring of vital signs as medically indicated until 
the subject is deemed medically stable in the opinion of the 
Investigator. 
3. Hospitalization may be indicated. 
4. Subjects who experience a Grade 4 reaction should be 
permanently discontinued from study. Subjects who 
experience a grade 3 reaction may be discontinued. 
Discussion with the Sponsor is recommended  


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5.6.3.1 
Listeriosis and Listeria Infection - Identification and 
Management 
A person with (wt) listeriosis usually presents with fever and muscle aches, sometimes 
preceded by diarrhea or other gastrointestinal symptoms. Almost everyone who is 
diagnosed with listeriosis has an "invasive" infection, in which the bacteria spread 
beyond the gastrointestinal tract. The symptoms vary with the infected person.  Pregnant 
women typically experience fever and other non-specific symptoms, such as fatigue and 
aches. However, infections during pregnancy can lead to miscarriage, stillbirth, 
premature delivery, or life-threatening infection of the newborn.  In people other than 
pregnant women, symptoms can include headache, stiff neck, confusion, loss of balance, 
and convulsions in addition to fever and muscle aches.  Listeriosis can present in 
different ways. In older adults and people with immunocompromising conditions, 
septicemia and meningitis are the most common clinical presentations.[23]  Subjects 
may need 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 patients, diagnosis 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), or amniotic fluid/placenta (in the setting of pregnancy). Stool samples are 
of limited use and are not recommended. 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.  You can expect that the 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.[23] 
Listeriosis is treated with a wide range of antibiotics.  In preclinical studies, wt-Lm and 
ADXS11-001 are susceptible to the lowest tested concentration of the following 
antimicrobial agents:
 
5.6.4 
Management and Surveillance of Listeria During Study 
Participation 
A subject who experiences a fever (CTCAE Grade 1 or greater) 24 hours following the 
completion of ADXS11-001 infusion should be started on NSAIDS, hydration and other 
appropriate measures to treat the fever.  In the event that the fever persists or worsens 
48 hours following the completion of ADXS11-001 infusion then oral or broad spectrum 
IV antibiotics should be considered based on the subject’s medical condition.  If the fever 
remains unresponsive to oral/IV antibiotics 72 hours following the completion of the 
infusion then a blood culture should be obtained to evaluate for listeremia and determine 
the appropriate treatment course for the subject.   


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All subjects will receive a 6 month course of an oral antibiotic regimen as a prophylactic 
measure approximately 72 hours following the completion of the last dose of ADXS11-
001 treatment or at the time of study discontinuation. This additional safety measure is 
intended to eradicate Lm from the body.  
Lm surveillance monitoring will also be initiated following the completion of the last 
dose of ADXS11-001 treatment or at the time of study discontinuation. This monitoring 
will include obtaining a blood sample for CBC, CMP, including CRP and ESR, and 
blood cultures for the detection of listeria. Testing will be performed on all subjects who 
have received at least one dose of ADXS11-001 and occur every 4 months (±2 weeks) for 
3 years. 
Should a diagnosis of listeriosis occur at any point after treatment with ADXS11-001 is 
completed immediate, intensive IV antibiotic treatment (e.g. Ampicillin +/- Gentamicin 
or other IV antibiotic regimen as indicated) is required. An infectious disease consult 
should be obtained. Based on each individual subject’s case and at the discretion of the 
treating physician, the removal of any foreign medical object that has been present since 
treatment with ADXS11-001 was initiated may be warranted.  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 listeriosis and the potential for delayed 
listeremia/listeriosis.  Educational materials for the investigator, research staff, health 
care providers and patients will be prepared and educational training performed.  
5.7 
Diet/Activity/Other Considerations 
5.7.1 
Diet 
Subjects should maintain a normal diet unless modifications are required to manage an 
AE such as diarrhea, nausea or vomiting. 
5.7.2 
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 male and female study candidates with reproductive potential must be 
advised of the importance of avoiding pregnancy during trial 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), 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 


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abstinence, and who have a sterile partner (eg, vasectomy) should be considered of 
childbearing potential. 
All women of childbearing potential must have a negative pregnancy test within 72 hours 
prior to receiving ADXS11-001.  The minimum sensitivity of the pregnancy test must be 
25 IU/L or equivalent units of human chorionic gonadotropin.  If the pregnancy test is 
positive, the patient must not receive ADXS11-001 and may not be enrolled in the study. 
Male subjects may be enrolled if they are willing to use an adequate method of 
contraception.  Women of childbearing potential may be enrolled if they are willing to 
use 2 methods of birth control.  The 2 birth control methods can be 2 barrier methods or a 
barrier method plus a hormonal method to prevent pregnancy. 
The following are considered adequate barrier methods of contraception: diaphragm, 
condom (by the partner), copper intrauterine device, sponge, or spermicide.  Appropriate 
hormonal contraceptives will include any registered and marketed contraceptive agent 
that contains an 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 males and female study candidates of reproductive potential  
must adhere to the contraception requirement (described above) from Visit 1 through 120 
days post last ADXS11-001 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. 
5.7.3 
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 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.  If a male 
subject impregnates his female partner the study personnel at the site must be informed 
immediately and the pregnancy reported to the Sponsor and followed as described above 
and in Section 7.2.2. 
5.7.4 
Use in Nursing Women 
It is unknown whether ADXS11-001 is excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment. 


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5.7.5 
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 patient; 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 newly implanted artificial (prosthetic) joints, implants and/or devices which is 
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.  
On study, surgeries and/or procedures must be scheduled following the completion of 7 
day course of prophylactic antibiotics post ADXS11-001 infusion.  In addition, 
“recommended antibiotic prophylaxis” per institution standards for respective 
surgeries/and or procedures must be followed.  
5.8 
Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial 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 trial is 
inappropriate, the trial plan is violated, or for administrative and/or other safety reasons.  
Specific details regarding discontinuation or withdrawal are provided in Section 7.1.5. 
A subject can be discontinued from the treatment for any of the following reasons: 
•
Screen Failure
•
Adverse Event/Serious Adverse Event
•
Lost to Follow-Up
•
Disease Progression, radiographic and/or clinical
•
Death
•
Withdrawal of Consent by Subject
•
Investigator Decision/Study Non-Compliance by Subject


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•
Achieved Complete Remission
•
Completed Study (maximum 24 months of study treatment)
•
Other (specify)
In all cases, the reason for and date of withdrawal must be recorded in the eCRF and in 
the patient's medical records.  The patient must be followed up to establish whether the 
reason was an AE, and, if so, this must be reported. 
When a subject discontinues/withdraws prior to treatment completion, all applicable 
activities scheduled for the final assessment (End of Therapy assessments) should be 
performed at the time of discontinuation.  Any AEs that are present at the time of 
discontinuation/withdrawal should be followed in accordance with the safety 
requirements outlined in Section 7.2. 
The investigator must make every effort to contact subjects who discontinue the study 
prematurely or are lost to follow-up and to schedule the end of therapy assessments.  
Attempts to contact such subjects must be documented in the patient’s records (e.g., times 
and dates of attempted telephone contact, receipt for sending a registered letter). 
5.9 
Subject Replacement Strategy 
Non-evaluable subjects will be replaced in order to achieve the total number of subjects. 
5.10 Treatment after Initial Evidence of Radiologic Disease Progression 
Immunotherapy may produce antitumor effects by potentiating endogenous cancer-
specific immune response.  The response patterns seen with such an approach may extend 
beyond the typical time course of responses seen with cytotoxic agents and can manifest 
as a clinical response after an initial increase in tumor burden or even the appearance of 
new lesions.  If radiological imaging shows progressive disease (PD), subjects may 
continue on study with the option of continuing treatment, provided there is: 
•
no deterioration in ECOG performance status
•
absence of signs and symptoms (including worsening of laboratory values)
indicating disease progression
•
absence of rapid progression of disease
•
absence of progressive tumor at critical anatomical sites (e.g., cord compression)
requiring urgent alternative medical intervention
Tumor assessment should be repeated >4 weeks later to confirm PD.  If repeat imaging 
shows CR, partial response (PR) or stable disease (SD) compared to the baseline scan, 
treatments may be continued or resumed.  If repeat imaging shows continued progression 


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of disease, subjects will be discontinued from study therapy, unless the basis for the PD 
assessment is enlarged tumor-draining lymph nodes in the presence of a target tumor 
reduction.  In determining whether or not tumor burden has increased or decreased, 
Investigators should consider all target lesions as well as non-target lesions. 
5.11 Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
•
Quality or quantity of data recording is inaccurate or incomplete
•
Poor adherence to protocol and regulatory requirements
•
Incidence or severity of adverse drug reaction in this or other studies indicates a
potential health hazard to subjects
•
Plans to modify or discontinue the development of the study treatment
In the event of Sponsor decision to no longer supply study treatment, ample notification 
will be provided so that appropriate adjustments to subject treatment can be made. 


