Clinical trial NCT02291055
Conditions: Cervical Cancer Cancer Head and Neck Cancer
Sponsor: Advaxis, Inc.
Start date: 2015-04-01; Completion date: 2020-11-20
Enrollment: 75 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This was a multicenter, open-label, 2-part randomized study of MEDI4736 administered as monotherapy or in combination with ADXS11-001 to participants with recurrent/persistent or metastatic squamous or non-squamous carcinoma of the cervix or metastatic human papillomaviruses (HPV)+ squamous cell carcinoma of the head and neck (SCCHN).

Detailed description:
The study was conducted in 2 parts Part A (dose-escalation and expansion) and Part B (expansion).

Part A:

Part A of the study was a Phase 1 dose escalation evaluation of the combination treatment of ADXS11-001 at a fixed dose of 1×10\^9 colony-forming units (CFU) administered intravenously (IV) every 4 weeks (Q4W) and escalating doses of MEDI4736 (3 mg/kg and 10 mg/kg) administered IV every 2 weeks (Q2W) to determine the safety and tolerability of the combination and to identify a recommended Phase 2 dose (RP2D). Part A also included an expansion cohort of participants with metastatic SCCHN only. Once the RP2D was identified, the expansion cohort of Part A of the study were to commence.

Part B:

Part B of the study was a Phase 2 design in which participants who had failed at least 1 prior systemic treatment for their recurrent, persistent or metastatic cervical cancer were enrolled and randomized 1:1 to receive either MEDI4736 10 mg/kg alone or MEDI4736 10 mg/kg in combination with ADXS11-001 1×10\^9 CFU.

Arms: arm 1: Participants with cervical cancer received MEDI4736 3 milligrams per kilogram (mg/kg) intravenous (IV) infusion every 2 weeks (Q2W) at an infusion rate of approximately 60 minutes followed by ADXS11-001 1×10\^9 CFU IV infusion every 4 weeks (Q4W) at an infusion rate of approximately 60 minutes. Treatment cycles were 8-week in duration and participants were to continue therapy for up to 1 year or until documented progression, unacceptable toxicity, withdrawal of consent, or other treatment discontinuation criteria were met. arm 2: Participants with cervical cancer and SCCHN received MEDI4736 10 mg/kg IV infusion Q2W at an infusion rate of approximately 60 minutes followed by ADXS11-001 1×10\^9 CFU IV infusion Q4W at an infusion rate of approximately 60 minutes. Treatment cycles were 8-week in duration and participants were to continue therapy for up to 1 year or until documented progression, unacceptable toxicity, withdrawal of consent, or other treatment discontinuation criteria were met. arm 3: Participants with SCCHN received MEDI4736 10 mg/kg IV infusion Q2W at an infusion rate of approximately 60 minutes followed by ADXS11-001 1×10\^9 CFU IV infusion Q4W at an infusion rate of approximately 60 minutes. Treatment cycles were 8-week in duration and participants were to continue therapy for up to 1 year or until documented progression, unacceptable toxicity, withdrawal of consent, or other treatment discontinuation criteria were met. arm 4: Participants with cervical cancer received MEDI4736 10 mg/kg IV infusion Q2W at an infusion rate of approximately 60 minutes. Treatment cycles were 8-week in duration and participants were to continue therapy for up to 1 year or until documented progression, unacceptable toxicity, withdrawal of consent, or other treatment discontinuation criteria were met. arm 5: Participants with cervical cancer received MEDI4736 10 mg/kg IV infusion Q2W at an infusion rate of approximately 60 minutes followed by ADXS11-001 1×10\^9 CFU IV infusion Q4W at an infusion rate of approximately 60 minutes. Treatment cycles were 8-week in duration and participants were to continue therapy for up to 1 year or until documented progression, unacceptable toxicity, withdrawal of consent, or other treatment discontinuation criteria were met.
Interventions: intervention 1: ADXS11-001 intervention 2: MEDI4736
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
PROTOCOL ADXS001-04 
PHASE 1-2 STUDY OF ADXS11-001 or MEDI4736 ALONE OR IN 
COMBINATION IN RECURRENT/METASTATIC CERVICAL OR 
HPV+ HEAD & NECK CANCER 
SPONSOR: 
Advaxis, Inc. 
305 College Road East 
Princeton, NJ 08540 
609-452-9813 (office)
609-452-9818 (fax)
IND NUMBER:  
16256 
EudraCT NUMBER: 
N/A 
Original: 
October 9, 2014 
Amendment 1.1: 
February 2, 2015 
Amendment 2: 
May 8, 2015 
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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SIGNATURE PAGE 
 
Protocol No.: 
ADXS001-04 
Title: 
Phase 1-2 Study of ADXS11-001 or MEDI4736 Alone or 
In Combination In Recurrent/ Metastatic Cervical or HPV+ 
Head & Neck Cancer 
Amendment 2: 
May 8, 2015 
 
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 Harmonization (ICH) Guidelines, local ethical and legal 
requirements, and the spirit of the Declaration of Helsinki. 
 
Investigator Name:  
 
 _____________________________________  
 _________________________ 
Signature 
Date 
 
 _____________________________________  
 _________________________ 
Printed Investigator Name 
 
 
 
 
    Site # 


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Table of Contents 
PROTOCOL ADXS001-04 ..................................................................................................... i 
IND NUMBER:   
16256...................................................................................................... i 
EudraCT NUMBER: N/A .................................................................................................... i 
Confidentiality Statement ....................................................................................................... i 
PROTOCOL APPROVAL .................................................................................................... ii 
Protocol Number: 
ADXS001-04 ........................................................................................ ii 
Prepared by: ............................................................................................................................ ii 
Approved by: ........................................................................................................................... ii 
SIGNATURE PAGE .............................................................................................................. iii 
Protocol No.: 
ADXS001-04 ....................................................................................... iii 
Investigator Name:................................................................................................................. iii 
Table of Contents ..................................................................................................................... iv 
List of Figures ........................................................................................................................ viii 
1.0 
Summary ...................................................................................................................... 11 
2.0 
Trial Design .................................................................................................................. 13 
2.1 
ADXS11-001 + MEDI4736 Combination Therapy ........................................ 13 
2.2 
ADXS11-001 vs MEDI4736 vs ADXS11-001 +MEDI4736 ......................... 14 
2.3 
Trial Diagram .................................................................................................. 15 
3.0 
Objectives & Hypotheses ............................................................................................. 15 
3.1 
Part A - Primary Objectives & Hypothesis ..................................................... 15 
3.2 
Part A - Secondary Objective ......................................................................... 16 
3.3 
Part A - Exploratory Objective ....................................................................... 16 
3.4 
Part B - Primary Objectives & Hypothesis ..................................................... 16 
3.5 
Part B - Exploratory Objective ....................................................................... 16 
4.0 
Background & Rationale .............................................................................................. 16 
4.1 
Background ..................................................................................................... 16 


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4.1.1 ADXS11-001 Immunotherapy ............................................................ 16 
4.1.2 MEDI4736 .......................................................................................... 18 
4.1.3 Preclinical and Clinical Trial Data ...................................................... 20 
4.2 
Rationale ......................................................................................................... 20 
4.2.1 Rationale for the Combination ADXS11-001 & MEDI4736 ............. 20 
4.2.2 Rationale for Trial and Selected Subject Population .......................... 24 
4.2.3 Rationale for Dose Selection/Regimen/Modification ......................... 25 
4.2.4 Rationale for Endpoints ...................................................................... 28 
5.0 
Methodology ................................................................................................................ 29 
5.1 
Entry Criteria .................................................................................................. 29 
5.1.1 Inclusion Criteria ................................................................................ 29 
5.1.2 Subject Exclusion Criteria .................................................................. 32 
5.2 
Trial Treatments .............................................................................................. 35 
5.2.1 Dose Selection/Modification .............................................................. 35 
5.2.2 Timing of Dose Administration .......................................................... 42 
5.2.3 Trial Blinding/Masking ....................................................................... 43 
5.3 
Randomization or Treatment Allocation ........................................................ 43 
5.4 
Stratification .................................................................................................... 43 
5.5 
Concomitant Medications/Vaccinations (allowed & prohibited) ................... 43 
5.5.1 Acceptable Concomitant Medications ................................................ 43 
5.5.2 Prohibited Concomitant Medications ................................................. 44 
5.6 
Supportive Care Guidelines ............................................................................ 45 
5.6.1 Cytokine Release Syndrome ............................................................... 45 
5.6.2 Diarrhea............................................................................................... 46 
5.6.3 Nausea/vomiting: ................................................................................ 47 
5.6.4 Management of Infusion Reactions .................................................... 47 
5.6.5 Listeremia ........................................................................................... 49 


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5.7 
Diet/Activity/Other Considerations ................................................................ 49 
5.7.1 Diet ...................................................................................................... 49 
5.7.2 Contraception ...................................................................................... 49 
5.7.3 Use in Pregnancy ................................................................................ 50 
5.7.4 Use in Nursing Women ....................................................................... 50 
5.8 
Subject Withdrawal/Discontinuation Criteria ................................................. 51 
5.9 
Subject Replacement Strategy ........................................................................ 52 
5.10 
Clinical Criteria for Early Trial Termination .................................................. 52 
6.0 
Trial Flow Chart ........................................................................................................... 53 
6.1 
Trial Flow Chart for Combination (Part A) .................................................... 53 
6.2 
Trial Flow Chart for ADXS11-001 Monotherapy (Part B) ............................ 55 
6.3 
Trial Flow Chart for MEDI4736 Monotherapy arm (Part B) ......................... 57 
6.4 
Trial Flow Chart for Combination Therapy (Part B) ...................................... 59 
6.5 
Retreatment Flow Chart .................................................................................. 61 
7.0 
Trial Procedures ........................................................................................................... 61 
7.1 
Trial Procedures .............................................................................................. 61 
7.1.1 Administrative Procedures .................................................................. 62 
7.1.2 Clinical Procedures/Assessments........................................................ 64 
7.1.3 Other Procedures ................................................................................. 77 
7.1.4 Visit Requirements.............................................................................. 77 
7.2 
Assessing and Recording Adverse Events ...................................................... 82 
7.2.1 Definition and Reporting of an Overdose ........................................... 83 
7.2.2 Reporting of Pregnancy and Lactation to the Sponsor ....................... 84 
7.2.3 Immediate Reporting of Adverse Events to the Sponsor .................... 84 
7.2.4 Evaluating Adverse Events ................................................................. 89 
7.2.5 Sponsor Responsibility for Reporting Adverse Events ...................... 89 
8.0 
Statistical Analysis Plan ............................................................................................... 90 


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8.1 
Statistical Analysis Plan Summary ................................................................. 90 
8.2 
Safety Monitoring ........................................................................................... 91 
9.0 
Labeling, Packaging, Storage and Return of Clinical Supplies ................................... 91 
9.1 
Investigational Product ................................................................................... 91 
9.2 
Packaging and Labeling Information .............................................................. 91 
9.3 
Clinical Supplies Disclosure ........................................................................... 91 
9.4 
Storage and Handling Requirements .............................................................. 91 
9.5 
Returns and Reconciliation ............................................................................. 92 
10.0 Administrative and Regulatory Details ........................................................................ 92 
10.1 
Confidentiality ................................................................................................ 92 
10.2 
Compliance with Financial Disclosure Requirements .................................... 93 
10.3 
Compliance with Law, Audit and Debarment ................................................ 93 
10.4 
Compliance with Trial Registration and Results Posting Requirements ........ 94 
10.5 
Quality Management System .......................................................................... 94 
10.6 
Data Management ........................................................................................... 95 
11.0 List of References ......................................................................................................... 95 
12.0 Summary of Changes ................................................................................................... 98 
13.0 Appendices ................................................................................................................... 99 
13.1 
ECOG Performance Status ............................................................................. 99 
13.2 
Common Terminology Criteria for Adverse Events V4.03 (CTCAE) ........... 99 
13.3 
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors ............................................................ 99 
14.0 Abbreviations ............................................................................................................. 100 
 
 
 


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List of Tables 
Table 1 
Adequate Organ Function Laboratory Values ................................................ 31 
Table 2 
Trial Treatment ............................................................................................... 35 
Table 3 
Treatment Modification Guidelines for ADXS11-001 Cytokine Release 
Syndrome symptoms ....................................................................................... 40 
Table 4 
Dose Modification Guidelines for Immune-related Adverse Events - 
MEDI4736 Monotherapy and Combination Arms ......................................... 41 
Table 5 
Treatment Guidelines for Infusion Reactions ................................................. 48 
Table 6 
Tumor Response Evaluation:  Comparison of RECIST 1.1 and irRECIST ... 70 
Table 7 
Best Overall Response (RECIST 1.1) ............................................................. 71 
Table 8 
Immune-related Best Overall Response (irBOR) ........................................... 72 
Table 9 
Laboratory Tests ........................................................................................... 76 
Table 10 
Evaluating Adverse Events .......................................................................... 89 
List of Figures 
Figure 1 
 3 + 3 Design Schematic .................................. ................................................34 