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6 STUDY EVALUATIONS 
6.1 
Schedule of Events 
Study Procedure 
Screening2 
9 Week Treatment Cycle1 
End of 
Therapy3 
Follow-Up 
Weeks 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Administrative Procedures 
Informed consent 
X 
Eligibility Criteria / Subject ID Card
X 
Demographics/Medical History 
X 
Prior Cancer History 
X 
Prior/Concomitant Therapies & Procedures 
X 
X 
X 
X 
X 
X4 
Prophylactic Medication6 
X 
X 
X 
ADXS11-001 Administration7
X 
X 
X 
Dispense/Prescribe Oral Prophylactic 
Antibiotics 8 
X 
X 
X 
X 
Phone Call 
X4,5 
Clinical Procedures/Assessments 
Review Adverse Events9 
X 
X 
X 
X 
X 
X4 
Vital signs/Weight10
X 
X 
X 
X 
X 
Physical Examination 
X 
X 
X 
X 
X 
ECOG Performance Status 
X 
X 
X 
X 
X 
Laboratory Procedures/Assessments11
CBC with Differential 
X 
X 
X 
X 
X 
Serum Chemistry Panel 
X 
X 
X 
X 
X 
Coagulation Profile 
X 
X 
X 
X 
X 


 
 
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Study Procedure 
Screening2 
9 Week Treatment Cycle1 
End of 
Therapy3 
Follow-Up 
Weeks 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Urine Dipstick 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
Urine Pregnancy Test12 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
Lm Surveillance Monitoring13  
 
 
 
 
 
 
 
 
 
 
 
X 
Efficacy Measurements 
Tumor Imaging17 
X 
 
 
 
 
 
 
 
X 
 
 
 
1  Repeating 9-week treatment cycles.  Study cycles will be numbered sequentially. 
2  Screening/Baseline tumor evaluations will be performed within 28 days prior to first dose of study treatment.     
3  End of Therapy is not a visit.  Assessments noted here must be completed upon the decision to discontinue a subject from study treatment. 
4  Safety Follow-Up will be conducted via a telephone call 30 days (± 5 days) after the last ADXS11-001 infusion to confirm the resolution of any new or 
ongoing adverse events and serious adverse events.  All ongoing events must be followed through resolution. 
5  Survival Follow-Up will be conducted at each visit during the Lm Surveillance period and via a telephone call every 3 months (± 2 weeks) after the Lm 
Surveillance period to determine survival status for all study subjects. 
6  Subjects will be pretreated with prophylactic regimen at least
 before each ADXS11-001 infusion.   
7  The initial ADXS11-001 administration will identify Day 1 of Cycle 1.  ADXS11-001 may be administered ± 7 days within each scheduled infusion.   
8  All Subjects will receive a 7-day course of oral antibiotic therapy starting approximately 72 hours after administration of ADXS11-001. All subjects will also 
receive an additional 6 month oral antibiotic course to be initiated approximately 72 hours following the last dose of study treatment or anytime upon 
discontinuation of study treatment.   
9  Adverse events and serious adverse events will be assessed from the time Informed Consent is obtained through 30 days after the last ADXS11-001 infusion 
is administered.  
10  Height will be measured at screening only.  Monitor vital signs immediately
for the first 4 hours following the 
completion of every ADXS11-001 infusion. 
11  C1D1 Safety labs do not need to be repeated if screening labs are collected within 3 days of dosing.   All laboratory procedures are to be completed and 
assessed by the investigator within 3 days prior to the administration of ADXS11-001 to confirm lab criteria for study treatment are met. 
12  Urine pregnancy tests must be performed within 72 hours prior to each ADXS11-001 infusion for female subjects of childbearing potential.  If the urine test 
is positive or cannot be confirmed as negative, a serum pregnancy test will be required. 
13   Lm Surveillance Monitoring will include a 6-month course of oral antibiotics and routine monitoring of CBC, CMP (including CRP, ESR) and blood 
cultures.  Following completion of the last dose of study treatment or following study discontinuation, all assessments will be performed every 4 months (±2 
weeks) for 3 years. 
14  Baseline tumor imaging and assessments must be performed within 28 days prior to the first ADXS11-001 infusion in the first study cycle.  Subsequent 
tumor imaging and assessments will be conducted at Week 8 (±1 week) for the duration of study participation.  Radiologic progression, not accompanied by 
clinical deterioration, should be confirmed ≥4 weeks later. 


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7 TRIAL PROCEDURES 
7.1 
Trial Procedures 
The Schedule of Events - Section 6.1 summarizes the trial procedures to be performed at 
each visit.  Individual trial 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. 
Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor for 
reasons related to subject safety.  In some cases, such evaluation/testing may be 
potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the subject.  In these 
cases, such evaluations/testing will be performed in accordance with those regulations. 
7.1.1 
Administrative Procedures 
7.1.1.1 
Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial. 
Consent must be documented by the subject’s dated signature on the most current 
Institutional Review Board/Independent Ethics Committee (IRB/IEC) approved ICF 
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 trial. 
The initial ICF, any subsequent revised written ICF 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 trial.  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 informed consent will adhere to IRB/IEC requirements, applicable laws and 
regulations, and Sponsor requirements. 
7.1.1.2 
Eligibility Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified 
designee to ensure that the subject qualifies for the trial. 


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7.1.1.3 
Subject Identification Card 
All subjects will be given a Subject Identification Card identifying them as participants in 
a research trial.  The card will contain trial 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 written informed consent. 
7.1.1.4 
Demographic/Medical History 
Demographic information and a medical history will be obtained by the investigator or 
qualified designee.  Medical history will include all active conditions and any condition 
that are considered to be clinically significant by the Investigator. 
7.1.1.5 
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 (eg, systemic, radiation and surgeries). 
7.1.1.6 
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 patient from 28 
days prior to screening and up to and including 30 days after the last administration of 
ADXS11-001; the information will be recorded in the 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.  
Protocol-mandated prophylactic medications and antibiotics should also be captured in 
the eCRF. 
7.1.2 
Clinical Procedures/Assessments 
7.1.2.1 
Adverse/Serious Adverse Event Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential 
new or worsening serious events from the time written informed consent is obtained 
through 30 days after the last ADXS11-001 dose is administered. Adverse experiences.  
Serious events experienced during this time will be graded, reported and recorded on the 
eCRF according to NCI CTCAE v 4.0 (Section 12.2).  Toxicities will be characterized in 
terms regarding seriousness, causality, toxicity grading, and action taken with regard to 
trial treatment. 
Please refer to Section 7.2 for detailed information regarding the assessment and 
recording of AEs. 


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7.1.2.2 
Physical Examination 
The investigator or qualified designee will perform an evaluation by body system. 
7.1.2.3 
Vital Sign Measurement 
The investigator or qualified designee will measure and record vital signs (including 
blood pressure, pulse rate, respiratory rate, and temperature) at Screening, prior to each 
ADXS11-001 administration and
 for the first 4 hours 
following each infusion.  Weight will be collected prior to each ADXS11-001 infusion.  
Height will be measured at screening only. 
7.1.2.4 
Eastern Cooperative Oncology Group Performance Scale 
The investigator or qualified designee will assess ECOG status (see Section 12.1). 
7.1.3 
Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial 
are provided below.  The total amount of blood to be drawn over the course of the trial 
(from pre-trial to trial discontinuation), including approximate blood volumes drawn by 
visit and by sample type per subject will be based on local laboratory requirements. 
7.1.3.1 
Laboratory Safety Evaluations 
Laboratory tests for hematology, chemistry, urinalysis, Lm surveillance and others are 
specified in Table 8. 
Subjects must meet all lab criteria prior to dosing.  Laboratory tests can be performed no 
more than 3 days prior to dosing.  If screening laboratory tests are performed within 3 
days prior to initial study treatment, they can be used for C1D1 labs.  Results must be 
reviewed by the investigator or qualified designee and found to be acceptable prior to 
each dose of trial treatment. 


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Table 8  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 
PT (INR) 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
Specific gravity  
aPTT 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
Microscopic exam (If abnormal) 
Lm surveillance* blood cultures 
Absolute Neutrophil Count 
Carbon Dioxide ‡ (CO2 or bicarbonate) 
Urine pregnancy test † 
Calcium 
Chloride 
Creatinine 
C-Reactive Protein (CRP)*
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. Following completion of study treatment all assessments
will be performed every 4 months (±2 weeks) for 3 years.


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7.1.4 
Efficacy Measurements 
7.1.4.1 
Tumor Imaging and Assessment of Disease 
CT and MRI will be considered the best currently available and reproducible methods to 
measure target lesions selected for response assessment.  Conventional CT should be 
performed with contiguous cuts of 10 mm or less.  Spiral CT scan should be performed 
using a 5 mm contiguous reconstruction algorithm (as a general rule, lesion diameter 
should be no less than double the slice thickness).  Lesions on chest x-rays will be 
acceptable as measurable lesions when they are clearly defined and surrounded by 
aerated lung; however, CT is preferable.  Ultrasound is not an acceptable method to 
measure disease. 
Assessment of disease will be done using both RECIST 1.1 criteria and irRECIST 
criteria.  All subjects who have completed one 9-week cycle of ADXS11-001 treatment 
will be considered evaluable for response. 
7.1.4.2 
Measurable and Non-Measurable Lesions and Disease 
Measurable lesions will be those that can be accurately measured in at least one 
dimension with the longest diameter ≥2.0 cm (for spiral CT scan or MRI scan, ≥1.0 cm).  
Measurable disease will be present if the subject has 1 or more measurable lesions. 
Non-measurable lesions/disease will be all other lesions (or sites of disease), including 
small lesions (those with all measurements <2.0 cm or <1.0 cm with spiral CT/MRI), or 
any of the following:  bone lesions, leptomeningeal disease, ascites, pleural or pericardial 
effusion, lymphangitis, cutis/pulmonis, abdominal masses that are not confirmed and 
followed by imaging techniques, cystic lesions, and lesions occurring within a previously 
irradiated area unless they are documented as new lesions since the completion of 
radiation therapy. 
7.1.4.3 
Target/Non-Target Lesions 
All measurable lesions, up to a maximum of 2 per organ and 5 in total, should be 
identified as target lesions to be measured and recorded at baseline.  The target lesions 
should be representative of all involved organs.  Target lesions will be selected based on 
their size (the lesion with the longest diameter) and suitability for accurate repeated 
measurements.  At baseline, a sum of the longest diameters for all target lesions will be 
calculated and recorded as the baseline tumor burden.  The baseline sum will be used as 
the reference point to determine the objective tumor response of the target lesions. 


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Measurable lesions other than the target lesions and all sites of non-measurable disease 
will be identified as non-target lesions and will be recorded at baseline.  Non-target 
lesions will be evaluated at the same time points as target lesions. 
7.1.4.4 
Response in Measurable Lesions (RECIST 1.1) 
At baseline, the sum of the longest diameters (SumD) of all target lesions (up to 2 lesions 
per organ, up to total 5 lesions) is measured.  At each subsequent tumor assessment, the 
SumD of the target lesions and of new, measurable lesions (≥10; up to 2 new lesions per 
organ, total 5 new lesions) are added together to provide the total measurable tumor 
burden (TMTB): 
TMTB = SumD target lesions + SumD new, measurable lesions 
Percentage changes in TMTB per assessment time point describe the size and growth 
kinetics of both old and new measurable lesions as they appear.  At each tumor 
assessment, the response in target and new measurable lesions is defined based on the 
change in TMTB. 
•
Complete Response (CR): Disappearance of all target lesions.  Any pathological
lymph nodes (whether target or non-target) must have reduction in short axis to
<10 mm.
•
Partial Response (PR): At least a 30% decrease in the sum of diameters of target
lesions, taking as reference the baseline sum diameters.
•
Progressive Disease (PD): At least a 20% increase in the sum of diameters of
target lesions, taking as reference the smallest sum on study (this includes the
baseline sum if that is the smallest on study).  In addition to the relative increase
of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
(Note: the appearance of one or more new lesions is also considered progression).
•
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient
increase to qualify for PD, taking as reference the smallest sum diameters while
on study.
7.1.4.5 
Immune-Related Response in Measurable Lesions (irRECIST) 
In addition to evaluation using RECIST 1.1 criteria, an immune response adaptation of 
RECIST will be applied to this trial.  The essential differences between irRECIST and 
RECIST criteria are as follows: 
•
New measureable lesions do not necessarily constitute progressive disease and
they should be added into the total tumor burden.  New non-measurable lesions do
not constitute disease progression but will prevent the determination of an irCR.


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•
Apparent disease progression should be confirmed after 4 weeks in the absence of
symptoms consistent with clinical deterioration.
At baseline, the sum of the longest diameters (SumD) of all target lesions (2 per organ 
and 5 in total) is measured.  At each subsequent tumor assessment, the SumD of the 
target lesions and of new, measurable lesions (≥10 mm [lymph nodes ≥15 mm in shortest 
diameter]; up to 2 new lesions per organ, total 5 new lesions) are added together to 
provide the total measurable tumor burden (TMTB): 
TMTB = SumD target lesions + SumD new, measurable lesions 
Percentage changes in TMTB per assessment time point describe the size and growth 
kinetics of both old and new measurable lesions as they appear.  At each tumor 
assessment, the response in target and new measurable lesions is defined based on the 
change in TMTB (after ruling out irPD) as follows: 
Complete Response (irCR):  complete disappearance of all target and new, measurable 
lesions, with the exceptions of lymph nodes which must decrease to <10 mm in short axis 
Partial Response (irPR):  decrease in TMTB ≥30% relative to baseline (see below) 
Stable Disease (irSD):  not meeting criteria for irCR or irPR, in absence of irPD 
Progressive Disease (irPD):  increase in TMTB ≥20% relative to nadir 
7.1.4.6 
Response in Non-Measurable Lesions (RECIST 1.1) 
While some non-target lesions may actually be measurable, they need not be measured 
and instead should be assessed only qualitatively. 
•
Complete Response (CR): Disappearance of all non-target lesions and
normalization of tumor marker level. All lymph nodes must be non-pathological
in size (<10mm short axis).
•
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or
maintenance of tumor marker level above the normal limits.
•
Progressive Disease (PD): Unequivocal progression of existing non-target lesions.
(Note: the appearance of one or more new lesions is also considered progression).
When the patient also has measurable disease, to achieve ‘unequivocal progression’ on 
the basis of non-target disease, there must be an overall level of substantial worsening in 
non-target disease such that, even in presence of SD or PR in target disease, the overall 
tumor burden has increased sufficiently to merit discontinuation of therapy. 
In the event that the patient has only non-measurable disease, the same general concepts 
apply as noted above, however, in this instance there is no measurable disease assessment 


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to factor into the interpretation of an increase in non-measurable disease burden.  Because 
worsening in non-target disease cannot be easily quantified, a useful test that can be 
applied when assessing subjects for unequivocal progression is to consider if the increase 
in overall disease burden based on the change in non-measurable disease is comparable in 
magnitude to the increase that would be required to declare PD for measurable disease 
(ie, an increase in tumor burden representing an additional 73% increase in ‘volume’ 
which is equivalent to a 20% increase diameter in a measurable lesion). 
7.1.4.7 
Immune-Related Response in Non-Measurable Lesions 
(irRECIST) 
At each tumor assessment, the presence of any new, non-measurable lesions is assessed.  
The presence of such lesions will rule out an overall response of irCR.  An increase in the 
size or number of new, non-measurable lesions does not necessarily imply an overall 
response of irPD; if these lesions become measurable (≥10 mm) at a subsequent tumor 
assessment, their measurement will at that point start to contribute to the TMTB. 
In addition, the response in non-target lesions is defined as follows: 
Complete Response (irCR):  complete disappearance of all non-target lesions 
Stable Disease (irSD):  non-target lesions are stable 
Progressive Disease (irPD):  unequivocal increases in number or size of non-target 
lesions.  To achieve unequivocal progression of non-target lesions, there must be an 
overall level of substantial worsening of non-target disease that is of a magnitude that the 
treating physician would feel it is important to change therapy. 
NOTE:  Equivocal findings of progression of non-target lesions (eg, small and uncertain 
new lesions; cystic changes or necrosis in existing lesions) should be considered irSD, 
and treatment may continue until the next scheduled assessment. 
7.1.4.8 
Overall Response 
Overall response will be determined based on RECIST 1.1 criteria and by irRECIST 
criteria (Table 9).  Overall response according to irRECIST is derived from the responses 
in measurable lesions (based on TMTB) and the presence of any non-measurable lesions. 
Table 9  Tumor Response Evaluation: Comparison of RECIST 1.1 and 
irRECIST 
Criteria 
RECIST1.1 
irRECIST 
New measurable 
lesions (≥ 10 mm) 
Always represents PD 
Incorporated into tumor burden 