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1.0 
SUMMARY 
Sponsor: 
Advaxis, Inc. 
Name of Finished Product: 
ADXS11-001 
MEDI4736 
Type of Treatment: 
ADXS11-001:  Lm-LLO Immunotherapy 
MEDI4736: MEDI4736 is a human monoclonal 
antibody (mAb) of the IgG1κ subclass that inhibits 
binding of programmed cell death-1 ligand (PD-L1) 
to programmed cell death-1 (PD-1) and CD8 
Study Title: 
Phase 1-2 Study of ADXS11-001 or MEDI4736 Alone or In Combination 
In Recurrent/ Metastatic Cervical or HPV+ Head & Neck Cancer 
Trial Phase 
Phase I/II 
Clinical Indication 
Locally advanced, or metastatic squamous or non-squamous carcinoma of 
the cervix or HPV+ squamous cell carcinoma of the Head and Neck 
Trial Type 
Interventional 
Study Centers 
Multicenter, US-only 
Route of Administration 
Intravenous (IV) 
Trial Blinding 
Open label, unblinded 
Number of Trial Subjects 
Approximately  66  
• 
6-18 in Phase 1 (Part A) portion of study 
• 
48 in Phase 2 (Part B) portion of study 
Estimated Duration of Trial 
Approximately 4 years 
Duration of Participation 
Each subject will participate in the trial for up to 4 years from the time the 
subject signs ICF through the final contact.  Treatment will continue for up 
to 1 year or until the subjects has either documented progression, 
unacceptable adverse events, withdrawn due to investigator’s discretion, 
subject withdraws consent, pregnancy, or noncompliance with study 
procedures or treatments.  During treatment, subjects who achieve a CR 
should receive at least 1 additional cycle of treatment.  Subjects who stop 
study treatment after a CR may be eligible for an additional 1 year of study 
retreatment if they progress within 1 year of stopping study treatment and 
the study is open.  After the end of treatment, each subject will be followed 
for adverse events for a minimum of 30 days and for serious adverse events 
for 90 days. 
Randomization Ratio 
There is no randomization in the Part A portion of the study.  The Part B 
portion of the study will have a 1:1:2 randomization of ADXS11-001: 
MEDI4736: ADXS11-001+MEDI4736, respectively 
Methodology 
This is a 2 part study in subjects with either metastatic squamous or non-
squamous carcinoma of the cervix or metastatic HPV+ squamous cell 
cancer of the head and neck (SCCHN).  Part A of the study is a Phase 1 
dose escalation evaluation of the combination of ADXS11-001 and 
MEDI4736.  The Phase 1 portion of the study will utilize a “3+3” design 
which will dictate dose escalation and de-escalations.  Once a maximum 
tolerated dose is identified and subjects from Part A have been followed for 
the 28-day DLT period, Part B of the study will commence.  Part B of the 


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Sponsor: 
Advaxis, Inc. 
Name of Finished Product: 
ADXS11-001 
MEDI4736 
Type of Treatment: 
ADXS11-001:  Lm-LLO Immunotherapy 
MEDI4736: MEDI4736 is a human monoclonal 
antibody (mAb) of the IgG1κ subclass that inhibits 
binding of programmed cell death-1 ligand (PD-L1) 
to programmed cell death-1 (PD-1) and CD8 
study will be a Phase 2 randomized design where subjects will be 
randomized 1:1:2 to ADXS11-001: MEDI4736: ADXS11-001+MEDI4736.  
Stratification will be based upon disease type. 
Safety will be assessed at every visit by comparing treatment-related 
adverse events (AEs), changes in physical examinations, vital signs 
measurements, and laboratory abnormalities. 
Criteria for Evaluation 
Safety: recorded AEs, changes in physical examinations, vital signs 
measurements and clinical laboratory evaluations 
Efficacy: Response rates as measured by RECIST 1.1 and irRECIST, 
duration of response, PFS 


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2.0 
TRIAL DESIGN 
Specific procedure to be performed during this trial, as well as the prescribed times and 
associated visit window are outlined in the Study Flow Charts - Section 6.0.  Details of each 
procedure are provided in Section 7.1 - Trial Procedures. 
This is a multi-center, open-label, 2 part randomized study of ADXS11-001 and MEDI4736 
administered as monotherapy or in combination to subjects with metastatic squamous or non-
squamous carcinoma of the cervix or metastatic HPV+ squamous cell carcinoma of the head 
and neck (SCCHN). 
2.1 
ADXS11-001 + MEDI4736 Combination Therapy 
Part A of the study will be Phase 1 analysis of ADXS11-001 given in combination with 
MEDI4736.  A standard 3+3 study design will guide enrollment, dose escalations, and de-
escalations during Part A.  The dose limiting toxicity (DLT) evaluation period will be 28 
days.  The dose of ADXS11-001 will be held at 1 x 109 cfu; escalating doses of MEDI4736 
(3 mg/kg and 10 mg/kg) will be evaluated as Dose Level 1 and Dose Level 2, respectively.  
Dose Level -1 will be ADXS11-001 (1 x 109 cfu ) and MEDI4736 (1 mg/kg), and will be 
explored if Dose Level 1 is not tolerated, as dictated by the 3+3 design.  ADXS11-001 will 
be dosed every 4 weeks.  MEDI4736 will be dosed every 2 weeks.  Subjects will continue on 
therapy for up to 1 year or until they discontinue due to documented progression, 
unacceptable toxicity, Investigator’s decision to withdraw the subject, subject withdraws 
consent, pregnancy of the subject, noncompliance with trial treatments or procedure 
requirements, administrative reasons, or withdrawal from the study.  The primary objective 
of Part A is to determine the saftey and tolerability of the treatment combination.  Secondary 
endpoints will include evaluation of response rates, duration of response and progression free 
survival (PFS) as determined by Response Evaluation Criteria in Solid Tumors (RECIST 1.1) 
and secondarily by irRECIST.  Response and progression will be determined by the 
investigator. 


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2.2 
ADXS11-001 vs MEDI4736 vs ADXS11-001 +MEDI4736 
Part B of the study will start once subjects from Part A have been followed through the 
28-day DLT period.  Part B will be a Phase 2 design which will randomize subjects 1:1:2 to 
ADXS11-001 : MEDI4736 : ADXS11-001+MEDI4736.  Randomization will be stratified 
based upon disease type.  ADX11-001 will be adminstered every 4 weeks.  MEDI4736 will 
be adminstered every 2 weeks.  
 
 
  Subjects will continue 
on therapy for up to 1 year or until they discontinue due to documented progression, 
unacceptable toxicity, investigator’s decision to withdraw the subject, subject withdraws 
consent, pregnancy of the subject, noncompliance with trial treatments or procedure 
requirements, administrative reasons, or withdrawal from the study.  Subjects who achieve a 
complete response (CR) should receive at least 1 additional cycle of treatment.  Crossover to 
another treatment arm will not be allowed.  Adverse events will be monitored throughout the 
study and graded in severity according to to the guidelines outlined in the National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. 
After the end of treatment, each subject, regardless of whether they particpate in Part A or 
Part B, will be followed for a minimum of 30 days for adverse event monitoring (serious 
adverse events will be collected for up to 90 days) after the end of treatment.  Subjects will 
have post treatment follow up visits for disease status, including non-study cancer treatment 
and disease progression, for up to 3 years.   
Safety and efficacy analysis will be performed for both parts of the study.  Subject 
disposition, demographic and baseline characteristics will be summarized separately for 
Part A and Part B.  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 drug will be included in the safety analyses. 
Statistical analysis for efficacy will be perrformed by treatment arm and disease type.  
Although it may lack statistical power, statistical testing for treatment comparisons will be 






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causes activation of the APC and results in a multifactorial stimulation of innate immunity 
including triggering Lm-specific PAMP (pathogen-associated molecular patterns) receptors, 
DAMP (damage-associated molecular patterns) receptors, and TLRs (toll-like receptors).  To 
the subject, this activation can manifest as flu-like symptoms or cytokine release symptoms 
that occur during or in the hours immediately following administration. 
Once inside the APC, ADXS11-001 can escape the phagolysosome into the cytoplasm of the 
APC where it secretes the tLLO-HPV-E7 fusion protein.  This peptide, along with other Lm 
peptides, is very rapidly ubiquitinated and transported to the proteasome where the peptides 
are broken down and cross-presented through MHC Class 1 and Class 2 MHC pathways.  
This cross-presentation, in immunologic context of responding to a “perceived” acute 
infection, stimulates the development of adaptive immunity culminating in HPV-specific T 
effector cells that infiltrate the tumor microenvironment and destroy tumor cells 
immunologically. 
Simply stated, the live attenuated vector is taken up into the immune system and presents the 
tumor antigen fused to immunogenic Lm peptides along with the rest of the Lm associated 
antigens.  The immune system then “perceives” the HPV-E7 expressing cells as potentially 
“Lm infected”, and generates CD8+ T cells that can infiltrate malignant tissue and destroy 
HPV-E7 expressing tumor cells. 
As a drug product, ADXS11-001 is administered as an IV infusion given every 3­4 weeks.  It 
is administered as a “therapeutic” vaccine or immunotherapy.  It has no direct effect on the 
tumor tissue, but is designed to stimulate the subject’s own immune system to generate an 
effective immune response targeting 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.  Collectively, the spectrum of clinical benefits is captured 
as relative delays in tumor progression and/or improved survival. 


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4.1.2 
MEDI4736 
MEDI4736 is a human monoclonal antibody (mAb) of the IgG1κ subclass that inhibits 
binding of programmed cell death-1 ligand (PD-L1) to programmed cell death-1 (PD-1) and 
CD8.  MEDI4736 is composed of 2 identical heavy chains and 2 identical light chains, with 
an overall molecular weight of approximately 149 kDa.  MEDI4736 contains a triple 
mutation in the constant domain of the IgG1 heavy chain that reduces binding to complement 
protein C1q and the Fcγ receptors involved in triggering effector function [1]. 
Immune responses directed against tumors are one of the body’s natural defenses against the 
growth and proliferation of cancer cells.  However, over time and under pressure from 
immune attack, cancers develop strategies to evade immune-mediated killing allowing them 
to develop unchecked.  One such mechanism involves upregulation of surface proteins that 
deliver inhibitory signals to cytotoxic T cells.  Programmed cell death ligand 1 is one such 
protein, and is upregulated in a broad range of cancers with a high frequency, with up to 88% 
expression in some indications.  In a number of these cancers, including lung [2], renal [3-5], 
pancreatic [6-8], and ovarian cancer [9], tumor cell expression of PD-L1 is associated with 
reduced survival and an unfavorable prognosis.  For example, in ovarian cancer, the 5-year 
survival rate in patients with low expression of PD-L1 was 80.2% compared to 52.6% in 
patients with high expression levels of PD-L1 [9].  In lung cancer, only 20% of patients with 
tumors expressing PD-L1 survived for more than 3 years compared to 49% of patients with 
tumors lacking PD-L1 expression [2].  Along with PD-L1 expression data generated 
internally, these data suggest that an antibody targeting PD-L1 has the potential to affect 
multiple solid tumor types. 
Programmed cell death ligand 1 is part of a complex system of receptors and ligands that are 
involved in controlling T-cell activation.  PD-L1 acts at multiple sites in the body to help 
regulate normal immune responses and is utilized by tumors to help evade detection and 
elimination by the host immune system tumor response.  In the lymph nodes, PD-L1 on 
antigen-presenting cells binds to PD-1 or CD80 on activated T cells and delivers an 
inhibitory signal to the T cell [10, 11].  This results in reduced T-cell activation and fewer 


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activated T cells in circulation.  In the tumor microenvironment, PD-L1 expressed on tumor 
cells binds to PD-1 and CD80 on activated T cells reaching the tumor.  This delivers an 
inhibitory signal to those T cells, preventing them from killing target cancer cells and 
protecting the tumor from immune elimination [12]. 
Based on in vitro studies, an antibody that blocks the interaction between PD-L1 and its 
receptors can relieve PD-L1-dependent immunosuppressive effects and enhance the 
cytotoxic activity of antitumor T cells [13].  The levels of tumor-infiltrating lymphocytes, 
and more specifically cytotoxic T cells, have been correlated with improved prognosis in a 
number of cancers including colorectal, melanoma, and lung [14], suggesting that an 
antitumor immune response is beneficial to patients.  Based on these findings, an anti-PD-L1 
antibody could be used therapeutically to enhance antitumor immune responses in patients 
with cancer.  Results of several preclinical studies using mouse tumor models support this 
hypothesis [15-18].  In these studies, antibodies directed against PD-L1 or its receptor, PD-1, 
demonstrated antitumor activity. 
Stimulating an antitumor immune response is a mechanism employed successfully by a 
number of approved cancer therapies.  For example, aldesleukin (Proleukin®), a recombinant 
human interleukin (IL)-2, in renal cancer [19] and sipuleucel-T (Provenge®) in prostate 
cancer [20] both directly stimulate immune activation.  Ipilimumab (Yervoy®) also stimulates 
the immune response, but does so by blocking the T-cell co-inhibitory molecule, CTLA-4, 
thereby removing an immunosuppressive signal. 
Blocking PD-L1 is an approach similar to CTLA-4 inhibition, but with some distinct 
differences.  First, the expression of CTLA-4 and its ligands is restricted to the hematopoietic 
system and thus, the site of action for molecules targeting CTLA-4 is solely the peripheral 
lymphoid organs.  In contrast, PD-L1 is expressed on cells of the hematopoietic system and 
on a range of tumor types.  Therefore, targeting PD-L1 should have additional effects within 
the tumor microenvironment.  Second, CTLA-4 plays an early and critical role in controlling 
T-cell activation.  This is reflected in the phenotype of CTLA-4 knockout mice, which die 
between 3 and 4 weeks of age due to lymphoproliferative disease and tissue destruction.  In 


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contrast, PD-L1 acts later in the process of T-cell activation [21] and is considered less 
critical to the control of initial T-cell activation.  This is reflected in the phenotype of PD-L1 
knockout mice, which are viable and have normal T-cell numbers and activation levels but 
show increased T-cell activation in response to antigen and increased susceptibility in certain 
autoimmune models [22, 23].  Similarly, mice lacking PD-1, a PD-L1 receptor, show strain-
specific phenotypes that are milder than those seen in CTLA-4 knockouts [24, 25].  
Therefore, inhibition of the PD-L1/PD-1 pathway might be expected to result in less toxicity 
relative to CTLA-4 inhibition.  In support of these findings, recent Phase 1 clinical studies 
assessing the tolerability of agents targeting PD-1 have demonstrated a toxicity profile that is 
more favorable than that of CTLA-4 [26-29]. 
4.1.3 
Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochure for detailed Preclinical and Clinical data. 
4.2 
Rationale 
4.2.1 
Rationale for the Combination ADXS11-001 & MEDI4736 
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 anal 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.  
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. 