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Criteria 
RECIST1.1 
irRECIST 
New non-
measurable lesions 
(< 10 mm) 
Always represents PD 
Does not define progression but 
precludes irCR 
Non-Target lesions 
Changes contribute to defining BOR of 
CR, PR, SD, and PD 
Contribute to defining irCR 
(complete disappearance required) 
CR 
Disappearance of all lesions 
Disappearance of all lesions 
PR 
≥ 30% decrease in the sum of the longest 
diameter of all target lesions compared 
with baseline, in absence of new lesions 
or unequivocal progression of non-target 
lesions 
≥ 30% decrease in tumor burden 
compared with baseline 
SD 
Neither sufficient shrinkage to qualify for 
PR nor sufficient increase to qualify for 
PD, taking as reference the smallest sum 
diameters while on study 
Neither a 30% decrease in tumor 
burden compared with baseline nor a 
20% increase compared with nadir 
can be established 
PD 
At least 20% increase in sum of diameters 
of target lesions, taking as reference the 
smallest sum on study. In addition to the 
relative increase of 20%, the sum must 
also demonstrate an absolute increase of 
at least 5mm.  The appearance of one or 
more new lesions is also considered 
progression. 
At least 20% increase in tumor 
burden compared with nadir (at any 
single time point)a 
irRECIST = immune-related Response Evaluation Criteria in Solid Tumors;  BOR = best overall response;  CR = 
complete response; irCR = immune-related complete response; PD = progressive disease;  PR = partial response; SD 
= stable disease; 
a  Patients with an initial finding of progressive disease (irPD) before or at the 8-week imaging assessment, but 
without rapid clinical deterioration, require confirmation of irPD with a second, consecutive scan obtained ≥ 4 
weeks from the initiation documentation.  Patients will continue to receive study treatment until irPD is confirmed at 
this later time point.  Best overall response (BOR) will therefore include responses occurring at any time before 
disease progression and after early progression (i.e., within the first 9 weeks of the study). 
7.1.4.8.1 
Best Overall Response (RECIST 1.1) 
The best overall response is the best response recorded from the start of the study 
treatment until the end of treatment taking into account any requirement for confirmation.  
The patient’s best overall response assignment will depend on the findings of both target 
and non-target disease and will also take into consideration the appearance of new lesions 
(Table 10). 
Table 10  Best Overall Response (RECIST 1.1) 
Target Lesions 
Non-Target Lesions 
Overall Response 
Baseline (Index) and 
New Measurable Lesions 
Baseline Lesions 
Unequivocal New 
Lesions 
CR 
CR 
No 
CR 


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Target Lesions 
Non-Target Lesions 
Overall Response 
Baseline (Index) and 
New Measurable Lesions 
Baseline Lesions 
Unequivocal New 
Lesions 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
NE 
No 
PR 
PR 
Non-PD or NE 
No 
PR 
SD 
Non-PD or NE 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response; NE = not evaluable at a particular time point; PR = partial response; SD = stable disease; PD 
= progressive disease 
7.1.4.8.2 
Immune-Related Best Overall Response (irRECIST) 
The immune-related best overall response (irBOR) is the best irRC overall response over 
the study as a whole, recorded between the date of first dose until the last tumor 
assessment prior to subsequent therapy (including tumor resection surgery) for the 
individual subject in the study (Table 11).  As with the primary definitions of tumor 
response, early progression (i.e., irPD occurring prior to Week 8) will not preclude an 
irBOR of irCR, irPR or irSD resulting from the Week 8 assessment.  An assessment of 
irPD at or after Week 8 will preclude a subsequent irBOR of irCR, irPR or irSD.  
However, any post-progression clinical activity in subjects with irBOR of irPD may be 
summarized for exploratory purposes. 
Table 11  Immune-Related Best Overall Response (irBOR) 
Target Lesions 
Baseline (Index) and 
New Measurable Lesions 
Non-Target Lesionsa 
irRC Overall Response 
Total Measurable 
Tumor Burden 
Baseline Lesions 
Unequivocal New 
Lesions 
irCR 
irCR 
No 
irCR 
irCR 
irSD 
No 
irPR 
irPR 
irCR or irSD 
No 
irPR 
irSD 
irCR or irSD 
No 
irSD 


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Target Lesions 
Baseline (Index) and 
New Measurable Lesions 
Non-Target Lesionsa 
irRC Overall Response 
Total Measurable 
Tumor Burden 
Baseline Lesions 
Unequivocal New 
Lesions 
irPD 
Any 
Yes or No 
irPD 
Any 
Unequivocal Progression 
Yes or No 
irPD 
Any 
Any 
Yes 
irPD 
irCR = immune-related complete response; irPR = immune-related partial response; irSD = immune-related stable 
disease; irPD = immune-related progressive disease 
a Any increase in the size or number of non-measurable lesions does not necessarily imply an overall response of 
irPD.  If these lesions become measurable (≥10 mm) at a subsequent assessment, their measurement will at that point 
start to contribute to the total measurable tumor burden.  To achieve unequivocal progression of non-target lesions, 
there must be substantial worsening in non-target disease that is of a magnitude that the Investigator feels it is 
important to change therapy.  Equivocal findings of progression of non-target lesions (e.g., small and uncertain new 
lesions; cystic changes or necrosis in existing lesions) should be considered irSD, and treatment may continue until 
the next assessment. 
7.1.5 
Other Procedures 
7.1.5.1 
Withdrawal/Discontinuation 
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
AEs that are present at the time of discontinuation/withdrawal should be followed in 
accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events. 
Treatment may continue until a study discontinuation criterion is met or for up to 2 years.  
Subjects who achieve a CR should receive at least 1 additional cycle of treatment. 
Any subject who is still deriving clinical benefit from ADXS11-001 therapy at the end of 
their 2 year treatment period or has achieved CR and subsequently progressed within 1 
year of stopping study treatment may be enrolled into a separate extension study, as 
available. 
7.1.6 
Visit Requirements 
Visit requirements are outlined in Section 6.1 – Schedule of Events.  Specific procedure-
related details are provided above in Section 7.1 - Trial Procedures. 


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7.1.6.1 
Screening 
Screening period – will start when the first screening evaluation is performed.  This does 
not include signing of informed consent or wash out periods.  Screening evaluations will 
be performed within 28 days prior to the first treatment administration, unless otherwise 
specified. 
Informed Consent - each subject must sign a copy of the most current IRB/IEC approved 
informed consent document.  A copy of the signed document will be maintained with the 
subject’s records. 
Inclusion/Exclusion Criteria - all inclusion and exclusion criteria will be reviewed by the 
Investigator or qualified designee to ensure that the subject qualifies for the trial. 
Prior/Concomitant Therapies and Procedures - past or current medical conditions, current 
medications, medications taken within 28 days of study entry, histological confirmation 
of cancer, tumor staging (refer to the most current American Joint Committee on Cancer 
Staging Manual, the 5th edition or higher), and prior cancer therapies and best 
response(s), if applicable. 
Pregnancy test - A rapid pregnancy test will be performed for all women of child bearing 
potential.  A positive rapid pregnancy test must be confirmed by serum pregnancy test 
(minimum sensitivity 25 IU/L or equivalent units of βHCG). 
Laboratory Procedures (hematology, chemistry, urinalysis, other) – see Section 7.1.3. 
Tumor Imaging/Disease Assessment - CT scan or MRI for determination of 
unidimensional measurements and disease response.  Baseline tumor imaging/disease 
assessment must be performed within 28 days prior to the first dose of ADXS11-001.  
Then imaging studies and tumor assessments will be performed every 9 weeks starting on 
Week 8 of every Cycle. 
7.1.6.2 
Treatment Period 
Subjects should arrive at the study center early on the days of their scheduled treatment in 
order to be evaluated, have laboratory specimens collected before treatment commences, 
allow for infusion timing, and take study prophylactic regimen as described in Section 
5.2.4. 
During the time the subjects are at the study site, the infusion line will be left in place to 
administer parenteral drugs, if necessary.  Subjects will remain at the study center for a 
minimum of 4 hours after ADXS11-001 administration for safety observation, and if 
necessary, treatment of side effects.  Subjects may receive NSAIDs and antiemetics per 
label or package insert on Day 1 and Day 2, as needed. 
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 


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Events and more frequently if clinically indicated.  AE/serious events  will be graded, 
reported and recorded on the eCRF according to NCI CTCAE v 4.0. Toxicities will be 
characterized in terms regarding seriousness, causality, toxicity grading, and action taken 
with regard to trial treatment. 
Physical Examination - evaluation by body system. 
Vital Signs - blood pressure, pulse rate, respiratory rate, and temperature will be checked 
and recorded prior to administration of ADXS11-001 and every
for the first 4 hours following the infusion.  Height and weight will be measured at 
screening, and weight will be measured pre-dose at every visit. 
ECOG Performance Status - according to ECOG criteria. 
Laboratory Procedures - according to Section 7.1.3. 
Prophylactic Medications – will be pretreated with prophylactic regimen on the day of 
dosing and completed at least 30 minutes before each ADXS11-001 infusion as outlined 
in Section 5.2.3.   
Prophylactic Antibiotics with Instructions – 
(1) During Study Treatment Phase - All subjects will receive a 7 day course of oral
antibiotic therapy starting approximately 72 hours (Day 4) after administration of
ADXS11-001.  Antibiotic therapy should consist of either 160 mg trimethoprim/800 mg
sulfamethoxazole (DS) tablet administered three times during the 7 consecutive days or
80 mg trimethoprim/400 mg sulfamethoxazole administered daily for 7 consecutive days
or for subjects with sulfa allergies, ampicillin 500 mg four times daily for 7 consecutive
days. ADXS11-001 is resistant to both streptomycin and chloramphenicol.  In the event a
subject experiences a persistent fever present at 72 hours after receiving ADXS11-001,
the oral regimen will be replaced by broad spectrum IV antibiotics administration. until a
blood culture is obtained and results are available. At this time, a specific IV antibiotic
regimen may be prescribed based on the results of the blood culture. Should a diagnosis
of listeriosis be made intensive IV antibiotic treatment must be initiated. Ampicillin +/-
Gentamicin is the preferred treatment regimen but other IV antibiotics may be used based
on the subject’s tolerance, culture and sensitivity results. An ID consult should be
obtained.
(2) Post Study Treatment - All subjects will receive a 6 month course of oral
trimethoprim/sulfamethoxazole or ampicillin for subjects with sulfa alleriges to be
initiated approximately 72 hours following the last dose of study treatment or at the time
of study discontinuation. Trimethoprim/sulfamethoxazole therapy should consist of either
160 mg trimethoprim/800 mg sulfamethoxazole (DS) tablet administered three times a
week or 80 mg trimethoprim/400 mg sulfamethoxazole administered daily for 7
consecutive days.  The dose of ampicillin consists of 500 mg four times daily for 6
months.


 
 
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Tumor Imaging/Disease Assessment - CT scan or MRI for determination of 
unidimensional measurements and disease response.  Imaging studies and tumor 
assessments will be performed every 9 weeks starting at Week 8 of Cycle 1. 
Pregnancy test - A rapid pregnancy test will be performed within 72 hours of each 
treatment administration (combination or monotherapy) for all women of child bearing 
potential prior to treatment.  A positive rapid pregnancy test must be confirmed, prior to 
dosing, by a serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of 
βHCG). 
7.1.6.3 
Safety Follow-up/Post-Treatment Visits 
Safety follow-up will be conducted via telephone call 30 days (±5 days) after the last 
ADXS11-001 infusion to confirm the resolution of any ongoing AEs and SAEs.  
Additional unscheduled visits may be considered as needed and at the discretion of the 
investigator. 
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. 
This surveillance monitoring phase will consist of a 6 month course of oral antibiotics, 
obtaining a blood sample to monitor CBC, CMP, including CRP and ESR, and blood 
cultures at regular intervals. This testing will be performed on all subjects who have 
received at least one dose of ADXS11-001. It will occur every 4 months (±2 weeks) for 3 
years beginning after the last dose of study treatment.  If a persistent increase in CRP 
and/or ESR is observed with negative blood cultures for listeria during this time the 
subject should be evaluated and treated, as appropriate, for another possible cause. In the 
event that a definite cause has not been identified then subjects must continue to be 
monitored closely, including another additional testing and a blood culture, for possible 
signs/symptoms of listeriosis.  This testing may be performed at the investigative site or 
at another acceptable location following consultation with the Sponsor. 
7.1.6.4 
Survival Follow-up 
 
Survival Follow-Up will be conducted at each visit during the Lm Surveillance period 
and via a telephone call every 3 months (± 2 weeks) after the Lm Surveillance period to 
determine survival status for all subjects.   
 
7.2 
Assessing and Recording Adverse Events 
An AE is defined as any untoward medical occurrence in a patient 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 


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adverse change in frequency and/or intensity) of a preexisting condition that is temporally 
associated with the use of the Sponsor’s product, is also an AE. 
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered AEs.  Examples of 
this may include, but are not limited to, onset of menses or menopause occurring at a 
physiologically appropriate time. 
The Sponsor’s product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including 
placebo or active comparator medication) or marketed, manufactured by, licensed by, 
provided by or distributed by Advaxis for human use. 
AEs may occur during the course of the use of Advaxis’ product in clinical trials or 
within the follow-up period specified by the protocol, or prescribed in clinical practice, 
from overdose (whether accidental or intentional), from abuse and from withdrawal. 
AEs 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. 
All AEs will be recorded from the time the consent form is signed through 30 days 
following cessation of treatment on the Adverse Event CRF forms/worksheets.  The 
reporting timeframe for AEs meeting any serious criteria is described in Section 7.2.3.1. 
7.2.1 
Overdose 
For purposes of this trial, an overdose will be defined as any ADXS11-001 dose 
exceeding the prescribed dose.  No specific information is available on the treatment of 
overdose of ADXS11-001.  In the event of an ADXS11-001 overdose, the subject should 
be observed closely for signs of toxicity.  Appropriate supportive treatment should be 
provided if clinically indicated. 
If an AE(s) is associated with (“results from”) the overdose of an Advaxis product, the 
AE(s) is reported as a SAE, even if no other seriousness criteria are met. 
If a dose of Advaxis’ product meeting the protocol definition of overdose is taken without 
any associated clinical symptoms or abnormal laboratory results, the overdose is reported 
as an AE. 
All reports of overdose with and without an AE must be reported within 24 hours to 
inVentiv Health Clinical Pharmacovigilance (Attn: iHC SAE Reporting; FAX 866-880-
9343 or email:  i3drugsafetyPV@inventivhealth.com). 


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7.2.2 
Reporting of 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), including the pregnancy of a male subject's female 
partner that occurs during the trial or within 120 days of completing the trial completing 
the trial, or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier.  All subjects and female partners of male 
subjects who become pregnant must be 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 serious events (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 inVentiv Health Clinical 
Pharmacovigilance (Attn: iHC SAE Reporting; FAX 866-880-9343 or email:  
i3drugsafetyPV@inventivhealth.com). 
7.2.3 
Immediate Reporting of Adverse Events to the Sponsor 
7.2.3.1 
Serious Adverse Events 
A serious adverse event is any AE occurring at any dose or during any use of Advaxis’ 
product 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
Progression of the cancer under study is not considered an AE unless it results in 
hospitalization or death. 
Any SAE, or follow up to a SAE, including death due to any cause other than progression 
of the cancer under study that occurs to any subject from the time the consent is signed 
through 30 days following cessation of treatment, whether or not related to Advaxis’ 


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product, must be reported within 24 hours to the Sponsor at inVentiv Health Clinical 
Pharmacovigilance (Attn: iHC SAE Reporting; FAX 866-880-9343 or email:  
i3drugsafetyPV@inventivhealth.com).  
Additionally, any SAE, considered by an investigator who is a qualified physician to be 
related to Advaxis’ product 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 inVentiv 
Health Clinical Pharmacovigilance (Attn: iHC SAE Reporting; FAX 866-880-9343 or 
email: i3drugsafetyPV@inventivhealth.com). 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by 
FDA, European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or 
other local regulators.  Investigators will cross reference this submission according to 
local regulations to the Advaxis Investigational Compound Number (IND, CSA, etc.) at 
the time of submission.  Additionally, investigators will submit a copy of these reports to 
inVentiv Health Clinical Pharmacovigilance (Attn: iHC SAE Reporting; FAX 866-880-
9343 or email:  i3drugsafetyPV@inventivhealth.com) at the time of submission to FDA. 
All subjects with SAEs must be followed up for outcome. 
7.2.4 
Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all AEs according to the NCI 
CTCAE v 4.0.  Any AE that changes CTCAE grade over the course of a given episode 
will have each change of grade recorded on the AE CRF/worksheets. 
All AEs regardless of CTCAE grade must also be evaluated for seriousness. 
The following attribution categories (Table 12) will be used in assessing the relationship 
between the AE and the study treatment: 
Table 12  Attribution Categories 
RELATIONSHIP 
ATTRIBUTION 
DESCRIPTION 
Unrelated to investigational 
agent/intervention
Unrelated 
The AE is clearly NOT related to the intervention 
Unlikely 
The AE is doubtfully related to the intervention 
Related to investigational 
agent/intervention
Possible 
The AE may be related to the intervention 
Probable 
The AE is likely related to the intervention 
Definite 
The AE is clearly related to the intervention 