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Various mechanisms have been proposed for the resistance of human solid tumors to immune 
recognition and obliteration, including the recruitment of regulatory T cells, 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 [30-32].  Cervical cancers are known to be infiltrated by 
regulatory T cells (Tregs) that are specific for HPV antigens.  The lack of CD8+ T cells 
migrating into the tumor cell nests, the induction of HPV16-specific regulatory T cells, and 
the influx of Tregs into the tumor prevent the immune system from eliminating malignant 
cells [33, 34].  Moreover, the ratio between the tumor-infiltrating CD8+ T cells and co-
infiltrating CD4+Foxp3+ regulatory T cells is an independent prognostic factor for overall 
survival [35], indicating the key role of these different types of T cells in cervical cancer. 
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. 
Antigen-induced activation and proliferation of T cells are regulated by the expression of 
both co-stimulatory and co-inhibitory receptors and their cognate ligands collectively 
referred to as immune “checkpoints”.  Signaling through these receptors modulates the 
initiation, amplification, and subsequent resolution of adaptive immune responses.  In the 
absence of co-inhibitory signaling, persistent T- cell activation can lead to excessive tissue 
damage in the setting of infection as well as autoimmunity.  In the context of cancer, in 
which immune responses are directed against antigens specifically or selectively expressed 
by tumor cells, these immune checkpoints can represent major obstacles to the generation 
and maintenance of clinically meaningful antitumor immunity.  Therefore, efforts have been 
made in the clinical arena to investigate blockade of immune checkpoints as a novel 
therapeutic approach to cancer. 


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CTLA-4 and PD-1 are 2 such checkpoint receptors being actively targeted in the clinic.   
 
 
 
 
 
 
 
 
 
PD-L1 has been reported to be expressed on the cell surface of 70% of HPV+ H&N 
squamous cell carcinoma (HPV-HNSCC) and only 29% of HPV negative tonsil cancers [38].  
PD-L1 expression was restricted to the tumor periphery at the interface between tumor cell 
nests and inflammatory stroma in most tumors and diffusely expressed throughout the tumor 
nests in a small percentage.  Similarly, for cervical dysplasia, PD-1 and PD-L1 expression on 
cervical T cells and dendritic cells, respectively, is associated with high-risk HPV positivity 
and the level of expression increases in parallel with increasing cervical intraepithelial 
neoplasia (CIN) grade up through invasive cervical cancer [39].  The majority of TILs found 
in cervical cancer express PD-1 and expression of PD-L1 correlates with impaired cell 
mediated immunity. 
While PD-L1 expression on SCCHN can be variable, PD-1 is always expressed on a high 
proportion of TILs – much higher than on peripheral blood T cells.  This difference in 
interferon gamma (IFN-γ) production between the PD-1(+) TILs are found to have a 
decreased ability to secrete IFN-γ and tumor necrosis factor alpha (TNFα) compared to 
PD­1(-) TILs and peripheral blood T cells suggesting that PD-1 expression within the tumor 
microenvironment marks TILs that are functionally suppressed in their capacity to produce 
effector cytokines. 


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The mechanism of action of ADXS11-001 includes the generation of tumor antigen (HPV 
E7) specific T-cells after presentation by a live attenuated bacterial vector.  In addition, there 
is a consistent reduction in both the relative number and function of Tregs and MDSCs in the 
tumor microenvironment, overcoming an important mechanism of immunologic tolerance.  
 
 
 
 
. 
Treatment with Lm-based vectors results in powerful stimulation of both innate and adaptive 
immunity.  Part of this response includes an up-regulation of the expression of PD-1 on 
antigen presenting cells and T-cells as well as an increase of PD-L1 expression on tissues.  
Increased interaction of these negative checkpoint ligands may limit the potential immune 
response associated with ADXS11-001 treatment. 
 
 
 
 
 
MEDI4736 binds to PD-L1 and prevents its ligation to PD-1 and subsequent inhibition of 
immune effector cells.  PD-1 expression on HPV-associated tumors is a mediator of immune 
tolerance, active in HPV-associated cancers, that is distinct from the activity of Tregs and 
MDSCs.  MEDI4736 is under clinical investigation in head and neck cancer and several 
other malignancies.  
 
 
Administering ADXS11-001 in combination with MEDI4736 to treat HPV-associated 
malignancies would potentially combine complimentary mechanisms of action in a 


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combination immunotherapy.  The ADXS11-001 vector would provide strong innate and 
adaptive stimulation with the live vector serving as the equivalent of multiple immune 
adjuvants and gain access to the cytoplasm of the APCs within the subject.  Inside the APCs 
the HPV-E7 peptide fused to tLLO would be secreted, ubiquitinated and cross-presented 
through both MHC Class 1 and Class 2 pathways resulting in HPV-specific T-cells.  
MEDI4736 would be able to block the negative inhibition of proliferation and T-cell 
activation caused by PD-1:  PD-L1 and PD-L2 binding which should result in a greater 
number of tumor antigen-specific T cells.  The Advaxis vector is also likely to increase 
PD­L1 expression by tumor cells along with PD-1 on lymphocytes.  Advaxis vectors have 
been shown to increase chemokine expression by tumors and chemokine receptor expression 
in tumor draining lymph nodes, which will help the T cells traffic to the tumor 
microenvironment.  Once they arrive at the tumors, MEDI4736 will block the PD-L1 
expressed on the surface or periphery of the tumors at the interface with the immunologic 
stroma allowing the activated T cells to better infiltrate the tumor microenvironment.  Upon 
their entry into the tumor microenvironment, the relative number of immunosuppressive 
Tregs and MDSCs will have been reduced and their immunosuppressive secretion of 
transforming growth factor (TGF) beta, IL-10 and arginase-1 markedly reduced, allowing 
better immunologic elimination of HPV-E7 expressing tumor cells.  In addition, Lm-LLO 
immunotherapy like ADXS11-001 can be given repeatedly without the development of 
neutralizing antibodies in the same manner as MEDI4736.  This allows for repeated 
administration of the vector along with MEDI4736 for extended repeating treatments.  
 
 
  This study will investigate the safety of these 2 agents in combination. 
4.2.2 
Rationale for Trial and Selected Subject Population 
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.  Both cervical cancer and SCCHN resist 


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immunologic clearance in part, through the development of immunologic tolerance that is 
mediated by expression of ligands for immunologic checkpoints such as PD-L1 on tumor 
tissue, and the presence of HPV-specific regulatory T cells and MDSCs within the tumor 
microenvironment. 
Cervical cancer and HPV+ SCCHN have a significant rate of successful treatment from 
primary surgery often followed by radiation and chemotherapy.  However, approximately 
33% of cervical cancers recur after primary therapy.  The majority of recurrent cervical 
cancers are not considered curable, and the subject will ultimately die from the malignancy.  
Globally, cervical cancer is the number 2 cause of cancer death for women.  Similarly, 
10­25% of subjects with HPV+ oropharyngeal cancer will experience progression within 
3 years of completing primary therapy and have a 2-year survival of approximately 54% 
[41, 42].  The incidence of HPV+ SCCHN is growing at an epidemic rate in western 
countries, including the USA. 
 
 
 
 
 
 
 
4.2.3 
Rationale for Dose Selection/Regimen/Modification 
4.2.3.1 
ADXS11-001 Dose Selection 
ADXS11-001 is a live attenuated Gram Positive bacterial immunotherapy vector.  Adverse 
events (AEs) 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 certain 
flu-like and cytokine release syndrome symptoms that are almost exclusively low grade, have 
an onset within hours of infusion, and have not been either cumulative or associated with any 


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delayed onset symptoms, including potential autoimmune symptoms.  These symptoms 
typically self-resolve, or respond readily to symptomatic treatment.  The symptoms appear to 
be related to the number of cfu infused over time.  Pretreatment with oral nonsteroidal anti-
inflammatory drugs (NSAIDs) and antiemetics reduces the incidence of these symptoms by 
almost 50%.  With ADXS11-001, live bacteria cannot be recovered from subjects after 
24 hours and a course of antibiotics is given on Day 4 to ensure clearance of the vector. 
There is no specific target blood level that needs to be achieved in order for ADXS11-001 to 
be effective in order 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 beyond the clinical observation of a maximum tolerated cfu.  In the current trial, the 
dose of 1 x 109 cfu was imposed. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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4.2.3.2 
MEDI4736 Dose Selection 
MEDI4736 has shown the following activity as an anti-PD-L1 molecule: 
• MEDI4736 binds to PD-L1 and blocks its interaction with PD-1 and CD80. 
• MEDI4736 can relieve PD-L1-mediated suppression of human T-cell activation in 
vitro. 
• MEDI4736 inhibits tumor growth in a xenograft model via a T-cell dependent 
mechanism. 
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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4.2.4 
Rationale for Endpoints 
4.2.4.1 
Efficacy Endpoints 
The evaluation of efficacy for both the parts of the study will utilize computer tomography 
(CT) to assess tumor response as well as PFS as measured by RECIST 1.1 and irRECIST.  
These endpoints are well established and commonly used to evaluate signs of clinical activity 
and efficacy. 
4.2.4.2 
Safety Endpoints 
The primary safety objective of this trial is to characterize the safety and tolerability of 
ADXS11-001 alone, MEDI4736 alone, and ADXS11-001 in combination with MEDI4736 in 
subjects with previously treated locally advanced or metastatic SSCHN or cervical cancer.  
The primary safety analysis will be based on subjects who experience toxicities as defined by 
NCI CTCAE v 4.03.  Safety will be assessed by quantifying the toxicities and grades, 
including SAEs and events of clinical interest (ECI) experienced by subjects who have 


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received ADXS11-001, MEDI4736, or ADXS11-001 + MEDI4736 combination therapy.  
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, and laboratory changes. 
4.2.4.3 
 
 
 
 
 
5.0 
METHODOLOGY 
5.1 
Entry Criteria 
5.1.1 
Inclusion Criteria 
This study will include subjects with either SCCHN or cervical cancer. 
For subjects with SCCHN to be eligible they must have: 
• Histopathological diagnosis of squamous cell cancer of the head & neck 
• Confirmation of HPV positivity.  Subjects with prior confirmation of HPV+ positivity 
will be eligible, provided documentation of the result is provided to sponsor.  
However if the subject’s HPV status is unknown, either fresh tumor tissue or 
formalin-fixed paraffin embedded tissue will need to be provided to a central or local 
lab for evaluation.  Details of sample requirement and shipping can be found in the 
study Laboratory Manual for samples being sent to the central laboratory. 
• Metastatic disease that is deemed incurable by local therapy 
• Must have received at least 1 platinum-based therapy for disease in the 
recurrent/metastatic setting.  Subjects must have either documented disease 
progression OR become intolerant to prior therapy in the metastatic setting. 
o Subjects who have received > 1 prior systemic therapy in the metastatic 
setting MAY be eligible only after consultation with the Sponsor. 


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For subjects with carcinoma of the cervix to be eligible they must have:  
• Histopathological diagnosis of squamous, non-squamous, adenosquamous, carcinoma 
or adenocarcinoma of the cervix 
• Metastatic disease that is deemed incurable by local therapy 
• Must have received at least 1 platinum-based therapy for disease in the 
recurrent/metastatic setting.  Subjects must have either documented disease 
progression OR become intolerant to prior therapy in the metastatic setting. 
o Subjects who have received > 1 prior systemic therapy in the metastatic 
setting MAY be eligible only after consultation with the Sponsor 
• HPV  positivity is NOT a requirement for eligibility 
ALL subjects must also: 
1. Have disease amenable and accessible for biopsy. This criterion applies to Part B 
only. 
2. Provide tissue from an 
, if available.   
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 a performance status of 0 or 1 on the ECOG Performance Scale. 
7. Demonstrate adequate organ function as defined in Table 1.   


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Table 1 
Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
Absolute neutrophil count (ANC) 
≥1,000 /mcL 
Platelets 
≥75,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L  
Renal 
Serum creatinine OR 
Measured or calculateda 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 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 
Creatinine clearance should be calculated per institutional standard. 
 
8. Female subjects of childbearing potential (not surgically sterilized or not free from 
menses for > 1 year): 
a. must have a negative urine or serum pregnancy test result 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. 
b. must be willing to use 2 methods of birth control through 120 days after the 
last dose of study treatment (Section 5.7.2). 
9. Male subjects must agree to use an adequate method of contraception starting with 
the first dose of study treatment through 120 days after the last dose of study therapy. 


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10. Must have a washout period of at least 14 days from completing prior standard of 
care therapy to the initiation of study therapy.  For subjects who have been treated 
with either prior investigational therapy, including, but not limited to anti-PD-1, anti-
PD-L1 or CTLA4 therapy, a washout period of 28 days is required*.  (* If a subject 
received a therapy where delayed toxicity is a concern or expected (e.g., skin reaction with RT or 
mucositis with 5FU) then additional wash out should be considered after discussion with the medical 
monitor.) 
5.1.2 
Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. Has not recovered (i.e., ≤Grade 1 or at baseline) from adverse events, with the 
exception of alopecia, due to a previously administered agent. 
2. Has any prior Grade ≥3 immune-related adverse event (irAE) while receiving 
immunotherapy, including anti-CTLA-4 treatment, or any unresolved irAE >Grade 1. 
3. Has any pulmonary, ocular, or central nervous system (CNS) toxicity  while receiving 
prior immunotherapy that has not resolved to <Grade 1. 
4. Requires additional immunosuppression beyond corticosteroids for resolution of 
immune-related AEs from prior immunotherapy. 
5. Is currently participating in or has participated in a study of an investigational agent 
or using an investigational device within 4 weeks of the first dose of treatment. 
6. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of' immunosuppressive therapy within 7 days prior to the first dose of trial 
treatment. 
7. Has any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for 
invasive malignancy within 2 years.  Concurrent use of hormones for non-cancer-


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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. 
b. Has known active CNS metastases and/or carcinomatous meningitis.  Subjects 
with previously treated brain metastases may participate provided they are 
stable (without evidence of progression by imaging for at least 4 weeks prior 
to the first dose of study drug 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 drug.  Note:  
subjects with ≤Grade 2 neuropathy are an exception to this criterion and may 
qualify for the study. 
8. Has an active autoimmune disease requiring systemic treatment within the past 
3 months or a documented history of clinically severe autoimmune disease, or a 
syndrome that requires systemic steroids or immunosuppressive agents.  Subjects 
with vitiligo or resolved childhood asthma/atopy would be an exception to this rule.  
Subjects that require intermittent use of bronchodilators or local steroid injections 
would not be excluded from the study.  Subjects with hypothyroidism stable on 
hormone replacement or Sjorgen’s syndrome will not be excluded from the study. 
9. Has evidence of interstitial lung disease or active, non-infectious pneumonitis, active 
or prior documented inflammatory bowel diseases (e.g., Crohn’s disease, ulcerative 
colitis) 
10. Has an active infection requiring systemic therapy.  Prior to dosing with study 
drug(s), the subject must be at least 5 half-lives from their last dose of antibiotic. 
11. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation 
for the full duration of the trial, or is not in the best interest of the subject to 
participate, in the opinion of the treating investigator. 


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12. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
13. Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies). 
14. Has known active hepatitis B (e.g., HBsAg reactive) or hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
15. Has irreversible toxicity that may be exacerbated by study drugs.  However, 
irreversible toxicity that is not reasonably expected to be exacerbated by study drug(s) 
may be included (e.g., hearing loss) after consultation with the sponsor medical 
monitor. 
16. Has a contraindication to administration of 
 
 
 
17. Has a known allergy to any component of the study drug(s) formulations. 
18. Has contraindication to administration of non-steroidal anti-inflammatory drugs 
(NSAIDs). 
19. Has a major surgical procedure (as defined by the investigator) within 30 days prior 
to the first dose of study drug(s) or still recovering from prior surgery. 
- 
Note: If subject received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting 
therapy at the discretion of the Investigator. 
20. Has received a live vaccine within 30 days prior to the first dose of trial treatment. 
21. In the opinion of the investigator, has rapidly progressing disease, OR has life 
expectancy of less than 6 months, OR would be unable to receive at least 1 cycle of 
therapy. 


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22. Has uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable 
angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, or 
psychiatric illness/social situations that would limit compliance with study 
requirement, substantially increase risk of incurring AEs from MEDI4736 or 
compromise the ability of the subject to give written informed consent. 
23. Has a history of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced 
pneumonitis, organizing pneumonia, risk of pulmonary toxicity, or evidence of active 
pneumonitis on screening chest CT scan. 
5.2 
Trial Treatments 
The treatments to be used in this trial are outlined below in Table 2.  Trial treatment should 
begin on the day of randomization or as close as possible to the date on which treatment is 
allocated/assigned. 
Table 2 
Trial Treatment 
Drug 
Dose 
Route of 
Administration 
Regimen 
Part A (Combination therapy) 
ADXS11-001 
1 x 109 (fixed) 
IV infusion 
Q4W 
MEDI4736a 
3 mg/kg (starting dose) 
IV infusion 
Q2W 
Part B 
ADXS11-001 (monotherapy) 
1 x 109 (fixed) 
IV infusion 
Q4W 
MEDI4736 (monotherapy) 
10 mg/kg 
IV infusion 
Q2W 
Combination 
RP2D 
IV infusion 
Q2W 
a 
In Phase 1, the MEDI4736 3 mg/kg starting dose will be escalated/de-escalated to determine a recommended dose 
for Phase 2 combination therapy; in Phase 2, the MEDI4736 monotherapy dose will be 10 mg/kg 
 
5.2.1 
Dose Selection/Modification 
5.2.1.1 
Dose Selection 
The rationale for selection of doses to be used in this trial is provided in Section 4.2.3 –
Rationale for Dose Selection. 


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Details on the dose calculation, preparation and administration are provided in the Pharmacy 
Manual.  Dose levels to be explored in Part A are shown below. 
Dose Level 
ADX11-001 
MEDI4736 
1 
1 x 109 cfu (Q4wks) 
3 mg/kg (Q2wks) 
2 
1 x 109 cfu (Q4wks) 
10 mg/kg (Q2wks) 
-1 
1 x 109 cfu (Q4wks) 
1 mg/kg (Q2wks) 
 
Part A of the study is a Phase 1 3+3 design of ADXS11-001 and MEDI4736 combination 
therapy.  MEDI4736 and ADXS11-001 will be administered in sequential cohorts of 
3­6 subjects with a minimum of 48 hours between initial dosing for each of the first 
3 subjects enrolled in the study.  The first cohort will enroll a minimum of 3 subjects 
according to a standard 3+3 design shown schematically below. 
Figure 1 
3 + 3 Design Schematic 
 
• Subjects in the first cohort will receive a dose of MEDI4736 at 3 mg/kg and 
ADXS11-001 1 x 109 cfu (Dose Level 1). 


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• If no DLTs are experienced, the next dose level of ADXS11-001 1 x 109 cfu + 
MEDI4736 at 10 mg/kg (Dose Level 2) will be explored. 
• If 1 DLT is experienced, 3 additional subjects will be enrolled.  If there is 1 DLT 
among 6 subjects, the next dose level will be explored. 
• If ≥ 2 DLTs are observed in the first dose cohort, the starting dose of MEDI4736 will 
be de-escalated to 1 mg/kg and a dose de-escalation cohort will be enrolled (Dose 
Level -1). 
All decisions regarding dose escalation or de-escalation will be guided by the 3+3 study 
design and will be made by the sponsor in consultation with investigators.  The sponsor 
reserves the right to expand the number of subjects in each of the cohorts to better evaluate 
safety and tolerability, and to evaluate other doses. 
The dose that will be utilized in Part B will be the highest maximal dose level evaluated in 
Part A that has an observed DLT rate of <33%. 
Dose escalation/de-escalation decisions for MEDI4736 will use pre-defined DLT criteria 
(Section 5.2.1.1 – Dose Limiting Toxicities).  Subjects who complete the DLT period may 
dose-escalate to the RP2D if approved by the sponsor. 
5.2.1.2 
Dose Limiting Toxicities 
Dose-limiting toxicities will be evaluated during the Phase 1 combination dose-determination 
phase.  All toxicities will be graded using NCI CTCAE v 4.03.  The period for evaluating 
DLT will be from the first dose of investigational product through 28 days post initial dose 
for each subject.  The occurrence of any of the following will be considered a DLT, if judged 
by the investigator to be possibly, probably or definitely related to combination therapy. 
1. Any ≥Grade 4 irAE 
2. Any ≥Grade 3 colitis 
3. Any ≥Grade 3 non-infectious pneumonitis irrespective of duration 


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4. Any Grade 3 irAE, excluding colitis or pneumonitis, that does not downgrade to 
Grade 2 within 3 days after onset of the event despite optimal medical management 
including systemic corticosteroids or does not downgrade to ≤Grade 1 or baseline 
within 14 days of AE onset 
5. Liver transaminase elevation ≥5x but ≤8x ULN that does not downgrade to Grade 2 
within 5 days after onset with optimal medical management, including systemic 
corticosteroids.  Transaminase elevation >8x ULN or total bilirubin >5x ULN will be 
considered a DLT regardless of duration or reversibility. 
6. Any increase in AST or ALT >3x ULN and concurrent increase in total bilirubin >2x 
ULN (Hy’s Law). 
7. Bacterial meningitis documented by symptoms and confirmed by lumbar puncture 
culture results 
8. Listeremia: persistent (for 48-72 hours) symptoms consistent with listeremia (e.g., 
fever and muscle aches, often preceded by diarrhea or other gastrointestinal 
symptoms) 
9. ≥Grade 3 flu-like symptoms or cytokine release syndrome symptoms that persist for 
>24 hours after study drug administration despite symptomatic treatment. 
10. ≥Grade 2 allergic reaction (not due to antibiotic):  will receive no further doses. 
11. Any drug-related “non-irAE” ≥Grade 3 except for the exclusions listed below. 
• Grade 3 fatigue for ≤7days 
• Grade 3 endocrine disorder (thyroid, pituitary, and/or adrenal insufficiency) that is 
managed with or without systemic corticosteroid therapy and/or hormone 
replacement therapy and the subject is asymptomatic. 
• Grade 3 inflammatory reaction attributed to a local antitumor response (e.g., 
inflammatory reaction at sites of metastatic disease, lymph nodes, etc.). 


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• Concurrent vitiligo or alopecia of any AE grade 
• Grade 3 infusion-related reaction that resolves within 6 hours with appropriate 
clinical management. 
• Grade 3 or Grade 4 neutropenia that is not associated with fever or systemic infection 
that improves by at least 1 grade within 3 days.  Grade 3 or Grade 4 febrile 
neutropenia will be a DLT regardless of duration or reversibility. 
• Grade 3 or Grade 4 lymphopenia. 
• Grade 3 thrombocytopenia that is not associated with clinically significant bleeding 
that requires medical intervention, and improves by at least 1 grade within 3 days. 
• Isolated Grade 3 electrolyte abnormalities that are not associated with clinical signs or 
symptoms and are reversed with appropriate maximal medical intervention within 
3 days. 
irAEs are defined as AEs of immune nature (i.e., inflammatory) in the absence of a clear 
alternative etiology.  In the absence of clinical abnormality, repeat laboratory testing will be 
conducted to confirm significant laboratory findings prior to designation as a DLT.  While 
the rules for adjudicating DLTs in the context of dose escalation are specified above, an AE 
not listed above may be defined as a DLT after consultation with the sponsor and 
investigators, based on the emerging safety profile. 
5.2.1.3 
Treatment Modification 
In Part A, dose escalation/de-escalation for MEDI4736 in the combination will be based on 
defined DLT criteria (Section 5.2.1.1); the ADXS11-001 combination therapy dose is 1 x 109 
cfu (fixed).  In the event of DLT, the investigator will determine relatedness to the study 
treatment combination. 
With ADXS11-001 treatment, a clear pattern of treatment-related AEs consistent with 
cytokine release has emerged consisting of transient Grade 1 or 2 (mild-moderate) flu–like or 
cytokine release syndrome symptoms (such as chills, nausea and vomiting), the majority of 
which occur within the first 6 hours after infusion (see also Section 5.6.1).  Symptoms either 
self-resolve or respond quickly to symptomatic treatment.  There has been no evidence of 
listeriosis, no persistent symptoms, no delayed symptoms, and no evidence of cumulative 


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toxicity in subsequent doses.  Treatment modification guidelines for cytokine release 
syndrome symptoms are shown in Table 3.  Treatment modification guidelines for irAEs are 
shown in Table 4 below. 
Table 3 
Treatment Modification Guidelines for ADXS11-001 Cytokine Release 
Syndrome symptoms 
Toxicity 
Grade 
Modification 
1st episode of symptoms 
associated with CRS (e.g. 
Nausea, vomiting, chills, rigors, 
hypotension, fever) 
1-2 
No modification on subsequent ADXS11-001 infusion 
3-4 
• 
Extend infusion time 
 
 
• 
Consider increasing prophylaxis dose of 
NSAIDS  
• 
Consider incorporating pretreatment fluids to 
manage hypotension. 
Second episode of CRS 
1-2 
No modifications 
3 
Discussion with sponsor required 
4 
If symptoms have not ameliorated from 
aforementioned modifications, subject should be 
discontinued from study 
 
 