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7.2.5 
Sponsor Responsibility for Reporting Adverse Events 
All AEs will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations. 
8 STATISTICAL CONSIDERATION 
8.1 
General Consideration 
Descriptive statistics will be employed to evaluate the endpoint and analyze the data.  
Summary statistics for continuous variables will include mean, standard deviation, 
median and range.  Categorical variables will be presented as frequency counts and 
percentages; and time-to-event variables will be summarized by Kaplan-Meier (KM) 
medians and survival plots.  Data listings will be created to support tables and present 
data.  The preliminary efficacy analysis will be conducted on the efficacy evaluable 
population and safety analysis will be performed on the safety population.  SAS 9.2 or 
higher will be used for data analysis. The details of statistical analysis will be described 
in the Statistical Analysis Plan (SAP).  The data will be tabulated and analyzed with 
respect to patient enrollment and disposition, demographic, and baseline characteristics. 
8.2 
Sample Size and the Design 
This is a multi-center, open-label, 2 stage monotherapy study of  ADXS11-001 in 
subjects with persistent/recurrent, loco-regional or metastatic SCCA of the anorectal 
canal that was previously treated in the metastatic setting. 
Primary Efficacy Measures are: 
1.
The overall response
2.
Progression-Free Survival (PFS)
We employed a 2-stage design for testing these 2 primary efficacy measures.  Simon’s 2-
stage method is not directly applicable because it is for single proportion type endpoint.  
However, we used Simon’s method with null and alternative response rates of 10% in 
Stage 1 and 20% in Stage 2 to obtain the total sample sizes for both stages and use the 
Multinomial Two-Stage approach proposed by Benny Zee, et al (1999) [24] to obtain the 
stopping probabilities. 
By Simon’s method, we need to enroll 31 subjects at Stage 1 and an additional 24 
subjects in Stage 2 if 3 or more responses are observed in Stage 1.  Based on this sample 
size plan, we formed the following 2 endpoints, 2-stage framework: 
In Stage 1 of the study, we will enroll 31 subjects.  The safety and efficacy data of the 
subjects will be evaluated.  After 31 evaluable subjects have been enrolled, further 
accrual will be temporarily stopped in Stage 1 for an efficacy interim analysis evaluation.  
If the efficacy from Stage 1 demonstrates a response rate >10% or 6-month PFS >20%, 


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the enrollment will re-open to Stage 2.  The enrollment will be complete in Stage 2 when 
an additional 24 evaluable have been accrued (total from Stages 1 and 2 = 55). 
The hypothesis testing in Stage 1 is given in the following: 
•
Stage 1:
o
Null Hypothesis (H0): Response rates (r1) <10% and 6-month PFS rate (p1) 
<20%;
o
Alternative Hypothesis (Ha): Response rates (r1) ≥10% or 6-month PFS rate
(p1) ≥20%
•
Stage 2:
o
Null Hypothesis (H0): Response rates (r2) < 25% and 6-month PFS rate (p2) <
50%;
o
Alternative Hypothesis (Ha): Response rates (r2) ≥ 25% or 6-month PFS rate
(p2) ≥ 50%
Using the Multinomial Two-Stage approach proposed by Benny Zee, et al (1999),[24] we 
simulated 50,000 trials to examine the Type I and II errors under this design assumption.  
The following estimates, including Type I and II errors, from these simulations are 
summarized in the following table. 
Type I 
Type II 
Type I Error  = 0.03236 
ASN for H0    = 32.20192 
P(stop early | H0) = 0.94992 
Power         = 0.924 
8.3 
Analysis of Study Endpoints 
8.3.1 
Analysis of Primary Endpoints for Efficacy 
The following are the primary efficacy endpoints for both phases; 
1.
Overall Tumor Response (measured by RECIST 1.1);
2.
Progression-Free Survival (PFS)
These endpoints are well established and commonly used to evaluate signs of clinical 
activity and efficacy. 
The overall tumor response rates will be tabulated for all patients by treatment stage.  
PFS is defined as the time from treatment start until disease progression or death 
whichever occurred earlier.  Patients who have not progressed or who are still alive at the 
time of evaluation will be censored for the analysis. 


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KM method will be used for estimating median times for PFS.  The 95% confidence 
intervals of the medians will be presented. 
Subject disposition, demographic and baseline subject characteristics will be summarized 
separately for Stage 1 and Stage 2.  AEs will be classified and summarized by type, 
incidence, severity, and causality.  All AEs will be summarized by subject, treatment, and 
disease.  All subjects who receive at least 1 dose of ADXS11-001 will be included in the 
safety analyses. 
8.4 
Safety Monitoring 
An external Data Safety Monitoring Committee will not be established for this study.  A 
periodic safety review will be applied by an internal safety review team with medical 
capabilities to review individual and summary data collected in the safety and clinical 
databases.  Findings having immediate implication for the management of subjects on 
study will be communicated to all Investigators in the timeframe associated with 
unexpected and drug-related SAEs. 
8.5 
Analysis of Safety Data 
All AEs will be summarized by patient, treatment, and prior recurrence history 
(aggressive [recurrence within 2 years]/non-aggressive). 
The NCI CTCAE v 4.0 will be used for AE grading (Grades 1 to 4).  AEs will be 
classified using the Medical Dictionary for Regulatory Activities (MedDRA®) coding 
system. 
The overall incidence of AEs will be summarized and classified by body system and by 
treatment group.  An AE will be summarized if the onset date occurs anytime during 
study treatment or up to 30 days after the last dose of study treatment; or, if it occurs 
prior to Day 1 and worsens while on therapy.  The type, incidence, severity, and causality 
of each AE, the duration of the event, and any required treatment interventions will be 
tabulated. 
Physical examination results will be presented in the patient data listings.  Vital sign 
measurements will be summarized at each infusion using descriptive statistics.  The 
incidence of clinically significant laboratory abnormalities will be presented, and 
laboratory data will be summarized at each infusion by the NCI CTCAE v 4.0 toxicity 
grades.  Laboratory data will be presented for patients having Grade 3 or 4 changes from 
baseline. 


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9 LABELING, PACKAGING, STORAGE AND RETURN OF 
CLINICAL SUPPLIES 
9.1 
Investigational Product 
The investigator shall take responsibility for and shall take all steps to maintain 
appropriate records and ensure appropriate supply, storage, handling, distribution and 
usage of investigational product in accordance with the protocol and any applicable laws 
and regulations. 
9.2 
Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 
9.3 
Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment.  Drug identity (name, strength) is included in the 
label text; random code/disclosure envelopes or lists are not provided. 
9.4 
Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label. 
Receipt and dispensing of trial medication must be recorded by an authorized person at 
the trial site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
9.5 
Safety Precautions 
ADXS11-001 is a live strain of Listeria monocytogenes (Lm) that has been attenuated 
such that it is cleared by severe combined immunodeficiency (SCID) mice lacking 
cellular immunity and gamma interferon knock-out mice lacking adaptive immunity.  It 
has also been altered such that it is impossible for it to recombine with wild-type Lm.  
Wild-type Listeria is Gram-positive, non-spore-forming, facultative bacilli that are 
hemolytic and catalase-positive.  Although healthy adults and children can contract a 


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wild-type Listeria infection, they do not usually become seriously ill.  People at risk of 
severe illness from wild-type Listeria are pregnant women, newborns, and persons with 
impaired immune function.[25] 
Even though ADXS11-001 is non-pathogenic, all Lm species are classified as
according to the BMBL 5th Edition.  In the US there currently is no method to reclassify 
Advaxis attenuated Lm strains in a manner that differentiates them from the more virulent 
wild type parent strain 10403S.  Universal precautions and institutional guidelines should 
be used when handling investigational drugs and human specimens. 
Precautions as stated in the BMBL 5th Edition include:[25] 
Wild-type L. monocytogenes poses a potential hazard to laboratory personnel. 
The Gram-positive, non-spore-forming, aerobic bacilli are hemolytic and 
catalase-positive. Bacteria have been isolated from soil, dust, human food, 
animals, and asymptomatic humans. Most cases of listeriosis have arisen from 
eating contaminated food products, most notably soft cheeses, raw meat, and 
unwashed raw vegetables.  Although healthy adults and children can contract a 
Listeria infection, they do not usually become seriously ill. At risk of severe illness 
are pregnant women, newborns, and persons with impaired immune function. 
Laboratory Hazards:  Wild-type Listeria monocytogenes may be ubiquitous in the 
environment and may be found in feces, cerebrospinal fluid (CSF), and blood, as 
well as food and environmental materials.  Ingestion is the most common mode of 
exposure, but wild-type Listeria can also cause eye and skin infections following a 
direct exposure.  Wild-type Lm infections in pregnant women occur most often in 
the third trimester and may precipitate labor.  Transplacental transmission of Lm 
poses a grave risk to the fetus and may result in disseminated abscesses 
contributing to a mortality rate of nearly 100%. 
Recommended Precautions:  
 practices, containment equipment, and 
facilities are recommended for activities with clinical specimens and cultures 
known or suspected to contain the agent.  Gloves and eye protection should be worn 
while handling the agent.  Pregnant women who work with Listeria monocytogenes 
in the clinical or research laboratory setting should be fully informed of the 
potential hazards associated with the organism, including potential risks to the 
fetus. 


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9.6 
Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies 
received from Advaxis or designee, the amount dispensed for each subject and the 
amount remaining at the conclusion of the trial. 
Upon completion or termination of the study, all unused and/or partially used 
investigational product will be destroyed at the site per institutional policy. 
9.7 
Destruction of ADXS11-001 
It will be the investigator’s responsibility to ensure that procedures for proper disposal 
have been established according to applicable regulations, guidelines, and institutional 
procedures and that: 
•
Written authorization for disposal/destruction has been granted by Advaxis
•
Arrangements have been made for the disposal
•
Appropriate records of the disposal have been documented
Refer to the Pharmacy Manual for ADXS11-001 for drug destruction details. 
10 ADMINISTRATIVE AND REGULATORY DETAILS 
10.1 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. 
10.2 Compliance with Financial Disclosure Requirements 
Financial Disclosure requirements are outlined in the US 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 


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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 United States for these purposes. 
10.3 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. 
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. 
10.4 Compliance with Trial Registration and Results Posting 
Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and 
the Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial 
is solely responsible for determining whether the trial and its results are subject to the 
requirements for submission to the Clinical Trials Data Bank, 
http://www.clinicaltrials.gov.  Information posted will allow subjects to identify 
potentially appropriate trials for their disease conditions and pursue participation by 
calling a central contact number for further information on appropriate trial locations and 
trial site contact information. 
10.5 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 


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functional area standard operating procedures (SOPs) to ensure that trials are conducted 
and data are generated, documented, and reported in compliance with the protocol, 
accepted standards of Good Clinical Practice, and all applicable federal, state, and local 
laws, rules and regulations relating to the conduct of the clinical trial. 
10.6 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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11 LIST OF REFERENCES 
1.
Wallecha, A., et al., Multiple effector mechanisms induced by recombinant
Listeria monocytogenes anticancer immunotherapeutics. Adv Appl Microbiol,
2009. 66: p. 1-27.
2.
Rothman, J. and Y. Paterson, Live-attenuated Listeria-based immunotherapy.
Expert Rev Vaccines, 2013. 12(5): p. 493-504.
3.
Basu, P., Mehta A., Jain M., Gupta S., Nagarkar R., Kumar V. , ADXS11-001
immunotherapy:  final safety and survival from a phase 2 study in recurrent
cervical cancer. J Clin Oncol, 2014. 32(5s): p. Abstract 5610.
4.
312.81(a)., C.F.R., http://www.ecfr.gov/cgi-bin/text-
idx?SID=7a7c00086ed31e9ffc8b4ce8a73e5543&mc=true&node=pt21.5.312&rg
n=div5#se21.5.312_181. 2015.
5.
Nakagawa, M., et al., Persistence of human papillomavirus type 16 infection is
associated with lack of cytotoxic T lymphocyte response to the E6 antigens. J
Infect Dis, 2000. 182(2): p. 595-8.
6.
Welters, M.J., et al., Frequent display of human papillomavirus type 16 E6-
specific memory t-Helper cells in the healthy population as witness of previous
viral encounter. Cancer Res, 2003. 63(3): p. 636-41.
7.
de Jong, A., et al., Human papillomavirus type 16-positive cervical cancer is
associated with impaired CD4+ T-cell immunity against early antigens E2 and
E6. Cancer Res, 2004. 64(15): p. 5449-55.
8.
Ajani, J.A., et al., Prognostic factors derived from a prospective database dictate
clinical biology of anal cancer: the intergroup trial (RTOG 98-11). Cancer, 2010.
116(17): p. 4007-13.
9.
Selvarajah, G.T. and J. Kirpensteijn, Prognostic and predictive biomarkers of
canine osteosarcoma. Vet J, 2010. 185(1): p. 28-35.
10.
Bergman, P.J., et al., Amputation and carboplatin for treatment of dogs with
osteosarcoma: 48 cases (1991 to 1993). J Vet Intern Med, 1996. 10(2): p. 76-81.
11.
Ferlay J, S.I., Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM,
Forman D, Bray, F., GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality
Worldwide: IARC CancerBase No. 11 [Internet].  Lyon, France: International
Agency for Research on Cancer; 2013. http://globocan.iarc.fr, accessed on April
26, 2015.
12.
American Cancer Society 2015.
http://www.cancer.org/cancer/cervicalcancer/detailedguide/cervical-cancer-key-
statistics, accessed on April 26, 2015.
13.
Maciag, P.C., S. Radulovic, and J. Rothman, The first clinical use of a live-
attenuated Listeria monocytogenes vaccine: a Phase I safety study of Lm-LLO-E7
in patients with advanced carcinoma of the cervix. Vaccine, 2009. 27(30): p.
3975-83.
14.
Beebe, J.L. and E.W. Koneman, Recovery of uncommon bacteria from blood:
association with neoplastic disease. Clin Microbiol Rev, 1995. 8(3): p. 336-56.
15.
Le Monnier, A., et al., Listeria monocytogenes: a rare complication of
ventriculoperitoneal shunt in children. J Clin Microbiol, 2011. 49(11): p. 3924-7.
16.
Dominguez, E.A., A.A. Patil, and W.M. Johnson, Ventriculoperitoneal shunt
infection due to Listeria monocytogenes. Clin Infect Dis, 1994. 19(1): p. 223-4.


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17.
Winslow, D.L. and M.L. Steele, Listeria bacteremia and peritonitis associated
with a peritoneovenous shunt: successful treatment with sulfamethoxazole and
trimethoprim. J Infect Dis, 1984. 149(5): p. 820.
18.
Charlier, C., et al., Listeria monocytogenes-associated joint and bone infections: a
study of 43 consecutive cases. Clin Infect Dis, 2012. 54(2): p. 240-8.
19.
Grupp, S.A., et al., Chimeric antigen receptor-modified T cells for acute lymphoid
leukemia. N Engl J Med, 2013. 368(16): p. 1509-18.
20.
Winkler, U., et al., Cytokine-release syndrome in patients with B-cell chronic
lymphocytic leukemia and high lymphocyte counts after treatment with an anti-
CD20 monoclonal antibody (rituximab, IDEC-C2B8). Blood, 1999. 94(7): p.
2217-24.
21.
Lee, D.W., et al., Current concepts in the diagnosis and management of cytokine
release syndrome. Blood, 2014. 124(2): p. 188-95.
22.
Tocilizumab, Package Insert. Genetech, Inc., 2014.
23.
http://www.cdc.gov/listeria accessed September 23, 2015.
24.
Zee, B., et al., Multinomial phase II cancer trials incorporating response and
early progression. J Biopharm Stat, 1999. 9(2): p. 351-63.
25.
Chosewood LC, W.D., editors, Biosafety in microbiological and biomedical
laboratories (BMBL) 5th ed. US Department of Health and Human Services.
http://www.cdc.gov/biosafety/publications/bmbl5/index.htm, 2009.


 
 
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12 APPENDICES 
12.1 ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease performance without 
restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., light 
housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to 
carry out any work activities. Up and about more than 50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined to bed or 
chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally 
confined to bed or chair. 
5 
Dead. 
*  As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am 
J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair. 
12.2 Common Terminology Criteria for Adverse Events V4.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting.  
(http://ctep.cancer.gov/reporting/ctc.html). 
12.3 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria 
for Evaluating Response in Solid Tumors 
RECIST version 1.1* will be used in this study for assessment of tumor response.  While 
either CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging 
technique in this study . 
In addition, volumetric analysis will be explored by central review for response 
assessment. 
 
 
 
 
 
 


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13 SUMMARY OF CHANGES 
# 
Section 
Page 
Revision 
Rationale 
1 
List of Abbreviations 
8-9
Updated to include CMP, CRP, ESR, 
TNFα and PI3K.  Deleted GGT, LEEP. 
Administrative update. 
2 
Synopsis 
10-
11 
Updated length of subject trial duration 
from 4 to 6 years, included the 6 month 
oral antibiotic course and Lm 
Surveillance Monitoring requirements. 
Updated adverse event tracking to 
extend until completion of the Lm 
Surveillance Monitoring phase.  Added 
Lm Surveillance Monitoring as a safety 
evaluation criterion. 
Administrative update in 
support of the FDA 
recommendations. 
3 
2 TRIAL DESIGN and 
throughout protocol, 
where applicable 
12 
Updated the Stage 1 primary objective 
of 6-month PFS rate from 25% to 20% 
as a requirement for initiation of Stage 2 
in order to align more closely with the 
rates achieved in similar patient 
populations with later stage HPV-related 
cancer. 
Added paragraph detailing safety 
follow-up and Survival follow-up 
frequency.   
Clarified that patients still deriving 
clinical benefit from ADXS11-001 
therapy at the end of their 2-year 
treatment period or at the end of the 
study may be enrolled into a separate 
extension study, as available.  
Sponsor decision based on 
discussions with key 
opinion leaders involved in 
the treatment of patients 
with persistent/recurrent, 
loco-regional or metastatic 
squamous cell carcinoma 
of the anorectal canal. 
Administrative update in 
support of the FDA 
recommendations. 
Administrative update. 
4 
2 TRIAL DESIGN and 
throughout protocol, 
where applicable 
12 
Revised ADXS11-001 dose level from 
1x109 CFU to 5x109 CFU.   
Sponsor decision based on 
clinical rationale and 
potential for higher doses 
to result in better clinical 
response 
5 
4.2.1.1 Summary of 
Safety of ADXS11-001 
16 
Section was updated with safety data 
information. 
Safety administrative 
update  
6 
4.2.2  Delayed/Late 
Listeria Infection 
18-
19 
Safety section added describing the 
clinical experience to-date with Lm 
clearance and the description of the 
index case of delayed/late listeria 
infection.  
Per FDA Safety Section, 
revised to inform 
investigators/patients on 
the recent delayed/late 
listeria event.  