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Table 4 
Dose Modification Guidelines for Immune-related Adverse Events - MEDI4736 Monotherapy and Combination Arms 
Severity 
Immune-related Adverse Events (irAEs)a 
All Other Events 
Grade 1 
None 
None 
Grade 2 
For endocrinopathy:  Hold MEDI4736/Combination dose; do not hold ADXS11-001 (unless during combination therapy). 
When endocrinopathy is controlled, resume MEDI4736/Combination administration at next scheduled dose. 
For dermatologic irAEs:  MEDI4736/Combination may be dosed at the next scheduled time point. 
For pneumonitis:  Hold MEDI4736/Combination until resolution to ≤Grade 1.  
If resolution to ≤ Grade 1 occurs within 3 days of the initiation of maximal supportive care (including corticosteroids)b, resume 
MEDI4736/Combination administration at next scheduled dose.  Otherwise, discontinue MEDI4736/Combination. 
For all other irAEs:  Hold MEDI4736/Combination until resolution to ≤Grade 1. 
If resolution to ≤Grade 1 does not occur within 30 days of irAE onset, discontinue MEDI4736/Combination 
Hold 
MEDI4736/Combination 
until resolution to 
≤Grade 1 or baseline. 
If resolution to ≤Grade 1 
does not occur within 
30 days, discontinue 
MEDI4736/ Combination 
Grade 3 
For endocrinopathy:  Hold MEDI4736/Combination dose.  
When endocrinopathy is controlled, resume MEDI4736/Combination administration at next scheduled dose. 
For dermatologic irAEs:  Hold MEDI4736/Combination until resolution to ≤Grade 1 or baseline.  
If resolution to ≤Grade 1 or baseline does not occur within 30 days, discontinue MEDI4736/Combination. 
For elevations in transaminases: For elevations in transaminases up to 8 × ULN, hold MEDI4736/Combination until resolution to ≤Grade 1 
or baseline. If elevations downgrade to ≤Grade 2 within 7 days or resolve to ≤Grade 1 or baseline within 14 days of onset, resume 
MEDI4736/Combination administration at next scheduled dose. Otherwise, discontinue MEDI4736/Combination. 
For elevations in transaminases >8 × ULN, discontinue MEDI4736/Combination. 
For elevations in bilirubin: For elevations in bilirubin up to 5 × ULN, hold MEDI4736/Combination until resolution to ≤ Grade 1 or baseline. 
If elevations downgrade to ≤ Grade 2 (< 3 × ULN) within 7 days or resolve to ≤ Grade 1 or baseline within 14 days, resume 
MEDI4736/Combination administration at next scheduled dose. Otherwise, discontinue MEDI4736. 
For all other irAEs:  Discontinue MEDI4736/Combination. 
Hold 
MEDI4736/Combination 
until resolution to ≤Grade 
1 or baseline.  
For AEs that downgrade 
to ≤Grade 2 within 7 
days or resolve to 
≤Grade 1 or baseline 
within 14 days, resume 
MEDI4736/ Combination 
administration at next 
scheduled dose. 
Otherwise, discontinue 
MEDI4736/Combination. 
Grade 4 
Discontinue MEDI4736/Combination. 
Discontinue 
MEDI4736/Combination. 
AE = adverse event; irAE = immune-related adverse event; ULN = upper limit of normal. 
a 
Management of irAEs may require administration of immunosuppressive medications (and/or hormone replacement therapy for endocrinopathies).  Resolution of irAEs managed in this manner in 
the timeframes specified is acceptable. 
b 
Subjects who require corticosteroids for resolution must have discontinued corticosteroids.  Subject can restart study therapy upon resolution of irAE and cessation of corticosteroid treatment for 14 
days. 


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5.2.2 
Timing of Dose Administration 
Trial treatment should be administered after all procedures/assessments have been completed 
as detailed in the Study Flow Charts (Section 6.0).  Trial treatment may be administered 
 
 due to administrative reasons but only 
after consultation with the sponsor.  All trial treatments will be administered on an outpatient 
basis.  The Procedures Manual contains specific instructions for dose calculation, 
reconstitution, preparation of the infusion fluid, and administration. 
5.2.2.1 
Combination Dosing (Part A & Part B) 
For Combination dosing, MEDI4736 will be given Q2W (Weeks 1, 3, 5, and 7 of each 8-
week cycle) and ADXS11-001 will be given Q4W (Weeks 1 and 5 of each 8-week cycle).On 
days when both treatments are administered (Weeks 1 and 5 of each cycle), subjects will first 
receive the MEDI4736 infusion in 250 mL 
  
 after end of MEDI4736 infusion, subjects should be premedicated 
with NSAIDS and oral antiemetics (Section 7.1.4.2).  The ADXS11-001 infusion can begin 
 after the subject has been premedicated.  When given the same day as 
MEDI4736, ADXS11-001 will be given in 100 mL of normal saline 
, to 
reduce the potential for fluid overload.    
Any subject administered ADXS11-001 will also receive antibiotics.  Specific details of 
antibiotic regimen are provided in Section 7.1.4.2. 
5.2.2.2 
ADXS11-001 Monotherapy (Part B) 
In Part B , the dose for ADXS11-001 monotherapy will be 1 x 109 cfu administered in 
250 mL of normal saline infused 
 Q4W (Weeks 1 and 5 in each 8-week 
cycle).  Subjects should be premedicated with NSAIDS and oral antiemetics and received 
antibiotic as indicated in Section 7.1.4.2. 


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5.2.2.3 
MEDI4736 Monotherapy (Part B) 
In Part B, the dose for MEDI4736 monotherapy will be 10 mg/kg administered in 250 mL of 
normal saline infused 
 in duration Q2W (Weeks 1, 3, 5, and 7 
in each 8-week cycle). 
5.2.3 
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 in Part A will receive combination therapy.  Subjects participating in Part B will 
be allocated by random assignment 1:1:2 to ADXS11-001 monotherapy, MEDI4736 
monotherapy, or ADXS11-001+ MEDI4736 combination therapy. 
5.4 
Stratification 
In Part B, all 3 treatment arms will be stratified by disease (SCCHN or cervical cancer). 
5.5 
Concomitant Medications/Vaccinations (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 trial therapy or 
vaccination 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 trial therapy or vaccination schedule requires the mutual agreement of the 
Investigator, the Sponsor, and the subject. 
5.5.1 
Acceptable Concomitant Medications 
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 


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medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids.  If changes occur during the trial period, documentation of drug dosage, 
frequency, route, and date may also be included on the CRF. 
All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded.  Concomitant 
medications, administered after 30 days after the last dose of trial treatment, for SAEs and 
ECIs should be recorded as defined in Section 7.2. 
5.5.2 
Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 
• Anti-cancer therapy including but not limited to, hormonal, chemotherapy, 
radiation therapy, treatment with targeting agents (e.g. 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 and MEDI4736 
• Live vaccines (e.g., 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.   
• Chronic use of systemic glucocorticoids have the potential to reduce the immune 
response therefore should be used with caution. However, glucocorticoids should 


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be considered to manage symptoms of cytokine release (e.g. Fever, headache, 
hypotension, chills, rigors, etc.).  Topical use of steroids is allowed.  The 
occasional use of steroids for the treatment of COPD and or asthma is allowed.  
• Anti-infectives should be avoided, except where mandated by the protocol.  
However, subjects with a documented infectious complication should receive oral 
or IV antibiotics or other anti-infective agents as considered appropriate by the 
treating investigator for a given infectious condition, according to standard 
institutional practice. 
• Acetaminophen should not be substituted for the selected NSAID for pretreatment 
prophylaxis since acetaminophen does not have similar anti-inflammatory 
properties that could ameliorate cytokine release syndrome symptoms.  
Acetaminophen can be used after dosing for supportive care measures. 
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  
Subjects may receive other medications that the investigator deems to be medically 
necessary. 
The Exclusion Criteria describe other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.6 
Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator including but not limited to the items outlined below. 
5.6.1 
Cytokine Release Syndrome 
CRS per CTCAE V4.03 is characterized clinically by nausea, headache, tachycardia, 
hypotension, rash and shortness of breath.  These side effects can develop soon after the 
administration of the Lm-LLO immunotherapies and can last for several hours.  The clinical 


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syndrome is caused by a sudden increase in TNFα, IFNγ and IL-6 release, all of which have 
been shown to occur after Lm-LLO immunotherapy administration, resulting from the body’s 
immune response to the therapy. 
o Symptoms associated with CRS have been seen in subjects with ADXS11-001 
administration. Symptoms are often grade 1-2 and transient, resolving with 
symptomatic management within 30 minutes-1 hour. In rare instance <5%, grade 3 
rigors and hypotension have been seen.  
o Prophylaxis with NSAIDs and anti-emetics have been shown to reduce both the 
severity, time to resolution and incidence.  Supportive measure which include fluids 
for hypotension and continued use of NSAIDs are recommended. 
o In cases of grade 3 hypotension that are not responsive to IV fluids consider use of low 
dose systemic corticosteroids (e.g. 100 mg, IV hydrocortisone infused over 30 seconds 
every 2 hours until resolution to Grade 1 or baseline or 500 mg IV hydrocortisone 
infused over 10 minutes every 2 hours until resolution to Grade 1 or baseline). 
For subjects who experience symptoms associated with CRS, refer to Table 3 for treatment 
modifications for subsequent infusions  
5.6.2 
Diarrhea 
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus).  In symptomatic subjects, infectious 
etiologies should be ruled out, and if symptoms are persistent and/or severe, endoscopic 
evaluation should be considered. 
o All subjects who experience diarrhea should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid 
and electrolytes should be substituted via IV infusion. 


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5.6.3 
Nausea/vomiting:  
Nausea and vomiting should be treated aggressively.  Consideration should be given in 
subsequent cycles to the administration of prophylactic antiemetic therapy according to 
standard institutional practice.  Subjects should be strongly encouraged to maintain liberal 
oral fluid intake. 
5.6.4 
Management of Infusion Reactions   
With any infusional therapy there is the possibility of an infusion reaction.  Signs and 
symptoms usually develop during or shortly after drug infusion and generally resolve 
completely within 24 hours of completion of infusion.  Signs/symptoms 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; 
pruritus/itching; rash/desquamation; rigors/chills; sweating (diaphoresis); tachycardia; tumor 
pain (onset or exacerbation of tumor pain due to treatment); urticaria (hives, welts, wheals); 
vomiting.  See Table 5 for treatment guidelines for subjects who experience an infusion 
reaction. 
 
 


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Table 5 
Treatment 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. 
2. Additional appropriate medical therapy may include but is not limited 
to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
3. 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. 
2. Additional appropriate medical therapy may include but is not limited 
to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
3. Increase monitoring of vital signs as medically indicated until the 
subject is deemed medically stable in the opinion of the investigator. 
4. Hospitalization may be indicated. 
5. Subject experiencing Grade 4 reactions will be permanently 
discontinued from further trial treatment administration.  Subjects 
with Grade 3 reactions may continue after discussion with the 
sponsor. 


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5.6.5 
Listeremia 
Persistent (for 48-72 hours) symptoms consistent with listeremia (e.g., fever and muscle aches, 
often preceded by diarrhea or other gastrointestinal symptoms) will require obtaining a 
quantitative blood culture.  Symptoms that persist for >72 hours following dosing must be 
treated with an IV course of an appropriate antibiotic such as amoxicillin, ampicillin, 
ciprofloxacin, erythromycin, gentamycin, penicillin, trimethoprim/sulfamethoxazole, or 
vancomycin. ADXS11-001 is resistant to both streptomycin and chloramphenicol.  Clinical 
sepsis requiring intensive care admission and/or pressors will automatically result in 
discontinuation of further doses. 
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 
The study drug(s) may have adverse effects on a fetus in utero.  Furthermore, it is not known 
if the study drug(s) has transient adverse effects on the composition of sperm.  Non-pregnant, 
non-breast-feeding women may be enrolled if they are willing to use 2 methods of birth 
control or are considered highly unlikely to conceive.  Highly unlikely to conceive is defined 
as 1) surgically sterilized, 2) postmenopausal (has not had menses for greater than 1 year), or 
3) not heterosexually active for the duration of the study.  The 2 birth control methods can be 
either 2 barrier methods or a barrier method plus a hormonal method to prevent pregnancy.  
Males may enroll if they are willing to use 1 method of birth control.  Subjects should start 
using birth control from screening throughout the study period up to 120 days after the last 
dose of study therapy. 
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 


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estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents). 
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate 
in the study they must adhere to the contraception requirement (described above) for the 
duration of the study and during the follow-up period defined in Section 7.2.2 - Reporting of 
Pregnancy and Lactation to the Sponsor.  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 serious adverse experience (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 the study drug(s) 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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5.8 
Subject 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 7.1.3 – Other Procedures. 
A subject must be discontinued from the trial, with no further data reporting, for the 
following reasons: 
• The subject withdraws consent 
• Subject death 
• The subject is lost to follow-up 
A subject must be discontinued from study treatment, but will continue to be followed, for 
the following reasons: 
• Confirmed radiographic disease progression 
o Note: For unconfirmed radiographic disease progression, please see RECIST 
1.1 criteria 
o Note: A subject may continue on treatment with confirmed radiographic 
progression if clinically stable or clinically improved, please see RECIST 1.1 
criteria, after discussion with the sponsor. 
• Unacceptable adverse experiences as described in Section 7.2 
• Investigator’s decision to withdraw the subject 
• The subject has a confirmed positive serum pregnancy test 
• Noncompliance with trial treatment or procedure requirements 
• Completed 12 months of treatment with study drug(s) 
o Note: 12 months of study medication is calculated from the date of first dose.  
Subjects who stop treatment after 12 months may be eligible for additional 
study treatment if they progress after stopping study treatment provided they 
meet the requirements detailed in Section 7.1.4.2.1. 
• Administrative reasons 
• Sponsor decision to terminate the trial 


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• Subject is determined to have met one or more of the exclusion criteria for study 
participation at study entry and continuing investigational therapy might constitute a 
safety risk 
The End of Treatment and Follow-up visit procedures are listed in Section 6.0 - Study Flow 
Chart and Section 7.1.4 -Visit Requirements.  After the end of treatment, each subject will be 
followed for 30 days for adverse event monitoring (90 days for serious adverse event 
monitoring or the initiation of a new anticancer therapy as described in Section 7.2.3.1).  
Subjects who discontinue for reasons other than progressive disease will have post-treatment 
follow-up tumor assessments until disease progression, initiating a non-study cancer 
treatment, withdrawing consent or becoming lost to follow-up. 
5.9 
Subject Replacement Strategy 
During Part A, subjects who discontinue for any reason other than toxicity will be replaced. 
During Part B, subjects will not be replaced. 
5.10 
Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a 
potential health hazard to subjects 
4. Plans to modify or discontinue the development of the study drug 
In the event of Sponsor decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made. 












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Trial Period: 
Screening Phase 
Treatment Period 
End of Treatment 
Treatment Cycle/Title: 
Pre-
screening  
Screening  
Wk
1 
Wk 
2  
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Discon 
Follow-up 
Phone Call 
Follow up 
Follow Up 
Scheduling Window (Days): 
 
-28 to -1 
± 31 
 
± 3 
 
± 3 
 
± 3 
 
At time of 
Discon 
30 days post 
90 days 
post 
Every 8 
weeks post 
PK Assessment7 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Immunogenicity (ADA) Assessment (serum)8 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
1 – The +/- 3 day window does not apply to Cycle 1 Week 1.  This window is only applicable in subsequent cycles. 
2 - ECG and O2 saturation by pulse oximetry at baseline screening only 
3 - Tumor Assessments will be done in screening and Week 1 (± 1 week), starting at Cycle 2.  Evaluations will continue every 8 weeks (± 1 week) during treatment and for subjects 
in follow up who discontinue treatment for reasons other than disease progression; duration of follow up will be up to 3 years. 
4 - Screening lab that are done within 5 days of initiating treatment can be used for C1D1 laboratory tests.   
5 
6 - 
) 
7 - PK Assessment:  Serum will be collected at Cycle 1 Day 1 (pre-dose and end of infusion), at Weeks 3 and 5 (pre-dose only) and at Week 7 (pre-dose and end of infusion).  For all 
subsequent cycles, serum will be collected at Week 7 (pre-dose only) with the exception of Cycle 3 where serum will be collected at Week 7 (pre-dose and end of infusion). 
Serum will also be collected at end of treatment and at the 90-day post treatment follow up visit.  
8 - Immunogenicity (ADA) Assessment:  Serum will be collected at Cycle 1 Day 1 (pre-dose only), at Weeks 5 and 7 (pre-dose only).  For all subsequent cycles, serum will be 
collected at Week 7 (pre-dose only).  Serum will also be collected at end of treatment and at the 90-day post treatment follow up visit.  
9 -
10
 
 




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Trial Period: 
Screening Phase 
Treatment Period 
End of Treatment 
Treatment Cycle/Title: 
Pre-
screening  
Screening  
Wk1 
Wk 
2  
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Discon 
Follow-up 
Phone Call 
Follow up 
Follow Up 
Scheduling Window (Days): 
 
-28 to -1 
± 31 
 
± 3 
 
± 3 
 
± 3 
 
At time of 
Discon 
30 days post 
90 days post 
Every 8 weeks 
post 
PK Assessment10 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Immunogenicity (ADA) Assessment (serum)11 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
1 - The +/- 3 day window does not apply to Cycle 1, Week 1.  This window is only applicable in all subsequent cycles. 
2 - Subjects will receive prophylactic NSAIDS and antiemetics 
before each ADXS11-001 infusion.  Subjects will also receive a course of oral antibiotics to 
be started 3 days after each ADXS11-001 infusion 
3 - ECG and O2 saturation by pulse oximetry at baseline screening only 
4 - Vital signs are to be monitored
following each ADXS11-001 infusion. 
5 - Tumor Assessments will be done in screening and Week 1 (± 1 week), starting at Cycle 2.  Evaluations will continue every 8 weeks (± 1 week) during treatment and for subjects 
in follow up who discontinue treatment for reasons other than disease progression; duration of follow up will be up to 3 years. 
6 - Screening lab that are done within 5 days of initiating treatment can be used for C1D1 laboratory tests. 
7 -
8 -  
 
9 - 
 
10 - PK Assessment:  Serum will be collected at Cycle 1 Day 1 (pre-dose and end of infusion), at Weeks 3 and 5 (pre-dose only) and at Week 7 (pre-dose and end of infusion).  For 
all subsequent cycles, serum will be collected at Week 7 (pre-dose only) with the exception of Cycle 3 where serum will be collected at Week 7 (pre-dose and end of infusion). 
Serum will also be collected at end of treatment and at the 90-day post treatment follow up visit.  
11 - Immunogenicity (ADA) Assessment:  Serum will be collected at Cycle 1 Day 1 (pre-dose only), at Weeks 5 and 7 (pre-dose only).  For all subsequent cycles, serum will be 
collected at Week 7 (pre-dose only).  Serum will also be collected at end of treatment and at the 90-day post treatment follow up visit.  
12 -
13 -
 


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6.5 
Retreatment Flow Chart 
 
Rebaseline 
Retreatment Period (up to 1 Year) 
Every 8 weeks 
Week 
1 
Week 
3 
Week 
5 
Week 
7 
Week 
8 
After 1 year of 
retreatment 
Informed re-consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion 
criteria 
X 
X 
 
 
 
 
 
Medical history (update) 
X 
 
 
 
 
 
 
Prior/Concomitant 
medication 
X 
X 
X 
X 
X 
 
 
MEDI4736 Administration 
 
X 
X 
X 
X 
 
 
Prophylactic Medications1 
(ADXS11-001 only) 
 
X 
 
X 
 
 
 
ADXS11-001 
Administration 
 
X 
 
X 
 
 
 
PO antibiotics and 
instructions2 
(ADXS11-001 only) 
 
X 
 
X 
 
 
 
AE/SAE Assessment3 
 
X 
X 
X 
X 
 
 
Physical examination4 
X 
X 
X 
X 
X 
 
 
Vital signs5 
X 
X 
X 
X 
X 
 
 
ECOG performance status 
X 
X 
X 
X 
X 
 
 
CBC with Differential6 
X 
X 
X 
X 
X 
 
 
Chemistry Panel6,7 
X 
X 
X 
X 
X 
 
 
PT/INR and aPTT7 
X 
X 
X 
X 
X 
 
 
Urinalysis7 
X 
X 
X 
X 
X 
 
 
T3, T4 and TSH7 
X 
X 
X 
X 
X 
 
 
Pregnancy test 
X 
X 
X 
X 
X 
 
 
Tumor Imaging8 
 
X 
 
 
 
 
X 
1 - Subjects will receive prophylactic NSAIDS and antiemetics
before each ADXS11-001 
infusion 
2 - Subjects will receive a course of oral antibiotics to be started 3 days after each ADXS11-001 infusion 
3 
Safety Follow up will be conducted via telephone.  Safety Follow up at 30 days (± 1 week) for AEs and at 90 days (± 
1 week) for SAEs. 
4 
ECG and O2 saturation by pulse oximetry at re-baseline only 
5 - Vital signs are to be monitored
following each ADXS11-001 infusion. 
6 - Subjects must meet hepatic and renal function eligibility criteria prior to dosing 
7 – Refer to Table 9 for a full listing of laboratory tests 
8 – Tumor Assessments will be on Week 1 (± 1 week), starting at Cycle 2.  Evaluations will continue every 8 weeks (± 
1 week) during treatment and continue for subjects in follow up who discontinue retreatment for reasons other than 
disease progression; duration of follow up will be up to 3 years. 
 
7.0 
TRIAL PROCEDURES 
7.1 
Trial Procedures 
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedure details are described in detail below.  It may be necessary to 


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perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator. 
Additional evaluations/testing deemed necessary by the Sponsor for reasons related to 
subject safety will be incorporated into a protocol amendment but can be implemented prior 
to IRB approval for safety concerns.  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 a consent form along with 
the dated signature of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial. 
The pre-screen consents, initial informed consent form, any subsequent revised initial 
informed consent form, any re-consent forms and any written information provided to the 
subject must receive the IRB’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. 
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level. 
The informed consent will adhere to IRB requirements, applicable laws and regulations and 
Sponsor requirements. 


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7.1.1.2 
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. 
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 
Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator.  Details regarding the disease 
for which the subject has enrolled in this study will be recorded separately and not listed as 
medical history. 
7.1.1.5 
Prior and Concomitant Medications Review 
7.1.1.5.1 
Prior Medications 
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days before starting the trial.  Treatment for the disease for which the subject has 
enrolled in this study will be recorded separately and not listed as a prior medication. 
7.1.1.5.2 
Concomitant Medications/Therapies 
The investigator or qualified designee will record medication/therapy, if any, taken by the 
subject during the trial.  All medications/therapies related to reportable SAEs and ECIs 
should be recorded as defined in Section 7.2. 


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7.1.1.6 
Disease Details and Treatments 
7.1.1.6.1 
Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease 
status. 
7.1.1.6.2 
Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 
7.1.2 
Clinical Procedures/Assessments 
7.1.2.1 
Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new 
or worsening AEs as specified in the Trial Flow Chart and more frequently if clinically 
indicated.  Adverse experiences will be graded and recorded throughout the study and during 
the follow-up period according to NCI CTCAE Version 4.03 (see Section 13.2).  Toxicities 
will be characterized in terms regarding seriousness, causality, toxicity grading, and action 
taken with regard to trial treatment. 
All AEs of unknown etiology associated with the study drug(s) exposure should be evaluated 
to determine if it is possibly an event of clinical interest (ECI) of a potentially immunologic 
etiology (irAE).  See Section 5.2.1.1 regarding the identification, evaluation and management 
of AEs of a potential immunological etiology. 
Please refer to Section 7.2 for detailed information regarding the assessment and recording of 
AEs. 
7.1.2.2 
Physical Examination 
The investigator or qualified designee will perform a physical examination during the 
screening period (including baseline screening ECG and O2 saturation by pulse oximetry), 
prior to the administration of each dose of trial treatment and at treatment discontinuation as 


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specified in the Trial Flow Chart (Section 6.0).  Clinically significant abnormal findings 
should be recorded as medical history. 
7.1.2.3 
Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment, 
 
following each ADXS11-001 infusion and at treatment discontinuation as specified in the 
Trial Flow Chart (Section 6.0).  Vital signs should include temperature, pulse, respiratory 
rate, and blood pressure.  Height will be measured at screening only and weight will be 
measured pre-dose at each visit. 
7.1.2.4 
Eastern Cooperative Oncology Group (ECOG) Performance 
Scale 
The investigator or qualified designee will assess ECOG status (see Section13.1 ECOG 
Performance Status) at screening, prior to the administration of each dose of trial treatment 
and discontinuation of trial treatment as specified in the Trial Flow Chart- Section 6.1. 
7.1.2.5 
Tumor Imaging and Assessment of Disease 
Computed tomography (CT) and magnetic resonance imaging (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. 


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7.1.2.6 
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 ≥10 mm (for spiral CT scan or MRI scan, ≥5 mm).  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 <10 mm or <5 mm 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. 
7.1.2.7 
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. 
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. 
7.1.2.8 
Response in Measureable 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 (≥10mm; up to 2 new lesions per organ, 


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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. 
7.1.2.9 
Immune-Related Response in Measureable 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. 
Apparent disease progression should be confirmed after 4 weeks in the absence of symptoms 
consistent with clinical deterioration. 


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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 
 
7.1.2.10 
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-


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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 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 (i.e., an increase in 
tumor burden representing an additional 73% increase in ‘volume’ which is equivalent to a 
20% increase diameter in a measurable lesion). 
7.1.2.11 
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 (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 scheduled assessment. 


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7.1.2.12 
Overall Response 
Overall response will be determined based on RECIST 1.1 criteria and by irRECIST criteria 
(Table 1).  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 6 
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 
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 9-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 8 weeks of the study). 
 
7.1.2.12.1 
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 


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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 7). 
Table 7 
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 
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 
 
7.1.2.12.2 
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 8).  As with the primary definitions of tumor response, early progression 
(i.e., irPD occurring prior to Week 9) will not preclude an irBOR of irCR, irPR or irSD 
resulting from the Week 9 assessment.  An assessment of irPD at or after Week 9 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. 


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Table 8 
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 
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. 
 
7.1.2.13 
 Correlative Studies Blood 
Sampling 
7.1.2.13.1 
 
 
 
 
 
 
 
 
   


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7.1.2.13.2 
Correlative Studies Blood Sampling 
 Details for collection, storage and shipping can be found in the Laboratory Manual. 
• 
 
 
• 
 
 


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• PK Assessment:  Serum will be collected at Cycle 1 Day 1 (pre-dose and end of 
infusion), at Weeks 3 and 5 (pre-dose only) and at Week 7 (pre-dose and end of 
infusion).  For all subsequent cycles, serum will be collected at Week 7 (pre-dose 
only) with the exception of Cycle 3 where serum will be collected at Week 7 (pre-
dose and end of infusion). Serum will also be collected at end of treatment and at the 
90-day post treatment follow up visit.  
• Immunogenicity (ADA) Assessment:  Serum will be collected at Cycle 1 Day 1 
(pre-dose only), at Weeks 5 and 7 (pre-dose only).  For all subsequent cycles, serum 
will be collected at Week 7 (pre-dose only).  Serum will also be collected at end of 
treatment and at the 90-day post treatment follow up visit.  
• 
• 
7.1.2.14 
Safety Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below.  The total amount of blood/tissue to be drawn/collected over the course of 
the trial (from pre-trial to post-trial visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per subject can be found in the Laboratory 
Manual. 


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7.1.2.14.1 
Laboratory Safety Evaluations (Hematology, Chemistry and 
Urinalysis) 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 9.  
The total amount of blood/tissue to be drawn/collected over the course of the trial (from pre-
trial to post-trial visits), including approximate blood/tissue volumes drawn/collected by visit 
and by sample type per subject can be found in the Laboratory Manual. 
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 5 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 9 
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  
Total thriiodothyronine (T3) 
Absolute Neutrophil Count 
Carbon Dioxide ‡ 
results are noted) 
Free tyroxine (T4) 
 
  (CO2 or biocarbonate) 
Urine pregnancy test † 
Thyroid stimulating hormone (TSH) 
 
Creatinine 
 
PK 
 
Calcium 
 
 
 
Chloride 
 
Blood for correlative studies 
 
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. 
 