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# 
Section 
Page 
Revision 
Rationale 
7 
ADXS11-001 Rationale 
for Dose Selection and 
Regimen 
19-
21 
Section was revised for clarity and 
details of the rationale for increasing 
ADXS11-001 dose.  
Based on previous clinical 
experience with ADXS11-
001, patients with 
advanced HPV disease may 
receive added benefit to 
treating with higher doses 
and repeating treatments 
until progression or 
complete response with 
ADXS11-001.  
8 
4.2.4 Study Stopping 
Rules 
21-
22 
New section added as a safety 
precaution for the increased ADXS11-
001 dose.   
Administrative update in 
support of the FDA 
recommendations. 
9 
5.1.2 Exclusion Criteria 
(6.b) 
25 
Revised to allow intermittent use of 
inhaled steroids in addition to the 
bronchodilators or local steroid 
injections, with sponsor approval. 
Administrative update 
10 
5.1.2 Exclusion Criteria 
(#10) 
26 
New exclusion criterion was added to 
exclude subjects with implanted devices 
that pose high risks for colonization or 
inability of removal. 
Exclusion criteria added to 
mitigate risk of 
colonization of foreign 
bodies and medical devices  
11 
5.1.2 Exclusion Criteria 
(#11) 
26 
New exclusion criterion was added to 
exclude subjects who are receiving or 
are expected to receive treatment with  
TNF blocking agent(s) during study 
participation or in future. 
Exclusion criteria added to 
mitigate risk of listeria 
infection.  
12 
5.1.2 Exclusion Criteria 
(#12) 
26 
New exclusion criterion was added to 
exclude subjects who are receiving or 
are expected to receive treatment with  
PI3K inhibitor(s) during study 
participation or in future. 
Exclusion criteria added to 
mitigate risk of listeria 
infection.  
13 
5.1.2 Exclusion Criteria 
(#13) 
26 
New exclusion criterion was added to 
exclude subjects with a known 
contraindication (e.g. 
allergies/sensitivities) to the 
administration of trimethoprim 
sulfamethoxazole and/or ampicillin. 
Deleted Exclusion Criterion: Has 
contraindication to administration of 
amoxicillin, ampicillin, ciprofloxacin, 
erythromycin, gentamycin, penicillin, 
and trimethoprim/sulfamethoxazole. 
Exclusion criterion added 
based on FDA 
recommendation of 
prophylaxis and 6-month 
antibiotic treatment. 


 
 
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5.1.2 Exclusion Criteria 
(#18) 
26 
Revised exclusion criterion regarding 
major surgeries to exclude subjects who 
have undergone a major surgery or had 
a newly implanted artificial (prosthetic) 
joint(s), implants and/or devices where a 
minimum of 6 weeks has not elapsed 
from the time of surgery.  Additional 
requirements for the resolution of all 
toxicities and/or complications was 
included.  
Exclusion criteria added as 
a required safety update to 
mitigate potential listeria 
events. 
15 
Table 5 Treatment 
Delay/Discontinuation 
Guidelines for Drug-
Related Adverse Events 
28 
Timing clarified for restarting (added 
‘or baseline’ for non-heme grade 2-3 
toxicities) and corrected for 
discontinuing subjects (changed within 
12 weeks to within 3 weeks). 
Administrative update 
16 
5.2.2 Administration of 
ADXS11-001 
28 
New paragraph added to note that 
ADXS11-001 must not be administered 
via central venous catheter or infusion 
port and that the central venous catheter 
or infusion port must not be used for 72 
hours following the ADXS11-001 
infusion until the subject receives the 
first dose of oral antibiotics. 
Safety update to mitigate 
potential listeria events. 
17 
5.2.4 Pretreatment 
Prophylaxis Regimen 
29 
Section updated to include IV fluid 
hydration and revised for consistent 
formatting.  Additional NSAID and 
antiemetic administrations were revised 
to be given per label or package insert. 
Administrative update 
18 
5.2.5 ADXS11-001 
Dosing 
29 
All subjects will now receive a 7 day 
course of oral antibiotics (instead of 3 
day course) following each ADXS11-
001 treatment. 
Administrative update in 
support of the FDA 
recommendations. 
19 
5.5.1 Acceptable 
Concomitant Therapies 
and Procedures 
30 
‘Study subjects should be reminded that 
acetaminophen or other NSAIDs (other 
than naproxen or ibuprofen) should not 
be used for pretreatment prophylaxis 
since these medications can interfere 
with treatment’ was deleted from the 
first paragraph. 
Administrative update.   
20 
5.5.2 Prohibited 
Concomitant Therapies  
31 
Added PI3K inhibitors and TNFα 
blocking agents to the list of prohibited 
therapies and restricted chronic use of 
systemic glucocorticoids, as they have 
the potential to reduce immune 
response. 
Safety update to include 
FDA recommendations.  


 
 
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5.6.3.1 Listeriosis and 
Listeria Infection -
Identification and 
Management   
37 
New sections provide information on 
the identification process and 
management of potential/confirmed 
listeria infection. 
Safety administrative 
change added to provide 
information on the 
identification and 
management of listeria. 
22 
5.6.4 Management and 
Surveillance of Listeria 
During Study 
Participation 
37-
38 
New sections provide information on 
the mitigation of and management of 
listeria infection. 
Safety administrative 
change added to provide 
information on the 
identification and 
management of listeria. 
23 
5.7.5 Major and Minor 
Surgeries and ADXS11-
001 Treatment 
40  
New section added to describe the 
minimum time period required between 
major surgery and treatment 
administration for patients prior to and 
during study treatment. 
Safety update to mitigate 
potential listeria events. 
24 
6.1 Schedule of Events 
43-
44 
Added Lm Surveillance Monitoring 
schedule which includes a 6 month post 
ADXS11-001 antibiotic 
(Trimethoprim/Sulfamethoxazole) 
treatment to mitigate the risk of delayed 
listeria infection. 
Text clarified in the table and footnotes 
for consistency with the revised 
corresponding study procedure. 
Safety updates and 
administrative 
clarifications per FDA 
recommendation. 
25 
7.1.2.1 Adverse/Serious 
Adverse Event 
Monitoring 
46 
In addition to administrative corrections, 
the section revised to include adverse 
and serious adverse events to be 
collected from the time written informed 
consent is obtained through 30 days 
after the last ADXS11-001 dose is 
administered.   
Administrative update   
26 
7.1.3 Laboratory 
Procedures/Assessments 
47 
Text revised to note the total amount of 
blood to be drawn over the course of the 
trial will be based on local laboratory 
requirements (previously noted that they 
can be found in the Laboratory Manual). 
Administrative update   
27 
Table 8 Laboratory Tests 
48 
Additional lab tests including Lm Blood 
cultures, ESR and CRP was added to the 
table.   
Table footnotes updated to detail Lm 
Surveillance Monitoring requirements. 
Safety update to include 
FDA recommendations for 
the identification of listeria 
infection. 
28 
7.1.6.2 Treatment Period 
56 
Administrative clarifications made to 
section including NSAID and antiemetic 
administration post ADXS11-001 
infusion to be given per label or package 
insert on Day 1 and Day 2, as needed. 
Safety update based on 
FDA recommendation. 


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prophylactic antibiotic instructions 
during the Study Treatment Phase and 
Post Study Treatment.   
29 
7.1.6.3 Safety Follow-
up/Post-Treatment Visits 
58 
New paragraphs added regarding the 
updated Lm Surveillance Monitoring.  
Safety update based on 
FDA recommendation. 
30 
7.1.6.4 Survival Follow-
up 
58 
Section revised to show survival follow-
up to be conducted at each visit during 
the Lm Surveillance Period and via 
telephone every 3 months (± 2 weeks) 
after the Lm Surveillance period to 
determine survival status for all 
subjects. 
Administrative update 
31 
7.2.3.1 Serious Adverse 
Events 
60 
Deleted ”or the initiation of new 
anti-cancer therapy, whichever is 
earlier, ” from the timing of SAE 
collection.   
Administrative update 
32 
8.2 Sample Size and the 
Design 
62-
63 
PFS percentage changed from 25% to 
20% throughout the section. 
Reference corrected ‘Benny Zee, et al 
(1999)’ 
Administrative update 
33 
9.4 Storage and Handling 
Requirements 
65 
Storage temperature for ADXS11-001 
was changed to -80°C (±10°C) based on 
stability data.  
Safety administrative 
change