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7.1.3 
Other Procedures 
7.1.3.1 
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 
adverse events which 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.  Subjects who a) attain a CR or b) complete 12 months of 
treatment may discontinue treatment with the option of restarting treatment if they meet the 
criteria specified in Section 7.1.4.2.1.  After discontinuing treatment following assessment of 
CR, these subjects should return to the site for a Safety Follow-up Visit (described in 
Section 7.1.4.3.1) and then proceed to the Follow-Up Period of the study (described in 
Section 7.1.5.3.2). 
7.1.4 
Visit Requirements 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.  Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures. 
7.1.4.1 
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 


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Medical History/Prior and Concomitant Medications - 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 fifth edition or higher), and prior cancer therapies and best 
response(s), if applicable. 
Complete physical exam - including baseline ECG and O2 saturation by pulse oximetry 
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. 
HPV genotyping – specimen collection for confirming HPV+ will be collected for SCCHN 
subjects, if necessary.  Details regarding collection, preparation and shipping specimen can 
be found in the laboratory manual. 
Laboratory Procedures (hematology, chemistry, urinalysis, other) – must be performed 
within 28 days prior to first dose of study treatment.  Screening lab that are done within 5 
days of initiating treatment can be used for C1D1 laboratory tests. 
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 study treatment.   
Analysis of 
 – 
 
 
 
 
 


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Correlative studies: Blood will be collected as indicated in Section 7.1.2.13.2. 
7.1.4.2 
Treatment Period 
Subjects will be treated for up to 1 year.  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 
NSAIDs and antiemetic medication, as described below. 
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 
 after study treatment for safety observation, and if necessary, treatment 
of side effects.  Subjects may receive NSAIDs every 4 hours and antiemetics every 8 hours 
after receiving each ADXS11­001 infusion, 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 Events and more 
frequently if clinically indicated.  Adverse events will be graded and recorded throughout the 
study and follow-up according to NCI CTCAE v 4.03.  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 any infusions and 
 following 
the ADXS11-001 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. 


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Laboratory Procedures (hematology, chemistry, urinalysis, other) – must be performed no 
more than 3 days prior to dosing.  Screening lab that are done within 5 days of initiating 
treatment can be used for C1D1 laboratory tests.  Please see Section 7.1.2.14.1 for details. 
Prophylactic Medications – Subjects will receive a dose of NSAIDS (e.g. naproxen or 
ibuprofen) and antiemetics (e.g. promethazine or ondansetron) 
 
prior to all ADXS11-001 infusions.  Subjects should continue to receive NSAIDS, every 4 
hours as needed, following the ADXS11-001 infusions.   
PO Antibiotics with Instructions – Subjects will receive a 3 day course of one of the 
following oral antibiotics (amoxicillin, ampicillin, ciprofloxacin, erythromycin, gentamycin, 
penicillin, trimethroprim/sulfamethoxazole, or vancomycin), to be started on Day 4 
(72 hours) after each ADXS11-001 infusion.  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 IV administration 
Correlative studies: Blood will be collected as indicated in Section 7.1.2.13.2. 
Analysis of 
 
 
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 8 weeks starting with Day 1 of Cycle 2. 
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 serum 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of βHCG). 


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7.1.4.2.1 
Re-Treatment Period 
Subjects who attain a CR during treatment or complete 1 year of treatment may discontinue 
treatment with the option of an additional 1 year of treatment at the same treatment they were 
previously assigned if: 
• during the first 12 months of the subject’s follow up period (Section 7.1.4.3.2), 
disease progression is noted 
• other subjects are still currently being treated 
• subject still meets eligibility criteria 
• sponsor and investigator are in agreement 
Subjects will be re-consented and must meet all baseline inclusion exclusion to receive 
subsequent therapy.  Eligibility criteria will only be evaluated prior to retreatment and not 
prior to every subsequent cycle. 
Retreatment Visit schedule is outlined in Section 6.5 – Retreatment Study Flow.  Re-baseline 
evaluations will be performed within 28 days prior to the first retreatment administration. 
7.1.4.3 
Post-Treatment Visits 
7.1.4.3.1 
Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days 
(±5 days) after the last dose of trial treatment or before the initiation of a new anti-cancer 
treatment, whichever comes first.  All AEs that occur prior to the Safety Follow-Up Visit 
should be recorded.  Subjects with an AE of Grade > 1 will be followed until the resolution 
of the AE to Grade 0­1 or until the beginning of a new anti-neoplastic therapy, whichever 
occurs first.  SAEs that occur within 90 days of the end of treatment or before initiation of a 
new anti-cancer treatment should also be followed and recorded. 


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7.1.4.3.2 
Follow-up Visits 
90 day post treatment visit – Blood will be collected for PK/ADA/
 markers on all 
subjects assigned to receive MEDI4736 monotherapy or Combination therapy. 
8-week post treatment visit - Subjects who discontinue trial treatment or retreatment for a 
reason other than disease progression should be assessed every 8 weeks (± 1 week) by 
radiologic imaging to monitor disease status for up to three years.  Every effort should be 
made to collect information regarding disease status until the start of new anti-neoplastic 
therapy, disease progression, death, end of the study or if the subject begins retreatment as 
detailed in Section 7.1.4.2.1. 
Subjects who are in the follow up phase and experience disease progression may have the 
option to be retreated, after discussion with the sponsor.  Details are provided in Section 6.5 
–Retreatment Flow Chart and Section 7.1.4.2.1– Retreatment Period 
7.2 
Assessing and Recording Adverse Events 
An adverse event 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 adverse event can therefore be any 
unfavorable and unintended sign, symptom, or disease temporally associated with the use of 
a medicinal product or protocol-specified procedure, whether or not considered related to the 
medicinal product or protocol-specified procedure.  Any worsening (i.e., any clinically 
significant adverse change in frequency and/or intensity) of a preexisting condition that is 
temporally associated with the use of the Sponsor’s product, is also an adverse event. 
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. 


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Adverse events 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. 
Adverse events 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 adverse events will be recorded from the time the consent form is signed through 30 days 
following cessation of treatment and at each examination on the Adverse Event case report 
forms/worksheets.  The reporting timeframe for adverse events meeting any serious criteria is 
described in Section 7.2.3.1. 
Adverse events will not be collected for subjects during the pre-screening period (for 
determination of archival tissue status) as long as that subject has not undergone any 
protocol-specified procedure or intervention.  If the subject requires a blood draw, fresh 
tumor biopsy etc., the subject is first required to provide consent to the main study and AEs 
will be captured according to guidelines for standard AE reporting. 
7.2.1 
Definition and Reporting of an Overdose  
For purposes of this trial, an overdose will be defined as any dose exceeding 20% over the 
prescribed dose of ADXS11-001 or MEDI4736.  No specific information is available on the 
treatment of overdose.  In the event of overdose, the subject should be observed closely for 
signs of toxicity.  Appropriate supportive treatment should be provided if clinically indicated. 
If an adverse event(s) is associated with (“results from”) the overdose of the study drug(s), 
the adverse event(s) is reported as a serious adverse event, 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 


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a non-serious Event of Clinical Interest (ECI), using the terminology “accidental or 
intentional overdose without adverse effect.” 
All reports of overdose with and without an adverse event must be reported within 24 hours 
to the Sponsor and within 2 working days hours to inVentiv Health Clinical 
Pharmacovigilance (Attn: iHC SAE Reporting; FAX 866-880-9343 or email:  
i3drugsafetyPV@inventivhealth.com). 
7.2.2 
Reporting of Pregnancy and Lactation to the Sponsor 
Although pregnancy and lactation are not considered adverse events, 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 adverse event occurring at any dose or during any use of 
Advaxis’ product that: 
• Results in death; 


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• 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 adverse event unless it results in 
hospitalization or death. 
Any serious adverse event, or follow up to a serious adverse event, 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 90 days following cessation of treatment, or the 
initiation of new anti-cancer therapy, whichever is earlier, whether or not related to Advaxis’ 
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). 
Non-serious Events of Clinical Interest will be forwarded to inVentiv Health Clinical 
Pharmacovigilance (Attn: iHC SAE Reporting; FAX 866-880-9343 or email:  
i3drugsafetyPV@inventivhealth.com) and will be handled in the same manner as SAEs. 
Additionally, any serious adverse event, 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 in the previous paragraph also must be 
reported immediately to the Sponsor. 


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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 serious adverse events must be followed up for outcome. 
7.2.3.2 
Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be recorded as such on the Adverse Event case report forms/worksheets and 
reported within 24 hours to the Sponsor and within 2 working days to inVentiv Health 
Clinical Pharmacovigilance (Attn: iHC SAE Reporting; FAX 866-880-9343 or email:  
i3drugsafetyPV@inventivhealth.com). 
Events of clinical interest for this trial include: 
1. Pneumonitis - Pneumonitis has been reported in association with use of anti-PD-
L1/anti-PD-1 antibodies [36].  Initial work-up should include a high-resolution CT 
scan, ruling out infection, and pulse oximetry.  Pulmonary consultation is 
recommended. 
2. Hypersensitivity Reactions - Hypersensitivity reactions as well as infusion-related 
reactions have been reported with anti-PD-L1 and anti-PD-1 therapy [36].  As with 
the administration of any foreign protein and/or other biologic agents, reactions 
following the infusion of mAbs can be caused by various mechanisms, including 


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acute anaphylactic (IgE-mediated) and anaphylactoid reactions against the mAb, and 
serum sickness.  Acute allergic reactions may occur, may be severe, and may result in 
death.  Acute allergic reactions may include hypotension, dyspnea, cyanosis, 
respiratory failure, urticaria, pruritis, angioedema, hypotonia, arthralgia, 
bronchospasm, wheeze, cough, dizziness, fatigue, headache, hypertension, myalgia, 
vomiting and unresponsiveness. 
o Subjects with Grade 1 and 2 hypersensitivity (including anaphylactic reaction) 
and infusion-related reactions should be treated according to standard medical 
practices.  If a subject experiences a grade 3 or 4 infusion reaction, the 
infusion will be discontinued immediately, and no subsequent infusions may 
be given.   
o A grade 3 or 4 infusion reaction will require immediate treatment, including 
the use of epinephrine, bronchodilators, and/or glucocorticoids for 
symptomatic bronchospasm; IV fluids and/or pressors for hypotension; and 
immediate and permanent discontinuation of study drug(s) with appropriate 
supportive care. 
3. Hepatic Function Abnormalities (Hepatotoxicity) - Increased transaminases have 
been reported during treatment with anti-PD-L1 [36].   
Hepatic function abnormality is defined as any increase in ALT or AST to greater 
than 3 x ULN and concurrent increase in bilirubin to greater than 2 x ULN (i.e., 
Hy’s Law cases).  Concurrent findings are those that derive from a single blood draw 
or from separate blood draws taken within 8 days of each other.  Follow-up 
investigations and inquiries will be initiated promptly by the investigational site to 
determine whether the findings are reproducible and/or whether there is objective 
evidence that clearly supports causation by a disease (e.g., cholelithiasis and bile duct 
obstruction with distended gallbladder) or an agent other than the investigational 
product(s). 


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If an event of hepatic function abnormality is considered to be related to a pre-
existing condition and does not represent a worsening of this condition and/or is 
considered to be within the range of normal physiological fluctuation for the subject, 
the event does not meet the definition of an AE and does not need to be recorded as 
such. 
If the underlying diagnosis for the hepatic function abnormality is known (including 
progression of pre-existing disease such as primary or metastatic malignancy), the 
diagnosis should be recorded as an AE/SAE. 
In the event a subject develops any of the following AEs, a detailed narrative of the event 
should be reported as an ECI to the Sponsor within 24 hours: 
• Grade ≥3 diarrhea 
• Grade ≥3 colitis 
• Grade ≥2 pneumonitis 
• Grade ≥3 hypo- or  hyperthyroidism 
Subjects should be assessed for possible ECIs prior to each dose.  Lab results should be 
evaluated and subjects should be asked for signs and symptoms suggestive of an immune-
related event.  Subjects who develop an ECI thought to be immune-related should have 
additional testing to rule out other etiologic causes.  If lab results or symptoms indicate a 
possible immune-related ECI, then additional testing should be performed to rule out other 
etiologic causes.  If no other cause is found, then it is assumed to be immune-related. 
ECIs that occur in any subject from the date of first dose through 90 days following cessation 
of treatment, or the initiation of a new anticancer therapy, whichever is earlier, whether or 
not related to the Advaxis’ product, must be reported within 24 hours to the Sponsor. 


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7.2.4 
Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0.  Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets. 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 
The following attribution categories will be used in assessing the relationship between the 
AE and the study drug: 
Table 10 
Evaluating Adverse Events 
 
7.2.5 
Sponsor Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations. 
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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8.0 
STATISTICAL ANALYSIS PLAN 
8.1 
Statistical Analysis Plan Summary 
This is a Phase 1-2 study of ADXS11-001 or MEDI4736 alone or combination in locally 
advanced, or metastatic, squamous or non-squamous carcinoma of the cervix or HPV+ 
squamous cell carcinoma of the head and neck. 
There are 2 phases in this study with different objectives.  For safety, the analysis will be 
performed for Part A and Part B separately and combined.  The efficacy analysis will be 
performed for Part A and Part B separately.  SAS 9.2 or higher will be used for data analysis. 
Subject disposition, demographic and baseline subject characteristics will be summarized 
separately for Part A and Part B.  Adverse events will be classified and summarized by type, 
incidence, severity, and causality.  All adverse events will be summarized by subject, 
treatment, and disease.  All subjects who receive at least 1 dose of study treatment will be 
included in the safety analyses. 
Statistical analysis for efficacy will be summarized by treatment arm and disease type.  
Although it may lack statistical power, statistical testing for treatment comparisons will be 
performed as a reference.  Tumor response will be evaluated by RECIST criteria and 
secondarily by irRECIST criteria.  The overall response rate will be summarized; frequency 
counts and percentage and will be tested by the Fisher’s Exact test.  PFS is defined as the 
time from randomization until objective tumor progression or death.  Subjects who have not 
progressed or who are still alive at the time of evaluation will be censored for the analysis.  
Kaplan-Meier (KM) curves and descriptive statistics will be used to summarize PFS.  The 
percentage of subjects with PFS and the 95% confidence intervals will be provided.  PFS and 
duration of response will be summarized using KM method and tested by the Log-Rank test 
controlled by disease type. 
Furthermore, the disease response will be tabulated for all subjects who receive 
ADXS11­001 monotherapy, MEDI4736 monotherapy or ADXS11-001 + MEDI4736 
combination therapy. 


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8.2 
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.   
9.0 
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. 


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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 
Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received 
from Advaxis or designee, the amount dispensed to and returned by the subjects 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.  It is the 
Investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, 
local and institutional guidelines and procedures, and provided that appropriate records of 
disposal are kept. 
10.0 
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 


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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 case record form (CRF).  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 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 Harmonization (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. 


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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 
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. 


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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. 
11.0 
LIST OF REFERENCES 
1. 
Oganesyan, V., et al., Crystallization and preliminary X-ray diffraction analysis 
of the complex between a human anti-interferon antibody fragment and 
human interferon alpha-2A. Acta Crystallogr Sect F Struct Biol Cryst 
Commun, 2009. 65(Pt 1): p. 14-6. 
2. 
Mu, C.Y., et al., High expression of PD-L1 in lung cancer may contribute to 
poor prognosis and tumor cells immune escape through suppressing tumor 
infiltrating dendritic cells maturation. Med Oncol, 2011. 28(3): p. 682-8. 
3. 
Thompson, R.H., et al., Costimulatory molecule B7-H1 in primary and 
metastatic clear cell renal cell carcinoma. Cancer, 2005. 104(10): p. 2084-91. 
4. 
Thompson, R.H., et al., Tumor B7-H1 is associated with poor prognosis in 
renal cell carcinoma patients with long-term follow-up. Cancer Res, 2006. 
66(7): p. 3381-5. 
5. 
Krambeck, A.E., et al., Survivin and b7-h1 are collaborative predictors of 
survival and represent potential therapeutic targets for patients with renal cell 
carcinoma. Clin Cancer Res, 2007. 13(6): p. 1749-56. 
6. 
Nomi, T., et al., Clinical significance and therapeutic potential of the 
programmed death-1 ligand/programmed death-1 pathway in human 
pancreatic cancer. Clin Cancer Res, 2007. 13(7): p. 2151-7. 
7. 
Loos, M., et al., Clinical significance and regulation of the costimulatory 
molecule B7-H1 in pancreatic cancer. Cancer Lett, 2008. 268(1): p. 98-109. 
8. 
Wang, L., et al., Clinical significance of B7-H1 and B7-1 expressions in 
pancreatic carcinoma. World J Surg, 2010. 34(5): p. 1059-65. 
9. 
Hamanishi, J., et al., Programmed cell death 1 ligand 1 and tumor-infiltrating 
CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc 
Natl Acad Sci U S A, 2007. 104(9): p. 3360-5. 
10. 
Keir, M.E., et al., PD-1 and its ligands in tolerance and immunity. Annu Rev 
Immunol, 2008. 26: p. 677-704. 


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11. 
Park, J.J., et al., B7-H1/CD80 interaction is required for the induction and 
maintenance of peripheral T-cell tolerance. Blood, 2010. 116(8): p. 1291-8. 
12. 
Zou, W. and L. Chen, Inhibitory B7-family molecules in the tumour 
microenvironment. Nat Rev Immunol, 2008. 8(6): p. 467-77. 
13. 
Blank, C., et al., Blockade of PD-L1 (B7-H1) augments human tumor-specific 
T cell responses in vitro. Int J Cancer, 2006. 119(2): p. 317-27. 
14. 
Pages, F., et al., Immune infiltration in human tumors: a prognostic factor that 
should not be ignored. Oncogene, 2010. 29(8): p. 1093-102. 
15. 
Hirano, F., et al., Blockade of B7-H1 and PD-1 by monoclonal antibodies 
potentiates cancer therapeutic immunity. Cancer Res, 2005. 65(3): p. 1089-
96. 
16. 
Iwai, Y., et al., Involvement of PD-L1 on tumor cells in the escape from host 
immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl 
Acad Sci U S A, 2002. 99(19): p. 12293-7. 
17. 
Okudaira, K., et al., Blockade of B7-H1 or B7-DC induces an anti-tumor effect 
in a mouse pancreatic cancer model. Int J Oncol, 2009. 35(4): p. 741-9. 
18. 
Zhang, C., et al., Anti-tumor immunotherapy by blockade of the PD-1/PD-L1 
pathway with recombinant human PD-1-IgV. Cytotherapy, 2008. 10(7): p. 
711-9. 
19. 
Schmidinger, M., M. Hejna, and C.C. Zielinski, Aldesleukin in advanced renal 
cell carcinoma. Expert Rev Anticancer Ther, 2004. 4(6): p. 957-80. 
20. 
Madan, R.A. and J.L. Gulley, Sipuleucel-T: harbinger of a new age of 
therapeutics for prostate cancer. Expert Rev Vaccines, 2011. 10(2): p. 141-
50. 
21. 
Fife, B.T. and J.A. Bluestone, Control of peripheral T-cell tolerance and 
autoimmunity via the CTLA-4 and PD-1 pathways. Immunol Rev, 2008. 224: 
p. 166-82. 
22. 
Dong, H., et al., Costimulating aberrant T cell responses by B7-H1 
autoantibodies in rheumatoid arthritis. J Clin Invest, 2003. 111(3): p. 363-70. 
23. 
Latchman, Y.E., et al., PD-L1-deficient mice show that PD-L1 on T cells, 
antigen-presenting cells, and host tissues negatively regulates T cells. Proc 
Natl Acad Sci U S A, 2004. 101(29): p. 10691-6. 
24. 
Nishimura, H., et al., Immunological studies on PD-1 deficient mice: 
implication of PD-1 as a negative regulator for B cell responses. Int Immunol, 
1998. 10(10): p. 1563-72. 
25. 
Nishimura, H., et al., Autoimmune dilated cardiomyopathy in PD-1 receptor-
deficient mice. Science, 2001. 291(5502): p. 319-22. 
26. 
Brahmer, J.R., et al., Phase I study of single-agent anti-programmed death-1 
(MDX-1106) in refractory solid tumors: safety, clinical activity, 
pharmacodynamics, and immunologic correlates. J Clin Oncol, 2010. 28(19): 
p. 3167-75. 
27. 
Berger, R., et al., Phase I safety and pharmacokinetic study of CT-011, a 
humanized antibody interacting with PD-1, in patients with advanced 
hematologic malignancies. Clin Cancer Res, 2008. 14(10): p. 3044-51. 


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28. 
Wolchok, J.D., et al., Ipilimumab efficacy and safety in patients with advanced 
melanoma: a retrospective analysis of HLA subtype from four trials. Cancer 
Immun, 2010. 10: p. 9. 
29. 
Topalian, S.L., et al., Safety, activity, and immune correlates of anti-PD-1 
antibody in cancer. N Engl J Med, 2012. 366(26): p. 2443-54. 
30. 
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. 
31. 
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. 
32. 
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. 
33. 
Piersma, S.J., et al., High number of intraepithelial CD8+ tumor-infiltrating 
lymphocytes is associated with the absence of lymph node metastases in 
patients with large early-stage cervical cancer. Cancer Res, 2007. 67(1): p. 
354-61. 
34. 
van der Burg, S.H., et al., Association of cervical cancer with the presence of 
CD4+ regulatory T cells specific for human papillomavirus antigens. Proc Natl 
Acad Sci U S A, 2007. 104(29): p. 12087-92. 
35. 
Jordanova, E.S., et al., Human leukocyte antigen class I, MHC class I chain-
related molecule A, and CD8+/regulatory T-cell ratio: which variable 
determines survival of cervical cancer patients? Clin Cancer Res, 2008. 
14(7): p. 2028-35. 
36. 
Brahmer, J.R., et al., Safety and activity of anti-PD-L1 antibody in patients 
with advanced cancer. N Engl J Med, 2012. 366(26): p. 2455-65. 
37. 
Porichis, F., et al., Responsiveness of HIV-specific CD4 T cells to PD-1 
blockade. Blood, 2011. 118(4): p. 965-74. 
38. 
Lyford-Pike, S., et al., Evidence for a role of the PD-1:PD-L1 pathway in 
immune resistance of HPV-associated head and neck squamous cell 
carcinoma. Cancer Res, 2013. 73(6): p. 1733-41. 
39. 
Yang, W., et al., Increased expression of programmed death (PD)-1 and its 
ligand PD-L1 correlates with impaired cell-mediated immunity in high-risk 
human papillomavirus-related cervical intraepithelial neoplasia. Immunology, 
2013. 139(4): p. 513-22. 
40. 
Smerage, J.B., et al., Circulating Tumor Cells and Response to 
Chemotherapy in Metastatic Breast Cancer: SWOG S0500. J Clin Oncol, 
2014. 
41. 
Ang, K.K., et al., Human papillomavirus and survival of patients with 
oropharyngeal cancer. N Engl J Med, 2010. 363(1): p. 24-35. 
42. 
Fakhry, C., et al., Human Papillomavirus and Overall Survival After 
Progression of Oropharyngeal Squamous Cell Carcinoma. J Clin Oncol, 
2014. 


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12.0 
SUMMARY OF CHANGES  
Section 
Page 
Revision 
Rationale 
General 
 
Minor editing, spelling and section placement changes 
were made throughout to clarify, correct and improve 
readability 
Administrative/clarifications 
General 
11 
Updated description of MEDI4736 in Summary 
Align 
General 
 
Added language throughout regarding antibiotic use 
Align 
General 
 
Removed all language regarding 
 in 
Part A (Phase 1) of the study 
Based on investigator feedback 
5.1.1 
31 
Revised lab eligibility in Table 1 
Aligned with current 
requirement in protocol  
5.1.2 
34 
Updated Exclusion #13 
Based on investigator feedback 
5.1.2 
34 
Updated Exclusion #16 
Align to update on allowed 
antibiotics 
5.1.2 
35 
Added Exclusion #18 regarding contraindication to 
NSAIDS 
To clarify required use of 
NSAIDs per protocol 
5.2.1.4 
42 
Table 3, Treatment Modification Guidelines 
Updated for clarity 
5.5.2 
51 
Added sentence regarding Acetaminophen use 
Clarification 
5.5.2 
51 
Updated Prohibited Medications list 
Clarification 
5.6 
52 
Revised Supportive Care Guidelines 
Updated for clarity 
5.6.1 
52 
Added Cytokine Release Syndrome supportive care 
guidelines 
Updated and expanded for 
clarity 
5.7.2 
59 
Included details of birth control requirement for male 
subjects 
Clarification 
6.0 
63 
Updated all Trial Flow Charts 
Clarifications and footnote 
corrections.  Remove tumor 
biopsies in Part A 
7.1.2.13.2 
86 
Updated Correlative Studies Blood Sampling 
Added additional text for 
clarification 
7.1.2.14.1 
88 
Added detail regarding lab test timing 
Clarification 
7.1.4.1 
90 
Include sentence regarding consent signing verse 
screening 
To ensure adequate time for 
protocol required wash out 
periods 
7.2.5 
105 
Removed Table 10 
Removed duplicate AE 
evaluation descriptions 
8.2 
108 
Added Safety Monitoring section 
Based on investigator feedback 
 


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13.0 
APPENDICES 
13.1 
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 Oken MM et al. 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. 
 
13.2 
Common Terminology Criteria for Adverse Events V4.03 
(CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.03 will be utilized for adverse event reporting. 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 
 
13.3 
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. 
* Eisenhauer EA, et al. New response evaluation criteria in solid tumors: Revised RECIST 
guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 
In addition, volumetric analysis will be explored by central review for response assessment. 
 


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14.0 
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 
CIN 
Cervical Intraepithelial Neoplasia 
CR 
Complete response 
CTL 
Cytotoxic T lymphocyte 
DCR 
Disease Control Rate 
DLT 
Dose limiting toxicity 
DTH 
delayed-type Hypersensitivity 
GGT 
Gamma glutyltransferase 
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 
LEEP 
Loop Electrosurgical Excision Procedure 
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 
MTD 
Maximum Tolerated Dose 
NCCN 
National Comprehensive Cancer Network 
NSAID 
Non-Steroidal Anti Inflammatory Drugs 
PBMC 
Peripheral blood mononuclear cell 
PR 
Partial response 
PSA 
Prostate-specific antigen 
RBC 
Red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SOC 
Standard of Care 
TAA 
Tumor Associated Antigen(s) 
TCR 
T-cell receptor 


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TIL 
Tumor infiltrating lymphocytes 
tLLO 
Truncated LLO 
Tregs 
Regulatory T cells 
wt-Lm 
wild type Listeria monocytogenes